Analysis and visualization of single-trial event-related potentials

NASA Technical Reports Server (NTRS)

Jung, T. P.; Makeig, S.; Westerfield, M.; Townsend, J.; Courchesne, E.; Sejnowski, T. J.

2001-01-01

In this study, a linear decomposition technique, independent component analysis (ICA), is applied to single-trial multichannel EEG data from event-related potential (ERP) experiments. Spatial filters derived by ICA blindly separate the input data into a sum of temporally independent and spatially fixed components arising from distinct or overlapping brain or extra-brain sources. Both the data and their decomposition are displayed using a new visualization tool, the "ERP image," that can clearly characterize single-trial variations in the amplitudes and latencies of evoked responses, particularly when sorted by a relevant behavioral or physiological variable. These tools were used to analyze data from a visual selective attention experiment on 28 control subjects plus 22 neurological patients whose EEG records were heavily contaminated with blink and other eye-movement artifacts. Results show that ICA can separate artifactual, stimulus-locked, response-locked, and non-event-related background EEG activities into separate components, a taxonomy not obtained from conventional signal averaging approaches. This method allows: (1) removal of pervasive artifacts of all types from single-trial EEG records, (2) identification and segregation of stimulus- and response-locked EEG components, (3) examination of differences in single-trial responses, and (4) separation of temporally distinct but spatially overlapping EEG oscillatory activities with distinct relationships to task events. The proposed methods also allow the interaction between ERPs and the ongoing EEG to be investigated directly. We studied the between-subject component stability of ICA decomposition of single-trial EEG epochs by clustering components with similar scalp maps and activation power spectra. Components accounting for blinks, eye movements, temporal muscle activity, event-related potentials, and event-modulated alpha activities were largely replicated across subjects. Applying ICA and ERP image visualization to the analysis of sets of single trials from event-related EEG (or MEG) experiments can increase the information available from ERP (or ERF) data. Copyright 2001 Wiley-Liss, Inc.

Knowledge translation studies in paediatric emergency medicine: A systematic review of the literature.

PubMed

Wilson, Catherine L; Johnson, David; Oakley, Ed

2016-02-01

Systematic review of knowledge translation studies focused on paediatric emergency care to describe and assess the interventions used in emergency department settings. Electronic databases were searched for knowledge translation studies conducted in the emergency department that included the care of children. Two researchers independently reviewed the studies. From 1305 publications identified, 15 studies of varied design were included. Four were cluster-controlled trials, two patient-level randomised controlled trials, two interrupted time series, one descriptive study and six before and after intervention studies. Knowledge translation interventions were predominantly aimed at the treating clinician, with some targeting the organisation. Studies assessed effectiveness of interventions over 6-12 months in before and after studies, and 3-28 months in cluster or patient level controlled trials. Changes in clinical practice were variable, with studies on single disease and single treatments in a single site showing greater improvement. Evidence for effective methods to translate knowledge into practice in paediatric emergency medicine is fairly limited. More optimal study designs with more explicit descriptions of interventions are needed to facilitate other groups to effectively apply these procedures in their own setting. © 2016 The Authors Journal of Paediatrics and Child Health © 2016 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) framework: protocol to determine a core outcome set for efficacy and effectiveness trials of alcohol screening and brief intervention.

PubMed

Shorter, G W; Heather, N; Bray, Jeremy W; Giles, E L; Holloway, A; Barbosa, C; Berman, A H; O'Donnell, A J; Clarke, M; Stockdale, K J; Newbury-Birch, D

2017-12-22

The evidence base to assess the efficacy and effectiveness of alcohol brief interventions (ABI) is weakened by variation in the outcomes measured and by inconsistent reporting. The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) project aims to develop a core outcome set (COS) and reporting guidance for its use in future trials of ABI in a range of settings. An international Special Interest Group was convened through INEBRIA (International Network on Brief Interventions for Alcohol and Other Drugs) to inform the development of a COS for trials of ABI. ORBITAL will incorporate a systematic review to map outcomes used in efficacy and effectiveness trials of ABI and their measurement properties, using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. This will support a multi-round Delphi study to prioritise outcomes. Delphi panellists will be drawn from a range of settings and stakeholder groups, and the Delphi study will also be used to determine if a single COS is relevant for all settings. A consensus meeting with key stakeholder representation will determine the final COS and associated guidance for its use in trials of ABI. ORBITAL will develop a COS for alcohol screening and brief intervention trials, with outcomes stratified into domains and guidance on outcome measurement instruments. The standardisation of ABI outcomes and their measurement will support the ongoing development of ABI studies and a systematic synthesis of emerging research findings. We will track the extent to which the COS delivers on this promise through an exploration of the use of the guidance in the decade following COS publication.

Trial latencies estimation of event-related potentials in EEG by means of genetic algorithms

NASA Astrophysics Data System (ADS)

Da Pelo, P.; De Tommaso, M.; Monaco, A.; Stramaglia, S.; Bellotti, R.; Tangaro, S.

2018-04-01

Objective. Event-related potentials (ERPs) are usually obtained by averaging thus neglecting the trial-to-trial latency variability in cognitive electroencephalography (EEG) responses. As a consequence the shape and the peak amplitude of the averaged ERP are smeared and reduced, respectively, when the single-trial latencies show a relevant variability. To date, the majority of the methodologies for single-trial latencies inference are iterative schemes providing suboptimal solutions, the most commonly used being the Woody’s algorithm. Approach. In this study, a global approach is developed by introducing a fitness function whose global maximum corresponds to the set of latencies which renders the trial signals most aligned as possible. A suitable genetic algorithm has been implemented to solve the optimization problem, characterized by new genetic operators tailored to the present problem. Main results. The results, on simulated trials, showed that the proposed algorithm performs better than Woody’s algorithm in all conditions, at the cost of an increased computational complexity (justified by the improved quality of the solution). Application of the proposed approach on real data trials, resulted in an increased correlation between latencies and reaction times w.r.t. the output from RIDE method. Significance. The above mentioned results on simulated and real data indicate that the proposed method, providing a better estimate of single-trial latencies, will open the way to more accurate study of neural responses as well as to the issue of relating the variability of latencies to the proper cognitive and behavioural correlates.

Aging and visual length discrimination: sequential dependencies, biases, and the effects of multiple implicit standards.

PubMed

Norman, J Farley; Cheeseman, Jacob R; Baxter, Michael W; Thomason, Kelsey E; Adkins, Olivia C; Rogers, Connor E

2014-05-01

Younger (20-25 years of age) and older (61-79 years) adults were evaluated for their ability to visually discriminate length. Almost all experiments that have utilized the method of single stimuli to date have required participants to judge test stimuli relative to a single implicit standard (for a rare exception, see Morgan, On the scaling of size judgements by orientational cues, Vision Research, 1992, 32, 1433-1445). In the current experiments, we not only asked participants to judge lengths relative to a single implicit standard, but they also compared test stimuli to two different implicit standards within the same blocks of trials. We analyzed our participants' judgments to evaluate whether significant sequential dependencies occurred. We found that while individual younger and older adults possessed similar length difference thresholds and exhibited similar overall biases, the judgments of older adults within individual blocks of trials were more strongly biased (than younger adults) by preceding responses (i.e., their judgments on any given trial were more strongly affected by responses to previously viewed stimuli). In addition, the judgments of both younger and older adults were more strongly biased by preceding responses in the blocks of trials with multiple implicit standards. Overall, our results are consistent with the operation of the tracking mechanism described by Criterion-setting theory (Lages and Treisman, Spatial frequency discrimination: Visual long-term memory or criterion setting? Vision Research, 1998, 38, 557-572). Copyright © 2014 Elsevier Ltd. All rights reserved.

Decision Criterion Dynamics in Animals Performing an Auditory Detection Task

PubMed Central

Mill, Robert W.; Alves-Pinto, Ana; Sumner, Christian J.

2014-01-01

Classical signal detection theory attributes bias in perceptual decisions to a threshold criterion, against which sensory excitation is compared. The optimal criterion setting depends on the signal level, which may vary over time, and about which the subject is naïve. Consequently, the subject must optimise its threshold by responding appropriately to feedback. Here a series of experiments was conducted, and a computational model applied, to determine how the decision bias of the ferret in an auditory signal detection task tracks changes in the stimulus level. The time scales of criterion dynamics were investigated by means of a yes-no signal-in-noise detection task, in which trials were grouped into blocks that alternately contained easy- and hard-to-detect signals. The responses of the ferrets implied both long- and short-term criterion dynamics. The animals exhibited a bias in favour of responding “yes” during blocks of harder trials, and vice versa. Moreover, the outcome of each single trial had a strong influence on the decision at the next trial. We demonstrate that the single-trial and block-level changes in bias are a manifestation of the same criterion update policy by fitting a model, in which the criterion is shifted by fixed amounts according to the outcome of the previous trial and decays strongly towards a resting value. The apparent block-level stabilisation of bias arises as the probabilities of outcomes and shifts on single trials mutually interact to establish equilibrium. To gain an intuition into how stable criterion distributions arise from specific parameter sets we develop a Markov model which accounts for the dynamic effects of criterion shifts. Our approach provides a framework for investigating the dynamics of decisions at different timescales in other species (e.g., humans) and in other psychological domains (e.g., vision, memory). PMID:25485733

Patients' preferences for selection of endpoints in cardiovascular clinical trials.

PubMed

Chow, Robert D; Wankhedkar, Kashmira P; Mete, Mihriye

2014-01-01

To reduce the duration and overall costs of cardiovascular trials, use of the combined endpoints in trial design has become commonplace. Though this methodology may serve the needs of investigators and trial sponsors, the preferences of patients or potential trial subjects in the trial design process has not been studied. To determine the preferences of patients in the design of cardiovascular trials. Participants were surveyed in a pilot study regarding preferences among various single endpoints commonly used in cardiovascular trials, preference for single vs. composite endpoints, and the likelihood of compliance with a heart medication if patients similar to them participated in the trial design process. One hundred adult English-speaking patients, 38% male, from a primary care ambulatory practice located in an urban setting. Among single endpoints, participants rated heart attack as significantly more important than death from other causes (4.53 vs. 3.69, p=0.004) on a scale of 1-6. Death from heart disease was rated as significantly more important than chest pain (4.73 vs. 2.47, p<0.001), angioplasty/PCI/CABG (4.73 vs. 2.43, p<0.001), and stroke (4.73 vs. 2.43, p<0.001). Participants also expressed a slight preference for combined endpoints over single endpoint (43% vs. 57%), incorporation of the opinions of the study patient population into the design of trials (48% vs. 41% for researchers), and a greater likelihood of medication compliance if patient preferences were considered during trial design (67% indicated a significant to major effect). Patients are able to make judgments and express preferences regarding trial design. They prefer that the opinions of the study population rather than the general population be incorporated into the design of the study. This novel approach to study design would not only incorporate patient preferences into medical decision making, but it also has the potential to improve compliance with cardiovascular medications.

Characterizing Oscillatory Bursts in Single-Trial EEG Data

NASA Technical Reports Server (NTRS)

Knuth, K. H.; Shah, A. S.; Lakatos, P.; Schroeder, C. E.

2004-01-01

Oscillatory bursts in numerous bands ranging from low (theta) to high frequencies (e.g., gamma) undoubtedly play an important role in cortical dynamics. Largely because of the inadequacy of existing analytic techniques. however, oscillatory bursts and their role in cortical processing remains poorly understood. To study oscillatory bursts effectively one must be able to isolate them and characterize them in the single trial. We describe a series of straightforward analysis techniques that produce useful indices of burst characteristics. First, stimulus-evoked responses are estimated using Differentially Variable Component Analysis (dVCA), and are subtracted from the single-trial. The single-trial characteristics of the evoked responses are stored to identify possible correlations with burst activity. Time-frequency (T-F), or wavelet, analyses are then applied to the single trial residuals. While T-F plots have been used in recent studies to identify and isolate bursts, we go further by fitting each burst in the T-F plot with a two-dimensional Gaussian. This provides a set of burst characteristics, such as, center time. burst duration, center frequency. frequency dispersion. and amplitude, all of which contribute to the accurate characterization of the individual burst. The burst phase can also be estimated. Burst characteristics can be quantified with several standard techniques (e.g.. histogramming and clustering), as well as Bayesian techniques (e.g., blocking) to allow a more parametric description analysis of the characteristics of oscillatory bursts, and the relationships of specific parameters to cortical excitability and stimulus integration.

Emotion Recognition from Single-Trial EEG Based on Kernel Fisher's Emotion Pattern and Imbalanced Quasiconformal Kernel Support Vector Machine

PubMed Central

Liu, Yi-Hung; Wu, Chien-Te; Cheng, Wei-Teng; Hsiao, Yu-Tsung; Chen, Po-Ming; Teng, Jyh-Tong

2014-01-01

Electroencephalogram-based emotion recognition (EEG-ER) has received increasing attention in the fields of health care, affective computing, and brain-computer interface (BCI). However, satisfactory ER performance within a bi-dimensional and non-discrete emotional space using single-trial EEG data remains a challenging task. To address this issue, we propose a three-layer scheme for single-trial EEG-ER. In the first layer, a set of spectral powers of different EEG frequency bands are extracted from multi-channel single-trial EEG signals. In the second layer, the kernel Fisher's discriminant analysis method is applied to further extract features with better discrimination ability from the EEG spectral powers. The feature vector produced by layer 2 is called a kernel Fisher's emotion pattern (KFEP), and is sent into layer 3 for further classification where the proposed imbalanced quasiconformal kernel support vector machine (IQK-SVM) serves as the emotion classifier. The outputs of the three layer EEG-ER system include labels of emotional valence and arousal. Furthermore, to collect effective training and testing datasets for the current EEG-ER system, we also use an emotion-induction paradigm in which a set of pictures selected from the International Affective Picture System (IAPS) are employed as emotion induction stimuli. The performance of the proposed three-layer solution is compared with that of other EEG spectral power-based features and emotion classifiers. Results on 10 healthy participants indicate that the proposed KFEP feature performs better than other spectral power features, and IQK-SVM outperforms traditional SVM in terms of the EEG-ER accuracy. Our findings also show that the proposed EEG-ER scheme achieves the highest classification accuracies of valence (82.68%) and arousal (84.79%) among all testing methods. PMID:25061837

Emotion recognition from single-trial EEG based on kernel Fisher's emotion pattern and imbalanced quasiconformal kernel support vector machine.

PubMed

Liu, Yi-Hung; Wu, Chien-Te; Cheng, Wei-Teng; Hsiao, Yu-Tsung; Chen, Po-Ming; Teng, Jyh-Tong

2014-07-24

Electroencephalogram-based emotion recognition (EEG-ER) has received increasing attention in the fields of health care, affective computing, and brain-computer interface (BCI). However, satisfactory ER performance within a bi-dimensional and non-discrete emotional space using single-trial EEG data remains a challenging task. To address this issue, we propose a three-layer scheme for single-trial EEG-ER. In the first layer, a set of spectral powers of different EEG frequency bands are extracted from multi-channel single-trial EEG signals. In the second layer, the kernel Fisher's discriminant analysis method is applied to further extract features with better discrimination ability from the EEG spectral powers. The feature vector produced by layer 2 is called a kernel Fisher's emotion pattern (KFEP), and is sent into layer 3 for further classification where the proposed imbalanced quasiconformal kernel support vector machine (IQK-SVM) serves as the emotion classifier. The outputs of the three layer EEG-ER system include labels of emotional valence and arousal. Furthermore, to collect effective training and testing datasets for the current EEG-ER system, we also use an emotion-induction paradigm in which a set of pictures selected from the International Affective Picture System (IAPS) are employed as emotion induction stimuli. The performance of the proposed three-layer solution is compared with that of other EEG spectral power-based features and emotion classifiers. Results on 10 healthy participants indicate that the proposed KFEP feature performs better than other spectral power features, and IQK-SVM outperforms traditional SVM in terms of the EEG-ER accuracy. Our findings also show that the proposed EEG-ER scheme achieves the highest classification accuracies of valence (82.68%) and arousal (84.79%) among all testing methods.

Comparison of data transformation procedures to enhance topographical accuracy in time-series analysis of the human EEG.

PubMed

Hauk, O; Keil, A; Elbert, T; Müller, M M

2002-01-30

We describe a methodology to apply current source density (CSD) and minimum norm (MN) estimation as pre-processing tools for time-series analysis of single trial EEG data. The performance of these methods is compared for the case of wavelet time-frequency analysis of simulated gamma-band activity. A reasonable comparison of CSD and MN on the single trial level requires regularization such that the corresponding transformed data sets have similar signal-to-noise ratios (SNRs). For region-of-interest approaches, it should be possible to optimize the SNR for single estimates rather than for the whole distributed solution. An effective implementation of the MN method is described. Simulated data sets were created by modulating the strengths of a radial and a tangential test dipole with wavelets in the frequency range of the gamma band, superimposed with simulated spatially uncorrelated noise. The MN and CSD transformed data sets as well as the average reference (AR) representation were subjected to wavelet frequency-domain analysis, and power spectra were mapped for relevant frequency bands. For both CSD and MN, the influence of noise can be sufficiently suppressed by regularization to yield meaningful information, but only MN represents both radial and tangential dipole sources appropriately as single peaks. Therefore, when relating wavelet power spectrum topographies to their neuronal generators, MN should be preferred.

Strategies to improve retention in randomised trials.

PubMed

Brueton, Valerie C; Tierney, Jayne; Stenning, Sally; Harding, Seeromanie; Meredith, Sarah; Nazareth, Irwin; Rait, Greta

2013-12-03

Loss to follow-up from randomised trials can introduce bias and reduce study power, affecting the generalisability, validity and reliability of results. Many strategies are used to reduce loss to follow-up and improve retention but few have been formally evaluated. To quantify the effect of strategies to improve retention on the proportion of participants retained in randomised trials and to investigate if the effect varied by trial strategy and trial setting. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PreMEDLINE, EMBASE, PsycINFO, DARE, CINAHL, Campbell Collaboration's Social, Psychological, Educational and Criminological Trials Register, and ERIC. We handsearched conference proceedings and publication reference lists for eligible retention trials. We also surveyed all UK Clinical Trials Units to identify further studies. We included eligible retention trials of randomised or quasi-randomised evaluations of strategies to increase retention that were embedded in 'host' randomised trials from all disease areas and healthcare settings. We excluded studies aiming to increase treatment compliance. We contacted authors to supplement or confirm data that we had extracted. For retention trials, we recorded data on the method of randomisation, type of strategy evaluated, comparator, primary outcome, planned sample size, numbers randomised and numbers retained. We used risk ratios (RR) to evaluate the effectiveness of the addition of strategies to improve retention. We assessed heterogeneity between trials using the Chi(2) and I(2) statistics. For main trials that hosted retention trials, we extracted data on disease area, intervention, population, healthcare setting, sequence generation and allocation concealment. We identified 38 eligible retention trials. Included trials evaluated six broad types of strategies to improve retention. These were incentives, communication strategies, new questionnaire format, participant case management, behavioural and methodological interventions. For 34 of the included trials, retention was response to postal and electronic questionnaires with or without medical test kits. For four trials, retention was the number of participants remaining in the trial. Included trials were conducted across a spectrum of disease areas, countries, healthcare and community settings. Strategies that improved trial retention were addition of monetary incentives compared with no incentive for return of trial-related postal questionnaires (RR 1.18; 95% CI 1.09 to 1.28, P value < 0.0001), addition of an offer of monetary incentive compared with no offer for return of electronic questionnaires (RR 1.25; 95% CI 1.14 to 1.38, P value < 0.00001) and an offer of a GBP20 voucher compared with GBP10 for return of postal questionnaires and biomedical test kits (RR 1.12; 95% CI 1.04 to 1.22, P value < 0.005). The evidence that shorter questionnaires are better than longer questionnaires was unclear (RR 1.04; 95% CI 1.00 to 1.08, P value = 0.07) and the evidence for questionnaires relevant to the disease/condition was also unclear (RR 1.07; 95% CI 1.01 to 1.14). Although each was based on the results of a single trial, recorded delivery of questionnaires seemed to be more effective than telephone reminders (RR 2.08; 95% CI 1.11 to 3.87, P value = 0.02) and a 'package' of postal communication strategies with reminder letters appeared to be better than standard procedures (RR 1.43; 95% CI 1.22 to 1.67, P value < 0.0001). An open trial design also appeared more effective than a blind trial design for return of questionnaires in one fracture prevention trial (RR 1.37; 95% CI 1.16 to 1.63, P value = 0.0003).There was no good evidence that the addition of a non-monetary incentive, an offer of a non-monetary incentive, 'enhanced' letters, letters delivered by priority post, additional reminders, or questionnaire question order either increased or decreased trial questionnaire response/retention. There was also no evidence that a telephone survey was either more or less effective than a monetary incentive and a questionnaire. As our analyses are based on single trials, the effect on questionnaire response of using offers of charity donations, sending reminders to trial sites and when a questionnaire is sent, may need further evaluation. Case management and behavioural strategies used for trial retention may also warrant further evaluation. Most of the retention trials that we identified evaluated questionnaire response. There were few evaluations of ways to improve participants returning to trial sites for trial follow-up. Monetary incentives and offers of monetary incentives increased postal and electronic questionnaire response. Some other strategies evaluated in single trials looked promising but need further evaluation. Application of the findings of this review would depend on trial setting, population, disease area, data collection and follow-up procedures.

Development and application of a unified balancing approach with multiple constraints

NASA Technical Reports Server (NTRS)

Zorzi, E. S.; Lee, C. C.; Giordano, J. C.

1985-01-01

The development of a general analytic approach to constrained balancing that is consistent with past influence coefficient methods is described. The approach uses Lagrange multipliers to impose orbit and/or weight constraints; these constraints are combined with the least squares minimization process to provide a set of coupled equations that result in a single solution form for determining correction weights. Proper selection of constraints results in the capability to: (1) balance higher speeds without disturbing previously balanced modes, thru the use of modal trial weight sets; (2) balance off-critical speeds; and (3) balance decoupled modes by use of a single balance plane. If no constraints are imposed, this solution form reduces to the general weighted least squares influence coefficient method. A test facility used to examine the use of the general constrained balancing procedure and application of modal trial weight ratios is also described.

Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis.

PubMed

Raggi, D; Miceli, R; Sonpavde, G; Giannatempo, P; Mariani, L; Galsky, M D; Bellmunt, J; Necchi, A

2016-01-01

The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status ≥1 and hepatic metastases. Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1-17.9] versus 31.9% [95% CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P < 0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284). When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P < 0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Addressing standards of care in resource-limited settings.

PubMed

Dawson, Liza; Klingman, Karin L; Marrazzo, Jeanne

2014-01-01

: The choice between "best-known" standards of care (SOC) or "best available" standards as the control arm in a clinical trial is a fundamental dilemma in clinical research in resource-limited settings (RLS). When the health system is delivering less than an optimal level of care, using highest standard of care in a clinical trial may produce results that cannot be implemented or sustained locally. On the other hand, using interventions that are more feasible in the local setting may involve suboptimal care, and clinical outcomes may be affected. The need for improved standards in health systems in RLS, and the difficulty in securing them, has led many researchers advocate for policy changes at the national or international level to improve clinical care more systemically. SOC decisions in a clinical trial affect the level of benefit provided to study participants and the policy implications of the trial findings. SOC choices should provide high-quality care to help advance the health care system in host countries participating in the trial, but balancing the scientific and ethical objectives of SOC choices is difficult, and there is no single formula for selecting the appropriate SOC. Despite the challenges, well-designed and conducted clinical trials can and should make significant contributions to health systems in RLS.

Implementing a low-cost web-based clinical trial management system for community studies: a case study.

PubMed

Geyer, John; Myers, Kathleen; Vander Stoep, Ann; McCarty, Carolyn; Palmer, Nancy; DeSalvo, Amy

2011-10-01

Clinical trials with multiple intervention locations and a single research coordinating center can be logistically difficult to implement. Increasingly, web-based systems are used to provide clinical trial support with many commercial, open source, and proprietary systems in use. New web-based tools are available which can be customized without programming expertise to deliver web-based clinical trial management and data collection functions. To demonstrate the feasibility of utilizing low-cost configurable applications to create a customized web-based data collection and study management system for a five intervention site randomized clinical trial establishing the efficacy of providing evidence-based treatment via teleconferencing to children with attention-deficit hyperactivity disorder. The sites are small communities that would not usually be included in traditional randomized trials. A major goal was to develop database that participants could access from computers in their home communities for direct data entry. Discussed is the selection process leading to the identification and utilization of a cost-effective and user-friendly set of tools capable of customization for data collection and study management tasks. An online assessment collection application, template-based web portal creation application, and web-accessible Access 2007 database were selected and customized to provide the following features: schedule appointments, administer and monitor online secure assessments, issue subject incentives, and securely transmit electronic documents between sites. Each tool was configured by users with limited programming expertise. As of June 2011, the system has successfully been used with 125 participants in 5 communities, who have completed 536 sets of assessment questionnaires, 8 community therapists, and 11 research staff at the research coordinating center. Total automation of processes is not possible with the current set of tools as each is loosely affiliated, creating some inefficiency. This system is best suited to investigations with a single data source e.g., psychosocial questionnaires. New web-based applications can be used by investigators with limited programming experience to implement user-friendly, efficient, and cost-effective tools for multi-site clinical trials with small distant communities. Such systems allow the inclusion in research of populations that are not usually involved in clinical trials.

Finding harmony so the music plays on: pragmatic trial design considerations to promote organizational sustainment of an empirically-supported behavior therapy.

PubMed

Hartzler, Bryan; Peavy, K Michelle; Jackson, T Ron; Carney, Molly

2016-01-22

Pragmatic trials of empirically-supported behavior therapies may inform clinical and policy decisions concerning therapy sustainment. This retrospective trial design paper describes and discusses pragmatic features of a hybrid type III implementation/effectiveness trial of a contingency management (CM) intervention at an opioid treatment program. Prior reporting (Hartzler et al., J Subst Abuse Treat 46:429-438, 2014; Hartzler, Subst Abuse Treat Prev Policy 10:30, 2015) notes success in recruiting program staff for voluntary participation, durable impacts of CM training on staff-level outcomes, provisional setting implementation of the intervention, documentation of clinical effectiveness, and post-trial sustainment of CM. Six pragmatic design features, and both scientific and practical bases for their inclusion in the trial, are presented: (1) a collaborative intervention design process, (2) voluntary recruitment of program staff for therapy training and implementation, (3) serial training outcome assessments, with quasi-experimental staff randomization to either single or multiple baseline assessment conditions, (4) designation of a 90-day period immediately after training in which the setting implemented the intervention on a provisional basis, (5) inclusive patient eligibility for receipt of the CM intervention, and (6) designation of two staff as local implementation leaders to oversee clinical/administrative issues in provisional implementation. Each pragmatic trial design feature is argued to have contributed to sustainment of CM. Contributions implicate the building of setting proprietorship for the CM intervention, culling of internal staff expertise in its delivery, iterative use of assessment methods that limited setting burden, documentation of setting-specific clinical effectiveness, expanded penetration of CM among staff during provisional implementation, and promotion of setting self-reliance in the oversight of sustainable implementation procedures. It is hoped this discussion offers ideas for how to impact local clinical and policy decisions via effective behavior therapy dissemination.

Ranking Cognitive Flexibility in a Group Setting of Rhesus Monkeys with a Set-Shifting Procedure.

PubMed

Shnitko, Tatiana A; Allen, Daicia C; Gonzales, Steven W; Walter, Nicole A R; Grant, Kathleen A

2017-01-01

Attentional set-shifting ability is an executive function underling cognitive flexibility in humans and animals. In humans, this function is typically observed during a single experimental session where dimensions of playing cards are used to measure flexibility in the face of changing rules for reinforcement (i.e., the Wisconsin Card Sorting Test (WCST)). In laboratory animals, particularly non-human primates, variants of the WCST involve extensive training and testing on a series of dimensional discriminations, usually in social isolation. In the present study, a novel experimental approach was used to assess attentional set-shifting simultaneously in 12 rhesus monkeys. Specifically, monkeys living in individual cages but in the same room were trained at the same time each day in a set-shifting task in the same housing environment. As opposed to the previous studies, each daily session began with a simple single-dimension discrimination regardless of the animal's performance on the previous session. A total of eight increasingly difficult, discriminations (sets) were possible in each daily 45 min session. Correct responses were reinforced under a second-order schedule of flavored food pellet delivery, and criteria for completing a set was 12 correct trials out of a running total of 15 trials. Monkeys progressed through the sets at their own pace and abilities. The results demonstrate that all 12 monkeys acquired the simple discrimination (the first set), but individual differences in the ability to progress through all eight sets were apparent. A performance index (PI) that encompassed progression through the sets, errors and session duration was calculated and used to rank each monkey's performance in relation to each other. Overall, this version of a set-shifting task results in an efficient assessment of reliable differences in cognitive flexibility in a group of monkeys.

Ranking Cognitive Flexibility in a Group Setting of Rhesus Monkeys with a Set-Shifting Procedure

PubMed Central

Shnitko, Tatiana A.; Allen, Daicia C.; Gonzales, Steven W.; Walter, Nicole A. R.; Grant, Kathleen A.

2017-01-01

Attentional set-shifting ability is an executive function underling cognitive flexibility in humans and animals. In humans, this function is typically observed during a single experimental session where dimensions of playing cards are used to measure flexibility in the face of changing rules for reinforcement (i.e., the Wisconsin Card Sorting Test (WCST)). In laboratory animals, particularly non-human primates, variants of the WCST involve extensive training and testing on a series of dimensional discriminations, usually in social isolation. In the present study, a novel experimental approach was used to assess attentional set-shifting simultaneously in 12 rhesus monkeys. Specifically, monkeys living in individual cages but in the same room were trained at the same time each day in a set-shifting task in the same housing environment. As opposed to the previous studies, each daily session began with a simple single-dimension discrimination regardless of the animal’s performance on the previous session. A total of eight increasingly difficult, discriminations (sets) were possible in each daily 45 min session. Correct responses were reinforced under a second-order schedule of flavored food pellet delivery, and criteria for completing a set was 12 correct trials out of a running total of 15 trials. Monkeys progressed through the sets at their own pace and abilities. The results demonstrate that all 12 monkeys acquired the simple discrimination (the first set), but individual differences in the ability to progress through all eight sets were apparent. A performance index (PI) that encompassed progression through the sets, errors and session duration was calculated and used to rank each monkey’s performance in relation to each other. Overall, this version of a set-shifting task results in an efficient assessment of reliable differences in cognitive flexibility in a group of monkeys. PMID:28386222

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing's sarcoma.

PubMed

Dutton, P; Love, S B; Billingham, L; Hassan, A B

2018-05-01

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.

The Effects of a Duathlon Simulation on Ventilatory Threshold and Running Economy

PubMed Central

Berry, Nathaniel T.; Wideman, Laurie; Shields, Edgar W.; Battaglini, Claudio L.

2016-01-01

Multisport events continue to grow in popularity among recreational, amateur, and professional athletes around the world. This study aimed to determine the compounding effects of the initial run and cycling legs of an International Triathlon Union (ITU) Duathlon simulation on maximal oxygen uptake (VO2max), ventilatory threshold (VT) and running economy (RE) within a thermoneutral, laboratory controlled setting. Seven highly trained multisport athletes completed three trials; Trial-1 consisted of a speed only VO2max treadmill protocol (SOVO2max) to determine VO2max, VT, and RE during a single-bout run; Trial-2 consisted of a 10 km run at 98% of VT followed by an incremental VO2max test on the cycle ergometer; Trial-3 consisted of a 10 km run and 30 km cycling bout at 98% of VT followed by a speed only treadmill test to determine the compounding effects of the initial legs of a duathlon on VO2max, VT, and RE. A repeated measures ANOVA was performed to determine differences between variables across trials. No difference in VO2max, VT (%VO2max), maximal HR, or maximal RPE was observed across trials. Oxygen consumption at VT was significantly lower during Trial-3 compared to Trial-1 (p = 0.01). This decrease was coupled with a significant reduction in running speed at VT (p = 0.015). A significant interaction between trial and running speed indicate that RE was significantly altered during Trial-3 compared to Trial-1 (p < 0.001). The first two legs of a laboratory based duathlon simulation negatively impact VT and RE. Our findings may provide a useful method to evaluate multisport athletes since a single-bout incremental treadmill test fails to reveal important alterations in physiological thresholds. Key points Decrease in relative oxygen uptake at VT (ml·kg-1·min-1) during the final leg of a duathlon simulation, compared to a single-bout maximal run. We observed a decrease in running speed at VT during the final leg of a duathlon simulation; resulting in an increase of more than 2 minutes to complete a 5 km run. During our study, highly trained athletes were unable to complete the final 5 km run at the same intensity that they completed the initial 10 km run (in a laboratory setting). A better understanding, and determination, of training loads during multisport training may help to better periodize training programs; additional research is required. PMID:27274661

Validation of post-operative residual contrast enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma.

PubMed

Ellingson, Benjamin M; Abrey, Lauren E; Nelson, Sarah J; Kaufmann, Timothy J; Garcia, Josep; Chinot, Olivier; Saran, Frank; Nishikawa, Ryo; Henriksson, Roger; Mason, Warren P; Wick, Wolfgang; Butowski, Nicholas; Ligon, Keith L; Gerstner, Elizabeth R; Colman, Howard; de Groot, John; Chang, Susan; Mellinghoff, Ingo; Young, Robert J; Alexander, Brian M; Colen, Rivka; Taylor, Jennie W; Arrillaga-Romany, Isabel; Mehta, Arnav; Huang, Raymond Y; Pope, Whitney B; Reardon, David; Batchelor, Tracy; Prados, Michael; Galanis, Evanthia; Wen, Patrick Y; Cloughesy, Timothy F

2018-04-05

In the current study, we pooled imaging data in newly diagnosed GBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between post-operative residual enhancing tumor volume and overall survival (OS). Data from 1,511 newly diagnosed GBM patients from 5 data sources were included in the current study: 1) a single institution database from UCLA (N=398; Discovery); 2) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N=262 from 8 centers; Confirmation); 3) the chemoradiation placebo arm from an international phase III trial (AVAglio; N=394 from 120 locations in 23 countries; Validation); 4) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N=404 from 120 locations in 23 countries; Exploratory Set 1); and 5) an Alliance (N0874) Phase I/II trial of vorinostat plus chemoradiation (N=53; Exploratory Set 2). Post-surgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, MGMT status, and residual tumor volume on OS. A log-linear relationship was observed between post-operative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Post-operative tumor volume is a prognostic factor for OS (P<0.01), regardless of therapy, age, and MGMT promoter methylation status. Post-surgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed glioblastoma treated with chemoradiation with or without concomitant experimental therapy.

Comparison of single agent versus combined chemotherapy in previously treated patients with advanced urothelial carcinoma: a meta-analysis.

PubMed

Wu, Xiao-Jun; Zhi, Yi; He, Peng; Zhou, Xiao-Zhou; Zheng, Ji; Chen, Zhi-Wen; Zhou, Zhan-Song

2016-01-01

Platinum-based chemotherapy is the standard treatment for advanced urothelial cancer (UC) and is generally used in the first-line setting. However, the optimal salvage treatment for previously treated UC patients is unclear. We conducted a systematic review of published clinical trials of single agent versus combined chemotherapy as salvage treatment in previously treated UC patients. Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All relevant studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), disease control rate (DCR), median progression-free and overall survival (PFS, OS), and grade 3/4 toxicities were extracted and analyzed using Comprehensive Meta Analysis software (Version 2.0). Fifty cohorts with 1,685 patients were included for analysis: 814 patients were treated with single agent chemotherapy and 871 with combined chemotherapy. Pooled OS was significantly higher at 1 year for combined chemotherapy than for single agent (relative risk [RR] 1.52; 95% CI: 1.01-2.37; P=0.03) but not for 2-year OS (RR 1.31; 95% CI: 0.92-1.85; P=0.064). Additionally, combined chemotherapy significantly improved ORR (RR 2.25; 95% CI: 1.60-3.18; P<0.001) and DCR (RR 1.12; 95% CI: 1.01-1.25, P=0.033) compared to single agent for advanced UC patients. As for grade 3 and 4 toxicities, more frequencies of leukopenia and thrombocytopenia were observed in the combined chemotherapy than in single agent group, while equivalent frequencies of anemia, nausea, vomiting, and diarrhea were found between the two groups. In comparison with single agent alone, combined chemotherapy as salvage treatment for advanced UC patients significantly improved ORR, DCR, and 1-year OS, but not 2-year OS. Our findings support the need to compare combined chemotherapy with single agent alone in the salvage setting in large prospective trials due to its potential survival benefit in advanced UC patients.

Test-Retest Reliability and Practice Effects of the Stability Evaluation Test.

PubMed

Williams, Richelle M; Corvo, Matthew A; Lam, Kenneth C; Williams, Travis A; Gilmer, Lesley K; McLeod, Tamara C Valovich

2017-01-17

Postural control plays an essential role in concussion evaluation. The Stability Evaluation Test (SET) aims to objectively analyze postural control by measuring sway velocity on the NeuroCom's VSR portable force platform (Natus, San Carlos, CA). To assess the test-retest reliability and practice effects of the SET protocol. Cohort. Research Laboratory. Fifty healthy adults (males=20, females=30, age=25.30±3.60 years, height=166.60±12.80 cm, mass=68.80±13.90 kg). All participants completed four trials of the SET. Each trial consisted of six 20-second balance tests with eyes closed, under the following conditions: double-leg firm (DFi), single-leg firm (SFi), tandem firm (TFi), double-leg foam (DFo), single-leg foam (SFo), and tandem foam (TFo). Each trial was separated by a 5-minute seated rest period. The dependent variable was sway velocity (deg/sec), with lower values indicating better balance. Sway velocity was recorded for each of the six conditions as well as a composite score for each trial. Test-retest reliability was analyzed across four trials with Intraclass Correlation Coefficients. Practice effects analyzed with repeated measures analysis of variance, followed by Tukey post-hoc comparisons for any significant main effects (p<.05). Sway velocity reliability values were good to excellent: DFi (ICC=0.88;95%CI:0.81,0.92), SFi (ICC=0.75;95%CI:0.61,0.85), TFi (ICC=0.84;95%CI:0.75,0.90), DFo (ICC=0.83;95%CI:0.74,0.90), SFo (ICC=0.82;95%CI:0.72,0.89), TFo (ICC=0.81;95%CI:0.69,0.88), and composite score (ICC=0.93;95%CI:0.88,0.95). Significant practice effects (p<.05) were noted on the SFi, DFo, SFo, TFo conditions, and composite scores. Our results suggest the SET has good to excellent reliability for the assessment of postural control in healthy adults. Due to the practice effects noted, a familiarization session is recommended (i.e., all 6 conditions) prior to recording the data. Future studies should evaluate injured patients to determine meaningful change scores during various injuries.

Cost-effectiveness of single versus double embryo transfer in IVF in relation to female age.

PubMed

van Loendersloot, Laura L; Moolenaar, Lobke M; van Wely, Madelon; Repping, Sjoerd; Bossuyt, Patrick M; Hompes, Peter G A; van der Veen, Fulco; Mol, Ben Willem J

2017-07-01

To evaluate the cost-effectiveness of single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available, as compared to double embryo transfer in relation to female age. We used a decision tree model to evaluate the costs from a healthcare provider perspective and the pregnancy rates of two embryo transfer policies: one fresh single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available (strategy I), and double embryo transfer (strategy II). The analysis was performed on an intention-to-treat basis. Sensitivity analyses were carried out to evaluate the robustness of our model and to identify which model parameters had the strongest impact on the results. SET followed by an additional frozen-thawed single embryo transfer if available was dominant, less costly and more effective, over DET in women under 32 years. In women aged 32 or older DET was more effective than SET followed by an additional frozen-thawed single embryo transfer if available but also more costly. SET followed by an additional frozen-thawed single embryo transfer should be the preferred strategy in women under 32 undergoing IVF. The choice for SET followed by an additional frozen-thawed single embryo transfer or DET in women aged 32 or older depends on individual patient preferences and on how much society is willing to pay for an extra child. There is a strong need for a randomized clinical trial comparing the cost and effects of SET followed by an additional frozen-thawed single embryo transfer and DET in the latter category of women. Copyright © 2017 Elsevier B.V. All rights reserved.

THE TESTOSTERONE TRIALS: THE DESIGN OF SEVEN COORDINATED TRIALS TO DETERMINE IF TESTOSTERONE TREATMENT BENEFITS ELDERLY MEN

PubMed Central

Snyder, Peter J; Ellenberg, Susan S; Cunningham, Glenn R; Matsumoto, Alvin M; Bhasin, Shalender; Barrett-Connor, Elizabeth; Gill, Thomas M; Farrar, John T; Cella, David; Rosen, Raymond C; Resnick, Susan M; Swerdloff, Ronald S; Cauley, Jane A; Cifelli, Denise; Fluharty, Laura; Pahor, Marco; Ensrud, Kristine E; Lewis, Cora E; Molitch, Mark E; Crandall, Jill P; Wang, Christina; Budoff, Matthew J; Wenger, Nanette K; Mohler, Emile R; Bild, Diane E; Cook, Nakela L; Keaveny, Tony M; Kopperdahl, David L; Lee, David; Schwartz, Ann V; Storer, Thomas W; Ershler, William B; Roy, Cindy N; Raffel, Leslie J; Romashkan, Sergei; Hadley, Evan

2014-01-01

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and determine definitively if testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this trial. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and also symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, treatment and monitoring and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data safety monitoring board (DSMB), the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in subject selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary end points for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential Limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one subject. Conclusions The Testosterone Trials were designed to determine definitively if testosterone treatment of elderly men with low testosterone would have any clinical benefit. Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort. PMID:24686158

The effect of resistance exercise on the thermic effect of food.

PubMed

Denzer, Charlene M; Young, John C

2003-09-01

The thermic effect of food (TEF) is the increment in energy expenditure above resting metabolic rate associated with the cost of absorption and processing of food for storage. Previous studies have shown that TEF is enhanced by aerobic endurance exercise of sufficient duration and intensity. The purpose of this study was to determine if a similar effect occurs with a single bout of resistance exercise (weightlifting). VO2 was measured in 9 healthy volunteers (3 males and 6 females) for 2 hours after ingestion of a 2760 kJ (660 kcal) carbohydrate meal with and without prior completion of a resistance training regimen (2 sets of 10 repetitions of 10 different exercises). The meal caused an immediate and persistent thermic effect in both the control and the exercise trial. Mean oxygen consumption over baseline increased 20% in the control trial and 34% in the exercise trial. TEF calculated from VO2 and RER (total area under the response curve above baseline) was 73% greater in the exercise trial compared with the control trial (159 +/- 18 vs. 92 +/- 14 KJ/2 hrs, p < .02). These results indicate that TEF in response to a carbohydrate meal is enhanced following a single bout of resistance exercise.

Physical analysis of breast cancer using dual-source computed tomography

NASA Astrophysics Data System (ADS)

Kim, H. J.; Lee, H. K.; Cho, J. H.

2014-12-01

This study was aimed to analyze various physical characteristics of breast cancer using dual-source computed tomography (CT). A phantom study and a clinical trial were performed in order and a 64-multidetector CT device was used for the examinations. In the phantom study, single-source (SS) CT was set up with a conventional scanning condition that is usually applied for breast CT examination and implementation was done at tube voltage of 120 kVp. Dual-source CT acquired images by irradiating X-ray sources with fast switching between two kilovoltage settings (80 and 140 kVp). After scanning, Hounsfield Unit (HU) values and radiation doses in a region of interest were measured and analyzed. In the clinical trial, the HU values were measured and analyzed after single-source computed tomography (SSCT) and dual-source CT in patients diagnosed with breast cancer. Also, the tumor size measured by dual-source CT was compared with the actual tumor size. The phantom study determined that the tumor region was especially measured by dual-source CT, while nylon fiber and specks region were especially measured by SSCT. The radiation dose was high with dual-source CT. The clinical trial showed a higher HU value of cancerous regions when scanned by dual-source CT compared with SSCT.

The informational role of knowledge of results in motor learning.

PubMed

Blackwell, J R; Newell, K M

1996-07-01

An experiment is reported that was set-up to examine the informational role of knowledge of results (KR) in the learning of a single-limb movement timing task. A group with KR practiced 200 trials a day for 5 days prior to receiving a sixth day of practice without KR. The performance of this group was contrasted to another group that practiced 200 trials without KR for one day. Traditional movement error and time series analyses revealed that KR serves to calibrate the movement outcome to the task demands and modulate the performance outcome relation between trials. The degree of systematic trial-to-trial modulation was strongly dependent upon the degree of error exhibited on any given trial, and was enhanced under no-KR conditions. Information in KR has both immediate and persistent influences on learning and performance that are dependent upon the task constraints and the skill level of the performer.

Single-trial classification of motor imagery differing in task complexity: a functional near-infrared spectroscopy study

PubMed Central

2011-01-01

Background For brain computer interfaces (BCIs), which may be valuable in neurorehabilitation, brain signals derived from mental activation can be monitored by non-invasive methods, such as functional near-infrared spectroscopy (fNIRS). Single-trial classification is important for this purpose and this was the aim of the presented study. In particular, we aimed to investigate a combined approach: 1) offline single-trial classification of brain signals derived from a novel wireless fNIRS instrument; 2) to use motor imagery (MI) as mental task thereby discriminating between MI signals in response to different tasks complexities, i.e. simple and complex MI tasks. Methods 12 subjects were asked to imagine either a simple finger-tapping task using their right thumb or a complex sequential finger-tapping task using all fingers of their right hand. fNIRS was recorded over secondary motor areas of the contralateral hemisphere. Using Fisher's linear discriminant analysis (FLDA) and cross validation, we selected for each subject a best-performing feature combination consisting of 1) one out of three channel, 2) an analysis time interval ranging from 5-15 s after stimulation onset and 3) up to four Δ[O2Hb] signal features (Δ[O2Hb] mean signal amplitudes, variance, skewness and kurtosis). Results The results of our single-trial classification showed that using the simple combination set of channels, time intervals and up to four Δ[O2Hb] signal features comprising Δ[O2Hb] mean signal amplitudes, variance, skewness and kurtosis, it was possible to discriminate single-trials of MI tasks differing in complexity, i.e. simple versus complex tasks (inter-task paired t-test p ≤ 0.001), over secondary motor areas with an average classification accuracy of 81%. Conclusions Although the classification accuracies look promising they are nevertheless subject of considerable subject-to-subject variability. In the discussion we address each of these aspects, their limitations for future approaches in single-trial classification and their relevance for neurorehabilitation. PMID:21682906

Multi-Tasking and Choice of Training Data Influencing Parietal ERP Expression and Single-Trial Detection-Relevance for Neuroscience and Clinical Applications.

PubMed

Kirchner, Elsa A; Kim, Su Kyoung

2018-01-01

Event-related potentials (ERPs) are often used in brain-computer interfaces (BCIs) for communication or system control for enhancing or regaining control for motor-disabled persons. Especially results from single-trial EEG classification approaches for BCIs support correlations between single-trial ERP detection performance and ERP expression. Hence, BCIs can be considered as a paradigm shift contributing to new methods with strong influence on both neuroscience and clinical applications. Here, we investigate the relevance of the choice of training data and classifier transfer for the interpretability of results from single-trial ERP detection. In our experiments, subjects performed a visual-motor oddball task with motor-task relevant infrequent ( targets ), motor-task irrelevant infrequent ( deviants ), and motor-task irrelevant frequent ( standards ) stimuli. Under dual-task condition, a secondary senso-motor task was performed, compared to the simple-task condition. For evaluation, average ERP analysis and single-trial detection analysis with different numbers of electrodes were performed. Further, classifier transfer was investigated between simple and dual task. Parietal positive ERPs evoked by target stimuli (but not by deviants) were expressed stronger under dual-task condition, which is discussed as an increase of task emphasis and brain processes involved in task coordination and change of task set. Highest classification performance was found for targets irrespective whether all 62, 6 or 2 parietal electrodes were used. Further, higher detection performance of targets compared to standards was achieved under dual-task compared to simple-task condition in case of training on data from 2 parietal electrodes corresponding to results of ERP average analysis. Classifier transfer between tasks improves classification performance in case that training took place on more varying examples (from dual task). In summary, we showed that P300 and overlaying parietal positive ERPs can successfully be detected while subjects are performing additional ongoing motor activity. This supports single-trial detection of ERPs evoked by target events to, e.g., infer a patient's attentional state during therapeutic intervention.

Multi-Tasking and Choice of Training Data Influencing Parietal ERP Expression and Single-Trial Detection—Relevance for Neuroscience and Clinical Applications

PubMed Central

Kirchner, Elsa A.; Kim, Su Kyoung

2018-01-01

Event-related potentials (ERPs) are often used in brain-computer interfaces (BCIs) for communication or system control for enhancing or regaining control for motor-disabled persons. Especially results from single-trial EEG classification approaches for BCIs support correlations between single-trial ERP detection performance and ERP expression. Hence, BCIs can be considered as a paradigm shift contributing to new methods with strong influence on both neuroscience and clinical applications. Here, we investigate the relevance of the choice of training data and classifier transfer for the interpretability of results from single-trial ERP detection. In our experiments, subjects performed a visual-motor oddball task with motor-task relevant infrequent (targets), motor-task irrelevant infrequent (deviants), and motor-task irrelevant frequent (standards) stimuli. Under dual-task condition, a secondary senso-motor task was performed, compared to the simple-task condition. For evaluation, average ERP analysis and single-trial detection analysis with different numbers of electrodes were performed. Further, classifier transfer was investigated between simple and dual task. Parietal positive ERPs evoked by target stimuli (but not by deviants) were expressed stronger under dual-task condition, which is discussed as an increase of task emphasis and brain processes involved in task coordination and change of task set. Highest classification performance was found for targets irrespective whether all 62, 6 or 2 parietal electrodes were used. Further, higher detection performance of targets compared to standards was achieved under dual-task compared to simple-task condition in case of training on data from 2 parietal electrodes corresponding to results of ERP average analysis. Classifier transfer between tasks improves classification performance in case that training took place on more varying examples (from dual task). In summary, we showed that P300 and overlaying parietal positive ERPs can successfully be detected while subjects are performing additional ongoing motor activity. This supports single-trial detection of ERPs evoked by target events to, e.g., infer a patient's attentional state during therapeutic intervention. PMID:29636660

Informing real-world practice with real-world evidence: the value of PRECIS-2.

PubMed

Neta, Gila; Johnson, Karin E

2018-05-21

Real-world evidence is needed to inform real-world practice. Pragmatic controlled trials are intended to provide such evidence by assessing the effectiveness of medicines and other interventions in real-world settings, as opposed to explanatory trials that assess efficacy in highly controlled settings. Dal-Ré and colleagues (BMC Med 16:49, 2018) recently performed a literature review of studies published between 2014 and 2017 to assess the degree to which studies that self-identified as pragmatic were truly so. The authors found that over one-third of randomized controlled trials of drugs and biologics that were self-labeled as pragmatic used placebo controls (as opposed to usual care), tested medicines before licensing, or were conducted in a single site. Further, they proposed that, in order to improve the reliability of the 'pragmatic' label, investigators should assess their trials using the PRECIS-2 tool upon submission to funders, ethics boards, or journals. We appreciate the value of PRECIS-2 as an indicator to assess the pragmatic versus explanatory features in a trial, and we herein highlight the potential challenges and opportunities that may arise with its systematic and widespread use.

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing’s sarcoma

PubMed Central

Dutton, P; Love, SB; Billingham, L; Hassan, AB

2016-01-01

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency. PMID:27587590

Single embryo transfer and IVF/ICSI outcome: a balanced appraisal.

PubMed

Gerris, Jan M R

2005-01-01

This review considers the value of single embryo transfer (SET) to prevent multiple pregnancies (MP) after IVF/ICSI. The incidence of MP (twins and higher order pregnancies) after IVF/ICSI is much higher (approximately 30%) than after natural conception (approximately 1%). Approximately half of all the neonates are multiples. The obstetric, neonatal and long-term consequences for the health of these children are enormous and costs incurred extremely high. Judicious SET is the only method to decrease this epidemic of iatrogenic multiple gestations. Clinical trials have shown that programmes with >50% of SET maintain high overall ongoing pregnancy rates ( approximately 30% per started cycle) while reducing the MP rate to <10%. Experience with SET remains largely European although the need to reduce MP is accepted worldwide. An important issue is how to select patients suitable for SET and embryos with a high putative implantation potential. The typical patient suitable for SET is young (aged <36 years) and in her first or second IVF/ICSI trial. Embryo selection is performed using one or a combination of embryo characteristics. Available evidence suggests that, for the overall population, day 3 and day 5 selection yield similar results but better than zygote selection results. Prospective studies correlating embryo characteristics with documented implantation potential, utilizing databases of individual embryos, are needed. The application of SET should be supported by other measures: reimbursement of IVF/ICSI (earned back by reducing costs), optimized cryopreservation to augment cumulative pregnancy rates per oocyte harvest and a standardized format for reporting results. To make SET the standard of care in the appropriate target group, there is a need for more clinical studies, for intensive counselling of patients, and for an increased sense of responsibility in patients, health care providers and health insurers.

Standardized versus Individualized Acupuncture for Chronic Low Back Pain: A Randomized Controlled Trial

PubMed Central

Pach, Daniel; Yang-Strobel, Xiaoli; Lüdtke, Rainer; Icke, Katja; Brinkhaus, Benno; Witt, Claudia M.

2013-01-01

We aimed to compare the effectiveness of standardized and individualized acupuncture treatment in patients with chronic low back pain. A single-center randomized controlled single-blind trial was performed in a general medical practice in Germany run by a Chinese-born medical doctor trained in western and Chinese medicine. One hundred and fifty outpatients with chronic low back pain were randomly allocated to two groups (78 standardized and 72 individualized acupuncture). Patients received either standardized acupuncture or individualized acupuncture. Treatment encompassed between 10 and 15 treatments based on individual symptoms with two treatments per week. The main outcome measure was the area under the curve (AUC) summarizing eight weeks of daily rated pain severity measured with a visual analogue scale (0 mm = no pain, 100 mm = worst imaginable pain). No significant differences between groups were observed for the AUC (individualized acupuncture mean: 1768.7 (95% CI, 1460.4; 2077.1); standardized acupuncture 1482.9 (1177.2; 1788.7); group difference, 285.8 (−33.9; 605.5) P = 0.080). In this single-center trial, individualized acupuncture was not superior to standardized acupuncture for patients suffering from chronic pain. As a next step, a multicenter noninferiority study should be performed to investigate whether standardised acupuncture treatment for chronic low back pain might be applicable in a broader usual care setting. This trial is registered with ClinicalTrials.gov NCT00758017. PMID:24288556

National Cancer Institute's Precision Medicine Initiatives for the new National Clinical Trials Network.

PubMed

Abrams, Jeffrey; Conley, Barbara; Mooney, Margaret; Zwiebel, James; Chen, Alice; Welch, John J; Takebe, Naoko; Malik, Shakun; McShane, Lisa; Korn, Edward; Williams, Mickey; Staudt, Louis; Doroshow, James

2014-01-01

The promise of precision medicine will only be fully realized if the research community can adapt its clinical trials methodology to study molecularly characterized tumors instead of the traditional histologic classification. Such trials will depend on adequate tissue collection, availability of quality controlled, high throughput molecular assays, and the ability to screen large numbers of tumors to find those with the desired molecular alterations. The National Cancer Institute's (NCI) new National Clinical Trials Network (NCTN) is well positioned to conduct such trials. The NCTN has the ability to seamlessly perform ethics review, register patients, manage data, and deliver investigational drugs across its many sites including both in cities and rural communities, academic centers, and private practices. The initial set of trials will focus on different questions: (1) Exceptional Responders Initiative-why do a minority of patients with solid tumors or lymphoma respond very well to some drugs even if the majority do not?; (2) NCI MATCH trial-can molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment?; (3) ALCHEMIST trial-will targeted epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting?; and (4) Lung Cancer Master Protocol trial for advanced squamous cell lung cancer-is there an advantage to developing drugs for small subsets of molecularly characterized tumors in a single, multiarm trial design? These studies will hopefully spawn a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy.

Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: Study protocol for a randomised controlled trial

PubMed Central

2012-01-01

Background Children with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain. Methods/design This study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05. Discussion This clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting. Trial registration Current Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20 PMID:22647439

Effectiveness of a self-management program for dual sensory impaired seniors in aged care settings: study protocol for a cluster randomized controlled trial

PubMed Central

2013-01-01

Background Five to 25 percent of residents in aged care settings have a combined hearing and visual sensory impairment. Usual care is generally restricted to single sensory impairment, neglecting the consequences of dual sensory impairment on social participation and autonomy. The aim of this study is to evaluate the effectiveness of a self-management program for seniors who acquired dual sensory impairment at old age. Methods/Design In a cluster randomized, single-blind controlled trial, with aged care settings as the unit of randomization, the effectiveness of a self-management program will be compared to usual care. A minimum of 14 and maximum of 20 settings will be randomized to either the intervention cluster or the control cluster, aiming to include a total of 132 seniors with dual sensory impairment. Each senior will be linked to a licensed practical nurse working at the setting. During a five to six month intervention period, nurses at the intervention clusters will be trained in a self-management program to support and empower seniors to use self-management strategies. In two separate diaries, nurses keep track of the interviews with the seniors and their reflections on their own learning process. Nurses of the control clusters offer care as usual. At senior level, the primary outcome is the social participation of the seniors measured using the Hearing Handicap Questionnaire and the Activity Card Sort, and secondary outcomes are mood, autonomy and quality of life. At nurse level, the outcome is job satisfaction. Effectiveness will be evaluated using linear mixed model analysis. Discussion The results of this study will provide evidence for the effectiveness of the Self-Management Program for seniors with dual sensory impairment living in aged care settings. The findings are expected to contribute to the knowledge on the program’s potential to enhance social participation and autonomy of the seniors, as well as increasing the job satisfaction of the licensed practical nurses. Furthermore, an extensive process evaluation will take place which will offer insight in the quality and feasibility of the sampling and intervention process. If it is shown to be effective and feasible, this Self-Management Program could be widely disseminated. Clinical trials registration ClinicalTrials.gov, NCT01217502. PMID:24099315

Single-case experimental design yielded an effect estimate corresponding to a randomized controlled trial.

PubMed

Shadish, William R; Rindskopf, David M; Boyajian, Jonathan G

2016-08-01

We reanalyzed data from a previous randomized crossover design that administered high or low doses of intravenous immunoglobulin (IgG) to 12 patients with hypogammaglobulinaemia over 12 time points, with crossover after time 6. The objective was to see if results corresponded when analyzed as a set of single-case experimental designs vs. as a usual randomized controlled trial (RCT). Two blinded statisticians independently analyzed results. One analyzed the RCT comparing mean outcomes of group A (high dose IgG) to group B (low dose IgG) at the usual trial end point (time 6 in this case). The other analyzed all 12 time points for the group B patients as six single-case experimental designs analyzed together in a Bayesian nonlinear framework. In the randomized trial, group A [M = 794.93; standard deviation (SD) = 90.48] had significantly higher serum IgG levels at time six than group B (M = 283.89; SD = 71.10) (t = 10.88; df = 10; P < 0.001), yielding a mean difference of MD = 511.05 [standard error (SE) = 46.98]. For the single-case experimental designs, the effect from an intrinsically nonlinear regression was also significant and comparable in size with overlapping confidence intervals: MD = 495.00, SE = 54.41, and t = 495.00/54.41 = 9.10. Subsequent exploratory analyses indicated that how trend was modeled made a difference to these conclusions. The results of single-case experimental designs accurately approximated results from an RCT, although more work is needed to understand the conditions under which this holds. Copyright © 2016 Elsevier Inc. All rights reserved.

Feasibility of a multicentre, randomised controlled trial of laparoscopic versus open colorectal surgery in the acute setting: the LaCeS feasibility trial protocol.

PubMed

Harji, Deena; Marshall, Helen; Gordon, Katie; Crow, Hannah; Hiley, Victoria; Burke, Dermot; Griffiths, Ben; Moriarty, Catherine; Twiddy, Maureen; O'Dwyer, John L; Verjee, Azmina; Brown, Julia; Sagar, Peter

2018-02-22

Acute colorectal surgery forms a significant proportion of emergency admissions within the National Health Service. There is limited evidence to suggest minimally invasive surgery may be associated with improved clinical outcomes in this cohort of patients. Consequently, there is a need to assess the clinical effectiveness and cost-effectiveness of laparoscopic surgery in the acute colorectal setting. However,emergency colorectal surgical trials have previously been difficult to conduct due to issues surrounding recruitment and equipoise. The LaCeS (randomised controlled trial of Laparoscopic versus open Colorectal Surgery in the acute setting) feasibility trial will determine the feasibility of conducting a definitive, phase III trial of laparoscopic versus open acute colorectal resection. The LaCeS feasibility trial is a prospective, multicentre, single-blinded, parallel group, pragmatic randomised controlled feasibility trial. Patients will be randomised on a 1:1 basis to receive eitherlaparoscopic or open surgery. The trial aims to recruit at least 66 patients from five acute general surgical units across the UK. Patients over the age of 18 with a diagnosis of acute colorectal pathology requiring resection on clinical and radiological/endoscopic investigations, with a National Confidential Enquiry into Patient Outcome and Death classification of urgent will be considered eligible for participation. The primary outcome is recruitment. Secondary outcomes include assessing the safety profile of laparoscopic surgery using intraoperative and postoperative complication rates, conversion rates and patient-safety indicators as surrogate markers. Clinical and patient-reported outcomes will also be reported. The trial will contain an embedded qualitative study to assess clinician and patient acceptability of trial processes. The LaCeS feasibility trial is approved by the Yorkshire and The Humber, Bradford Leeds Research Ethics Committee (REC reference: 15/ YH/0542). The results from the trial will be presented at national and international colorectal conferences and will be submitted for publication to peer-reviewed journals. ISRCTN15681041; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Critical appraisal of clinical trials in multiple system atrophy: Toward better quality.

PubMed

Castro Caldas, Ana; Levin, Johannes; Djaldetti, Ruth; Rascol, Olivier; Wenning, Gregor; Ferreira, Joaquim J

2017-10-01

Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

'In situ simulation' versus 'off site simulation' in obstetric emergencies and their effect on knowledge, safety attitudes, team performance, stress, and motivation: study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background Unexpected obstetric emergencies threaten the safety of pregnant women. As emergencies are rare, they are difficult to learn. Therefore, simulation-based medical education (SBME) seems relevant. In non-systematic reviews on SBME, medical simulation has been suggested to be associated with improved learner outcomes. However, many questions on how SBME can be optimized remain unanswered. One unresolved issue is how 'in situ simulation' (ISS) versus 'off site simulation' (OSS) impact learning. ISS means simulation-based training in the actual patient care unit (in other words, the labor room and operating room). OSS means training in facilities away from the actual patient care unit, either at a simulation centre or in hospital rooms that have been set up for this purpose. Methods and design The objective of this randomized trial is to study the effect of ISS versus OSS on individual learning outcome, safety attitude, motivation, stress, and team performance amongst multi-professional obstetric-anesthesia teams. The trial is a single-centre randomized superiority trial including 100 participants. The inclusion criteria were health-care professionals employed at the department of obstetrics or anesthesia at Rigshospitalet, Copenhagen, who were working on shifts and gave written informed consent. Exclusion criteria were managers with staff responsibilities, and staff who were actively taking part in preparation of the trial. The same obstetric multi-professional training was conducted in the two simulation settings. The experimental group was exposed to training in the ISS setting, and the control group in the OSS setting. The primary outcome is the individual score on a knowledge test. Exploratory outcomes are individual scores on a safety attitudes questionnaire, a stress inventory, salivary cortisol levels, an intrinsic motivation inventory, results from a questionnaire evaluating perceptions of the simulation and suggested changes needed in the organization, a team-based score on video-assessed team performance and on selected clinical performance. Discussion The perspective is to provide new knowledge on contextual effects of different simulation settings. Trial registration ClincialTrials.gov NCT01792674. PMID:23870501

A Fully Automated Trial Selection Method for Optimization of Motor Imagery Based Brain-Computer Interface.

PubMed

Zhou, Bangyan; Wu, Xiaopei; Lv, Zhao; Zhang, Lei; Guo, Xiaojin

2016-01-01

Independent component analysis (ICA) as a promising spatial filtering method can separate motor-related independent components (MRICs) from the multichannel electroencephalogram (EEG) signals. However, the unpredictable burst interferences may significantly degrade the performance of ICA-based brain-computer interface (BCI) system. In this study, we proposed a new algorithm frame to address this issue by combining the single-trial-based ICA filter with zero-training classifier. We developed a two-round data selection method to identify automatically the badly corrupted EEG trials in the training set. The "high quality" training trials were utilized to optimize the ICA filter. In addition, we proposed an accuracy-matrix method to locate the artifact data segments within a single trial and investigated which types of artifacts can influence the performance of the ICA-based MIBCIs. Twenty-six EEG datasets of three-class motor imagery were used to validate the proposed methods, and the classification accuracies were compared with that obtained by frequently used common spatial pattern (CSP) spatial filtering algorithm. The experimental results demonstrated that the proposed optimizing strategy could effectively improve the stability, practicality and classification performance of ICA-based MIBCI. The study revealed that rational use of ICA method may be crucial in building a practical ICA-based MIBCI system.

Impact of 4.0% chlorhexidine cleansing of the umbilical cord on mortality and omphalitis among newborns of Sylhet, Bangladesh: design of a community-based cluster randomized trial.

PubMed

Mullany, Luke C; El Arifeen, Shams; Winch, Peter J; Shah, Rasheduzzaman; Mannan, Ishtiaq; Rahman, Syed M; Rahman, Mohammad R; Darmstadt, Gary L; Ahmed, Saifuddin; Santosham, Mathuram; Black, Robert E; Baqui, Abdullah H

2009-10-21

The World Health Organization recommends dry cord care for newborns but this recommendation may not be optimal in low resource settings where most births take place in an unclean environment and infections account for up to half of neonatal deaths. A previous trial in Nepal indicated that umbilical cord cleansing with 4.0% chlorhexidine could substantially reduce mortality and omphalitis risk, but policy changes await additional community-based data. The Projahnmo Chlorhexidine study was a three-year, cluster-randomized, community-based trial to assess the impact of three cord care regimens on neonatal mortality and omphalitis. Women were recruited mid-pregnancy, received a basic package of maternal and neonatal health promotion messages, and were followed to pregnancy outcome. Newborns were visited at home by local village-based workers whose areas were randomized to either 1) single- or 2) 7-day cord cleansing with 4.0% chlorhexidine, or 3) promotion of dry cord care as recommended by WHO. All mothers received basic messages regarding hand-washing, clean cord cutting, and avoidance of harmful home-base applications to the cord. Death within 28 days and omphalitis were the primary outcomes; these were monitored directly through home visits by community health workers on days 1, 3, 6, 9, 15, and 28 after birth. Due to report in early 2010, the Projahnmo Chlorhexidine Study examines the impact of multiple or single chlorhexidine cleansing of the cord on neonatal mortality and omphalitis among newborns of rural Sylhet District, Bangladesh. The results of this trial will be interpreted in conjunction with a similarly designed trial previously conducted in Nepal, and will have implications for policy guidelines for optimal cord care of newborns in low resource settings in Asia. ClinicalTrials.gov (NCT00434408).

Assessing the challenges of multi-scope clinical research sites: an example from NIH HIV/AIDS clinical trials networks.

PubMed

Rosas, Scott R; Cope, Marie T; Villa, Christie; Motevalli, Mahnaz; Utech, Jill; Schouten, Jeffrey T

2014-04-01

Large-scale, multi-network clinical trials are seen as a means for efficient and effective utilization of resources with greater responsiveness to new discoveries. Formal structures instituted within the National Institutes of Health (NIH) HIV/AIDS Clinical Trials facilitate collaboration and coordination across networks and emphasize an integrated approach to HIV/AIDS vaccine, prevention and therapeutics clinical trials. This study examines the joint usage of clinical research sites as means of gaining efficiency, extending capacity, and adding scientific value to the networks. A semi-structured questionnaire covering eight clinical management domains was administered to 74 (62% of sites) clinical site coordinators at single- and multi-network sites to identify challenges and efficiencies related to clinical trials management activities and coordination with multi-network units. Overall, respondents at multi-network sites did not report more challenges than single-network sites, but did report unique challenges to overcome including in the areas of study prioritization, community engagement, staff education and training, and policies and procedures. The majority of multi-network sites reported that such affiliations do allow for the consolidation and cost-sharing of research functions. Suggestions for increasing the efficiency or performance of multi-network sites included streamlining standards and requirements, consolidating protocol activation methods, using a single cross-network coordinating centre, and creating common budget and payment mechanisms. The results of this assessment provide important information to consider in the design and management of multi-network configurations for the NIH HIV/AIDS Clinical Trials Networks, as well as others contemplating and promoting the concept of multi-network settings. © 2013 John Wiley & Sons Ltd.

Measuring the effects of a visual or auditory Stroop task on dual-task costs during obstacle crossing.

PubMed

Worden, Timothy A; Mendes, Matthew; Singh, Pratham; Vallis, Lori Ann

2016-10-01

Successful planning and execution of motor strategies while concurrently performing a cognitive task has been previously examined, but unfortunately the varied and numerous cognitive tasks studied has limited our fundamental understanding of how the central nervous system successfully integrates and executes these tasks simultaneously. To gain a better understanding of these mechanisms we used a set of cognitive tasks requiring similar central executive function processes and response outputs but requiring different perceptual mechanisms to perform the motor task. Thirteen healthy young adults (20.6±1.6years old) were instrumented with kinematic markers (60Hz) and completed 5 practice, 10 single-task obstacle walking trials and two 40 trial experimental blocks. Each block contained 20 trials of seated (single-task) trials followed by 20 cognitive and obstacle (30% lower leg length) crossing trials (dual-task). Blocks were randomly presented and included either an auditory Stroop task (AST; central interference only) or a visual Stroop task (VST; combined central and structural interference). Higher accuracy rates and shorter response times were observed for the VST versus AST single-task trials (p<0.05). Conversely, for the obstacle stepping performance, larger dual task costs were observed for the VST as compared to the AST for clearance measures (the VST induced larger clearance values for both the leading and trailing feet), indicating VST tasks caused greater interference for obstacle crossing (p<0.05). These results supported the hypothesis that structural interference has a larger effect on motor performance in a dual-task situation compared to cognitive tasks that pose interference at only the central processing stage. Copyright © 2016 Elsevier B.V. All rights reserved.

Reducing multi-sensor data to a single time course that reveals experimental effects

PubMed Central

2013-01-01

Background Multi-sensor technologies such as EEG, MEG, and ECoG result in high-dimensional data sets. Given the high temporal resolution of such techniques, scientific questions very often focus on the time-course of an experimental effect. In many studies, researchers focus on a single sensor or the average over a subset of sensors covering a “region of interest” (ROI). However, single-sensor or ROI analyses ignore the fact that the spatial focus of activity is constantly changing, and fail to make full use of the information distributed over the sensor array. Methods We describe a technique that exploits the optimality and simplicity of matched spatial filters in order to reduce experimental effects in multivariate time series data to a single time course. Each (multi-sensor) time sample of each trial is replaced with its projection onto a spatial filter that is matched to an observed experimental effect, estimated from the remaining trials (Effect-Matched Spatial filtering, or EMS filtering). The resulting set of time courses (one per trial) can be used to reveal the temporal evolution of an experimental effect, which distinguishes this approach from techniques that reveal the temporal evolution of an anatomical source or region of interest. Results We illustrate the technique with data from a dual-task experiment and use it to track the temporal evolution of brain activity during the psychological refractory period. We demonstrate its effectiveness in separating the means of two experimental conditions, and in significantly improving the signal-to-noise ratio at the single-trial level. It is fast to compute and results in readily-interpretable time courses and topographies. The technique can be applied to any data-analysis question that can be posed independently at each sensor, and we provide one example, using linear regression, that highlights the versatility of the technique. Conclusion The approach described here combines established techniques in a way that strikes a balance between power, simplicity, speed of processing, and interpretability. We have used it to provide a direct view of parallel and serial processes in the human brain that previously could only be measured indirectly. An implementation of the technique in MatLab is freely available via the internet. PMID:24125590

A prospective 10-year study of metal ceramic single crowns and fixed dental prosthesis retainers in private practice settings.

PubMed

Reitemeier, Bernd; Hänsel, Kristina; Kastner, Christian; Weber, Anke; Walter, Michael H

2013-03-01

Metal ceramic restorations are widely used in prosthodontics, but long-term data on their clinical performance in private practice settings based on prospective trials are sparse. This clinical trial was designed to provide realistic long-term survival rates for different outcomes related to tooth loss, crown loss, and metal ceramic defect. Ninety-five participants were provided with 190 noble metal ceramic single crowns and 138 participants with 276 fixed dental prosthesis retainer crowns on vital posterior teeth. Follow-up examinations were scheduled 2 weeks after insertion, annually up to 8 years, and after 10 years. Kaplan-Meier survival analyses, Mantel-Cox logrank tests, and Cox regression analyses were conducted. Because of variations in the time of the last examinations, the maximum observation period was 12.1 years. For the primary outcome 'loss of crown or tooth', the Kaplan-Meier survival rate was 94.3% ±1.8% (standard error) at 8.0 years (last outcome event) for single crowns and 94.4% ±1.5% at 11.0 years for fixed dental prosthesis retainer crowns. The difference between the survival functions was not significant (P>.05). For the secondary outcome 'metal ceramic defect', the survival rate was 88.8% ±3.2% at 11.0 years for single crowns and 81.7% ±3.5% at 11.0 years for fixed dental prosthesis retainer crowns. In Cox regression models, the only significant covariates for the outcome event 'metal ceramic defect' were bruxism in the medical history (single crowns) and signs and symptoms of bruxism (fixed dental prosthesis retainer crowns) with hazard ratios of 3.065 (95% CI 1.063 - 8.832) and 2.554 (95% CI 1.307 - 4.992). Metal ceramic crowns provided in private practice settings show good longevity. Bruxism appears to indicate a risk for metal ceramic defects. Copyright © 2013 The Editorial Council of the Journal of Prosthetic Dentistry. Published by Mosby, Inc. All rights reserved.

Single dose treatment of malaria - current status and perspectives.

PubMed

Mischlinger, Johannes; Agnandji, Selidji T; Ramharter, Michael

2016-07-01

Despite increased international efforts for control and ultimate elimination, malaria remains a major health problem. Currently, artemisinin-based combination therapies are the treatment of choice for uncomplicated malaria exhibiting high efficacy in clinical trial settings in sub-Saharan Africa. However, their administration over a three-day period is associated with important problems of treatment adherence resulting in markedly reduced effectiveness of currently recommended antimalarials under real world settings. Antimalarial drug candidates and antimalarial drug combinations currently under advanced clinical development for the indication as single dose antimalarial therapy. Expert commentary: Several new drug candidates and combinations are currently undergoing pivotal proof-of-concept studies or clinical development programmes. The development of a single dose combination therapy would constitute a breakthrough in the control of malaria. Such an innovative treatment approach would simultaneously close the effectiveness gap of current three-day therapies and revolutionize population based interventions in the context of malaria elimination campaigns.

Balance circuit classes to improve balance among rehabilitation inpatients: a protocol for a randomised controlled trial

PubMed Central

2013-01-01

Background Impaired balance and mobility are common among rehabilitation inpatients. Poor balance and mobility lead to an increased risk of falling. Specific balance exercise has been shown to improve balance and reduce falls within the community setting. However few studies have measured the effects of balance exercises on balance within the inpatient setting. The aim of this randomised controlled trial is to investigate whether the addition of circuit classes targeting balance to usual therapy lead to greater improvements in balance among rehabilitation inpatients than usual therapy alone. Methods/Design A single centre, randomised controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. One hundred and sixty two patients admitted to the general rehabilitation ward at Bankstown-Lidcombe Hospital will be recruited. Eligible participants will have no medical contraindications to exercise and will be able to: fully weight bear; stand unaided independently for at least 30 seconds; and participate in group therapy sessions with minimal supervision. Participants will be randomly allocated to an intervention group or usual-care control group. Both groups will receive standard rehabilitation intervention that includes physiotherapy mobility training and exercise for at least two hours on each week day. The intervention group will also receive six 1-hour circuit classes of supervised balance exercises designed to maximise the ability to make postural adjustments in standing, stepping and walking. The primary outcome is balance. Balance will be assessed by measuring the total time the participant can stand unsupported in five different positions; feet apart, feet together, semi-tandem, tandem and single-leg-stance. Secondary outcomes include mobility, self reported physical functioning, falls and hospital readmissions. Performance on the outcome measures will be assessed before randomisation and at two-weeks and three-months after randomisation by physiotherapists unaware of intervention group allocation. Discussion This study will determine the impact of additional balance circuit classes on balance among rehabilitation inpatients. The results will provide essential information to guide evidence-based physiotherapy at the study site as well as across other rehabilitation inpatient settings. Trial registration The protocol for this study is registered with the Australian New Zealand, Clinical Trials Registry: ACTRN=12611000412932 PMID:23870654

[Non-pharmacological treatment of dementia in geriatric psychiatry care units : Scoping review].

PubMed

Göhner, Anne; Hüll, Michael; Voigt-Radloff, Sebastian

2018-02-01

The number of persons suffering from dementia will continuously increase in the coming years; therefore, evidence-based interventions are needed in geriatric psychiatric care. When evidence is poor scoping reviews may help to identify knowledge gaps and needs for research. To present an overview of clinical trials on non-pharmacological treatment for elderly with dementia in hospitals, wards and nursing homes, specializing in gerontopsychiatric care. A systematic search was carried out by one of the authors for clinical trials (randomized controlled, controlled and single group pre-post design, English and German, 1998-2014) in PsycINFO, PubMED, PSYNDEX and the Cochrane Library as well as a manual search in two relevant German peer-reviewed journals. Two authors included studies according to a priori defined inclusion criteria. One author extracted data after consulting the second author in cases of ambiguity. The risk of bias of the studies was not assessed. A total of 77 studies were identified, 29 studies on restructured treatment pathways or settings, 14 trials on environmental changes and 34 studies on therapeutic single or group interventions. Both the methodological quality of the studies and the evidence for the efficacy of non-pharmacological treatment were limited. There are clear indications for an advantage of specialized environments and treatment settings for the elderly with dementia in hospitals, wards and nursing homes. There are consistent indications for positive effects of psychosocial activation alone or in combination with cognitive or physical activation, partly with high-quality study designs. This is consistent with the German S3 guidelines for dementia. For single interventions, such as electroconvulsive therapy or horticultural activities, the level of evidence remains limited.

Phase II Trials for Heterogeneous Patient Populations with a Time-to-Event Endpoint.

PubMed

Jung, Sin-Ho

2017-07-01

In this paper, we consider a single-arm phase II trial with a time-to-event end-point. We assume that the study population has multiple subpopulations with different prognosis, but the study treatment is expected to be similarly efficacious across the subpopulations. We review a stratified one-sample log-rank test and present its sample size calculation method under some practical design settings. Our sample size method requires specification of the prevalence of subpopulations. We observe that the power of the resulting sample size is not very sensitive to misspecification of the prevalence.

Psychological therapy for inpatients receiving acute mental health care: A systematic review and meta-analysis of controlled trials.

PubMed

Paterson, Charlotte; Karatzias, Thanos; Dickson, Adele; Harper, Sean; Dougall, Nadine; Hutton, Paul

2018-04-16

The effectiveness of psychological therapies for those receiving acute adult mental health inpatient care remains unclear, partly because of the difficulty in conducting randomized controlled trials (RCTs) in this setting. The aim of this meta-analysis was to synthesize evidence from all controlled trials of psychological therapy carried out with this group, to estimate its effects on a number of important outcomes and examine whether the presence of randomization and rater blinding moderated these estimates. A systematic review and meta-analysis of all controlled trials of psychological therapy delivered in acute inpatient settings was conducted, with a focus on psychotic symptoms, readmissions or emotional distress (anxiety and depression). Studies were identified through ASSIA, EMBASE, CINAHL, Cochrane, MEDLINE, and PsycINFO using a combination of the key terms 'inpatient', 'psychological therapy', and 'acute'. No restriction was placed on diagnosis. The moderating effect of the use of assessor-blind RCT methodology was examined via subgroup and sensitivity analyses. Overall, psychological therapy was associated with small-to-moderate improvements in psychotic symptoms at end of therapy but the effect was smaller and not significant at follow-up. Psychological therapy was also associated with reduced readmissions, depression, and anxiety. The use of single-blind randomized controlled trial methodology was associated with significantly reduced benefits on psychotic symptoms and was also associated with reduced benefits on readmission and depression; however, these reductions were not statistically significant. The provision of psychological therapy to acute psychiatric inpatients is associated with improvements; however, the use of single-blind RCT methodology was associated with reduced therapy-attributable improvements. Whether this is a consequence of increased internal validity or reduced external validity is unclear. Trials with both high internal and external validity are now required to establish what type, format, and intensity of brief psychological therapy is required to achieve sustained benefits. Clinical implications: This review provides the first meta-analytical synthesis of brief psychological therapy delivered in acute psychiatric inpatient settings. This review suggests that brief psychological therapy may be associated with reduced emotional distress and readmissions. The evidence in this review is of limited quality. The type, format, and intensity of brief psychological therapy required to achieve sustained benefits are yet to be established. © 2018 The British Psychological Society.

Out-of-hospital tracheal intubation with single-use versus reusable metal laryngoscope blades: a multicenter randomized controlled trial.

PubMed

Jabre, Patricia; Galinski, Michel; Ricard-Hibon, Agnes; Devaud, Marie Laure; Ruscev, Mirko; Kulstad, Erik; Vicaut, Eric; Adnet, Fréderic; Margenet, Alain; Marty, Jean; Combes, Xavier

2011-03-01

Emergency tracheal intubation is reported to be more difficult with single-use plastic than with reusable metal laryngoscope blades in both inhospital and out-of-hospital settings. Single-use metal blades have been developed but have not been compared with conventional metal blades. This controlled trial compares the efficacy and safety of single-use metal blades with reusable metal blades in out-of-hospital emergency tracheal intubation. This randomized controlled trial was carried out in France with out-of-hospital emergency medical units (Services de Médecine d'Urgence et de Réanimation). This was a multicenter prospective noninferiority randomized controlled trial in adult out-of-hospital patients requiring emergency tracheal intubation. Patients were randomly assigned to either single-use or reusable metal laryngoscope blades and intubated by a senior physician or a nurse anesthetist. The primary outcome was first-pass intubation success. Secondary outcomes were incidence of difficult intubation, need for alternate airway devices, and early intubation-related complications (esophageal intubation, mainstem intubation, vomiting, pulmonary aspiration, dental trauma, bronchospasm or laryngospasm, ventricular tachycardia, arterial desaturation, hypotension, or cardiac arrest). The study included 817 patients, including 409 intubated with single-use blades and 408 with a reusable blade. First-pass intubation success was similar in both groups: 292 (71.4%) for single-use blades, 290 (71.1%) for reusable blades. The 95% confidence interval (CI) for the difference in treatments (0.3%; 95% CI -5.9% to 6.5%) did not include the prespecified inferiority margin of -7%. There was no difference in rate of difficult intubation (difference 3%; 95% CI -7% to 2%), need for alternate airway (difference 4%; 95% CI -8% to 1%), or early complication rate (difference 3%; 95% CI -3% to 8%). First-pass out-of-hospital tracheal intubation success with single-use metal laryngoscopy blades was noninferior to first-pass success with reusable metal laryngoscope blades. Copyright © 2010 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

A Randomized Controlled Trial of an Activity Specific Exercise Program for Individuals With Alzheimer Disease in Long-term Care Settings

PubMed Central

Roach, Kathryn E.; Tappen, Ruth M.; Kirk-Sanchez, Neva; Williams, Christine L.; Loewenstein, David

2011-01-01

Objective To determine whether an activity specific exercise program could improve ability to perform basic mobility activities in long-term care residents with Alzheimer disease (AD). Design Randomized, controlled, single-blinded clinical trial. Setting Residents of 7 long-term care facilities. Participants Eighty-two long-term care residents with mild to severe AD. Intervention An activity specific exercise program was compared to a walking program and to an attention control. Measurements Ability to perform bed mobility and transfers were assessed using the subscales of the Acute Care Index of Function; functional mobility was measured using the 6-Minute Walk test. Results Subjects receiving the activity specific exercise program improved in ability to perform transfers, whereas subjects in the other 2 groups declined. PMID:21937893

Statin-Induced Cardioprotection Against Ischemia-Reperfusion Injury: Potential Drug-Drug Interactions. Lesson to be Learnt by Translating Results from Animal Models to the Clinical Settings.

PubMed

Birnbaum, Gilad D; Birnbaum, Itamar; Ye, Yumei; Birnbaum, Yochai

2015-01-01

Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials.

Single-trial lie detection using a combined fNIRS-polygraph system

PubMed Central

Bhutta, M. Raheel; Hong, Melissa J.; Kim, Yun-Hee; Hong, Keum-Shik

2015-01-01

Deception is a human behavior that many people experience in daily life. It involves complex neuronal activities in addition to several physiological changes in the body. A polygraph, which can measure some of the physiological responses from the body, has been widely employed in lie-detection. Many researchers, however, believe that lie detection can become more precise if the neuronal changes that occur in the process of deception can be isolated and measured. In this study, we combine both measures (i.e., physiological and neuronal changes) for enhanced lie-detection. Specifically, to investigate the deception-related hemodynamic response, functional near-infrared spectroscopy (fNIRS) is applied at the prefrontal cortex besides a commercially available polygraph system. A mock crime scenario with a single-trial stimulus is set up as a deception protocol. The acquired data are classified into “true” and “lie” classes based on the fNIRS-based hemoglobin-concentration changes and polygraph-based physiological signal changes. Linear discriminant analysis is utilized as a classifier. The results indicate that the combined fNIRS-polygraph system delivers much higher classification accuracy than that of a singular system. This study demonstrates a plausible solution toward single-trial lie-detection by combining fNIRS and the polygraph. PMID:26082733

Automated single-trial assessment of laser-evoked potentials as an objective functional diagnostic tool for the nociceptive system.

PubMed

Hatem, S M; Hu, L; Ragé, M; Gierasimowicz, A; Plaghki, L; Bouhassira, D; Attal, N; Iannetti, G D; Mouraux, A

2012-12-01

To assess the clinical usefulness of an automated analysis of event-related potentials (ERPs). Nociceptive laser-evoked potentials (LEPs) and non-nociceptive somatosensory electrically-evoked potentials (SEPs) were recorded in 37 patients with syringomyelia and 21 controls. LEP and SEP peak amplitudes and latencies were estimated using a single-trial automated approach based on time-frequency wavelet filtering and multiple linear regression, as well as a conventional approach based on visual inspection. The amplitudes and latencies of normal and abnormal LEP and SEP peaks were identified reliably using both approaches, with similar sensitivity and specificity. Because the automated approach provided an unbiased solution to account for average waveforms where no ERP could be identified visually, it revealed significant differences between patients and controls that were not revealed using the visual approach. The automated analysis of ERPs characterized reliably and objectively LEP and SEP waveforms in patients. The automated single-trial analysis can be used to characterize normal and abnormal ERPs with a similar sensitivity and specificity as visual inspection. While this does not justify its use in a routine clinical setting, the technique could be useful to avoid observer-dependent biases in clinical research. Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Single-trial effective brain connectivity patterns enhance discriminability of mental imagery tasks

NASA Astrophysics Data System (ADS)

Rathee, Dheeraj; Cecotti, Hubert; Prasad, Girijesh

2017-10-01

Objective. The majority of the current approaches of connectivity based brain-computer interface (BCI) systems focus on distinguishing between different motor imagery (MI) tasks. Brain regions associated with MI are anatomically close to each other, hence these BCI systems suffer from low performances. Our objective is to introduce single-trial connectivity feature based BCI system for cognition imagery (CI) based tasks wherein the associated brain regions are located relatively far away as compared to those for MI. Approach. We implemented time-domain partial Granger causality (PGC) for the estimation of the connectivity features in a BCI setting. The proposed hypothesis has been verified with two publically available datasets involving MI and CI tasks. Main results. The results support the conclusion that connectivity based features can provide a better performance than a classical signal processing framework based on bandpass features coupled with spatial filtering for CI tasks, including word generation, subtraction, and spatial navigation. These results show for the first time that connectivity features can provide a reliable performance for imagery-based BCI system. Significance. We show that single-trial connectivity features for mixed imagery tasks (i.e. combination of CI and MI) can outperform the features obtained by current state-of-the-art method and hence can be successfully applied for BCI applications.

Dissociative Global and Local Task-Switching Costs Across Younger Adults, Middle-Aged Adults, Older Adults, and Very Mild Alzheimer Disease Individuals

PubMed Central

Huff, Mark J.; Balota, David A.; Minear, Meredith; Aschenbrenner, Andrew J.; Duchek, Janet M.

2015-01-01

A task-switching paradigm was used to examine differences in attentional control across younger adults, middle-aged adults, healthy older adults, and individuals classified in the earliest detectable stage of Alzheimer's disease (AD). A large sample of participants (570) completed a switching task in which participants were cued to classify the letter (consonant/vowel) or number (odd/even) task-set dimension of a bivalent stimulus (e.g., A 14), respectively. A Pure block consisting of single-task trials and a Switch block consisting of nonswitch and switch trials were completed. Local (switch vs. nonswitch trials) and global (nonswitch vs. pure trials) costs in mean error rates, mean response latencies, underlying reaction time distributions, along with stimulus-response congruency effects were computed. Local costs in errors were group invariant, but global costs in errors systematically increased as a function of age and AD. Response latencies yielded a strong dissociation: Local costs decreased across groups whereas global costs increased across groups. Vincentile distribution analyses revealed that the dissociation of local and global costs primarily occurred in the slowest response latencies. Stimulus-response congruency effects within the Switch block were particularly robust in accuracy in the very mild AD group. We argue that the results are consistent with the notion that the impaired groups show a reduced local cost because the task sets are not as well tuned, and hence produce minimal cost on switch trials. In contrast, global costs increase because of the additional burden on working memory of maintaining two task sets. PMID:26652720

'In situ simulation' versus 'off site simulation' in obstetric emergencies and their effect on knowledge, safety attitudes, team performance, stress, and motivation: study protocol for a randomized controlled trial.

PubMed

Sørensen, Jette Led; Van der Vleuten, Cees; Lindschou, Jane; Gluud, Christian; Østergaard, Doris; LeBlanc, Vicki; Johansen, Marianne; Ekelund, Kim; Albrechtsen, Charlotte Krebs; Pedersen, Berit Woetman; Kjærgaard, Hanne; Weikop, Pia; Ottesen, Bent

2013-07-17

Unexpected obstetric emergencies threaten the safety of pregnant women. As emergencies are rare, they are difficult to learn. Therefore, simulation-based medical education (SBME) seems relevant. In non-systematic reviews on SBME, medical simulation has been suggested to be associated with improved learner outcomes. However, many questions on how SBME can be optimized remain unanswered. One unresolved issue is how 'in situ simulation' (ISS) versus 'off site simulation' (OSS) impact learning. ISS means simulation-based training in the actual patient care unit (in other words, the labor room and operating room). OSS means training in facilities away from the actual patient care unit, either at a simulation centre or in hospital rooms that have been set up for this purpose. The objective of this randomized trial is to study the effect of ISS versus OSS on individual learning outcome, safety attitude, motivation, stress, and team performance amongst multi-professional obstetric-anesthesia teams.The trial is a single-centre randomized superiority trial including 100 participants. The inclusion criteria were health-care professionals employed at the department of obstetrics or anesthesia at Rigshospitalet, Copenhagen, who were working on shifts and gave written informed consent. Exclusion criteria were managers with staff responsibilities, and staff who were actively taking part in preparation of the trial. The same obstetric multi-professional training was conducted in the two simulation settings. The experimental group was exposed to training in the ISS setting, and the control group in the OSS setting. The primary outcome is the individual score on a knowledge test. Exploratory outcomes are individual scores on a safety attitudes questionnaire, a stress inventory, salivary cortisol levels, an intrinsic motivation inventory, results from a questionnaire evaluating perceptions of the simulation and suggested changes needed in the organization, a team-based score on video-assessed team performance and on selected clinical performance. The perspective is to provide new knowledge on contextual effects of different simulation settings. ClincialTrials.gov NCT01792674.

Clamp-Crushing versus stapler hepatectomy for transection of the parenchyma in elective hepatic resection (CRUNSH) - A randomized controlled trial (NCT01049607)

PubMed Central

2011-01-01

Background Hepatic resection is still associated with significant morbidity. Although the period of parenchymal transection presents a crucial step during the operation, uncertainty persists regarding the optimal technique of transection. It was the aim of the present randomized controlled trial to evaluate the efficacy and safety of hepatic resection using the technique of stapler hepatectomy compared to the simple clamp-crushing technique. Methods/Design The CRUNSH Trial is a prospective randomized controlled single-center trial with a two-group parallel design. Patients scheduled for elective hepatic resection without extrahepatic resection at the Department of General-, Visceral- and Transplantation Surgery, University of Heidelberg are enrolled into the trial and randomized intraoperatively to hepatic resection by the clamp-crushing technique and stapler hepatectomy, respectively. The primary endpoint is total intraoperative blood loss. A set of general and surgical variables are documented as secondary endpoints. Patients and outcome-assessors are blinded for the treatment intervention. Discussion The CRUNSH Trial is the first randomized controlled trial to evaluate efficacy and safety of stapler hepatectomy compared to the clamp-crushing technique for parenchymal transection during elective hepatic resection. Trial Registration ClinicalTrials.gov: NCT01049607 PMID:21888669

Early termination of cardiovascular trials as a consequence of poor accrual: analysis of ClinicalTrials.gov 2006–2015

PubMed Central

Baldi, Ileana; Lanera, Corrado; Berchialla, Paola; Gregori, Dario

2017-01-01

Objectives To present a snapshot of experimental cardiovascular research with a focus on geographical and temporal patterns of early termination due to poor accrual. Setting The Aggregate Analysis of ClinicalTrials.gov (AACT) database, reflecting ClinicalTrials.gov as of 27 March 2016. Design The AACT database was searched for all cardiovascular clinical trials that started from January 2006 up to December 2015. Results Thirteen thousand and seven hundred twenty-nine cardiovascular trials were identified. Of these, 8900 (65%) were classified as closed studies. Globally, 11% of closed trials were terminated. This proportion varied from 9.6% to 14% for trials recruiting from Europe and Americas, respectively, with a slightly decreasing trend (p=0.02) over the study period. The most common reason for trials failing to complete was poor accrual (41%). Intercontinental trials exhibited lower figures of poor accrual as the reason for their early stopping, as compared with trials recruiting in a single continent (28% vs 44%, p=0.002). Conclusions Poor accrual significantly challenges the successful completion of cardiovascular clinical trials. Findings are suggestive of a positive effect of globalisation of cardiovascular clinical research on the achievement of enrolment goals within a reasonable time frame. PMID:28619765

An exemplar-familiarity model predicts short-term and long-term probe recognition across diverse forms of memory search.

PubMed

Nosofsky, Robert M; Cox, Gregory E; Cao, Rui; Shiffrin, Richard M

2014-11-01

Experiments were conducted to test a modern exemplar-familiarity model on its ability to account for both short-term and long-term probe recognition within the same memory-search paradigm. Also, making connections to the literature on attention and visual search, the model was used to interpret differences in probe-recognition performance across diverse conditions that manipulated relations between targets and foils across trials. Subjects saw lists of from 1 to 16 items followed by a single item recognition probe. In a varied-mapping condition, targets and foils could switch roles across trials; in a consistent-mapping condition, targets and foils never switched roles; and in an all-new condition, on each trial a completely new set of items formed the memory set. In the varied-mapping and all-new conditions, mean correct response times (RTs) and error proportions were curvilinear increasing functions of memory set size, with the RT results closely resembling ones from hybrid visual-memory search experiments reported by Wolfe (2012). In the consistent-mapping condition, new-probe RTs were invariant with set size, whereas old-probe RTs increased slightly with increasing study-test lag. With appropriate choice of psychologically interpretable free parameters, the model accounted well for the complete set of results. The work provides support for the hypothesis that a common set of processes involving exemplar-based familiarity may govern long-term and short-term probe recognition across wide varieties of memory- search conditions. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Sampling-based ensemble segmentation against inter-operator variability

NASA Astrophysics Data System (ADS)

Huo, Jing; Okada, Kazunori; Pope, Whitney; Brown, Matthew

2011-03-01

Inconsistency and a lack of reproducibility are commonly associated with semi-automated segmentation methods. In this study, we developed an ensemble approach to improve reproducibility and applied it to glioblastoma multiforme (GBM) brain tumor segmentation on T1-weigted contrast enhanced MR volumes. The proposed approach combines samplingbased simulations and ensemble segmentation into a single framework; it generates a set of segmentations by perturbing user initialization and user-specified internal parameters, then fuses the set of segmentations into a single consensus result. Three combination algorithms were applied: majority voting, averaging and expectation-maximization (EM). The reproducibility of the proposed framework was evaluated by a controlled experiment on 16 tumor cases from a multicenter drug trial. The ensemble framework had significantly better reproducibility than the individual base Otsu thresholding method (p<.001).

Efficacy and Safety of Nitazoxanide, Albendazole, and Nitazoxanide-Albendazole against Trichuris trichiura Infection: A Randomized Controlled Trial

PubMed Central

Speich, Benjamin; Ame, Shaali M.; Ali, Said M.; Alles, Rainer; Hattendorf, Jan; Utzinger, Jürg; Albonico, Marco; Keiser, Jennifer

2012-01-01

Background The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate. Methodology The efficacy and safety of a single oral dose of nitazoxanide (1,000 mg), or albendazole (400 mg), and a nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug administered separately on two consecutive days, were assessed in a double-blind, randomized, placebo-controlled trial in two schools on Pemba, Tanzania. Cure and egg reduction rates were calculated by per-protocol analysis and by available case analysis. Adverse events were assessed and graded before treatment and four times after treatment. Principal Findings Complete data for the per-protocol analysis were available from 533 T. trichiura-positive children. Cure rates against T. trichiura were low regardless of the treatment (nitazoxanide-albendazole, 16.0%; albendazole, 14.5%; and nitazoxanide, 6.6%). Egg reduction rates were 54.9% for the nitazoxanide-albendazole combination, 45.6% for single albendazole, and 13.4% for single nitazoxanide. Similar cure and egg reduction rates were calculated using the available case analysis. Children receiving nitazoxanide had significantly more adverse events compared to placebo recipients. Most of the adverse events were mild and had resolved within 24 hours posttreatment. Conclusions/Significance Nitazoxanide shows no effect on T. trichiura infection. The low efficacy of albendazole against T. trichiura in the current setting characterized by high anthelmintic drug pressure is confirmed. There is a pressing need to develop new anthelmintics against trichuriasis. Trial Registration Controlled-Trials.com ISRCTN08336605 PMID:22679525

Single-trial EEG RSVP classification using convolutional neural networks

NASA Astrophysics Data System (ADS)

Shamwell, Jared; Lee, Hyungtae; Kwon, Heesung; Marathe, Amar R.; Lawhern, Vernon; Nothwang, William

2016-05-01

Traditionally, Brain-Computer Interfaces (BCI) have been explored as a means to return function to paralyzed or otherwise debilitated individuals. An emerging use for BCIs is in human-autonomy sensor fusion where physiological data from healthy subjects is combined with machine-generated information to enhance the capabilities of artificial systems. While human-autonomy fusion of physiological data and computer vision have been shown to improve classification during visual search tasks, to date these approaches have relied on separately trained classification models for each modality. We aim to improve human-autonomy classification performance by developing a single framework that builds codependent models of human electroencephalograph (EEG) and image data to generate fused target estimates. As a first step, we developed a novel convolutional neural network (CNN) architecture and applied it to EEG recordings of subjects classifying target and non-target image presentations during a rapid serial visual presentation (RSVP) image triage task. The low signal-to-noise ratio (SNR) of EEG inherently limits the accuracy of single-trial classification and when combined with the high dimensionality of EEG recordings, extremely large training sets are needed to prevent overfitting and achieve accurate classification from raw EEG data. This paper explores a new deep CNN architecture for generalized multi-class, single-trial EEG classification across subjects. We compare classification performance from the generalized CNN architecture trained across all subjects to the individualized XDAWN, HDCA, and CSP neural classifiers which are trained and tested on single subjects. Preliminary results show that our CNN meets and slightly exceeds the performance of the other classifiers despite being trained across subjects.

Trend-Centric Motion Visualization: Designing and Applying a New Strategy for Analyzing Scientific Motion Collections.

PubMed

Schroeder, David; Korsakov, Fedor; Knipe, Carissa Mai-Ping; Thorson, Lauren; Ellingson, Arin M; Nuckley, David; Carlis, John; Keefe, Daniel F

2014-12-01

In biomechanics studies, researchers collect, via experiments or simulations, datasets with hundreds or thousands of trials, each describing the same type of motion (e.g., a neck flexion-extension exercise) but under different conditions (e.g., different patients, different disease states, pre- and post-treatment). Analyzing similarities and differences across all of the trials in these collections is a major challenge. Visualizing a single trial at a time does not work, and the typical alternative of juxtaposing multiple trials in a single visual display leads to complex, difficult-to-interpret visualizations. We address this problem via a new strategy that organizes the analysis around motion trends rather than trials. This new strategy matches the cognitive approach that scientists would like to take when analyzing motion collections. We introduce several technical innovations making trend-centric motion visualization possible. First, an algorithm detects a motion collection's trends via time-dependent clustering. Second, a 2D graphical technique visualizes how trials leave and join trends. Third, a 3D graphical technique, using a median 3D motion plus a visual variance indicator, visualizes the biomechanics of the set of trials within each trend. These innovations are combined to create an interactive exploratory visualization tool, which we designed through an iterative process in collaboration with both domain scientists and a traditionally-trained graphic designer. We report on insights generated during this design process and demonstrate the tool's effectiveness via a validation study with synthetic data and feedback from expert musculoskeletal biomechanics researchers who used the tool to analyze the effects of disc degeneration on human spinal kinematics.

A unified framework for the evaluation of surrogate endpoints in mental-health clinical trials.

PubMed

Molenberghs, Geert; Burzykowski, Tomasz; Alonso, Ariel; Assam, Pryseley; Tilahun, Abel; Buyse, Marc

2010-06-01

For a number of reasons, surrogate endpoints are considered instead of the so-called true endpoint in clinical studies, especially when such endpoints can be measured earlier, and/or with less burden for patient and experimenter. Surrogate endpoints may occur more frequently than their standard counterparts. For these reasons, it is not surprising that the use of surrogate endpoints in clinical practice is increasing. Building on the seminal work of Prentice(1) and Freedman et al.,(2) Buyse et al. (3) framed the evaluation exercise within a meta-analytic setting, in an effort to overcome difficulties that necessarily surround evaluation efforts based on a single trial. In this article, we review the meta-analytic approach for continuous outcomes, discuss extensions to non-normal and longitudinal settings, as well as proposals to unify the somewhat disparate collection of validation measures currently on the market. Implications for design and for predicting the effect of treatment in a new trial, based on the surrogate, are discussed. A case study in schizophrenia is analysed.

Cognitive remediation therapy (CRT) in a specialist inpatient eating disorder service for children and adolescents: CAN-CRT study protocol for a pilot randomised controlled trial.

PubMed

Giombini, Lucia; Nesbitt, Sophie; Cox, Hannah; Foxall, Anna; Sharia, Teo; Easter, Abigail; Tchanturia, Kate

2018-03-26

Research on treatments for young people (YP) with anorexia nervosa (AN) is scarce. Evidence supports the use of cognitive remediation therapy (CRT) to improve central coherence and set-shifting, inefficiencies that can negatively impact on prognosis. The study aims to evaluate the feasibility of individual CRT in an inpatient setting for YP aged 10-18 years with AN and to qualitatively examine YP's and their parents experiences. In a single-centre, pilot, randomised controlled trial, 80 patients aged 10-18 years with AN will be randomly allocated to the immediate or delayed CRT group, in addition to standard treatment. A repeated measures design will be conducted across 3 time points. The data will provide evidence regarding the feasibility of individual CRT in YP with AN, informing directions of further development of CRT. The study is in preparation for a definitive randomised controlled trial. The aim of this manuscript is to describe the study protocol. Copyright © 2018 John Wiley & Sons, Ltd and Eating Disorders Association.

Multiple linear regression to estimate time-frequency electrophysiological responses in single trials

PubMed Central

Hu, L.; Zhang, Z.G.; Mouraux, A.; Iannetti, G.D.

2015-01-01

Transient sensory, motor or cognitive event elicit not only phase-locked event-related potentials (ERPs) in the ongoing electroencephalogram (EEG), but also induce non-phase-locked modulations of ongoing EEG oscillations. These modulations can be detected when single-trial waveforms are analysed in the time-frequency domain, and consist in stimulus-induced decreases (event-related desynchronization, ERD) or increases (event-related synchronization, ERS) of synchrony in the activity of the underlying neuronal populations. ERD and ERS reflect changes in the parameters that control oscillations in neuronal networks and, depending on the frequency at which they occur, represent neuronal mechanisms involved in cortical activation, inhibition and binding. ERD and ERS are commonly estimated by averaging the time-frequency decomposition of single trials. However, their trial-to-trial variability that can reflect physiologically-important information is lost by across-trial averaging. Here, we aim to (1) develop novel approaches to explore single-trial parameters (including latency, frequency and magnitude) of ERP/ERD/ERS; (2) disclose the relationship between estimated single-trial parameters and other experimental factors (e.g., perceived intensity). We found that (1) stimulus-elicited ERP/ERD/ERS can be correctly separated using principal component analysis (PCA) decomposition with Varimax rotation on the single-trial time-frequency distributions; (2) time-frequency multiple linear regression with dispersion term (TF-MLRd) enhances the signal-to-noise ratio of ERP/ERD/ERS in single trials, and provides an unbiased estimation of their latency, frequency, and magnitude at single-trial level; (3) these estimates can be meaningfully correlated with each other and with other experimental factors at single-trial level (e.g., perceived stimulus intensity and ERP magnitude). The methods described in this article allow exploring fully non-phase-locked stimulus-induced cortical oscillations, obtaining single-trial estimate of response latency, frequency, and magnitude. This permits within-subject statistical comparisons, correlation with pre-stimulus features, and integration of simultaneously-recorded EEG and fMRI. PMID:25665966

Randomized single versus double embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis.

PubMed

Kjellberg, Ann Thurin; Carlsson, Per; Bergh, Christina

2006-01-01

Transfer of several embryos after IVF results in a high multiple birth rate associated with increased morbidity and high costs for the neonatal care. In a previous randomized trial we demonstrated that a single embryo transfer (SET) strategy, including one fresh single embryo transfer and, if no live birth, one additional frozen-thawed SET, resulted in a live-birth rate that was not substantially lower than after double embryo transfer (DET) but markedly reduced the multiple birth rate. We compared costs for maternal health care and productivity losses and paediatric costs for the SET and DET strategies. In addition, maternal and paediatric outcomes between the two groups were compared. The SET strategy resulted in lower average total costs from treatment until 6 months after delivery. There were a few more deliveries with at least one live-born child in the DET group. The incremental cost per extra delivery in the DET alternative was high, 71 940. The rates of prematurely born and low birthweight children were significantly lower with the SET strategy. There were also markedly fewer maternal and paediatric complications in the SET group. The SET strategy is superior to the DET strategy, when number of deliveries with at least one live-born child, incremental cost-effectiveness ratio and maternal and paediatric complications are taken into consideration. The findings do not support continuing transfers of two embryos in this group of patients.

Efficacy and Safety of Oritavancin Relative to Vancomycin for Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the Outpatient Setting: Results From the SOLO Clinical Trials.

PubMed

Lodise, Thomas P; Redell, Mark; Armstrong, Shannon O; Sulham, Katherine A; Corey, G Ralph

2017-01-01

The objective of this analysis was to evaluate the efficacy and safety of oritavancin compared with vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSIs) who received treatment in the outpatient setting in the Phase 3 SOLO clinical trials. SOLO I and SOLO II were 2 identically designed comparative, multicenter, double-blind, randomized studies to evaluate the efficacy and safety of a single 1200-mg dose of intravenous (IV) oritavancin versus 7-10 days of twice-daily IV vancomycin for the treatment of ABSSSI. Protocols were amended to allow enrolled patients to complete their entire course of antimicrobial therapy in an outpatient setting. The primary efficacy outcome was a composite endpoint (cessation of spread or reduction in size of the baseline lesion, absence of fever, and no rescue antibiotic at early clinical evaluation [ECE]) (48 to 72 hours). Key secondary endpoints included investigator-assessed clinical cure 7 to 14 days after end of treatment (posttherapy evaluation [PTE]) and 20% or greater reduction in lesion area at ECE. Safety was assessed until day 60. Seven hundred ninety-two patients (oritavancin, 392; vancomycin, 400) received entire course of treatment in the outpatient setting. Efficacy response rates at ECE and PTE were similar (primary composite endpoint at ECE: 80.4% vs 77.5% for oritavancin and vancomycin, respectively) as was incidence of adverse events. Five patients (1.3%) who received oritavancin and 9 (2.3%) vancomycin patients were subsequently admitted to a hospital. Oritavancin provides a single-dose alternative to multidose vancomycin for treatment of ABSSSI in the outpatient setting. © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Dynamic Trial-by-Trial Recoding of Task-Set Representations in the Frontoparietal Cortex Mediates Behavioral Flexibility

PubMed Central

Qiao, Lei; Zhang, Lijie

2017-01-01

Cognitive flexibility forms the core of the extraordinary ability of humans to adapt, but the precise neural mechanisms underlying our ability to nimbly shift between task sets remain poorly understood. Recent functional magnetic resonance imaging (fMRI) studies employing multivoxel pattern analysis (MVPA) have shown that a currently relevant task set can be decoded from activity patterns in the frontoparietal cortex, but whether these regions support the dynamic transformation of task sets from trial to trial is not clear. Here, we combined a cued task-switching protocol with human (both sexes) fMRI, and harnessed representational similarity analysis (RSA) to facilitate a novel assessment of trial-by-trial changes in neural task-set representations. We first used MVPA to define task-sensitive frontoparietal and visual regions and found that neural task-set representations on switch trials are less stably encoded than on repeat trials. We then exploited RSA to show that the neural representational pattern dissimilarity across consecutive trials is greater for switch trials than for repeat trials, and that the degree of this pattern dissimilarity predicts behavior. Moreover, the overall neural pattern of representational dissimilarities followed from the assumption that repeating sets, compared with switching sets, results in stronger neural task representations. Finally, when moving from cue to target phase within a trial, pattern dissimilarities tracked the transformation from previous-trial task representations to the currently relevant set. These results provide neural evidence for the longstanding assumptions of an effortful task-set reconfiguration process hampered by task-set inertia, and they demonstrate that frontoparietal and stimulus processing regions support “dynamic adaptive coding,” flexibly representing changing task sets in a trial-by-trial fashion. SIGNIFICANCE STATEMENT Humans can fluently switch between different tasks, reflecting an ability to dynamically configure “task sets,” rule representations that link stimuli to appropriate responses. Recent studies show that neural signals in frontal and parietal brain regions can tell us which of two tasks a person is currently performing. However, it is not known whether these regions are also involved in dynamically reconfiguring task-set representations when switching between tasks. Here we measured human brain activity during task switching and tracked the similarity of neural task-set representations from trial to trial. We show that frontal and parietal brain regions flexibly recode changing task sets in a trial-by-trial fashion, and that task-set similarity over consecutive trials predicts behavior. PMID:28972126

Single versus double embryo transfer: cost-effectiveness analysis alongside a randomized clinical trial.

PubMed

Fiddelers, Audrey A A; van Montfoort, Aafke P A; Dirksen, Carmen D; Dumoulin, John C M; Land, Jolande A; Dunselman, Gerard A J; Janssen, J Marij; Severens, Johan L; Evers, Johannes L H

2006-08-01

Twin pregnancies after IVF are still frequent and are considered high-risk pregnancies leading to high costs. Transferring one embryo can reduce the twin pregnancy rate. We compared cost-effectiveness of one fresh cycle elective single embryo transfer (eSET) versus one fresh cycle double embryo transfer (DET) in an unselected patient population. Patients starting their first IVF cycle were randomized between eSET and DET. Societal costs per couple were determined empirically, from hormonal stimulation up to 42 weeks after embryo transfer. An incremental cost-effectiveness ratio (ICER) was calculated, representing additional costs per successful pregnancy. Successful pregnancy rates were 20.8% for eSET and 39.6% for DET. Societal costs per couple were significantly lower after eSET (7334 euro) compared with DET (10,924 euro). The ICER of DET compared with eSET was 19,096 euro, meaning that each additional successful pregnancy in the DET group will cost 19,096 euro extra. One cycle eSET was less expensive, but also less effective compared to one cycle DET. It depends on the society's willingness to pay for one extra successful pregnancy, whether one cycle DET is preferred from a cost-effectiveness point of view.

Probabilistic pharmacokinetic models of decompression sickness in humans, part 1: Coupled perfusion-limited compartments.

PubMed

Murphy, F Gregory; Hada, Ethan A; Doolette, David J; Howle, Laurens E

2017-07-01

Decompression sickness (DCS) is a disease caused by gas bubbles forming in body tissues following a reduction in ambient pressure, such as occurs in scuba diving. Probabilistic models for quantifying the risk of DCS are typically composed of a collection of independent, perfusion-limited theoretical tissue compartments which describe gas content or bubble volume within these compartments. It has been previously shown that 'pharmacokinetic' gas content models, with compartments coupled in series, show promise as predictors of the incidence of DCS. The mechanism of coupling can be through perfusion or diffusion. This work examines the application of five novel pharmacokinetic structures with compartments coupled by perfusion to the prediction of the probability and time of onset of DCS in humans. We optimize these models against a training set of human dive trial data consisting of 4335 exposures with 223 DCS cases. Further, we examine the extrapolation quality of the models on an additional set of human dive trial data consisting of 3140 exposures with 147 DCS cases. We find that pharmacokinetic models describe the incidence of DCS for single air bounce dives better than a single-compartment, perfusion-limited model. We further find the U.S. Navy LEM-NMRI98 is a better predictor of DCS risk for the entire training set than any of our pharmacokinetic models. However, one of the pharmacokinetic models we consider, the CS2T3 model, is a better predictor of DCS risk for single air bounce dives and oxygen decompression dives. Additionally, we find that LEM-NMRI98 outperforms CS2T3 on the extrapolation data. Copyright © 2017 Elsevier Ltd. All rights reserved.

Treating Acute Insomnia: A Randomized Controlled Trial of a “Single-Shot” of Cognitive Behavioral Therapy for Insomnia

PubMed Central

Ellis, Jason G.; Cushing, Toby; Germain, Anne

2015-01-01

Study Objectives: Despite considerable evidence supporting cognitive behavioral therapy for insomnia (CBT-I) for chronic insomnia, it remains untested within the context of acute insomnia. This study examined the efficacy of a single session of CBT-I, with an accompanying self-help pamphlet, for individuals with acute insomnia. Design: A pragmatic parallel group randomized controlled trial. Setting: Community. Participants: Forty adults (mean age 32.9 ± 13.72 y) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined insomnia disorder, except a self-reported duration of less than 3 mo (i.e., acute insomnia), who reported no previous exposure to CBT-I and were not currently taking medication for sleep. Interventions: A single 60- to 70-min session of CBT-I (n = 20), with an accompanying self-help pamphlet, or wait list control group (n = 20). All subjects were offered a full individual course of CBT-I on completion of the study, regardless of group allocation. Measurements and Results: Subjects completed sleep diaries and the Insomnia Severity Index (ISI) pretreatment and 1 mo following treatment. There were no between-group differences on baseline ISI scores or subjective sleep continuity. The intervention group reported significantly lower ISI scores than controls (t(38) 2.24, P < 0.05) at follow-up. Further, using proposed ISI scores for identifying insomnia caseness (i.e., ≥ 10), 60% of those in the CBT-I group had remitted by 1 mo compared to 15% of those in the control group. Conclusions: This single session of cognitive behavioral therapy for insomnia (CBT-I) is sufficiently efficacious for a significant proportion of those with acute insomnia. The results are discussed in terms of integrating this brief form of CBT-I into the “stepped care” model of insomnia. Trial Registration: Testing the efficacy of an early intervention for acute insomnia (SRCTN05891695) http://www.controlled-trials.com/ISRCTN05891695. Citation: Ellis JG, Cushing T, Germain A. Treating acute insomnia: a randomized controlled trial of a “single-shot” of cognitive behavioral therapy for insomnia. SLEEP 2015;38(6):971–978. PMID:25515106

The impact of alternate weekly collections on waste arisings.

PubMed

Williams, I D; Cole, C

2013-02-15

Residual waste is commonly collected separately from recyclable and organic materials. Different forms of collection and disposal are used internationally since regional or municipal authorities have to adapt to their own circumstances. Many authorities have adopted an alternate weekly collection (AWC) of residual waste and recyclables to force/encourage householders to recycle; however, the degree to which they achieve waste reduction has yet to be reliably quantified. This study reports on how the introduction of AWCs affects household waste arisings. The paper evaluates single and dual stream collection methods and compares their performance with the previous system. Household waste collection trials were conducted between March and June 2009 in England (Lichfield). The trials examined changes to frequency of collection, type of container issued, amounts of sorting required of residents, household participation and productivity levels. A survey of households was completed before any changes were implemented. The quantity of recyclates collected was examined for 2008/2009 and 2009/2010. The study showed that the AWC scheme positively impacted on recycling rates and household behaviour, with no adverse impacts on public participation, household waste arisings or the local environment. No public health problems were reported. Both trials saw an increase in the quantities of recyclates collected per household during the trial period compared to the same period of time in the previous year. The dual stream performed better than the single stream, collecting an average of 5.94 kg/hh/week compared to an average of 5.63 kg/hh/week. The single stream system showed a greater increase in the weight of material collected (0.53 kg/hh/week vs. 0.48 kg/hh/week). Participation and set-out rates showed an increase during the trial period. The single stream option (comingled materials in one container) outperformed the dual stream service. The reduction in costs and improved productivity were the principal reasons used for extending the trial and making changes to the district's waste collections. The study clearly demonstrates the benefits of local authorities and universities collaborating and identifies practical logistical and operational issues that need to be anticipated. Copyright © 2012 Elsevier B.V. All rights reserved.

Temporal Trends and Predictors for Cancer Clinical Trial Availability for Medically Underserved Populations

PubMed Central

Lakoduk, Ashley M.; Priddy, Laurin L.; Yan, Jingsheng; Xie, Xian-Jin

2015-01-01

Background. Lack of access to available cancer clinical trials has been cited as a key factor limiting trial accrual, particularly among medically underserved populations. We examined the trends and factors in clinical trial availability within a major U.S. safety-net hospital system. Materials and Methods. We identified cancer clinical trials activated at the Harold C. Simmons Cancer from 1991 to 2014 and recorded the characteristics of the trials that were and were not activated at the Parkland Health and Hospital System satellite site. We used univariate and multivariate logistic regression to determine the association between trial characteristics and nonactivation status, and chi-square analysis to determine the association between the trial characteristics and the reasons for nonactivation. Results. A total of 773 trials were identified, of which 152 (20%) were not activated at Parkland. In multivariable analysis, nonactivation at Parkland was associated with trial year, sponsor, and phase. Compared with the 1991–2006 period, clinical trials in the 2007–2014 period were almost eightfold more likely not to be activated at Parkland. The most common reasons for nonactivation at Parkland were an inability to perform the study procedures (27%) and the startup costs (15%). Conclusion. Over time, in this single-center setting, a decreasing proportion of cancer clinical trials were available to underserved populations. Trial complexity and costs appeared to account for much of this trend. Efforts to overcome these barriers will be key to equitable access to clinical trials, efficient accrual, and the generalizability of the results. Implications for Practice: Despite numerous calls to increase and diversify cancer clinical trial accrual, the present study found that cancer clinical trial activation rates in a safety-net setting for medically underserved populations have decreased substantially in recent years. The principal reasons for study nonactivation were expenses and an inability to perform the study-related procedures, reflecting the increasing costs and complexity of cancer clinical trials. Future efforts need to focus on strategies to mitigate the increasing disparity in access to clinical research and cutting-edge therapies, which also threatens to hinder study accrual, completion rates, and generalizability. PMID:26018661

Automatic Setting Procedure for Exoskeleton-Assisted Overground Gait: Proof of Concept on Stroke Population

PubMed Central

Gandolla, Marta; Guanziroli, Eleonora; D'Angelo, Andrea; Cannaviello, Giovanni; Molteni, Franco; Pedrocchi, Alessandra

2018-01-01

Stroke-related locomotor impairments are often associated with abnormal timing and intensity of recruitment of the affected and non-affected lower limb muscles. Restoring the proper lower limbs muscles activation is a key factor to facilitate recovery of gait capacity and performance, and to reduce maladaptive plasticity. Ekso is a wearable powered exoskeleton robot able to support over-ground gait training. The user controls the exoskeleton by triggering each single step during the gait cycle. The fine-tuning of the exoskeleton control system is crucial—it is set according to the residual functional abilities of the patient, and it needs to ensure lower limbs powered gait to be the most physiological as possible. This work focuses on the definition of an automatic calibration procedure able to detect the best Ekso setting for each patient. EMG activity has been recorded from Tibialis Anterior, Soleus, Rectus Femoris, and Semitendinosus muscles in a group of 7 healthy controls and 13 neurological patients. EMG signals have been processed so to obtain muscles activation patterns. The mean muscular activation pattern derived from the controls cohort has been set as reference. The developed automatic calibration procedure requires the patient to perform overground walking trials supported by the exoskeleton while changing parameters setting. The Gait Metric index is calculated for each trial, where the closer the performance is to the normative muscular activation pattern, in terms of both relative amplitude and timing, the higher the Gait Metric index is. The trial with the best Gait Metric index corresponds to the best parameters set. It has to be noted that the automatic computational calibration procedure is based on the same number of overground walking trials, and the same experimental set-up as in the current manual calibration procedure. The proposed approach allows supporting the rehabilitation team in the setting procedure. It has been demonstrated to be robust, and to be in agreement with the current gold standard (i.e., manual calibration performed by an expert engineer). The use of a graphical user interface is a promising tool for the effective use of an automatic procedure in a clinical context. PMID:29615890

Automatic Setting Procedure for Exoskeleton-Assisted Overground Gait: Proof of Concept on Stroke Population.

PubMed

Gandolla, Marta; Guanziroli, Eleonora; D'Angelo, Andrea; Cannaviello, Giovanni; Molteni, Franco; Pedrocchi, Alessandra

2018-01-01

Stroke-related locomotor impairments are often associated with abnormal timing and intensity of recruitment of the affected and non-affected lower limb muscles. Restoring the proper lower limbs muscles activation is a key factor to facilitate recovery of gait capacity and performance, and to reduce maladaptive plasticity. Ekso is a wearable powered exoskeleton robot able to support over-ground gait training. The user controls the exoskeleton by triggering each single step during the gait cycle. The fine-tuning of the exoskeleton control system is crucial-it is set according to the residual functional abilities of the patient, and it needs to ensure lower limbs powered gait to be the most physiological as possible. This work focuses on the definition of an automatic calibration procedure able to detect the best Ekso setting for each patient. EMG activity has been recorded from Tibialis Anterior, Soleus, Rectus Femoris, and Semitendinosus muscles in a group of 7 healthy controls and 13 neurological patients. EMG signals have been processed so to obtain muscles activation patterns. The mean muscular activation pattern derived from the controls cohort has been set as reference. The developed automatic calibration procedure requires the patient to perform overground walking trials supported by the exoskeleton while changing parameters setting. The Gait Metric index is calculated for each trial, where the closer the performance is to the normative muscular activation pattern, in terms of both relative amplitude and timing, the higher the Gait Metric index is. The trial with the best Gait Metric index corresponds to the best parameters set. It has to be noted that the automatic computational calibration procedure is based on the same number of overground walking trials, and the same experimental set-up as in the current manual calibration procedure. The proposed approach allows supporting the rehabilitation team in the setting procedure. It has been demonstrated to be robust, and to be in agreement with the current gold standard (i.e., manual calibration performed by an expert engineer). The use of a graphical user interface is a promising tool for the effective use of an automatic procedure in a clinical context.

A statistical characterization of the finger tapping test: modeling, estimation, and applications.

PubMed

Austin, Daniel; McNames, James; Klein, Krystal; Jimison, Holly; Pavel, Misha

2015-03-01

Sensory-motor performance is indicative of both cognitive and physical function. The Halstead-Reitan finger tapping test is a measure of sensory-motor speed commonly used to assess function as part of a neuropsychological evaluation. Despite the widespread use of this test, the underlying motor and cognitive processes driving tapping behavior during the test are not well characterized or understood. This lack of understanding may make clinical inferences from test results about health or disease state less accurate because important aspects of the task such as variability or fatigue are unmeasured. To overcome these limitations, we enhanced the tapper with a sensor that enables us to more fully characterize all the aspects of tapping. This modification enabled us to decompose the tapping performance into six component phases and represent each phase with a set of parameters having clear functional interpretation. This results in a set of 29 total parameters for each trial, including change in tapping over time, and trial-to-trial and tap-to-tap variability. These parameters can be used to more precisely link different aspects of cognition or motor function to tapping behavior. We demonstrate the benefits of this new instrument with a simple hypothesis-driven trial comparing single and dual-task tapping.

Computerised cognitive–behavioural therapy for depression in adolescents: feasibility results and 4-month outcomes of a UK randomised controlled trial

PubMed Central

Wright, Barry; Tindall, Lucy; Littlewood, Elizabeth; Allgar, Victoria; Abeles, Paul; Trépel, Dominic; Ali, Shehzad

2017-01-01

Objectives Computer-administered cognitive–behavioural therapy (CCBT) may be a promising treatment for adolescents with depression, particularly due to its increased availability and accessibility. The feasibility of delivering a randomised controlled trial (RCT) comparing a CCBT program (Stressbusters) with an attention control (self-help websites) for adolescent depression was evaluated. Design Single centre RCT feasibility study. Setting The trial was run within community and clinical settings in York, UK. Participants Adolescents (aged 12–18) with low mood/depression were assessed for eligibility, 91 of whom met the inclusion criteria and were consented and randomised to Stressbusters (n=45) or websites (n=46) using remote computerised single allocation. Those with comorbid physical illness were included but those with psychosis, active suicidality or postnatal depression were not. Interventions An eight-session CCBT program (Stressbusters) designed for use with adolescents with low mood/depression was compared with an attention control (accessing low mood self-help websites). Primary and secondary outcome measures Participants completed mood and quality of life measures and a service Use Questionnaire throughout completion of the trial and 4 months post intervention. Measures included the Beck Depression Inventory (BDI) (primary outcome measure), Mood and Feelings Questionnaire (MFQ), Spence Children's Anxiety Scale (SCAS), the EuroQol five dimensions questionnaire (youth) (EQ-5D-Y) and Health Utility Index Mark 2 (HUI-2). Changes in self-reported measures and completion rates were assessed by treatment group. Results From baseline to 4 months post intervention, BDI scores and MFQ scores decreased for the Stressbusters group but increased in the website group. Quality of life, as measured by the EQ-5D-Y, increased for both groups while costs at 4 months were similar to baseline. Good feasibility outcomes were found, suggesting the trial process to be feasible and acceptable for adolescents with depression. Conclusions With modifications, a fully powered RCT is achievable to investigate a promising treatment for adolescent depression in a climate where child mental health service resources are limited. Trial registration number ISRCTN31219579. PMID:28132000

DataHigh: Graphical user interface for visualizing and interacting with high-dimensional neural activity

PubMed Central

Cowley, Benjamin R.; Kaufman, Matthew T.; Butler, Zachary S.; Churchland, Mark M.; Ryu, Stephen I.; Shenoy, Krishna V.; Yu, Byron M.

2014-01-01

Objective Analyzing and interpreting the activity of a heterogeneous population of neurons can be challenging, especially as the number of neurons, experimental trials, and experimental conditions increases. One approach is to extract a set of latent variables that succinctly captures the prominent co-fluctuation patterns across the neural population. A key problem is that the number of latent variables needed to adequately describe the population activity is often greater than three, thereby preventing direct visualization of the latent space. By visualizing a small number of 2-d projections of the latent space or each latent variable individually, it is easy to miss salient features of the population activity. Approach To address this limitation, we developed a Matlab graphical user interface (called DataHigh) that allows the user to quickly and smoothly navigate through a continuum of different 2-d projections of the latent space. We also implemented a suite of additional visualization tools (including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses) and an optional tool for performing dimensionality reduction. Main results To demonstrate the utility and versatility of DataHigh, we used it to analyze single-trial spike count and single-trial timecourse population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded using single electrodes. Significance DataHigh was developed to fulfill a need for visualization in exploratory neural data analysis, which can provide intuition that is critical for building scientific hypotheses and models of population activity. PMID:24216250

DataHigh: graphical user interface for visualizing and interacting with high-dimensional neural activity

NASA Astrophysics Data System (ADS)

Cowley, Benjamin R.; Kaufman, Matthew T.; Butler, Zachary S.; Churchland, Mark M.; Ryu, Stephen I.; Shenoy, Krishna V.; Yu, Byron M.

2013-12-01

Objective. Analyzing and interpreting the activity of a heterogeneous population of neurons can be challenging, especially as the number of neurons, experimental trials, and experimental conditions increases. One approach is to extract a set of latent variables that succinctly captures the prominent co-fluctuation patterns across the neural population. A key problem is that the number of latent variables needed to adequately describe the population activity is often greater than 3, thereby preventing direct visualization of the latent space. By visualizing a small number of 2-d projections of the latent space or each latent variable individually, it is easy to miss salient features of the population activity. Approach. To address this limitation, we developed a Matlab graphical user interface (called DataHigh) that allows the user to quickly and smoothly navigate through a continuum of different 2-d projections of the latent space. We also implemented a suite of additional visualization tools (including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses) and an optional tool for performing dimensionality reduction. Main results. To demonstrate the utility and versatility of DataHigh, we used it to analyze single-trial spike count and single-trial timecourse population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded using single electrodes. Significance. DataHigh was developed to fulfil a need for visualization in exploratory neural data analysis, which can provide intuition that is critical for building scientific hypotheses and models of population activity.

DataHigh: graphical user interface for visualizing and interacting with high-dimensional neural activity.

PubMed

Cowley, Benjamin R; Kaufman, Matthew T; Butler, Zachary S; Churchland, Mark M; Ryu, Stephen I; Shenoy, Krishna V; Yu, Byron M

2013-12-01

Analyzing and interpreting the activity of a heterogeneous population of neurons can be challenging, especially as the number of neurons, experimental trials, and experimental conditions increases. One approach is to extract a set of latent variables that succinctly captures the prominent co-fluctuation patterns across the neural population. A key problem is that the number of latent variables needed to adequately describe the population activity is often greater than 3, thereby preventing direct visualization of the latent space. By visualizing a small number of 2-d projections of the latent space or each latent variable individually, it is easy to miss salient features of the population activity. To address this limitation, we developed a Matlab graphical user interface (called DataHigh) that allows the user to quickly and smoothly navigate through a continuum of different 2-d projections of the latent space. We also implemented a suite of additional visualization tools (including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses) and an optional tool for performing dimensionality reduction. To demonstrate the utility and versatility of DataHigh, we used it to analyze single-trial spike count and single-trial timecourse population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded using single electrodes. DataHigh was developed to fulfil a need for visualization in exploratory neural data analysis, which can provide intuition that is critical for building scientific hypotheses and models of population activity.

Effectiveness and implementation aspects of interventions for preventing falls in elderly people in long-term care facilities: a systematic review of RCTs.

PubMed

Neyens, Jacques C; van Haastregt, Jolanda C; Dijcks, Béatrice P; Martens, Mark; van den Heuvel, Wim J; de Witte, Luc P; Schols, Jos M

2011-07-01

There is extensive literature on interventions to prevent or reduce falls in elderly people. These findings, however, were based mainly on studies of community-living persons. The primary aim of the present study was to report the effectiveness and implementation aspects of interventions aimed at reducing falls in elderly residents in long-term care facilities: a systematic review of randomized controlled trials (RCTs). MEDLINE, EMBASE, CINAHL, and hand searching of reference lists of included RCTs. RCTs that assessed fall incidents (falls, fallers, recurrent fallers, fall-related injuries) among elderly residents in long-term care facilities were included in this narrative review. Two independent reviewers abstracted data: general program characteristics (setting, population, intervention program) and outcomes, detailed program characteristics (assessment, intervention content, individually tailored, multidisciplinary), and implementation aspects (feasibility, implications for practice). The CONSORT Statement 2001 Checklist was used regarding the quality of reporting RCTs. Twenty trials met the inclusion criteria. Seven trials, 4 multifactorial and 3 monofactorial, showed a significant reduction in the fall rate, the percentage of recurrent fallers, or both the fall rate and the percentage of persons sustaining femoral fractures. The positive effective programs were as follows: a comprehensive structured individual assessment with specific safety recommendations; a multidisciplinary program including general strategies tailored to the setting and strategies tailored specifically to residents; a multifaceted intervention including education, environmental adaptation, balance, resistance training, and hip protector; calcium plus vitamin D supplementation; vitamin D supplementation; a clinical medication review; and a multifactorial intervention (fall risk evaluation, specific and general interventions). In general, because of the limited number of included trials, the evidence is inconclusive for multifaceted and single interventions in long-term care facilities. Most of the reviewed studies did not find a significant positive effect on fall incidents. However, our data support the conclusions of Gillespie et al. that multifactorial interventions in long-term care populations seem more likely to be beneficial. However, single interventions (eg, targeting vitamin D insufficiency) can be effective. Furthermore, a careful approach is needed as programs to prevent falls in these settings may be ineffective or even may have adverse effects. This may occur especially when a program is not feasible for the setting in which it is implemented. Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.

Classification of Hand Grasp Kinetics and Types Using Movement-Related Cortical Potentials and EEG Rhythms.

PubMed

Jochumsen, Mads; Rovsing, Cecilie; Rovsing, Helene; Niazi, Imran Khan; Dremstrup, Kim; Kamavuako, Ernest Nlandu

2017-01-01

Detection of single-trial movement intentions from EEG is paramount for brain-computer interfacing in neurorehabilitation. These movement intentions contain task-related information and if this is decoded, the neurorehabilitation could potentially be optimized. The aim of this study was to classify single-trial movement intentions associated with two levels of force and speed and three different grasp types using EEG rhythms and components of the movement-related cortical potential (MRCP) as features. The feature importance was used to estimate encoding of discriminative information. Two data sets were used. 29 healthy subjects executed and imagined different hand movements, while EEG was recorded over the contralateral sensorimotor cortex. The following features were extracted: delta, theta, mu/alpha, beta, and gamma rhythms, readiness potential, negative slope, and motor potential of the MRCP. Sequential forward selection was performed, and classification was performed using linear discriminant analysis and support vector machines. Limited classification accuracies were obtained from the EEG rhythms and MRCP-components: 0.48 ± 0.05 (grasp types), 0.41 ± 0.07 (kinetic profiles, motor execution), and 0.39 ± 0.08 (kinetic profiles, motor imagination). Delta activity contributed the most but all features provided discriminative information. These findings suggest that information from the entire EEG spectrum is needed to discriminate between task-related parameters from single-trial movement intentions.

A randomized controlled trial of a community health worker intervention in a population of patients with multiple chronic diseases: Study design and protocol

PubMed Central

Kangovi, Shreya; Mitra, Nandita; Turr, Lindsey; Huo, Hairong; Grande, David; Long, Judith A.

2017-01-01

Upstream interventions – e.g. housing programs and community health worker interventions-address socioeconomic and behavioral factors that influence health outcomes across diseases. Studying these types of interventions in clinical trials raises a methodological challenge: how should researchers measure the effect of an upstream intervention in a sample of patients with different diseases? This paper addresses this question using an illustrative protocol of a randomized controlled trial of collaborative-goal setting versus goal-setting plus community health worker support among patients multiple chronic diseases: diabetes, obesity, hypertension and tobacco dependence. At study enrollment, patients met with their primary care providers to select one of their chronic diseases to focus on during the study, and to collaboratively set a goal for that disease. Patients randomly assigned to a community health worker also received six months of support to address socioeconomic and behavioral barriers to chronic disease control. The primary hypothesis was that there would be differences in patients’ selected chronic disease control as measured by HbA1c, body mass index, systolic blood pressure and cigarettes per day, between the goal-setting alone and community health worker support arms. To test this hypothesis, we will conduct a stratum specific multivariate analysis of variance which allows all patients (regardless of their selected chronic disease) to be included in a single model for the primary outcome. Population health researchers can use this approach to measure clinical outcomes across diseases. PMID:27965180

Missing data handling in non-inferiority and equivalence trials: A systematic review.

PubMed

Rabe, Brooke A; Day, Simon; Fiero, Mallorie H; Bell, Melanie L

2018-05-25

Non-inferiority (NI) and equivalence clinical trials test whether a new treatment is therapeutically no worse than, or equivalent to, an existing standard of care. Missing data in clinical trials have been shown to reduce statistical power and potentially bias estimates of effect size; however, in NI and equivalence trials, they present additional issues. For instance, they may decrease sensitivity to differences between treatment groups and bias toward the alternative hypothesis of NI (or equivalence). Our primary aim was to review the extent of and methods for handling missing data (model-based methods, single imputation, multiple imputation, complete case), the analysis sets used (Intention-To-Treat, Per-Protocol, or both), and whether sensitivity analyses were used to explore departures from assumptions about the missing data. We conducted a systematic review of NI and equivalence trials published between May 2015 and April 2016 by searching the PubMed database. Articles were reviewed primarily by 2 reviewers, with 6 articles reviewed by both reviewers to establish consensus. Of 109 selected articles, 93% reported some missing data in the primary outcome. Among those, 50% reported complete case analysis, and 28% reported single imputation approaches for handling missing data. Only 32% reported conducting analyses of both intention-to-treat and per-protocol populations. Only 11% conducted any sensitivity analyses to test assumptions with respect to missing data. Missing data are common in NI and equivalence trials, and they are often handled by methods which may bias estimates and lead to incorrect conclusions. Copyright © 2018 John Wiley & Sons, Ltd.

Current challenges for clinical trials of cardiovascular medical devices.

PubMed

Zannad, Faiez; Stough, Wendy Gattis; Piña, Ileana L; Mehran, Roxana; Abraham, William T; Anker, Stefan D; De Ferrari, Gaetano M; Farb, Andrew; Geller, Nancy L; Kieval, Robert S; Linde, Cecilia; Redberg, Rita F; Stein, Kenneth; Vincent, Alphons; Woehrle, Holger; Pocock, Stuart J

2014-07-15

Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Randomised trials comparing different healthcare settings: an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges.

PubMed

Corbett, Mark S; Watson, Judith; Eastwood, Alison

2016-10-19

We recently published a systematic review of different healthcare settings (such as outpatient, community or home) for administering intravenous chemotherapy, and concluded that performing conventionally designed randomised trials was difficult. The main problems were achieving adequate trial accrual rates and recruiting a study population which adequately represented the target population of interest. These issues stemmed from the fact that potential participants may have had pre-trial perceptions about the trial settings they may be allocated; such preferences will sometimes be strong enough for patients to decline an invitation to participate in a trial. A patient preference trial design (in which patients can choose, or be randomised to, an intervention) may have obviated these recruitment issues, although none of the trials used such a design. In order to gain a better understanding of the broader prevalence and extent of these preference issues (and any other methodological challenges), we undertook an exploratory review of settings trials in any area of healthcare treatment research. We searched The Cochrane Library and Google Scholar and used snowballing methods to identify trials comparing different healthcare settings. Trial accrual was affected by patient preferences for a setting in 15 of the 16 identified studies; birth setting trials were the most markedly affected, with between 68 % and 85 % of eligible women declining to participate specifically because of preference for a particular healthcare setting. Recruitment into substance abuse and chemotherapy setting studies was also notably affected by preferences. Only four trials used a preference design: the proportion of eligible patients choosing to participate via a preference group ranged from between 33 % and 67 %. In trials of healthcare settings, accrual may be seriously affected by patient preferences. The use of trial designs which incorporate a preference component should therefore strongly be considered. When designing such trials, investigators should consider settings to be complex interventions, which are likely to have linked components which may be difficult to control for. Careful thought is also needed regarding the choice of comparator settings and the most appropriate outcome measures to be used.

Do all patients in the phase I oncology trials need to be hospitalized? Domestic but outstanding issues for globalization of drug development in Japan.

PubMed

Shimomura, Akihiko; Kondo, Shunsuke; Kobayashi, Noriko; Iwasa, Satoru; Kitano, Shigehisa; Tamura, Kenji; Fujiwara, Yutaka; Yamamoto, Noboru

2017-08-01

Most trials investigating new drugs around the world, including phase I trials, are conducted in outpatient clinics. However, in Japan, regulatory authority requirements and traditional domestic guidelines often require hospitalization of phase I study participants. Patients participating in single-agent phase I clinical trials at National Cancer Center Hospital between December 1996 and August 2014 were monitored. Toxicity requiring hospitalization is defined as toxicity that needs intensive treatment. Study designs were classified into three types: first-in-human (FIH) study, dose-escalation study (conventional dose-escalation study to determine maximum tolerated dose (MTD) in Japanese patients), and dose-finding study (to assess safety and pharmacokinetic profiles up to the MTD previously determined in the West). A total of 945 patients who participated in a variety of single-agent phase I clinical trials between December 1996 and August 2014 were included in this study. Patients participated in one of three study types: dose-escalation (n = 582, 62%), first-in-human (n = 129, 14%), or dose-finding (n = 234, 25%). A total of 76 study drugs were evaluated as part of this pool of phase I studies. Subdivided by mechanism of action, 20 (26%) were cytotoxic, 50 (66%) were molecularly targeted, and 6 (8%) were immune checkpoint inhibitor. Thirty-six patients (3.8%) had severe toxicities requiring hospitalization during the first cycle. The overall number of toxicities requiring hospitalization and/or grade 4 toxicities during any cycle was 5.0%. The frequency of severe toxicity that needs to be hospitalized was unexpectedly low. The data did not demonstrate the need for hospitalization in the phase I trials, suggesting that phase I trials in Japan could be conducted in outpatient settings.

Trend-Centric Motion Visualization: Designing and Applying a new Strategy for Analyzing Scientific Motion Collections

PubMed Central

Schroeder, David; Korsakov, Fedor; Knipe, Carissa Mai-Ping; Thorson, Lauren; Ellingson, Arin M.; Nuckley, David; Carlis, John; Keefe, Daniel F

2017-01-01

In biomechanics studies, researchers collect, via experiments or simulations, datasets with hundreds or thousands of trials, each describing the same type of motion (e.g., a neck flexion-extension exercise) but under different conditions (e.g., different patients, different disease states, pre- and post-treatment). Analyzing similarities and differences across all of the trials in these collections is a major challenge. Visualizing a single trial at a time does not work, and the typical alternative of juxtaposing multiple trials in a single visual display leads to complex, difficult-to-interpret visualizations. We address this problem via a new strategy that organizes the analysis around motion trends rather than trials. This new strategy matches the cognitive approach that scientists would like to take when analyzing motion collections. We introduce several technical innovations making trend-centric motion visualization possible. First, an algorithm detects a motion collection’s trends via time-dependent clustering. Second, a 2D graphical technique visualizes how trials leave and join trends. Third, a 3D graphical technique, using a median 3D motion plus a visual variance indicator, visualizes the biomechanics of the set of trials within each trend. These innovations are combined to create an interactive exploratory visualization tool, which we designed through an iterative process in collaboration with both domain scientists and a traditionally-trained graphic designer. We report on insights generated during this design process and demonstrate the tool’s effectiveness via a validation study with synthetic data and feedback from expert musculoskeletal biomechanics researchers who used the tool to analyze the effects of disc degeneration on human spinal kinematics. PMID:26356978

Effectiveness of a self-management program for dual sensory impaired seniors in aged care settings: study protocol for a cluster randomized controlled trial.

PubMed

Roets-Merken, Lieve M; Graff, Maud J L; Zuidema, Sytse U; Hermsen, Pieter G J M; Teerenstra, Steven; Kempen, Gertrudis I J M; Vernooij-Dassen, Myrra J F J

2013-10-07

Five to 25 percent of residents in aged care settings have a combined hearing and visual sensory impairment. Usual care is generally restricted to single sensory impairment, neglecting the consequences of dual sensory impairment on social participation and autonomy. The aim of this study is to evaluate the effectiveness of a self-management program for seniors who acquired dual sensory impairment at old age. In a cluster randomized, single-blind controlled trial, with aged care settings as the unit of randomization, the effectiveness of a self-management program will be compared to usual care. A minimum of 14 and maximum of 20 settings will be randomized to either the intervention cluster or the control cluster, aiming to include a total of 132 seniors with dual sensory impairment. Each senior will be linked to a licensed practical nurse working at the setting. During a five to six month intervention period, nurses at the intervention clusters will be trained in a self-management program to support and empower seniors to use self-management strategies. In two separate diaries, nurses keep track of the interviews with the seniors and their reflections on their own learning process. Nurses of the control clusters offer care as usual. At senior level, the primary outcome is the social participation of the seniors measured using the Hearing Handicap Questionnaire and the Activity Card Sort, and secondary outcomes are mood, autonomy and quality of life. At nurse level, the outcome is job satisfaction. Effectiveness will be evaluated using linear mixed model analysis. The results of this study will provide evidence for the effectiveness of the Self-Management Program for seniors with dual sensory impairment living in aged care settings. The findings are expected to contribute to the knowledge on the program's potential to enhance social participation and autonomy of the seniors, as well as increasing the job satisfaction of the licensed practical nurses. Furthermore, an extensive process evaluation will take place which will offer insight in the quality and feasibility of the sampling and intervention process. If it is shown to be effective and feasible, this Self-Management Program could be widely disseminated. ClinicalTrials.gov, NCT01217502.

A single-arm pilot study of guided self-help treatment based cognitive behavioral therapy for bulimia nervosa in Japanese clinical settings.

PubMed

Setsu, R; Asano, K; Numata, N; Tanaka, M; Ibuki, H; Yamamoto, T; Uragami, R; Matsumoto, J; Hirano, Y; Iyo, M; Shimizu, E; Nakazato, M

2018-04-25

Guided self-help treatments based on cognitive behavioral therapy (CBT-GSH) are regarded as a first-line effective treatment for bulimia nervosa (BN). With limited application for CBT-GSH in Japanese clinical settings, we conducted a single arm pilot study in order to confirm the acceptability and availability of CBT-GSH in Japan. 25 women with BN received 16-20 sessions of face-to-face CBT-GSH. Primary outcomes were the completion rate of intervention and abstinence rates from objective bingeing and purging as assessed by the Eating Disorder Examination. Secondary outcomes were other self-report measurements of the frequency of bingeing and purging, and characteristic psychopathologies of eating disorders. Assessments were conducted before CBT as baseline as well as after CBT. 92% (23/25) of the participants completed the CBT sessions. After CBT-GSH, 40% (10/25) of the participants (intention-to-treat) achieved symptom abstinence. The mean binge and purge episodes during the previous 28 days improved from 21.88 to 10.96 (50% reduction) and from 22.44 to 10.88 (52% reduction), each (before CBT-GSH to after CBT-GSH), and the within-group effect sizes were medium (Cohen's d = 0.67, 0.65, each). Our study provided a preliminary evidence about the feasibility of CBT-GSH in Japanese clinical settings for the future. Trial registration This study was registered retrospectively in the national UMIN Clinical Trials Registry on July 10, 2013 (registration ID: UMIN000011120).

21 CFR 886.1405 - Ophthalmic trial lens set.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Ophthalmic trial lens set. 886.1405 Section 886...) MEDICAL DEVICES OPHTHALMIC DEVICES Diagnostic Devices § 886.1405 Ophthalmic trial lens set. (a) Identification. An ophthalmic trial lens set is a device that is a set of lenses of various dioptric powers...

A randomised controlled trial of three or one breathing technique training sessions for breathlessness in people with malignant lung disease.

PubMed

Johnson, Miriam J; Kanaan, Mona; Richardson, Gerry; Nabb, Samantha; Torgerson, David; English, Anne; Barton, Rachael; Booth, Sara

2015-09-07

About 90 % of patients with intra-thoracic malignancy experience breathlessness. Breathing training is helpful, but it is unknown whether repeated sessions are needed. The present study aims to test whether three sessions are better than one for breathlessness in this population. This is a multi-centre randomised controlled non-blinded parallel arm trial. Participants were allocated to three sessions or single (1:2 ratio) using central computer-generated block randomisation by an independent Trials Unit and stratified for centre. The setting was respiratory, oncology or palliative care clinics at eight UK centres. Inclusion criteria were people with intrathoracic cancer and refractory breathlessness, expected prognosis ≥3 months, and no prior experience of breathing training. The trial intervention was a complex breathlessness intervention (breathing training, anxiety management, relaxation, pacing, and prioritisation) delivered over three hour-long sessions at weekly intervals, or during a single hour-long session. The main primary outcome was worst breathlessness over the previous 24 hours ('worst'), by numerical rating scale (0 = none; 10 = worst imaginable). Our primary analysis was area under the curve (AUC) 'worst' from baseline to 4 weeks. All analyses were by intention to treat. Between April 2011 and October 2013, 156 consenting participants were randomised (52 three; 104 single). Overall, the 'worst' score reduced from 6.81 (SD, 1.89) to 5.84 (2.39). Primary analysis [n = 124 (79 %)], showed no between-arm difference in the AUC: three sessions 22.86 (7.12) vs single session 22.58 (7.10); P value = 0.83); mean difference 0.2, 95 % CIs (-2.31 to 2.97). Complete case analysis showed a non-significant reduction in QALYs with three sessions (mean difference -0.006, 95 % CIs -0.018 to 0.006). Sensitivity analyses found similar results. The probability of the single session being cost-effective (threshold value of £20,000 per QALY) was over 80 %. There was no evidence that three sessions conferred additional benefits, including cost-effectiveness, over one. A single session of breathing training seems appropriate and minimises patient burden. Registry: ISRCTN; ISRCTN49387307; http://www.isrctn.com/ISRCTN49387307 ; registration date: 25/01/2011.

Clinical trials of homoeopathy.

PubMed Central

Kleijnen, J; Knipschild, P; ter Riet, G

1991-01-01

OBJECTIVE--To establish whether there is evidence of the efficacy of homoeopathy from controlled trials in humans. DESIGN--Criteria based meta-analysis. Assessment of the methodological quality of 107 controlled trials in 96 published reports found after an extensive search. Trials were scored using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. SETTING--Controlled trials published world wide. MAIN OUTCOME MEASURES--Results of the trials with the best methodological quality. Trials of classical homoeopathy and several modern varieties were considered separately. RESULTS--In 14 trials some form of classical homoeopathy was tested and in 58 trials the same single homoeopathic treatment was given to patients with comparable conventional diagnosis. Combinations of several homoeopathic treatments were tested in 26 trials; isopathy was tested in nine trials. Most trials seemed to be of very low quality, but there were many exceptions. The results showed a positive trend regardless of the quality of the trial or the variety of homeopathy used. Overall, of the 105 trials with interpretable results, 81 trials indicated positive results whereas in 24 trials no positive effects of homoeopathy were found. The results of the review may be complicated by publication bias, especially in such a controversial subject as homoeopathy. CONCLUSIONS--At the moment the evidence of clinical trials is positive but not sufficient to draw definitive conclusions because most trials are of low methodological quality and because of the unknown role of publication bias. This indicates that there is a legitimate case for further evaluation of homoeopathy, but only by means of well performed trials. PMID:1825800

A single-blind trial of reflexology for irritable bowel syndrome.

PubMed Central

Tovey, Philip

2002-01-01

BACKGROUND: Irritable bowel syndrome (IBS) is a significant problem for primary care, as treatment options are limited and it can frequently develop into a chronic condition. Complementary and alternative medicine, including reflexology, is being turned to increasingly in an attempt to manage symptoms. There are currently no studies which address the effectiveness of reflexology for IBS. Despite this, it continues to be advocated and used. AIM: To provide the first evidence on the effectiveness of reflexology in the management of the core defining symptoms of IBS. DESIGN OF STUDY: A single-blind trial carried out in primary care settings. SETTING: Thirty-four participants diagnosed with IBS on the basis of the Rome Criteria. METHOD: Participants were allocated to receive either a reflexology foot massage or a non-reflexology foot massage control group. RESULTS: On none of the three symptoms monitored--abdominal pain, constipation/diarrhoea, and abdominal distention--was there a statistically or clinically significant difference between reflexology and control groups. CONCLUSION: On the basis of these results there is nothing to suggest that reflexology produces any specific benefit for patients with IBS. There is currently no evidence to support its use. However this was one (relatively) small scale study; further research that, for example, assesses the impact of therapist (professional and lay) versus therapy, is still needed. PMID:11791811

Effectiveness and Cost-Effectiveness of Occupation-Based Occupational Therapy Using the Aid for Decision Making in Occupation Choice (ADOC) for Older Residents: Pilot Cluster Randomized Controlled Trial

PubMed Central

Nagayama, Hirofumi; Tomori, Kounosuke; Ohno, Kanta; Takahashi, Kayoko; Ogahara, Kakuya; Sawada, Tatsunori; Uezu, Sei; Nagatani, Ryutaro; Yamauchi, Keita

2016-01-01

Background Care-home residents are mostly inactive, have little interaction with staff, and are dependent on staff to engage in daily occupations. We recently developed an iPad application called the Aid for Decision-making in Occupation Choice (ADOC) to promote shared decision-making in activities and occupation-based goal setting by choosing from illustrations describing daily activities. This study aimed to evaluate if interventions based on occupation-based goal setting using the ADOC could focus on meaningful activities to improve quality of life and independent activities of daily living, with greater cost-effectiveness than an impairment-based approach as well as to evaluate the feasibility of conducting a large cluster, randomized controlled trial. Method In this single (assessor)-blind pilot cluster randomized controlled trial, the intervention group (ADOC group) received occupational therapy based on occupation-based goal setting using the ADOC, and the interventions were focused on meaningful occupations. The control group underwent an impairment-based approach focused on restoring capacities, without goal setting tools. In both groups, the 20-minute individualized intervention sessions were conducted twice a week for 4 months. Main Outcome Measures Short Form-36 (SF-36) score, SF-6D utility score, quality adjusted life years (QALY), Barthel Index, and total care cost. Results We randomized and analyzed 12 facilities (44 participants, 18.5% drop-out rate), with 6 facilities each allocated to the ADOC (n = 23) and control (n = 21) groups. After the 4-month intervention, the ADOC group had a significantly greater change in the BI score, with improved scores (P = 0.027, 95% CI 0.41 to 6.87, intracluster correlation coefficient = 0.14). No other outcome was significantly different. The incremental cost-effectiveness ratio, calculated using the change in BI score, was $63.1. Conclusion The results suggest that occupational therapy using the ADOC for older residents might be effective and cost-effective. We also found that conducting an RCT in the occupational therapy setting is feasible. Trial Registration UMIN Clinical Trials Registry UMIN000012994 PMID:26930191

Involving patients in setting priorities for healthcare improvement: a cluster randomized trial

PubMed Central

2014-01-01

Background Patients are increasingly seen as active partners in healthcare. While patient involvement in individual clinical decisions has been extensively studied, no trial has assessed how patients can effectively be involved in collective healthcare decisions affecting the population. The goal of this study was to test the impact of involving patients in setting healthcare improvement priorities for chronic care at the community level. Methods Design: Cluster randomized controlled trial. Local communities were randomized in intervention (priority setting with patient involvement) and control sites (no patient involvement). Setting: Communities in a canadian region were required to set priorities for improving chronic disease management in primary care, from a list of 37 validated quality indicators. Intervention: Patients were consulted in writing, before participating in face-to-face deliberation with professionals. Control: Professionals established priorities among themselves, without patient involvement. Participants: A total of 172 individuals from six communities participated in the study, including 83 chronic disease patients, and 89 health professionals. Outcomes: The primary outcome was the level of agreement between patients’ and professionals’ priorities. Secondary outcomes included professionals’ intention to use the selected quality indicators, and the costs of patient involvement. Results Priorities established with patients were more aligned with core generic components of the Medical Home and Chronic Care Model, including: access to primary care, self-care support, patient participation in clinical decisions, and partnership with community organizations (p < 0.01). Priorities established by professionals alone placed more emphasis on the technical quality of single disease management. The involvement intervention fostered mutual influence between patients and professionals, which resulted in a 41% increase in agreement on common priorities (95%CI: +12% to +58%, p < 0.01). Professionals’ intention to use the selected quality indicators was similar in intervention and control sites. Patient involvement increased the costs of the prioritization process by 17%, and required 10% more time to reach consensus on common priorities. Conclusions Patient involvement can change priorities driving healthcare improvement at the population level. Future research should test the generalizability of these findings to other contexts, and assess its impact on patient care. Trial registration The Netherlands National Trial Register #NTR2496. PMID:24555508

Is dibotermin alfa a cost-effective substitute for autologous iliac crest bone graft in single level lumbar interbody spine fusion?

PubMed

Svedbom, Axel; Paech, Daniel; Leonard, Catherine; Donnell, David; Song, Fujian; Boszcyk, Bronek; Rothenfluh, Dominique A; Lloyd, Andrew; Borgman, Benny

2015-11-01

To evaluate the cost-effectiveness of dibotermin alfa compared with autologous iliac crest bone graft (ICBG) for patients undergoing single level lumbar interbody spinal fusion in a UK hospital setting. An individual patient data (IPD) meta-analysis of six randomized controlled clinical trials and two single arm trials compared dibotermin alfa on an absorbable collagen implantation matrix (ACIM) (n = 456) and ICBG (n = 244) on resource use, re-operation rates, and SF-6D (Short form 6-dimension) health utility (total N = 700). Failure-related second surgery, operating time, post-operative hospital stay, and quality-adjusted life years (QALYs) derived from the IPD meta-analysis were included as inputs in an economic evaluation undertaken to assess the cost-effectiveness of dibotermin alfa/ACIM versus ICBG for patients undergoing single level lumbar interbody spinal fusion. A four year time horizon and the United Kingdom (UK) National Health Service (NHS) and Personal Social Services (PSS) perspective was adopted in the base case, with sensitivity analyses performed to gauge parameter uncertainty. In the base case analysis, patients treated using dibotermin alfa/ACIM (12 mg pack) accrued 0.055 incremental QALYs at an incremental cost of £ 737, compared with patients treated with ICBG. This resulted in an incremental cost-effectiveness ratio (ICER) of £ 13,523, indicating that at a willingness-to-pay threshold of £ 20,000, dibotermin alfa/ACIM is a cost-effective intervention relative to ICBG from the NHS and PSS perspective. In a UK hospital setting, dibotermin alfa/ACIM is a cost-effective substitute for ICBG for patients who require lumbar interbody arthrodesis.

Effect of unilateral knee extensor fatigue on force and balance of the contralateral limb.

PubMed

Arora, Shruti; Budden, Shawn; Byrne, Jeannette M; Behm, David G

2015-10-01

Fatigue in one limb can decrease force production in the homologous muscle as well as other muscles of the non-fatigued limb affecting balance. The objective of the study was to examine the effect of unilateral knee extensor fatigue on the non-fatigued limb's standing balance, muscle force and activation. Sixteen healthy male subjects performed pre-fatigue balance trials, warm-up exercises, maximum voluntary isometric contractions, a knee extensors fatigue protocol, and post-fatigue balance trials. The fatigue protocol consisted of sets of 15 consecutive isometric contractions of 16 s each with 4 s recovery between repetitions, which were performed at 30% peak force for the dominant knee extensor muscles. Additional sets of contractions continued until a 50% decrease in MVIC knee extensor force was observed. Pre- and post-fatigue balance assessment consisted of transition from double to single leg standing and also single leg standing trials, which were performed bilaterally and in randomized order. The peak force and F100 were significantly decreased by 44.8% (ES = 2.54) and 39.9% (ES = 0.59), respectively, for the fatigued limb post-fatigue. There were no significant changes in the non-fatigued limb's muscle force, activation, muscle onset timing or postural stability parameters. While the lack of change in non-fatigued limb force production is in agreement with some of the previous literature in this area, the lack of effect on postural measures directly contradicts earlier work. It is hypothesized that discrepancies in the duration and the intensity of the fatigue protocol may have accounted for this discrepancy.

Collecting and analysing cost data for complex public health trials: reflections on practice.

PubMed

Batura, Neha; Pulkki-Brännström, Anni-Maria; Agrawal, Priya; Bagra, Archana; Haghparast-Bidgoli, Hassan; Bozzani, Fiammetta; Colbourn, Tim; Greco, Giulia; Hossain, Tanvir; Sinha, Rajesh; Thapa, Bidur; Skordis-Worrall, Jolene

2014-01-01

Current guidelines for the conduct of cost-effectiveness analysis (CEA) are mainly applicable to facility-based interventions in high-income settings. Differences in the unit of analysis and the high cost of data collection can make these guidelines challenging to follow within public health trials in low- and middle- income settings. This paper reflects on the challenges experienced within our own work and proposes solutions that may be useful to others attempting to collect, analyse, and compare cost data between public health research sites in low- and middle- income countries. We describe the generally accepted methods (norms) for collecting and analysing cost data in a single-site trial from the provider perspective. We then describe our own experience applying these methods within eight comparable cluster randomised, controlled, trials. We describe the strategies used to maximise adherence to the norm, highlight ways in which we deviated from the norm, and reflect on the learning and limitations that resulted. When the expenses incurred by a number of small research sites are used to estimate the cost-effectiveness of delivering an intervention on a national scale, then deciding which expenses constitute 'start-up' costs will be a nontrivial decision that may differ among sites. Similarly, the decision to include or exclude research or monitoring and evaluation costs can have a significant impact on the findings. We separated out research costs and argued that monitoring and evaluation costs should be reported as part of the total trial cost. The human resource constraints that we experienced are also likely to be common to other trials. As we did not have an economist in each site, we collaborated with key personnel at each site who were trained to use a standardised cost collection tool. This approach both accommodated our resource constraints and served as a knowledge sharing and capacity building process within the research teams. Given the practical reality of conducting randomised, controlled trials of public health interventions in low- and middle- income countries, it is not always possible to adhere to prescribed guidelines for the analysis of cost effectiveness. Compromises are frequently required as researchers seek a pragmatic balance between rigor and feasibility. There is no single solution to this tension but researchers are encouraged to be mindful of the limitations that accompany compromise, whilst being reassured that meaningful analyses can still be conducted with the resulting data.

Evaluating effectiveness and cost-effectiveness of a group psychological intervention using cognitive behavioural strategies for women with common mental disorders in conflict-affected rural Pakistan: study protocol for a randomised controlled trial.

PubMed

Chiumento, Anna; Hamdani, Syed Usman; Khan, Muhammad Naseem; Dawson, Katie; Bryant, Richard A; Sijbrandij, Marit; Nazir, Huma; Akhtar, Parveen; Masood, Aqsa; Wang, Duolao; van Ommeren, Mark; Rahman, Atif

2017-04-26

The impact of humanitarian disasters upon mental health is well recognised. The evidence for psychological interventions for mental health is mounting, but few interventions have been rigorously tested in humanitarian settings. To be sustainable in humanitarian settings interventions need to be short, simple, deliverable by nonspecialists under supervision, and adopt a transdiagnostic approach where an array of mental health outcomes are addressed simultaneously. These elements have been incorporated into the newly developed WHO Problem Management Plus (PM+) Group intervention. The aim of this trial is to evaluate the locally adapted PM+ Group intervention for women in Swat, Pakistan. This PM+ Group trial is a two-arm, single-blind, cluster randomised controlled trial conducted in a community-based setting with women in rural Pakistan. PM+ is delivered in partnership with the Lady Health Worker (LHW) Programme which provides community-based health care to women in Pakistan. Thirty-four LHW clusters will be randomised in a 1:1 allocation ratio using a permuted-block randomisation method. Participants screened and found to meet the inclusion criteria will be allocated to either the PM+ intervention group (n = 306), or the control arm (n = 306). The manualised PM+ intervention involves five sessions, each lasting 3 h, and introduces four strategies applied by participants to problems that they are facing. It is delivered by local female facilitators with a minimum of 16 years of education who are provided with targeted training and supervision. The primary outcome is individual psychological distress, measured by levels of anxiety and depression on the Hospital Anxiety and Depression Scale at 20 weeks after baseline. Secondary outcomes include major depression, post-traumatic stress disorder, levels of social support, levels of functioning, and economic effectiveness. Intervention acceptability will be explored through an embedded qualitative study. The PM+ Group trial will provide important evidence on the effectiveness of an empirically supported psychological treatment delivered by nonspecialists in a humanitarian setting. If proven effective, the qualitative component will inform strategies for PM+ Group scale-up in health systems in other humanitarian settings. Australian New Zealand Clinical Trials Registry, identifier: ACTRN12616000037404. Registered on 19 January 2016; WHO Protocol ID RPC705, v.4, 2 November 2015.

Fibromyalgia Syndrome Module at OMERACT 9

PubMed Central

Mease, Philip; Arnold, Lesley M; Choy, Ernest H; Clauw, Daniel J.; Crofford, Leslie; Glass, Jennifer M; Martin, Susan A; Morea, Jessica; Simon, Lee; Strand, Vibeke; Williams, David A

2012-01-01

Objectives (1) Establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measures’ performance characteristics, (3) discuss development of a responder index for the assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, (6) establish a research agenda for work regarding outcomes research. Methods (1) Results of univariate and multivariate analysis of 10 different FM clinical trials of four different drugs, mapping key domains identified in previously presented patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, breakout discussions to vote on possible essential domains and reliable measures. (2) Updates presented regarding outcome measures’ status. (3) Presented update on objective markers to measure FM disease state. 4) The issue of cognitive dysfunction (dyscognition) in FM was reviewed. Results (1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials, dyscognition and depression in some trial, and domains of research interest include stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers. (2) FM domains’ outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing number of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed. Conclusions A multidimensional symptom core set is proposed for the evaluation of FM in clinical trials. There is ongoing research on improved measures of single domains and composite measures. PMID:19820221

Defining a Clinically Meaningful Effect for the Design and Interpretation of Randomized Controlled Trials

PubMed Central

Kraemer, Helena C.; Epstein, Robert S.; Frank, Ellen; Haynes, Ginger; Laughren, Thomas P.; Mcnulty, James; Reed, Shelby D.; Sanchez, Juan; Leon, Andrew C.

2013-01-01

Objective: This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. Design: Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. Setting: The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. Participants: The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. Results: The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. Conclusion: There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials. PMID:23882433

Goal-setting intervention in patients with active asthma: protocol for a pilot cluster-randomised controlled trial

PubMed Central

2013-01-01

Background Supporting self-management behaviours is recommended guidance for people with asthma. Preliminary work suggests that a brief, intensive, patient-centred intervention may be successful in supporting people with asthma to participate in life roles and activities they value. We seek to assess the feasibility of undertaking a cluster-randomised controlled trial (cRCT) of a brief, goal-setting intervention delivered in the context of an asthma review consultation. Methods/design A two armed, single-blinded, multi-centre, cluster-randomised controlled feasibility trial will be conducted in UK primary care. Randomisation will take place at the practice level. We aim to recruit a total of 80 primary care patients with active asthma from at least eight practices across two health boards in Scotland (10 patients per practice resulting in ~40 in each arm). Patients in the intervention arm will be asked to complete a novel goal-setting tool immediately prior to an asthma review consultation. This will be used to underpin a focussed discussion about their goals during the asthma review. A tailored management plan will then be negotiated to facilitate achieving their prioritised goals. Patients in the control arm will receive a usual care guideline-based review of asthma. Data on quality of life, asthma control and patient confidence will be collected from both arms at baseline and 3 and 6 months post-intervention. Data on health services resource use will be collected from all patient records 6 months pre- and post-intervention. Semi-structured interviews will be carried out with healthcare staff and a purposive sample of patients to elicit their views and experiences of the trial. The outcomes of interest in this feasibility trial are the ability to recruit patients and healthcare staff, the optimal method of delivering the intervention within routine clinical practice, and acceptability and perceived utility of the intervention among patients and staff. Trial registration ISRCTN18912042 PMID:24021033

Evaluation of Safety and Efficacy of Qinming8631 DR Implantable Cardiac Pacemaker in Chinese Patients: A Prospective, Multicenter, Randomized Controlled Trial of the First Domestically Developed Pacemaker of China.

PubMed

Xiang, Mei-Xiang; Wang, Dong-Qi; Xu, Jing; Zhang, Zheng; Hu, Jian-Xin; Wang, Dong-Mei; Gu, Xiang; Liu, He-Ping; Guo, Tao; Yang, Xiang-Jun; Ling, Feng; Lin, Jia-Feng; Cai, Shang-Lang; Zhu, Guo-Bin; Wang, Jian-An

2016-11-20

High cost of imported pacemakers is a main obstacle for Chinese patients suffering from bradyarrhythmia, and a domestically developed pacemaker will help lower the burden. This study aimed to evaluate the safety and efficacy of Qinming8631 DR (Qinming Medical, Baoji, China), the first domestically developed dual-chamber pacemaker of China, compared with a commercially available pacemaker Talos DR (Biotronik, Berlin, Germany) in Chinese patients. A prospective randomized trial was conducted at 14 centers in China. Participants were randomized into trial (Qinming8631 DR) and control (Talos DR) groups. Parameters of the pacing systems were collected immediately after device implantation and during follow-ups. The effective pacing rate at 6-month follow-up was recorded as the primary end point. Electrical properties, magnet response, single- and double-pole polarity conversion, rate response function, and adverse events of the pacing system were analyzed. The Cochran-Mantel-Haenszel Chi-square test, paired t-test, and Wilcoxon signed-rank test were used for measuring primary qualitative outcomes and comparing normally and abnormally distributed measurement data. A total of 225 patients with a diagnosis of bradyarrhythmia and eligible for this study were randomly enrolled into the trial (n = 113) and control (n = 112) groups. They underwent successful pacemaker implantation with acceptable postoperative pacing threshold and sensitivity. Effective pacing rates of trial and control groups were comparable both in the full analysis set and the per protocol set (81.4% vs. 79.5%, P = 0.712 and 95.4% vs. 89.5%, P = 0.143, respectively). In both data sets, noninferiority of the trial group was above the predefined noninferiority limit(-9.5%). This study established the noninferiority of Qinming8631 DR to Talos DR. The safety and efficacy of Qinming8631 DR pacemaker were comparable to those of Talos DR in treating patients with cardiac bradyarrhythmia.

Selecting promising treatments in randomized Phase II cancer trials with an active control.

PubMed

Cheung, Ying Kuen

2009-01-01

The primary objective of Phase II cancer trials is to evaluate the potential efficacy of a new regimen in terms of its antitumor activity in a given type of cancer. Due to advances in oncology therapeutics and heterogeneity in the patient population, such evaluation can be interpreted objectively only in the presence of a prospective control group of an active standard treatment. This paper deals with the design problem of Phase II selection trials in which several experimental regimens are compared to an active control, with an objective to identify an experimental arm that is more effective than the control or to declare futility if no such treatment exists. Conducting a multi-arm randomized selection trial is a useful strategy to prioritize experimental treatments for further testing when many candidates are available, but the sample size required in such a trial with an active control could raise feasibility concerns. In this study, we extend the sequential probability ratio test for normal observations to the multi-arm selection setting. The proposed methods, allowing frequent interim monitoring, offer high likelihood of early trial termination, and as such enhance enrollment feasibility. The termination and selection criteria have closed form solutions and are easy to compute with respect to any given set of error constraints. The proposed methods are applied to design a selection trial in which combinations of sorafenib and erlotinib are compared to a control group in patients with non-small-cell lung cancer using a continuous endpoint of change in tumor size. The operating characteristics of the proposed methods are compared to that of a single-stage design via simulations: The sample size requirement is reduced substantially and is feasible at an early stage of drug development.

The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement.

PubMed

Tate, Robyn L; Perdices, Michael; Rosenkoetter, Ulrike; Shadish, William; Vohra, Sunita; Barlow, David H; Horner, Robert; Kazdin, Alan; Kratochwill, Thomas; McDonald, Skye; Sampson, Margaret; Shamseer, Larissa; Togher, Leanne; Albin, Richard; Backman, Catherine; Douglas, Jacinta; Evans, Jonathan J; Gast, David; Manolov, Rumen; Mitchell, Geoffrey; Nickels, Lyndsey; Nikles, Jane; Ownsworth, Tamara; Rose, Miranda; Schmid, Christopher H; Wilson, Barbara

2017-01-01

We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single-case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016 ) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. SCIENTIFIC ABSTRACT Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012 ). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008 ) provides suitable guidance for reporting between-groups intervention studies in the behavioural sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015 ; Vohra et al., 2015 ), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioural sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016 ) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated.

The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement †

PubMed Central

Tate, Robyn L.; Perdices, Michael; Rosenkoetter, Ulrike; Shadish, William; Vohra, Sunita; Barlow, David H.; Horner, Robert; Kazdin, Alan; Kratochwill, Thomas; McDonald, Skye; Sampson, Margaret; Shamseer, Larissa; Togher, Leanne; Albin, Richard; Backman, Catherine; Douglas, Jacinta; Evans, Jonathan J.; Gast, David; Manolov, Rumen; Mitchell, Geoffrey; Nickels, Lyndsey; Nikles, Jane; Ownsworth, Tamara; Rose, Miranda; Schmid, Christopher H.; Wilson, Barbara

2017-01-01

ABSTRACT We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single-case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. SCIENTIFIC ABSTRACT Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioural sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioural sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. PMID:27499422

Does recruitment source moderate treatment effectiveness? A subgroup analysis from the EVIDENT study, a randomised controlled trial of an internet intervention for depressive symptoms

PubMed Central

Gamon, Carla; Späth, Christina; Berger, Thomas; Meyer, Björn; Hohagen, Fritz; Hautzinger, Martin; Lutz, Wolfgang; Vettorazzi, Eik; Moritz, Steffen; Schröder, Johanna

2017-01-01

Objective This study aims to examine whether the effects of internet interventions for depression generalise to participants recruited in clinical settings. Design This study uses subgroup analysis of the results of a randomised, controlled, single-blind trial. Setting The study takes place in five diagnostic centres in Germany. Participants A total of 1013 people with mild to moderate depressive symptoms were recruited from clinical sources as well as internet forums, statutory insurance companies and other sources. Interventions This study uses either care-as-usual alone (control) or a 12-week internet intervention (Deprexis) plus usual care (intervention). Main outcome measures The primary outcome measure was self-rated depression severity (Patient Health Questionnaire-9) at 3 months and 6 months. Further measures ranged from demographic and clinical parameters to a measure of attitudes towards internet interventions (Attitudes towards Psychological Online Interventions Questionnaire). Results The recruitment source was only associated with very few of the examined demographic and clinical characteristics. Compared with participants recruited from clinical sources, participants recruited through insurance companies were more likely to be employed. Clinically recruited participants were as severely affected as those from other recruitment sources but more sceptical of internet interventions. The effectiveness of the intervention was not differentially associated with recruitment source (treatment by recruitment source interaction=0.28, p=0.84). Conclusion Our results support the hypothesis that the intervention we studied is effective across different recruitment sources including clinical settings. Trial registration number ClinicalTrials.gov NCT01636752. PMID:28710212

Publication bias was not a good reason to discourage trials with low power.

PubMed

Borm, George F; den Heijer, Martin; Zielhuis, Gerhard A

2009-01-01

The objective was to investigate whether it is justified to discourage trials with less than 80% power. Trials with low power are unlikely to produce conclusive results, but their findings can be used by pooling then in a meta-analysis. However, such an analysis may be biased, because trials with low power are likely to have a nonsignificant result and are less likely to be published than trials with a statistically significant outcome. We simulated several series of studies with varying degrees of publication bias and then calculated the "real" one-sided type I error and the bias of meta-analyses with a "nominal" error rate (significance level) of 2.5%. In single trials, in which heterogeneity was set at zero, low, and high, the error rates were 2.3%, 4.7%, and 16.5%, respectively. In multiple trials with 80%-90% power and a publication rate of 90% when the results were nonsignificant, the error rates could be as high as 5.1%. When the power was 50% and the publication rate of non-significant results was 60%, the error rates did not exceed 5.3%, whereas the bias was at most 15% of the difference used in the power calculation. The impact of publication bias does not warrant the exclusion of trials with 50% power.

A Simulation Study of Methods for Selecting Subgroup-Specific Doses in Phase I Trials

PubMed Central

Morita, Satoshi; Thall, Peter F.; Takeda, Kentaro

2016-01-01

Summary Patient heterogeneity may complicate dose-finding in phase I clinical trials if the dose-toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively, it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem, we consider a generalization of the continual reassessment method (O’Quigley, et al., 1990) based on a hierarchical Bayesian dose-toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup-specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to three alternative approaches, based on non-hierarchical models, that make different types of assumptions about within-subgroup dose-toxicity curves. The simulations show that the hierarchical model-based method is recommended in settings where the dose-toxicity curves are exchangeable between subgroups. We present practical guidelines for application, and provide computer programs for trial simulation and conduct. PMID:28111916

Single-trial dynamics of motor cortex and their applications to brain-machine interfaces

PubMed Central

Kao, Jonathan C.; Nuyujukian, Paul; Ryu, Stephen I.; Churchland, Mark M.; Cunningham, John P.; Shenoy, Krishna V.

2015-01-01

Increasing evidence suggests that neural population responses have their own internal drive, or dynamics, that describe how the neural population evolves through time. An important prediction of neural dynamical models is that previously observed neural activity is informative of noisy yet-to-be-observed activity on single-trials, and may thus have a denoising effect. To investigate this prediction, we built and characterized dynamical models of single-trial motor cortical activity. We find these models capture salient dynamical features of the neural population and are informative of future neural activity on single trials. To assess how neural dynamics may beneficially denoise single-trial neural activity, we incorporate neural dynamics into a brain–machine interface (BMI). In online experiments, we find that a neural dynamical BMI achieves substantially higher performance than its non-dynamical counterpart. These results provide evidence that neural dynamics beneficially inform the temporal evolution of neural activity on single trials and may directly impact the performance of BMIs. PMID:26220660

Single-trial laser-evoked potentials feature extraction for prediction of pain perception.

PubMed

Huang, Gan; Xiao, Ping; Hu, Li; Hung, Yeung Sam; Zhang, Zhiguo

2013-01-01

Pain is a highly subjective experience, and the availability of an objective assessment of pain perception would be of great importance for both basic and clinical applications. The objective of the present study is to develop a novel approach to extract pain-related features from single-trial laser-evoked potentials (LEPs) for classification of pain perception. The single-trial LEP feature extraction approach combines a spatial filtering using common spatial pattern (CSP) and a multiple linear regression (MLR). The CSP method is effective in separating laser-evoked EEG response from ongoing EEG activity, while MLR is capable of automatically estimating the amplitudes and latencies of N2 and P2 from single-trial LEP waveforms. The extracted single-trial LEP features are used in a Naïve Bayes classifier to classify different levels of pain perceived by the subjects. The experimental results show that the proposed single-trial LEP feature extraction approach can effectively extract pain-related LEP features for achieving high classification accuracy.

Balance circuit classes to improve balance among rehabilitation inpatients: a protocol for a randomised controlled trial.

PubMed

Treacy, Daniel; Schurr, Karl; Sherrington, Catherine

2013-07-20

Impaired balance and mobility are common among rehabilitation inpatients. Poor balance and mobility lead to an increased risk of falling. Specific balance exercise has been shown to improve balance and reduce falls within the community setting. However few studies have measured the effects of balance exercises on balance within the inpatient setting. A single centre, randomised controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. One hundred and sixty two patients admitted to the general rehabilitation ward at Bankstown-Lidcombe Hospital will be recruited. Eligible participants will have no medical contraindications to exercise and will be able to: fully weight bear; stand unaided independently for at least 30 seconds; and participate in group therapy sessions with minimal supervision. Participants will be randomly allocated to an intervention group or usual-care control group. Both groups will receive standard rehabilitation intervention that includes physiotherapy mobility training and exercise for at least two hours on each week day. The intervention group will also receive six 1-hour circuit classes of supervised balance exercises designed to maximise the ability to make postural adjustments in standing, stepping and walking. The primary outcome is balance. Balance will be assessed by measuring the total time the participant can stand unsupported in five different positions; feet apart, feet together, semi-tandem, tandem and single-leg-stance. Secondary outcomes include mobility, self reported physical functioning, falls and hospital readmissions. Performance on the outcome measures will be assessed before randomisation and at two-weeks and three-months after randomisation by physiotherapists unaware of intervention group allocation. This study will determine the impact of additional balance circuit classes on balance among rehabilitation inpatients. The results will provide essential information to guide evidence-based physiotherapy at the study site as well as across other rehabilitation inpatient settings. The protocol for this study is registered with the Australian New Zealand, Clinical Trials Registry: ACTRN=12611000412932.

On the origins of the task mixing cost in the cuing task-switching paradigm.

PubMed

Rubin, Orit; Meiran, Nachshon

2005-11-01

Poorer performance in conditions involving task repetition within blocks of mixed tasks relative to task repetition within blocks of single task is called mixing cost (MC). In 2 experiments exploring 2 hypotheses regarding the origins of MC, participants either switched between cued shape and color tasks, or they performed them as single tasks. Experiment 1 supported the hypothesis that mixed-tasks trials require the resolution of task ambiguity by showing that MC existed only with ambiguous stimuli that afforded both tasks and not with unambiguous stimuli affording only 1 task. Experiment 2 failed to support the hypothesis that holding multiple task sets in working memory (WM) generates MC by showing that systematic manipulation of the number of stimulus-response rules in WM did not affect MC. The results emphasize the role of competition management between task sets during task control.

Single-arm phase II trial design under parametric cure models.

PubMed

Wu, Jianrong

2015-01-01

The current practice of designing single-arm phase II survival trials is limited under the exponential model. Trial design under the exponential model may not be appropriate when a portion of patients are cured. There is no literature available for designing single-arm phase II trials under the parametric cure model. In this paper, a test statistic is proposed, and a sample size formula is derived for designing single-arm phase II trials under a class of parametric cure models. Extensive simulations showed that the proposed test and sample size formula perform very well under different scenarios. Copyright © 2015 John Wiley & Sons, Ltd.

A review of escitalopram and citalopram in child and adolescent depression.

PubMed

Carandang, Carlo; Jabbal, Rekha; Macbride, Angela; Elbe, Dean

2011-11-01

To review the basic pharmacology and published literature regarding escitalopram and citalopram in child and adolescent depression. A LITERATURE REVIEW WAS CONDUCTED USING THE SEARCH TERMS: 'escitalopram', 'citalopram', 'depression', 'randomized controlled trial', 'open label trial' and limits set to: Human trials, English Language and All Child (Age 0-18). Additional articles were identified from reference information and poster presentation data. Three prospective, randomized controlled trials (RCT) were found for escitalopram in pediatric depression, and two RCTs were found for citalopram. One RCT each for escitalopram and citalopram showed superiority over placebo on the primary out come measure. Adverse effects in escitalopram and citalopram trials were generally mild to moderate. Suicidality was not assessed systematically in all RCTs reviewed, but did not appear to be elevated over placebo in escitalopram RCTs. One trial reported numerically higher suicide related events for citalopram compared to placebo (14 vs. 5, p=0.06). At present, escitalopram and citalopram should be considered a second-line option for adolescent depression. The US Food and Drug Administration approval of escitalopram for treatment of adolescent depression was based on a single positive RCT. This is less evidence than typically required for approval of a drug for a new indication.

Big Data in Designing Clinical Trials: Opportunities and Challenges

PubMed Central

Mayo, Charles S.; Matuszak, Martha M.; Schipper, Matthew J.; Jolly, Shruti; Hayman, James A.; Ten Haken, Randall K.

2017-01-01

Emergence of big data analytics resource systems (BDARSs) as a part of routine practice in Radiation Oncology is on the horizon. Gradually, individual researchers, vendors, and professional societies are leading initiatives to create and demonstrate use of automated systems. What are the implications for design of clinical trials, as these systems emerge? Gold standard, randomized controlled trials (RCTs) have high internal validity for the patients and settings fitting constraints of the trial, but also have limitations including: reproducibility, generalizability to routine practice, infrequent external validation, selection bias, characterization of confounding factors, ethics, and use for rare events. BDARS present opportunities to augment and extend RCTs. Preliminary modeling using single- and muti-institutional BDARS may lead to better design and less cost. Standardizations in data elements, clinical processes, and nomenclatures used to decrease variability and increase veracity needed for automation and multi-institutional data pooling in BDARS also support ability to add clinical validation phases to clinical trial design and increase participation. However, volume and variety in BDARS present other technical, policy, and conceptual challenges including applicable statistical concepts, cloud-based technologies. In this summary, we will examine both the opportunities and the challenges for use of big data in design of clinical trials. PMID:28913177

Big Data in Designing Clinical Trials: Opportunities and Challenges.

PubMed

Mayo, Charles S; Matuszak, Martha M; Schipper, Matthew J; Jolly, Shruti; Hayman, James A; Ten Haken, Randall K

2017-01-01

Emergence of big data analytics resource systems (BDARSs) as a part of routine practice in Radiation Oncology is on the horizon. Gradually, individual researchers, vendors, and professional societies are leading initiatives to create and demonstrate use of automated systems. What are the implications for design of clinical trials, as these systems emerge? Gold standard, randomized controlled trials (RCTs) have high internal validity for the patients and settings fitting constraints of the trial, but also have limitations including: reproducibility, generalizability to routine practice, infrequent external validation, selection bias, characterization of confounding factors, ethics, and use for rare events. BDARS present opportunities to augment and extend RCTs. Preliminary modeling using single- and muti-institutional BDARS may lead to better design and less cost. Standardizations in data elements, clinical processes, and nomenclatures used to decrease variability and increase veracity needed for automation and multi-institutional data pooling in BDARS also support ability to add clinical validation phases to clinical trial design and increase participation. However, volume and variety in BDARS present other technical, policy, and conceptual challenges including applicable statistical concepts, cloud-based technologies. In this summary, we will examine both the opportunities and the challenges for use of big data in design of clinical trials.

Treatment effects of Ginkgo biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: meta-analysis of randomized controlled trials.

PubMed

Savaskan, Egemen; Mueller, Heiko; Hoerr, Robert; von Gunten, Armin; Gauthier, Serge

2018-03-01

ABSTRACTBackground:In randomized controlled trials, Ginkgo biloba extract EGb 761® has been found to be effective in the treatment of behavioral and psychological symptoms of dementia (BPSD). To assess the effects of EGb 761® on specific BPSD, we analyzed data from all randomized, placebo-controlled, at least 20-week, trials of EGb 761® enrolling patients with dementia (probable Alzheimer's disease (AD), probable vascular dementia or probable AD with cerebrovascular disease) who had clinically significant BPSD (Neuropsychiatric Inventory (NPI) total score at least 6). Data were pooled and joint analyses of NPI single item composite and caregiver distress scores were performed by meta-analysis with a fixed effects model. Four trials involving 1628 patients (EGb 761®, 814; placebo, 814) were identified; treatment duration was 22 or 24 weeks; the daily dose of EGb 761® was 240 mg in all trials. Pooled analyses including data from the full analysis sets of all trials (EGb 761®, 796 patients; placebo, 802 patients) revealed significant superiority of EGb 761® over placebo in total scores and 10 single symptom scores. Regarding caregiver distress scores, EGb 761®-treated patients improved significantly more than those receiving placebo in all symptoms except delusions, hallucinations, and elation/euphoria. The benefit of EGb 761® mainly consists of improvement in symptoms present at baseline, but the incidence of some symptoms was also decreased. Twenty two- to twenty four-week treatment with Ginkgo biloba extract EGb 761® improved BPSD (except psychotic-like features) and caregiver distress caused by such symptoms.

Care delivery and self-management strategies for children with epilepsy.

PubMed

Lindsay, Bruce; Bradley, Peter M

2010-12-08

Epilepsy care for children has been criticised for its lack of impact. Various service models and strategies have been developed in response to perceived inadequacies in care provision for children and their families. We set out to compare the effectiveness of specialist or dedicated teams or individuals in the care of children with epilepsy with usual care services. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library February issue, 2010), MEDLINE (1950 to March 2010), EMBASE (1988 to May 2006*), PsycINFO (1806 to March 2010) and CINAHL (1982 to March 2010).*Please note that as we currently do not have access to EMBASE, we have been unable to update this aspect of our searching. We included randomised controlled trials, controlled or matched trials, cohort studies or other prospective studies with a control group, or time series studies. Each review author independently selected studies, extracted data and assessed the quality of included studies. Four trials and five reports are included in this review. They report on four different education and counselling programmes for children, children and parents, or teenagers and parents. Each programme showed some benefits for the well-being of children with epilepsy, but each trial had methodological flaws and no single programme was evaluated by more than one study. While each of the programmes in this review showed some benefit to children with epilepsy their impacts were extremely variable. No programme showed benefits across the full range of outcomes. No study appears to have demonstrated any detrimental effects but the evidence in favour of any single programme is insufficient to make it possible to recommend one programme rather than another. More trials, carried out by independent research teams, are needed.

Comparison of rheumatoid arthritis clinical trial outcome measures: a simulation study.

PubMed

Anderson, Jennifer J; Bolognese, James A; Felson, David T

2003-11-01

Isolated studies have suggested that continuous measures of response may be better than predefined, dichotomous definitions (e.g., the American College of Rheumatology 20% improvement criteria [ACR20]) for discriminating between rheumatoid arthritis (RA) treatments. Our goal was to determine the statistical power of predefined dichotomous outcome measures (termed "a priori"), compared with that of continuous measures derived from trial data in which there was no predefined response threshold (termed "data driven"), and to evaluate the sensitivity to change of these measures in the context of different treatments and early versus later-stage disease. In order to generalize beyond results from a single trial, we performed simulation studies. We obtained summary data from trials comparing disease-modifying antirheumatic drugs (DMARDs) and from comparative coxib-placebo trials to test the power of 2 a priori outcomes, the ACR20 and improvement of the Disease Activity Score (DDAS), as well as 2 data-driven outcomes. We studied patients with early RA and those with later-stage RA (duration of <4 years and 4-9 years, respectively). We performed simulation studies, using the interrelationship of ACR core set measures in the trials to generate multiple trial data sets consistent with the original data. The data-driven outcomes had greater power than did the a priori measures. The DMARD comparison was more powerful in early disease than in later-stage disease (the sample sizes needed to achieve 80% power for the most powerful test were 64 for early disease versus 100 for later disease), but the coxib-versus-placebo comparison was less powerful in early disease than in later disease (the sample sizes needed to achieve 80% power were 200 and 100, respectively). When the effects of treatment on core set items were small and/or inconsistent, power was reduced, particularly for a less broadly based outcome (e.g., DDAS) compared with the ACR20. The simulation studies demonstrate that data-driven outcome definitions can provide better sensitivity to change than does the ACR20 or DDAS. Using such methods would improve power, but at the expense of trial standardization. The studies also show how patient population and treatment characteristics affect the power of specific outcome measures in RA clinical trials, and provide quantification of those effects.

Preliminary definition of improvement in juvenile arthritis.

PubMed

Giannini, E H; Ruperto, N; Ravelli, A; Lovell, D J; Felson, D T; Martini, A

1997-07-01

To identify a core set of outcome variables for the assessment of children with juvenile arthritis (JA), to use the core set to develop a definition of improvement to determine whether individual patients demonstrate clinically important improvement, and to promote this definition as a single efficacy measure in JA clinical trials. A core set of outcome variables was established using a combination of statistical and consensus formation techniques. Variables in the core set consisted of 1) physician global assessment of disease activity; 2) parent/patient assessment of overall well-being; 3) functional ability; 4) number of joints with active arthritis; 5) number of joints with limited range of motion; and 6) erythrocyte sedimentation rate. To establish a definition of improvement using this core set, 21 pediatric rheumatologists from 14 countries met, and, using consensus formation techniques, scored each of 72 patient profiles as improved or not improved. Using the physicians' consensus as the gold standard, the chi-square, sensitivity, and specificity were calculated for each of 240 possible definitions of improvement. Definitions with sensitivity or specificity of <80% were eliminated. The ability of the remaining definitions to discriminate between the effects of active agent and those of placebo, using actual trial data, was then observed. Each definition was also ranked for face validity, and the sum of the ranks was then multiplied by the kappa statistic. The definition of improvement with the highest final score was as follows: at least 30% improvement from baseline in 3 of any 6 variables in the core set, with no more than 1 of the remaining variables worsening by >30%. The second highest scoring definition was closely related to the first; the third highest was similar to the Paulus criteria used in adult rheumatoid arthritis trials, except with different variables. This indicates convergent validity of the process used. We propose a definition of improvement for JA. Use of a uniform definition will help standardize the conduct and reporting of clinical trials, and should help practitioners decide if a child with JA has responded adequately to therapy. We are in the process of prospectively validating this definition and several others that scored highly.

Reengineering a database for clinical trials management: lessons for system architects.

PubMed

Brandt, C A; Nadkarni, P; Marenco, L; Karras, B T; Lu, C; Schacter, L; Fisk, J M; Miller, P L

2000-10-01

This paper describes the process of enhancing Trial/DB, a database system for clinical studies management. The system's enhancements have been driven by the need to maximize the effectiveness of developer personnel in supporting numerous and diverse users, of study designers in setting up new studies, and of administrators in managing ongoing studies. Trial/DB was originally designed to work over a local area network within a single institution, and basic architectural changes were necessary to make it work over the Internet efficiently as well as securely. Further, as its use spread to diverse communities of users, changes were made to let the processes of study design and project management adapt to the working styles of the principal investigators and administrators for each study. The lessons learned in the process should prove instructive for system architects as well as managers of electronic patient record systems.

[Topiramate in substance-related and addictive disorders].

PubMed

Cohen, Johan; Dervaux, Alain; Laqueille, Xavier

2014-09-01

Drug treatments used in substance use disorders are not effective in all patients. To assess the effectiveness of topiramate use in the treatment of substance use disorders. Medline database from January 1966 to December 2013, Cochrane database and clinicaltrials.gov. We used keywords topiramate, addiction, substance abuse, alcohol, tobacco, nicotine, cocaine, methamphetamine, opiate, heroin, benzodiazepine, cannabis, bulimia nervosa, binge eating disorder, gambling. All clinical trials were included. Animal trials, laboratory tests, reviews, answers to writers, case-reports, case series and publications unrelated to the topic were excluded. Twenty-eight articles investigating the efficacy of topiramate in substance use were included. In alcohol-related disorder, several trials and a meta-analysis showed a reduction of days of consumption. In a single-center trial on tobacco-related disorder, topiramate was not found effective in reducing the carbon monoxide expired. In cocaine-related disorder, one single-center trial showed a reduction of days of consumption and two single-center trials have found a trend in favour of topiramate. In alcohol and cocaine co-dependency, a single-center trial found a trend in favour of topiramate. In methamphetamine-related disorder, a multicenter trial found a trend in favour of topiramate. In bulimia nervosa, two single-center trials showed a reduction in binge eating and compensatory behaviours. In binge eating disorder, several trials showed a reduction of binge eating and weight. In gambling, one single-center trial did not show any significant results. There were no randomized controlled trials found in opioid-related disorder, benzodiazepines-related disorder, and cannabis-related disorder. Definition of abstinence and methods to assess the efficacy of topiramate differed between trials. The methodological quality of included trials was variable, especially with no double-blind procedure in eight trials. Topiramate showed interest mainly in alcoholism, binge eating disorder and bulimia nervosa. No definitive conclusions can be reached for other substance use disorders such as nicotine dependence, cocaine dependence, amphetamine dependence or cannabis dependence and for gambling. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

An Intelligent Man-Machine Interface—Multi-Robot Control Adapted for Task Engagement Based on Single-Trial Detectability of P300

PubMed Central

Kirchner, Elsa A.; Kim, Su K.; Tabie, Marc; Wöhrle, Hendrik; Maurus, Michael; Kirchner, Frank

2016-01-01

Advanced man-machine interfaces (MMIs) are being developed for teleoperating robots at remote and hardly accessible places. Such MMIs make use of a virtual environment and can therefore make the operator immerse him-/herself into the environment of the robot. In this paper, we present our developed MMI for multi-robot control. Our MMI can adapt to changes in task load and task engagement online. Applying our approach of embedded Brain Reading we improve user support and efficiency of interaction. The level of task engagement was inferred from the single-trial detectability of P300-related brain activity that was naturally evoked during interaction. With our approach no secondary task is needed to measure task load. It is based on research results on the single-stimulus paradigm, distribution of brain resources and its effect on the P300 event-related component. It further considers effects of the modulation caused by a delayed reaction time on the P300 component evoked by complex responses to task-relevant messages. We prove our concept using single-trial based machine learning analysis, analysis of averaged event-related potentials and behavioral analysis. As main results we show (1) a significant improvement of runtime needed to perform the interaction tasks compared to a setting in which all subjects could easily perform the tasks. We show that (2) the single-trial detectability of the event-related potential P300 can be used to measure the changes in task load and task engagement during complex interaction while also being sensitive to the level of experience of the operator and (3) can be used to adapt the MMI individually to the different needs of users without increasing total workload. Our online adaptation of the proposed MMI is based on a continuous supervision of the operator's cognitive resources by means of embedded Brain Reading. Operators with different qualifications or capabilities receive only as many tasks as they can perform to avoid mental overload as well as mental underload. PMID:27445742

Relation between detection rate and inappropriate shocks in single versus dual chamber cardioverter-defibrillator – an analysis from the OPTION trial

PubMed Central

Kolb, Christof; Sturmer, Marcio; Babuty, Dominique; Sick, Peter; Davy, Jean Marc; Molon, Giulio; Schwab, Jörg Otto; Mantovani, Giuseppe; Wickliffe, Andrew; Lennerz, Carsten; Semmler, Verena; Siot, Pierre-Henri; Reif , Sebastian

2016-01-01

The programming of implantable cardioverter-defibrillators (ICDs) influences inappropriate shock rates. The aim of the study is to analyse rates of patients with appropriate and inappropriate shocks according to detection zones in the OPTION trial. All patients received dual chamber (DC) ICDs randomly assigned to be programmed either to single chamber (SC) or to DC settings including PARAD+ algorithm. In a post-hoc analysis, rates of patients with inappropriate and appropriate shocks were calculated for shocks triggered at heart rates ≥170 bpm (ventricular tachycardia zone) and at rates ≥200 bpm (ventricular fibrillation zone). In the SC group, higher rates of patients with total and inappropriate shocks were delivered at heart rates ≥170 bpm than at rates ≥200 bpm (total shocks: 21.1% vs. 16.6%; p = 0.002; inappropriate shocks: 7.6% vs. 4.5%, p = 0.016; appropriate shocks: 15.2% vs. 13.5%; p = n.s.). No such differences were observed in the DC group (total shocks: 14.3% vs. 12.6%; p = n.s.; inappropriate shocks: 3.9% vs. 3.6%; p = n.s.; appropriate shocks: 12.2% vs. 10.4%; p = n.s.). The higher frequency of patients with total shocks with SC settings than with DC settings that benefit from PARAD+ was driven by a higher percentage of patients with inappropriate shocks in the VT zone (170–200 bpm) in the SC population. PMID:26892534

The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement.

PubMed

Tate, Robyn L; Perdices, Michael; Rosenkoetter, Ulrike; Shadish, William; Vohra, Sunita; Barlow, David H; Horner, Robert; Kazdin, Alan; Kratochwill, Thomas; McDonald, Skye; Sampson, Margaret; Shamseer, Larissa; Togher, Leanne; Albin, Richard; Backman, Catherine; Douglas, Jacinta; Evans, Jonathan J; Gast, David; Manolov, Rumen; Mitchell, Geoffrey; Nickels, Lyndsey; Nikles, Jane; Ownsworth, Tamara; Rose, Miranda; Schmid, Christopher H; Wilson, Barbara

2016-07-01

We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single-case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioral sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioral sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. © 2016 The Author(s). Reprinted from: Tate RL, Perdices M, Rosenkoetter U, et al. The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement. Arch Sci Psychol. 2016;4:1–9.

Extended fault inversion with random slipmaps: a resolution test for the 2012 Mw 7.6 Nicoya, Costa Rica earthquake

NASA Astrophysics Data System (ADS)

López-Comino, José Ángel; Stich, Daniel; Ferreira, Ana M. G.; Morales, Jose

2015-09-01

Inversions for the full slip distribution of earthquakes provide detailed models of earthquake sources, but stability and non-uniqueness of the inversions is a major concern. The problem is underdetermined in any realistic setting, and significantly different slip distributions may translate to fairly similar seismograms. In such circumstances, inverting for a single best model may become overly dependent on the details of the procedure. Instead, we propose to perform extended fault inversion trough falsification. We generate a representative set of heterogeneous slipmaps, compute their forward predictions, and falsify inappropriate trial models that do not reproduce the data within a reasonable level of mismodelling. The remainder of surviving trial models forms our set of coequal solutions. The solution set may contain only members with similar slip distributions, or else uncover some fundamental ambiguity such as, for example, different patterns of main slip patches. For a feasibility study, we use teleseismic body wave recordings from the 2012 September 5 Nicoya, Costa Rica earthquake, although the inversion strategy can be applied to any type of seismic, geodetic or tsunami data for which we can handle the forward problem. We generate 10 000 pseudo-random, heterogeneous slip distributions assuming a von Karman autocorrelation function, keeping the rake angle, rupture velocity and slip velocity function fixed. The slip distribution of the 2012 Nicoya earthquake turns out to be relatively well constrained from 50 teleseismic waveforms. Two hundred fifty-two slip models with normalized L1-fit within 5 per cent from the global minimum from our solution set. They consistently show a single dominant slip patch around the hypocentre. Uncertainties are related to the details of the slip maximum, including the amount of peak slip (2-3.5 m), as well as the characteristics of peripheral slip below 1 m. Synthetic tests suggest that slip patterns such as Nicoya may be a fortunate case, while it may be more difficult to unambiguously reconstruct more distributed slip from teleseismic data.

A methodological approach for assessing the uptake of core outcome sets using ClinicalTrials.gov: findings from a review of randomised controlled trials of rheumatoid arthritis.

PubMed

Kirkham, Jamie J; Clarke, Mike; Williamson, Paula R

2017-05-17

Objective  To assess the uptake of the rheumatoid arthritis core outcome set using a new assessment method of calculating uptake from data in clinical trial registry entries. Design  Review of randomised trials. Setting  ClinicalTrials.gov. Subjects  273 randomised trials of drug interventions for the treatment of rheumatoid arthritis and registered in ClinicalTrials.gov between 2002 and 2016. Full publications were identified for completed studies from information in the trial registry or from an internet search using Google and the citation database Web of Science. Main outcome measure  The percentage of trials reporting or planning to measure the rheumatoid arthritis core outcome set calculated from the information presented in the trial registry and compared with the percentage reporting the rheumatoid arthritis core outcome set in the resulting trial publications. Results  The full rheumatoid arthritis core outcome set was reported in 81% (116/143) of trials identified on the registry as completed (or terminated) for which results were found in either the published literature or the registry. For trials identified on the registry as completed (or terminated), using information only available in the registry gives an estimate for uptake of 77% (145/189). Conclusions  The uptake of the rheumatoid arthritis core outcome set in clinical trials has continued to increase over time. Using the information on outcomes listed for completed or terminated studies in a trial registry provides a reasonable estimate of the uptake of a core outcome set and is a more efficient and up-to-date approach than examining the outcomes in published trial reports. The method proposed may provide an efficient approach for an up-to-date assessment of the uptake of the 300 core outcome sets already published. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Estimating Single-Trial Responses in EEG

NASA Technical Reports Server (NTRS)

Shah, A. S.; Knuth, K. H.; Truccolo, W. A.; Mehta, A. D.; Fu, K. G.; Johnston, T. A.; Ding, M.; Bressler, S. L.; Schroeder, C. E.; Clancy, Daniel (Technical Monitor)

2002-01-01

Accurate characterization of single-trial field potential responses is critical from a number of perspectives. For example, it allows differentiation of an evoked response from ongoing EEG. We previously developed the multiple component Event Related Potential (mcERP) algorithm to improve resolution of the single-trial evoked response. The mcERP model states that multiple components, each specified by a stereotypic waveform varying in latency and amplitude from trial to trial, comprise the evoked response. Application of the mcERP algorithm to simulated data with three independent, synthetic components has shown that the model is capable of separating these components and estimating their variability. Application of the model to single trial, visual evoked potentials recorded simultaneously from all V1 laminae in an awake, fixating macaque yielded local and far-field components. Certain local components estimated by the model were distributed in both granular and supragranular laminae. This suggests a linear coupling between the responses of thalamo-recipient neuronal ensembles and subsequent responses of supragranular neuronal ensembles, as predicted by the feedforward anatomy of V1. Our results indicate that the mcERP algorithm provides a valid estimation of single-trial responses. This will enable analyses that depend on trial-to-trial variations and those that require separation of the evoked response from background EEG rhythms

Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

PubMed Central

2011-01-01

Background Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Methods Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. Results Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin. Conclusions Lower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure. PMID:21401949

Strategies to improve retention in randomised trials

PubMed Central

Brueton, Valerie C; Tierney, Jayne; Stenning, Sally; Harding, Seeromanie; Meredith, Sarah; Nazareth, Irwin; Rait, Greta

2013-01-01

Background Loss to follow-up from randomised trials can introduce bias and reduce study power, affecting the generalisability, validity and reliability of results. Many strategies are used to reduce loss to follow-up and improve retention but few have been formally evaluated. Objectives To quantify the effect of strategies to improve retention on the proportion of participants retained in randomised trials and to investigate if the effect varied by trial strategy and trial setting. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PreMEDLINE, EMBASE, PsycINFO, DARE, CINAHL, Campbell Collaboration's Social, Psychological, Educational and Criminological Trials Register, and ERIC. We handsearched conference proceedings and publication reference lists for eligible retention trials. We also surveyed all UK Clinical Trials Units to identify further studies. Selection criteria We included eligible retention trials of randomised or quasi-randomised evaluations of strategies to increase retention that were embedded in 'host' randomised trials from all disease areas and healthcare settings. We excluded studies aiming to increase treatment compliance. Data collection and analysis We contacted authors to supplement or confirm data that we had extracted. For retention trials, we recorded data on the method of randomisation, type of strategy evaluated, comparator, primary outcome, planned sample size, numbers randomised and numbers retained. We used risk ratios (RR) to evaluate the effectiveness of the addition of strategies to improve retention. We assessed heterogeneity between trials using the Chi2 and I2 statistics. For main trials that hosted retention trials, we extracted data on disease area, intervention, population, healthcare setting, sequence generation and allocation concealment. Main results We identified 38 eligible retention trials. Included trials evaluated six broad types of strategies to improve retention. These were incentives, communication strategies, new questionnaire format, participant case management, behavioural and methodological interventions. For 34 of the included trials, retention was response to postal and electronic questionnaires with or without medical test kits. For four trials, retention was the number of participants remaining in the trial. Included trials were conducted across a spectrum of disease areas, countries, healthcare and community settings. Strategies that improved trial retention were addition of monetary incentives compared with no incentive for return of trial-related postal questionnaires (RR 1.18; 95% CI 1.09 to 1.28, P value < 0.0001), addition of an offer of monetary incentive compared with no offer for return of electronic questionnaires (RR 1.25; 95% CI 1.14 to 1.38, P value < 0.00001) and an offer of a GBP20 voucher compared with GBP10 for return of postal questionnaires and biomedical test kits (RR 1.12; 95% CI 1.04 to 1.22, P value < 0.005). The evidence that shorter questionnaires are better than longer questionnaires was unclear (RR 1.04; 95% CI 1.00 to 1.08, P value = 0.07) and the evidence for questionnaires relevant to the disease/condition was also unclear (RR 1.07; 95% CI 1.01 to 1.14). Although each was based on the results of a single trial, recorded delivery of questionnaires seemed to be more effective than telephone reminders (RR 2.08; 95% CI 1.11 to 3.87, P value = 0.02) and a 'package' of postal communication strategies with reminder letters appeared to be better than standard procedures (RR 1.43; 95% CI 1.22 to 1.67, P value < 0.0001). An open trial design also appeared more effective than a blind trial design for return of questionnaires in one fracture prevention trial (RR 1.37; 95% CI 1.16 to 1.63, P value = 0.0003). There was no good evidence that the addition of a non-monetary incentive, an offer of a non-monetary incentive, 'enhanced' letters, letters delivered by priority post, additional reminders, or questionnaire question order either increased or decreased trial questionnaire response/retention. There was also no evidence that a telephone survey was either more or less effective than a monetary incentive and a questionnaire. As our analyses are based on single trials, the effect on questionnaire response of using offers of charity donations, sending reminders to trial sites and when a questionnaire is sent, may need further evaluation. Case management and behavioural strategies used for trial retention may also warrant further evaluation. Authors' conclusions Most of the retention trials that we identified evaluated questionnaire response. There were few evaluations of ways to improve participants returning to trial sites for trial follow-up. Monetary incentives and offers of monetary incentives increased postal and electronic questionnaire response. Some other strategies evaluated in single trials looked promising but need further evaluation. Application of the findings of this review would depend on trial setting, population, disease area, data collection and follow-up procedures. PLAIN LANGUAGE SUMMARY Methods that might help to keep people in randomised trials Background Most trials follow people up to collect data through personal contact after they have been recruited. Some trials get data from other sources, such as routine collected data or disease registers. There are many ways to collect data from people in trials, and these include using letters, the internet, telephone calls, text messaging, face-to-face meetings or the return of medical test kits. Most trials have missing data, for example, because people are too busy to reply, are unable to attend a clinic, have moved or no longer want to participate. Sometimes data has not been recorded at study sites, or are not sent to the trial co-ordinating centre. Researchers call this 'loss to follow-up', 'drop out' or 'attrition' and it can affect the trial's results. For example, if the people with the most or least severe symptoms do not return questionnaires or attend a follow-up visit, this will bias the findings of the trial. Many methods are used by researchers to keep people in trials. These encourage people to send back data by questionnaire, return to a clinic or hospital for trial-related tests, or be seen by a health or community care worker. Study characteristics This review identified methods that encouraged people to stay in trials. We searched scientific databases for randomised studies (where people are allocated to one of two or more possible treatments in a random manner) or quasi-randomised studies (where allocation is not really random, e.g. based on date of birth, order in which they attended clinic) that compared methods of increasing retention in trials. We included trials of participants from any age, gender, ethnic, cultural, language and geographic groups. Key results The methods that appeared to work were offering or giving a small amount of money for return of a completed questionnaire and enclosing a small amount of money with a questionnaire with the promise of a further small amount of money for return of a filled in questionnaire. The effect of other ways to keep people in trials is still not clear and more research is needed to see if these really do work. Such methods are shorter questionnaires, sending questionnaires by recorded delivery, using a trial design where people know which treatment they will receive, sending specially designed letters with a reply self addressed stamped envelope followed by a number of reminders, offering a donation to charity or entry into a prize draw, sending a reminder to the study site about participants to follow-up, sending questionnaires close to the time the patient was last followed-up, managing peoples' follow-up, conducting follow-up by telephone and changing the order of questionnaire questions. Quality of evidence The methods that we identified were tested in trials run in many different disease areas and settings and, in some cases, were tested in only one trial. Therefore, more studies are needed to help decide whether our findings could be used in other research fields. PMID:24297482

Fibromyalgia syndrome module at OMERACT 9: domain construct.

PubMed

Mease, Philip; Arnold, Lesley M; Choy, Ernest H; Clauw, Daniel J; Crofford, Leslie J; Glass, Jennifer M; Martin, Susan A; Morea, Jessica; Simon, Lee; Strand, C Vibeke; Williams, David A

2009-10-01

The objective of the module was to (1) establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measure performance characteristics, (3) discuss development of a responder index for assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, and (6) establish a research agenda for outcomes research. Presentations at the module included: (1) Results of univariate and multivariate analysis of 10 FM clinical trials of 4 drugs, mapping key domains identified in previous patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, and breakout discussions to vote on possible essential domains and reliable measures; (2) Updates regarding outcome measure status; (3) Update on objective markers to measure FM disease state; and (4) Review of the issue of cognitive dysfunction (dyscognition) in FM. Consensus was reached as follows: (1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials; dyscognition and depression should be measured in some trials; and stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers were identified as domains of research interest. (2) FM domain outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing numbers of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed. In conclusion, a multidimensional symptom core set is proposed for evaluation of FM in clinical trials. Research on improved measures of single domains and composite measures is ongoing.

Development of a Multi-Centre Clinical Trial Data Archiving and Analysis Platform for Functional Imaging

NASA Astrophysics Data System (ADS)

Driscoll, Brandon; Jaffray, David; Coolens, Catherine

2014-03-01

Purpose: To provide clinicians & researchers participating in multi-centre clinical trials with a central repository for large volume dynamic imaging data as well as a set of tools for providing end-to-end testing and image analysis standards of practice. Methods: There are three main pieces to the data archiving and analysis system; the PACS server, the data analysis computer(s) and the high-speed networks that connect them. Each clinical trial is anonymized using a customizable anonymizer and is stored on a PACS only accessible by AE title access control. The remote analysis station consists of a single virtual machine per trial running on a powerful PC supporting multiple simultaneous instances. Imaging data management and analysis is performed within ClearCanvas Workstation® using custom designed plug-ins for kinetic modelling (The DCE-Tool®), quality assurance (The DCE-QA Tool) and RECIST. Results: A framework has been set up currently serving seven clinical trials spanning five hospitals with three more trials to be added over the next six months. After initial rapid image transfer (+ 2 MB/s), all data analysis is done server side making it robust and rapid. This has provided the ability to perform computationally expensive operations such as voxel-wise kinetic modelling on very large data archives (+20 GB/50k images/patient) remotely with minimal end-user hardware. Conclusions: This system is currently in its proof of concept stage but has been used successfully to send and analyze data from remote hospitals. Next steps will involve scaling up the system with a more powerful PACS and multiple high powered analysis machines as well as adding real-time review capabilities.

Collaborative Chronic Care Models for Mental Health Conditions: Cumulative Meta-Analysis and Meta-Regression to Guide Future Research and Implementation

PubMed Central

Grogan-Kaylor, Andrew; Perron, Brian E.; Kilbourne, Amy M.; Woltmann, Emily; Bauer, Mark S.

2013-01-01

Objective Prior meta-analysis indicates that collaborative chronic care models (CCMs) improve mental and physical health outcomes for individuals with mental disorders. This study aimed to investigate the stability of evidence over time and identify patient and intervention factors associated with CCM effects in order to facilitate implementation and sustainability of CCMs in clinical practice. Method We reviewed 53 CCM trials that analyzed depression, mental quality of life (QOL), or physical QOL outcomes. Cumulative meta-analysis and meta-regression were supplemented by descriptive investigations across and within trials. Results Most trials targeted depression in the primary care setting, and cumulative meta-analysis indicated that effect sizes favoring CCM quickly achieved significance for depression outcomes, and more recently achieved significance for mental and physical QOL. Four of six CCM elements (patient self-management support, clinical information systems, system redesign, and provider decision support) were common among reviewed trials, while two elements (healthcare organization support and linkages to community resources) were rare. No single CCM element was statistically associated with the success of the model. Similarly, meta-regression did not identify specific factors associated with CCM effectiveness. Nonetheless, results within individual trials suggest that increased illness severity predicts CCM outcomes. Conclusions Significant CCM trials have been derived primarily from four original CCM elements. Nonetheless, implementing and sustaining this established model will require healthcare organization support. While CCMs have typically been tested as population-based interventions, evidence supports stepped care application to more severely ill individuals. Future priorities include developing implementation strategies to support adoption and sustainability of the model in clinical settings while maximizing fit of this multi-component framework to local contextual factors. PMID:23938600

The effect of energy and traffic light labelling on parent and child fast food selection: a randomised controlled trial.

PubMed

Dodds, Pennie; Wolfenden, Luke; Chapman, Kathy; Wellard, Lyndal; Hughes, Clare; Wiggers, John

2014-02-01

Labelling of food from fast food restaurants at point-of-purchase has been suggested as one strategy to reduce population energy consumption and contribute to reductions in obesity prevalence. The aim of this study was to examine the effects of energy and single traffic light labelling systems on the energy content of child and adult intended food purchases. The study employed a randomised controlled trial design. English speaking parents of children aged between three and 12 years were recruited from an existing research cohort. Participants were mailed one of three hypothetical fast food menus. Menus differed in their labelling technique – either energy labels, single traffic light labels, or a no-label control. Participants then completed a telephone survey which assessed intended food purchases for both adult and child. The primary trial outcome was total energy of intended food purchase. A total of 329 participants completed the follow-up telephone interview. Eighty-two percent of the energy labelling group and 96% of the single traffic light labelling group reported noticing labelling information on their menu. There were no significant differences in total energy of intended purchases of parents, or intended purchases made by parents for children, between the menu labelling groups, or between menu labelling groups by socio-demographic subgroups. This study provided no evidence to suggest that energy labelling or single traffic light labelling alone were effective in reducing the energy of fast food items selected from hypothetical fast food menus for purchase. Additional complementary public health initiatives promoting the consumption of healthier foods identified by labelling, and which target other key drivers of menu item selection in this setting may be required.

Progressive learning in endoscopy simulation training improves clinical performance: a blinded randomized trial.

PubMed

Grover, Samir C; Scaffidi, Michael A; Khan, Rishad; Garg, Ankit; Al-Mazroui, Ahmed; Alomani, Tareq; Yu, Jeffrey J; Plener, Ian S; Al-Awamy, Mohamed; Yong, Elaine L; Cino, Maria; Ravindran, Nikila C; Zasowski, Mark; Grantcharov, Teodor P; Walsh, Catharine M

2017-11-01

A structured comprehensive curriculum (SCC) that uses simulation-based training (SBT) can improve clinical colonoscopy performance. This curriculum may be enhanced through the application of progressive learning, a training strategy centered on incrementally challenging learners. We aimed to determine whether a progressive learning-based curriculum (PLC) would lead to superior clinical performance compared with an SCC. This was a single-blinded randomized controlled trial conducted at a single academic center. Thirty-seven novice endoscopists were recruited and randomized to either a PLC (n = 18) or to an SCC (n = 19). The PLC comprised 6 hours of SBT, which progressed in complexity and difficulty. The SCC included 6 hours of SBT, with cases of random order of difficulty. Both groups received expert feedback and 4 hours of didactic teaching. Participants were assessed at baseline, immediately after training, and 4 to 6 weeks after training. The primary outcome was participants' performance during their first 2 clinical colonoscopies, as assessed by using the Joint Advisory Group Direct Observation of Procedural Skills assessment tool (JAG DOPS). Secondary outcomes were differences in endoscopic knowledge, technical and communication skills, and global performance in the simulated setting. The PLC group outperformed the SCC group during first and second clinical colonoscopies, measured by JAG DOPS (P < .001). Additionally, the PLC group had superior technical and communication skills and global performance in the simulated setting (P < .05). There were no differences between groups in endoscopic knowledge (P > .05). Our findings demonstrate the superiority of a PLC for endoscopic simulation, compared with an SCC. Challenging trainees progressively is a simple, theory-based approach to simulation whereby the performance of clinical colonoscopies can be improved. (Clinical trial registration number: NCT02000180.). Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Does a strategy to promote shared decision-making reduce medical practice variation in the choice of either single or double embryo transfer after in vitro fertilisation? A secondary analysis of a randomised controlled trial.

PubMed

Brabers, Anne E M; van Dijk, Liset; Groenewegen, Peter P; van Peperstraten, Arno M; de Jong, Judith D

2016-05-06

The hypothesis that shared decision-making (SDM) reduces medical practice variations is increasingly common, but no evidence is available. We aimed to elaborate further on this, and to perform a first exploratory analysis to examine this hypothesis. This analysis, based on a limited data set, examined how SDM is associated with variation in the choice of single embryo transfer (SET) or double embryo transfer (DET) after in vitro fertilisation (IVF). We examined variation between and within hospitals. A secondary analysis of a randomised controlled trial. 5 hospitals in the Netherlands. 222 couples (woman aged <40 years) on a waiting list for a first IVF cycle, who could choose between SET and DET (ie, ≥2 embryos available). SDM via a multifaceted strategy aimed to empower couples in deciding how many embryos should be transferred. The strategy consisted of decision aid, support of IVF nurse and the offer of reimbursement for an extra treatment cycle. Control group received standard IVF care. Difference in variation due to SDM in the choice of SET or DET, both between and within hospitals. There was large variation in the choice of SET or DET between hospitals in the control group. Lower variation between hospitals was observed in the group with SDM. Within most hospitals, variation in the choice of SET or DET appeared to increase due to SDM. Variation particularly increased in hospitals where mainly DET was chosen in the control group. Although based on a limited data set, our study gives a first insight that including patients' preferences through SDM results in less variation between hospitals, and indicates another pattern of variation within hospitals. Variation that results from patient preferences could be potentially named the informed patient rate. Our results provide the starting point for further research. NCT00315029; Post-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A randomized controlled trial of an activity specific exercise program for individuals with Alzheimer disease in long-term care settings.

PubMed

Roach, Kathryn E; Tappen, Ruth M; Kirk-Sanchez, Neva; Williams, Christine L; Loewenstein, David

2011-01-01

To determine whether an activity specific exercise program could improve ability to perform basic mobility activities in long-term care residents with Alzheimer disease (AD). Randomized, controlled, single-blinded clinical trial. Residents of 7 long-term care facilities. Eighty-two long-term care residents with mild to severe AD. An activity specific exercise program was compared to a walking program and to an attention control. Ability to perform bed mobility and transfers was assessed using the subscales of the Acute Care Index of Function; functional mobility was measured using the 6-Minute Walk test. Subjects receiving the activity specific exercise program improved in ability to perform transfers, whereas subjects in the other 2 groups declined.

Are exergames promoting mobility an attractive alternative to conventional self-regulated exercises for elderly people in a rehabilitation setting? Study protocol of a randomized controlled trial.

PubMed

Hasselmann, Viviane; Oesch, Peter; Fernandez-Luque, Luis; Bachmann, Stefan

2015-09-07

Maintaining mobility in elderly persons has become a primary goal within healthcare services. In older adults, exercise programs significantly reduce the risk of falling and death. Long-lasting and high-intensive multi-component exercises are most effective. In a rehabilitation setting, self-regulated exercises are conventionally taught by physiotherapists, using handouts. However, the adherence of elderly persons to executing these self-administered programs varies considerably. They are often considered tedious and boring, and thus prematurely stopped. The primary aim of this clinical trial is to determine whether elderly persons in a rehabilitation setting show higher adherence to self-regulated training when using exergames than when performing conventional exercises. The second objective is to explore which mode of exercise leads to greater improvement in balance performance. The study consists of a single blind, stratified, randomized control trial with two parallel groups. Once included, study participants will be stratified according to their balance and computer skills and randomly allocated to self-regulated training with conventional exercise programs or with exergames played with the Windows Kinect® sensor and FitBit® pedometer. In both groups, self-administered exercise programs will be taught by experienced physiotherapists and performed at the patient's own discretion during the ten days of intervention. The primary outcome is the performed daily training volume, collected by the participants in a logbook. Secondary outcomes are objective and subjective balance skills measured by an activity tracker and the Fall Efficacy Scale self-administered questionnaire. Both assessments will be performed at pre- and post-intervention. According to the available literature, this study is the first to compare conventional self-regulated exercises with exergames among older patients in a rehabilitation setting. Results of this study will contribute to our understanding of its motivational potential on exercise adherence in elderly persons and provide more insight into the potential effectiveness of exergames promoting mobility. The present clinical study has been registered on ClinicalTrials.gov under the identifier number: NCT02077049. The detailed trial protocol can be accessed online on: NCT02077049.

Feasibility and Efficacy of the Nintendo Wii Gaming System to Improve Balance Performance Post-Stroke: Protocol of a Phase II Randomized Controlled Trial in an Inpatient Rehabilitation Setting.

PubMed

Bower, Kelly J; Clark, Ross A; McGinley, Jennifer L; Martin, Clarissa L; Miller, Kimberly J

2013-04-01

Balance deficits following stroke are common and debilitating. Commercially available gaming systems, such as the Nintendo(®) (Kyoto, Japan) Wii™, have been widely adopted clinically; however, there is limited evidence supporting their feasibility and efficacy for improving balance performance following stroke. The aim of this trial is to investigate the clinical feasibility and efficacy of using the Nintendo Wii gaming system as an adjunct to standard care to improve balance performance following stroke in an inpatient rehabilitation setting. Thirty participants undergoing inpatient stroke rehabilitation will be recruited into this Phase II, single-blind, randomized controlled trial. Participants will be allocated into a Balance or Upper Limb Group, and both groups will perform activities using the Nintendo Wii in addition to their standard care. Participants will attend three 45-minute sessions per week, for a minimum of 2 and a maximum of 4 weeks. The main focus of the study is to investigate the feasibility of the intervention protocol. This will be evaluated through recruitment, retention, adherence, acceptability, and safety. The Step Test and Functional Reach Test will be the primary efficacy outcomes. Secondary outcomes will include force platform, mobility, and upper limb measures. Assessments will occur at baseline, 2 weeks, and 4 weeks after study entry. To the authors' knowledge, this will be the largest randomized clinical trial to investigate the feasibility and efficacy of the Nintendo Wii gaming system for improving balance performance in a stroke population. The results will inform the design of a Phase III multicenter trial.

Proposed variations of the stepped-wedge design can be used to accommodate multiple interventions

PubMed Central

Lyons, Vivian H; Li, Lingyu; Hughes, James P; Rowhani-Rahbar, Ali

2018-01-01

Objective Stepped wedge design (SWD) cluster randomized trials have traditionally been used for evaluating a single intervention. We aimed to explore design variants suitable for evaluating multiple interventions in a SWD trial. Study Design and Setting We identified four specific variants of the traditional SWD that would allow two interventions to be conducted within a single cluster randomized trial: Concurrent, Replacement, Supplementation and Factorial SWDs. These variants were chosen to flexibly accommodate study characteristics that limit a one-size-fits-all approach for multiple interventions. Results In the Concurrent SWD, each cluster receives only one intervention, unlike the other variants. The Replacement SWD supports two interventions that will not or cannot be employed at the same time. The Supplementation SWD is appropriate when the second intervention requires the presence of the first intervention, and the Factorial SWD supports the evaluation of intervention interactions. The precision for estimating intervention effects varies across the four variants. Conclusion Selection of the appropriate design variant should be driven by the research question while considering the trade-off between the number of steps, number of clusters, restrictions for concurrent implementation of the interventions, lingering effects of each intervention, and precision of the intervention effect estimates. PMID:28412466

Carbon monoxide gas sensing using zinc oxide deposited by successive ionic layer adhesion and reaction

NASA Astrophysics Data System (ADS)

Florido, E. A.; Dagaas, N. A. C.

2017-05-01

This study was aimed to determine the carbon monoxide (CO) gas sensing capability of zinc oxide (ZnO) film fabricated by successive ionic layer adsorption and reaction (SILAR) on glass substrate. Films consisting of a mixture of flower-like clusters of ZnO nanorods and nanowires were observed using scanning electron microscopy (SEM). Current-voltage characterization of the samples showed an average resistivity of 13.0 Ω-m. Carbon monoxide gas was synthesized by mixing the required amount of formic acid and excess sulfuric acid to produce CO gas concentrations of 100, 200, 300, 400, and 500 parts per million (ppm) v/v with five trials for each concentration. Two sets of data were obtained. One set consisted of the voltage response of the single film sensor while the other set were obtained from the double film sensor. The voltage response for the single film sensor and the double film sensor showed an average sensitivity of 0.0038 volts per ppm and 0.0024 volts per ppm, respectively. The concentration the single film can detect with a 2V output is 526 ppm while the double film sensor can detect up to 833 ppm with a 2V output. This shows that using the double film sensor is advantageous compared to single film sensor, because of its higher concentration range due to the larger surface area for the gas to interact. Moreover, the measured average resistance for the single film sensor was 10 MΩ while for the double film sensor the average resistance was 5 MΩ.

Bayesian Dose-Response Modeling in Sparse Data

NASA Astrophysics Data System (ADS)

Kim, Steven B.

This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a wrong parametric assumption. In this regard, we consider a robust experimental design which does not require any parametric assumption.

Warp-averaging event-related potentials.

PubMed

Wang, K; Begleiter, H; Porjesz, B

2001-10-01

To align the repeated single trials of the event-related potential (ERP) in order to get an improved estimate of the ERP. A new implementation of the dynamic time warping is applied to compute a warp-average of the single trials. The trilinear modeling method is applied to filter the single trials prior to alignment. Alignment is based on normalized signals and their estimated derivatives. These features reduce the misalignment due to aligning the random alpha waves, explaining amplitude differences in latency differences, or the seemingly small amplitudes of some components. Simulations and applications to visually evoked potentials show significant improvement over some commonly used methods. The new implementation of the dynamic time warping can be used to align the major components (P1, N1, P2, N2, P3) of the repeated single trials. The average of the aligned single trials is an improved estimate of the ERP. This could lead to more accurate results in subsequent analysis.

The Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 statement.

PubMed

Tate, Robyn L; Perdices, Michael; Rosenkoetter, Ulrike; Shadish, William; Vohra, Sunita; Barlow, David H; Horner, Robert; Kazdin, Alan; Kratochwill, Thomas; McDonald, Skye; Sampson, Margaret; Shamseer, Larissa; Togher, Leanne; Albin, Richard; Backman, Catherine; Douglas, Jacinta; Evans, Jonathan J; Gast, David; Manolov, Rumen; Mitchell, Geoffrey; Nickels, Lyndsey; Nikles, Jane; Ownsworth, Tamara; Rose, Miranda; Schmid, Christopher H; Wilson, Barbara

2016-06-01

We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single-case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioral sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioral sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. Supplemental materials: http://dx.doi.org/10.1037/arc0000026.supp. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Cost-effectiveness of a community-delivered multicomponent intervention compared with enhanced standard care of obese adolescents: cost-utility analysis alongside a randomised controlled trial (the HELP trial).

PubMed

Panca, Monica; Christie, Deborah; Cole, Tim J; Costa, Silvia; Gregson, John; Holt, Rebecca; Hudson, Lee D; Kessel, Anthony S; Kinra, Sanjay; Mathiot, Anne; Nazareth, Irwin; Wataranan, Jay; Wong, Ian Chi Kei; Viner, Russell M; Morris, Stephen

2018-02-15

To undertake a cost-utility analysis of a motivational multicomponent lifestyle-modification intervention in a community setting (the Healthy Eating Lifestyle Programme (HELP)) compared with enhanced standard care. Cost-utility analysis alongside a randomised controlled trial. Community settings in Greater London, England. 174 young people with obesity aged 12-19 years. Intervention participants received 12 one-to-one sessions across 6 months, addressing lifestyle behaviours and focusing on motivation to change and self-esteem rather than weight change, delivered by trained graduate health workers in community settings. Control participants received a single 1-hour one-to-one nurse-delivered session providing didactic weight-management advice. Mean costs and quality-adjusted life years (QALYs) per participant over a 1-year period using resource use data and utility values collected during the trial. Incremental cost-effectiveness ratio (ICER) was calculated and non-parametric bootstrapping was conducted to generate a cost-effectiveness acceptability curve (CEAC). Mean intervention costs per participant were £918 for HELP and £68 for enhanced standard care. There were no significant differences between the two groups in mean resource use per participant for any type of healthcare contact. Adjusted costs were significantly higher in the intervention group (mean incremental costs for HELP vs enhanced standard care £1003 (95% CI £837 to £1168)). There were no differences in adjusted QALYs between groups (mean QALYs gained 0.008 (95% CI -0.031 to 0.046)). The ICER of the HELP versus enhanced standard care was £120 630 per QALY gained. The CEAC shows that the probability that HELP was cost-effective relative to the enhanced standard care was 0.002 or 0.046, at a threshold of £20 000 or £30 000 per QALY gained. We did not find evidence that HELP was more effective than a single educational session in improving quality of life in a sample of adolescents with obesity. HELP was associated with higher costs, mainly due to the extra costs of delivering the intervention and therefore is not cost-effective. ISRCTN9984011. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Collecting and analysing cost data for complex public health trials: reflections on practice

PubMed Central

Batura, Neha; Pulkki-Brännström, Anni-Maria; Agrawal, Priya; Bagra, Archana; Haghparast-Bidgoli, Hassan; Bozzani, Fiammetta; Colbourn, Tim; Greco, Giulia; Hossain, Tanvir; Sinha, Rajesh; Thapa, Bidur; Skordis-Worrall, Jolene

2014-01-01

Background Current guidelines for the conduct of cost-effectiveness analysis (CEA) are mainly applicable to facility-based interventions in high-income settings. Differences in the unit of analysis and the high cost of data collection can make these guidelines challenging to follow within public health trials in low- and middle- income settings. Objective This paper reflects on the challenges experienced within our own work and proposes solutions that may be useful to others attempting to collect, analyse, and compare cost data between public health research sites in low- and middle-income countries. Design We describe the generally accepted methods (norms) for collecting and analysing cost data in a single-site trial from the provider perspective. We then describe our own experience applying these methods within eight comparable cluster randomised, controlled, trials. We describe the strategies used to maximise adherence to the norm, highlight ways in which we deviated from the norm, and reflect on the learning and limitations that resulted. Results When the expenses incurred by a number of small research sites are used to estimate the cost-effectiveness of delivering an intervention on a national scale, then deciding which expenses constitute ‘start-up’ costs will be a nontrivial decision that may differ among sites. Similarly, the decision to include or exclude research or monitoring and evaluation costs can have a significant impact on the findings. We separated out research costs and argued that monitoring and evaluation costs should be reported as part of the total trial cost. The human resource constraints that we experienced are also likely to be common to other trials. As we did not have an economist in each site, we collaborated with key personnel at each site who were trained to use a standardised cost collection tool. This approach both accommodated our resource constraints and served as a knowledge sharing and capacity building process within the research teams. Conclusions Given the practical reality of conducting randomised, controlled trials of public health interventions in low- and middle- income countries, it is not always possible to adhere to prescribed guidelines for the analysis of cost effectiveness. Compromises are frequently required as researchers seek a pragmatic balance between rigor and feasibility. There is no single solution to this tension but researchers are encouraged to be mindful of the limitations that accompany compromise, whilst being reassured that meaningful analyses can still be conducted with the resulting data. PMID:24565214

Increasing walking among older people: A test of behaviour change techniques using factorial randomised N-of-1 trials

PubMed Central

Nyman, Samuel R.; Goodwin, Kelly; Kwasnicka, Dominika; Callaway, Andrew

2016-01-01

Objective: Evaluations of techniques to promote physical activity usually adopt a randomised controlled trial (RCT). Such designs inform how a technique performs on average but cannot be used for treatment of individuals. Our objective was to conduct the first N-of-1 RCTs of behaviour change techniques with older people and test the effectiveness of the techniques for increasing walking within individuals. Design: Eight adults aged 60–87 were randomised to a 2 (goal-setting vs. active control) × 2 (self-monitoring vs. active control) factorial RCT over 62 days. The time series data were analysed for each single case using linear regressions. Main outcome measures: Walking was objectively measured using pedometers. Results: Compared to control days, goal-setting increased walking in 4 out of 8 individuals and self-monitoring increased walking in 7 out of 8 individuals. While the probability for self-monitoring to be effective in 7 out of 8 participants was beyond chance (p = .03), no intervention effect was significant for individual participants. Two participants had a significant but small linear decrease in walking over time. Conclusion: We demonstrate the utility of N-of-1 trials for advancing scientific enquiry of behaviour change and in practice for increasing older people’s physical activity. PMID:26387689

New developments in the treatment of multiple myeloma - clinical utility of daratumumab.

PubMed

McEllistrim, Cian; Krawczyk, Janusz; O'Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups.

New developments in the treatment of multiple myeloma – clinical utility of daratumumab

PubMed Central

McEllistrim, Cian; Krawczyk, Janusz; O’Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups. PMID:28442888

Trial type mixing substantially reduces the response set effect in the Stroop task.

PubMed

Hasshim, Nabil; Parris, Benjamin A

2017-03-20

The response set effect refers to the finding that an irrelevant incongruent colour-word produces greater interference when it is one of the response options (referred to as a response set trial), compared to when it is not (a non-response set trial). Despite being a key effect for models of selective attention, the magnitude of the effect varies considerably across studies. We report two within-subjects experiments that tested the hypothesis that presentation format modulates the magnitude of the response set effect. Trial types (e.g. response set, non-response set, neutral) were either presented in separate blocks (pure) or in blocks containing trials from all conditions presented randomly (mixed). In the first experiment we show that the response set effect is substantially reduced in the mixed block context as a result of a decrease in RTs to response set trials. By demonstrating the modulation of the response set effect under conditions of trial type mixing we present evidence that is difficult for models of the effect based on strategic, top-down biasing of attention to explain. In a second experiment we tested a stimulus-driven account of the response set effect by manipulating the number of colour-words that make up the non-response set of distractors. The results show that the greater the number of non-response set colour concepts, the smaller the response set effect. Alternative accounts of the data and its implications for research debating the automaticity of reading are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Effectiveness and Cost-Effectiveness of Occupation-Based Occupational Therapy Using the Aid for Decision Making in Occupation Choice (ADOC) for Older Residents: Pilot Cluster Randomized Controlled Trial.

PubMed

Nagayama, Hirofumi; Tomori, Kounosuke; Ohno, Kanta; Takahashi, Kayoko; Ogahara, Kakuya; Sawada, Tatsunori; Uezu, Sei; Nagatani, Ryutaro; Yamauchi, Keita

2016-01-01

Care-home residents are mostly inactive, have little interaction with staff, and are dependent on staff to engage in daily occupations. We recently developed an iPad application called the Aid for Decision-making in Occupation Choice (ADOC) to promote shared decision-making in activities and occupation-based goal setting by choosing from illustrations describing daily activities. This study aimed to evaluate if interventions based on occupation-based goal setting using the ADOC could focus on meaningful activities to improve quality of life and independent activities of daily living, with greater cost-effectiveness than an impairment-based approach as well as to evaluate the feasibility of conducting a large cluster, randomized controlled trial. In this single (assessor)-blind pilot cluster randomized controlled trial, the intervention group (ADOC group) received occupational therapy based on occupation-based goal setting using the ADOC, and the interventions were focused on meaningful occupations. The control group underwent an impairment-based approach focused on restoring capacities, without goal setting tools. In both groups, the 20-minute individualized intervention sessions were conducted twice a week for 4 months. Short Form-36 (SF-36) score, SF-6D utility score, quality adjusted life years (QALY), Barthel Index, and total care cost. We randomized and analyzed 12 facilities (44 participants, 18.5% drop-out rate), with 6 facilities each allocated to the ADOC (n = 23) and control (n = 21) groups. After the 4-month intervention, the ADOC group had a significantly greater change in the BI score, with improved scores (P = 0.027, 95% CI 0.41 to 6.87, intracluster correlation coefficient = 0.14). No other outcome was significantly different. The incremental cost-effectiveness ratio, calculated using the change in BI score, was $63.1. The results suggest that occupational therapy using the ADOC for older residents might be effective and cost-effective. We also found that conducting an RCT in the occupational therapy setting is feasible. UMIN Clinical Trials Registry UMIN000012994.

An automated and fast approach to detect single-trial visual evoked potentials with application to brain-computer interface.

PubMed

Tu, Yiheng; Hung, Yeung Sam; Hu, Li; Huang, Gan; Hu, Yong; Zhang, Zhiguo

2014-12-01

This study aims (1) to develop an automated and fast approach for detecting visual evoked potentials (VEPs) in single trials and (2) to apply the single-trial VEP detection approach in designing a real-time and high-performance brain-computer interface (BCI) system. The single-trial VEP detection approach uses common spatial pattern (CSP) as a spatial filter and wavelet filtering (WF) a temporal-spectral filter to jointly enhance the signal-to-noise ratio (SNR) of single-trial VEPs. The performance of the joint spatial-temporal-spectral filtering approach was assessed in a four-command VEP-based BCI system. The offline classification accuracy of the BCI system was significantly improved from 67.6±12.5% (raw data) to 97.3±2.1% (data filtered by CSP and WF). The proposed approach was successfully implemented in an online BCI system, where subjects could make 20 decisions in one minute with classification accuracy of 90%. The proposed single-trial detection approach is able to obtain robust and reliable VEP waveform in an automatic and fast way and it is applicable in VEP based online BCI systems. This approach provides a real-time and automated solution for single-trial detection of evoked potentials or event-related potentials (EPs/ERPs) in various paradigms, which could benefit many applications such as BCI and intraoperative monitoring. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

UVB phototherapy in an outpatient setting or at home: a pragmatic randomised single-blind trial designed to settle the discussion. The PLUTO study

PubMed Central

Koek, Mayke BG; Buskens, Erik; Steegmans, Paul HA; van Weelden, Huib; Bruijnzeel-Koomen, Carla AFM; Sigurdsson, Vigfús

2006-01-01

Background Home ultraviolet B (UVB) treatment is a much-debated treatment, especially with regard to effectiveness, safety and side effects. However, it is increasingly being prescribed, especially in the Netherlands. Despite ongoing discussions, no randomised research has been performed, and only two studies actually compare two groups of patients. Thus, firm evidence to support or discourage the use of home UVB phototherapy has not yet been obtained. This is the goal of the present study, the PLUTO study (Dutch acronym for "national trial on home UVB phototherapy for psoriasis"). Methods We designed a pragmatic randomised single-blind multi-centre trial. This trial is designed to evaluate the impact of home UVB treatment versus UVB phototherapy in a hospital outpatient clinic as to effectiveness, quality of life and cost-effectiveness. In total 196 patients with psoriasis who were clinically eligible for UVB phototherapy were included. Normally 85% of the patients treated with UVB show a relevant clinical response. With a power of 80% and a 0.05 significance level it will be possible to detect a reduction in effectiveness of 15%. Effectiveness will be determined by calculating differences in the Psoriasis Area and Severity Index (PASI) and the Self Administered PASI (SAPASI) scores. Quality of life is measured using several validated generic questionnaires and a disease-specific questionnaire. Other outcome measures include costs, side effects, dosimetry, concomitant use of medication and patient satisfaction. Patients are followed throughout the therapy and for 12 months thereafter. The study is no longer recruiting patients, and is expected to report in 2006. Discussion In the field of home UVB phototherapy this trial is the first randomised parallel group study. As such, this trial addresses the weaknesses encountered in previous studies. The pragmatic design ensures that the results can be well generalised to the target population. Because, in addition to effectiveness, aspects such as quality of life and cost-effectiveness are also taken into consideration, this study will produce valuable evidence to either support or discourage prescription of home UVB phototherapy. Trial registration Current controlled trials/Nederlands Trial register: ISRCTN83025173. Clinicaltrials.gov: NCT00150930 PMID:16882343

Reliability of Single-Leg Balance and Landing Tests in Rugby Union; Prospect of Using Postural Control to Monitor Fatigue

PubMed Central

Troester, Jordan C.; Jasmin, Jason G.; Duffield, Rob

2018-01-01

The present study examined the inter-trial (within test) and inter-test (between test) reliability of single-leg balance and single-leg landing measures performed on a force plate in professional rugby union players using commercially available software (SpartaMARS, Menlo Park, USA). Twenty-four players undertook test – re-test measures on two occasions (7 days apart) on the first training day of two respective pre-season weeks following 48h rest and similar weekly training loads. Two 20s single-leg balance trials were performed on a force plate with eyes closed. Three single-leg landing trials were performed by jumping off two feet and landing on one foot in the middle of a force plate 1m from the starting position. Single-leg balance results demonstrated acceptable inter-trial reliability (ICC = 0.60-0.81, CV = 11-13%) for sway velocity, anterior-posterior sway velocity, and mediolateral sway velocity variables. Acceptable inter-test reliability (ICC = 0.61-0.89, CV = 7-13%) was evident for all variables except mediolateral sway velocity on the dominant leg (ICC = 0.41, CV = 15%). Single-leg landing results only demonstrated acceptable inter-trial reliability for force based measures of relative peak landing force and impulse (ICC = 0.54-0.72, CV = 9-15%). Inter-test results indicate improved reliability through the averaging of three trials with force based measures again demonstrating acceptable reliability (ICC = 0.58-0.71, CV = 7-14%). Of the variables investigated here, total sway velocity and relative landing impulse are the most reliable measures of single-leg balance and landing performance, respectively. These measures should be considered for monitoring potential changes in postural control in professional rugby union. Key points Single-leg balance demonstrated acceptable inter-trial and inter-test reliability. Single-leg landing demonstrated good inter-trial and inter-test reliability for measures of relative peak landing force and relative impulse, but not time to stabilization. Of the variables investigated, sway velocity and relative landing impulse are the most reliable measures of single-leg balance and landing respectively, and should considered for monitoring changes in postural control. PMID:29769817

Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document

PubMed Central

2014-01-01

Background There is a need for more Comparative Effectiveness Research (CER) on Chinese medicine (CM) to inform clinical and policy decision-making. This document aims to provide consensus advice for the design of CER trials on CM for researchers. It broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making. Methods The Effectiveness Guidance Document (EGD) development was based on multiple consensus procedures (survey, written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders, including patients, clinicians, researchers and payers were involved in creating this document. Results Recommendations were developed for “using available data” and “future clinical studies”. The recommendations for future trials focus on randomized trials and cover the following areas: designing CER studies, treatments, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. Conclusion The present EGD provides the first systematic methodological guidance for future CER trials on CM and can be applied to single or multi-component treatments. While CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources, as well as greater consistency in trial design. PMID:24885146

Clinical trials in crisis: four simple methodologic fixes

PubMed Central

Vickers, Andrew J.

2014-01-01

There is growing consensus that the US clinical trials system is broken, with trial costs and complexity increasing exponentially, and many trials failing to accrue. Yet concerns about the expense and failure rate of randomized trials are only the tip of the iceberg; perhaps what should worry us most is the number of trials that are not even considered because of projected costs and poor accrual. Several initiatives, including the Clinical Trials Transformation Initiative and the “Sensible Guidelines Group” seek to push back against current trends in clinical trials, arguing that all aspects of trials - including design, approval, conduct, monitoring, analysis and dissemination - should be based on evidence rather than contemporary norms. Proposed here are four methodologic fixes for current clinical trials. The first two aim to simplify trials, reducing costs and increasing patient acceptability by dramatically reducing eligibility criteria - often to the single criterion that the consenting physician is uncertain which of the two randomized arms is optimal - and by clinical integration, investment in data infrastructure to bring routinely collected data up to research grade to be used as endpoints in trials. The second two methodologic fixes aim to shed barriers to accrual, either by cluster randomization of clinicians (in the case of modifications to existing treatment) or by early consent, where patients are offered the chance of being randomly selected to be offered a novel intervention if disease progresses at a subsequent point. Such solutions may be partial, or result in a new set of problems of their own. Yet the current crisis in clinical trials mandates innovative approaches: randomized trials have resulted in enormous benefits for patients and we need to ensure that they continue to do so. PMID:25278228

Clinical trials in crisis: Four simple methodologic fixes.

PubMed

Vickers, Andrew J

2014-12-01

There is growing consensus that the US clinical trials system is broken, with trial costs and complexity increasing exponentially, and many trials failing to accrue. Yet, concerns about the expense and failure rate of randomized trials are only the tip of the iceberg; perhaps what should worry us most is the number of trials that are not even considered because of projected costs and poor accrual. Several initiatives, including the Clinical Trials Transformation Initiative and the "Sensible Guidelines Group" seek to push back against current trends in clinical trials, arguing that all aspects of trials-including design, approval, conduct, monitoring, analysis, and dissemination-should be based on evidence rather than contemporary norms. Proposed here are four methodologic fixes for current clinical trials. The first two aim to simplify trials, reducing costs, and increasing patient acceptability by dramatically reducing eligibility criteria-often to the single criterion that the consenting physician is uncertain which of the two randomized arms is optimal-and by clinical integration, investment in data infrastructure to bring routinely collected data up to research grade to be used as endpoints in trials. The second two methodologic fixes aim to shed barriers to accrual, either by cluster randomization of clinicians (in the case of modifications to existing treatment) or by early consent, where patients are offered the chance of being randomly selected to be offered a novel intervention if disease progresses at a subsequent point. Such solutions may be partial, or result in a new set of problems of their own. Yet, the current crisis in clinical trials mandates innovative approaches: randomized trials have resulted in enormous benefits for patients, and we need to ensure that they continue to do so. © The Author(s) 2014.

Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials.gov.

PubMed

Hirsch, Bradford R; Califf, Robert M; Cheng, Steven K; Tasneem, Asba; Horton, John; Chiswell, Karen; Schulman, Kevin A; Dilts, David M; Abernethy, Amy P

2013-06-10

Clinical trials are essential to cancer care, and data about the current state of research in oncology are needed to develop benchmarks and set the stage for improvement. To perform a comprehensive analysis of the national oncology clinical research portfolio. All interventional clinical studies registered on ClinicalTrials.gov between October 2007 and September 2010 were identified using Medical Subject Heading terms and submitted conditions. They were reviewed to validate classification, subcategorized by cancer type, and stratified by design characteristics to facilitate comparison across cancer types and with other specialties. Of 40 970 interventional studies registered between October 2007 and September 2010, a total of 8942 (21.8%) focused on oncology. Compared with other specialties, oncology trials were more likely to be single arm (62.3% vs 23.8%; P < .001), open label (87.8% vs 47.3%; P < .001), and nonrandomized (63.9% vs 22.7%; P < .001). There was moderate but significant correlation between number of trials conducted by cancer type and associated incidence and mortality (Spearman rank correlation coefficient, 0.56 [P = .04] and 0.77 [P = .001], respectively). More than one-third of all oncology trials were conducted solely outside North America. There are significant variations between clinical trials in oncology and other diseases, as well as among trials within oncology. The differences must be better understood to improve both the impact of cancer research on clinical practice and the use of constrained resources.

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting.

PubMed

De Stefano, Valerio; Rocca, Bianca; Tosetto, Alberto; Soldati, Denise; Petrucci, Giovanna; Beggiato, Eloise; Bertozzi, Irene; Betti, Silvia; Carli, Giuseppe; Carpenedo, Monica; Cattaneo, Daniele; Cavalca, Viviana; Dragani, Alfredo; Elli, Elena; Finazzi, Guido; Iurlo, Alessandra; Lanzarone, Giuseppe; Lissandrini, Laura; Palandri, Francesca; Paoli, Chiara; Rambaldi, Alessandro; Ranalli, Paola; Randi, Maria Luigia; Ricco, Alessandra; Rossi, Elena; Ruggeri, Marco; Specchia, Giorgina; Timillero, Andrea; Turnu, Linda; Vianelli, Nicola; Vannucchi, Alessandro M; Rodeghiero, Francesco; Patrono, Carlo

2018-06-01

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A 2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB 2 , a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB 2 as a reliable end point for dose-finding studies of novel aspirin regimens.

OFF! Clip-on Repellent Device With Metofluthrin Tested on Aedes aegypti (Diptera: Culicidae) for Mortality at Different Time Intervals and Distances.

PubMed

Bibbs, Christopher S; Xue, Rui-De

2016-03-01

The OFF! Clip-on mosquito-repellent device was tested outdoors against Aedes aegypti (L.). A single treatment device was used against batches of caged adult, nonblood fed Ae. aegypti at multiple locations 0.3m from treatment center. Another set of cages was stationed 0.6m from treatment. A final set of cages was placed 0.9m away. Trials ran for durations of 5, 15, 30, and 60 min. Initial knockdown and mortality after 24 h was recorded. The devices had effective knockdown and mortality. This was not sustained at distances greater than 0.3m from the device.

Core outcome sets and trial registries.

PubMed

Clarke, Mike; Williamson, Paula

2015-05-14

Some reasons for registering trials might be considered as self-serving, such as satisfying the requirements of a journal in which the researchers wish to publish their eventual findings or publicising the trial to boost recruitment. Registry entries also help others, including systematic reviewers, to know about ongoing or unpublished studies and contribute to reducing research waste by making it clear what studies are ongoing. Other sources of research waste include inconsistency in outcome measurement across trials in the same area, missing data on important outcomes from some trials, and selective reporting of outcomes. One way to reduce this waste is through the use of core outcome sets: standardised sets of outcomes for research in specific areas of health and social care. These do not restrict the outcomes that will be measured, but provide the minimum to include if a trial is to be of the most use to potential users. We propose that trial registries, such as ISRCTN, encourage researchers to note their use of a core outcome set in their entry. This will help people searching for trials and those worried about selective reporting in closed trials. Trial registries can facilitate these efforts to make new trials as useful as possible and reduce waste. The outcomes section in the entry could prompt the researcher to consider using a core outcome set and facilitate the specification of that core outcome set and its component outcomes through linking to the original core outcome set. In doing this, registries will contribute to the global effort to ensure that trials answer important uncertainties, can be brought together in systematic reviews, and better serve their ultimate aim of improving health and well-being through improving health and social care.

Detection of P300 waves in single trials by the wavelet transform (WT).

PubMed

Demiralp, T; Ademoglu, A; Schürmann, M; Başar-Eroglu, C; Başar, E

1999-01-01

The P300 response is conventionally obtained by averaging the responses to the task-relevant (target) stimuli of the oddball paradigm. However, it is well known that cognitive ERP components show a high variability due to changes of cognitive state during an experimental session. With simple tasks such changes may not be demonstrable by the conventional method of averaging the sweeps chosen according to task-relevance. Therefore, the present work employed a response-based classification procedure to choose the trials containing the P300 component from the whole set of sweeps of an auditory oddball paradigm. For this purpose, the most significant response property reflecting the P300 wave was identified by using the wavelet transform (WT). The application of a 5 octave quadratic B-spline-WT on single sweeps yielded discrete coefficients in each octave with an appropriate time resolution for each frequency range. The main feature indicating a P300 response was the positivity of the 4th delta (0.5-4 Hz) coefficient (310-430 ms) after stimulus onset. The average of selected single sweeps from the whole set of data according to this criterion yielded more enhanced P300 waves compared with the average of the target responses, and the average of the remaining sweeps showed a significantly smaller positivity in the P300 latency range compared with the average of the non-target responses. The combination of sweeps classified according to the task-based and response-based criteria differed significantly. This suggests an influence of changes in cognitive state on the presence of the P300 wave which cannot be assessed by task performance alone. Copyright 1999 Academic Press.

Understanding the Physiological, Biomechanical, and Performance Effects of Body Armor Use

DTIC Science & Technology

2008-12-01

force plates were collected through a single data acquisition (DAQ) system and were time-synchronized. 2.1 Testing Equipment Figure 1. Examples of 3...For analysis purposes, it was scaled to the volunteer’s body mass (ml/kg/min). For walking trials, the force plate treadmill was set at a speed of...familiarized with walking and running on the force plate treadmill at these speeds. For familiarization, a volunteer first walked at 1.34 mls without any

Single-agent Taxane Versus Taxane-containing Combination Chemotherapy as Salvage Therapy for Advanced Urothelial Carcinoma.

PubMed

Sonpavde, Guru; Pond, Gregory R; Choueiri, Toni K; Mullane, Stephanie; Niegisch, Guenter; Albers, Peter; Necchi, Andrea; Di Lorenzo, Giuseppe; Buonerba, Carlo; Rozzi, Antonio; Matsumoto, Kazumasa; Lee, Jae-Lyun; Kitamura, Hiroshi; Kume, Haruki; Bellmunt, Joaquim

2016-04-01

Single-agent taxanes are commonly used as salvage systemic therapy for patients with advanced urothelial carcinoma (UC). To study the impact of combination chemotherapy delivering a taxane plus other chemotherapeutic agents compared with single-agent taxane as salvage therapy. Individual patient-level data from phase 2 trials of salvage systemic therapy were used. Trials evaluating either single agents (paclitaxel or docetaxel) or combination chemotherapy (taxane plus one other chemotherapeutic agent or more) following prior platinum-based therapy were used. Information regarding the known major baseline prognostic factors was required: time from prior chemotherapy, hemoglobin, performance status, albumin, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of prognostic factors and combination versus single-agent chemotherapy with overall survival (OS). Data were available from eight trials including 370 patients; two trials (n=109) evaluated single-agent chemotherapy with docetaxel (n=72) and cremophor-free paclitaxel (n=37), and six trials (n=261) evaluated combination chemotherapy with gemcitabine-paclitaxel (two trials, with n=99 and n=24), paclitaxel-cyclophosphamide (n=32), paclitaxel-ifosfamide-nedaplatin (n=45), docetaxel-ifosfamide-cisplatin (n=26), and paclitaxel-epirubicin (n=35). On multivariable analysis after adjustment for baseline prognostic factors, combination chemotherapy was independently and significantly associated with improved OS (hazard ratio: 0.60; 95% confidence interval, 0.45-0.82; p=0.001). The retrospective design of this analysis and the trial-eligible population were inherent limitations. Patients enrolled in trials of combination chemotherapy exhibited improved OS compared with patients enrolled in trials of single-agent chemotherapy as salvage therapy for advanced UC. Prospective randomized trials are required to validate a potential role for rational and tolerable combination chemotherapeutic regimens for the salvage therapy of advanced UC. This retrospective study suggests that a combination of chemotherapy agents may extend survival compared with single-agent chemotherapy in selected patients with metastatic urothelial cancer progressing after prior chemotherapy. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Social Stories™ to alleviate challenging behaviour and social difficulties exhibited by children with autism spectrum disorder in mainstream schools: design of a manualised training toolkit and feasibility study for a cluster randomised controlled trial with nested qualitative and cost-effectiveness components.

PubMed

Wright, Barry; Marshall, David; Adamson, Joy; Ainsworth, Hannah; Ali, Shehzad; Allgar, Victoria; Collingridge Moore, Danielle; Cook, Elizabeth; Dempster, Paul; Hackney, Lisa; McMillan, Dean; Trepél, Dominic; Williams, Chris

2016-01-01

A Social Story™ (Carol Gray) is a child-friendly intervention that is used to give children with autism spectrum disorders (ASDs) social information in situations where they have social difficulties. Limited evidence mainly using single-case designs suggests that they can reduce anxiety and challenging behaviour. The objectives were to conduct a systematic review, use this to develop a manualised intervention and run a feasibility trial to inform a fully powered randomised controlled trial (RCT) on their clinical effectiveness and cost-effectiveness in schools. This is a three-stage study following the Medical Research Council framework for complex interventions. Specifically, it involved a theoretical phase, a qualitative stage and a feasibility trial stage. Qualitative interviews and focus groups took place in Child and Adolescent Mental Health Service and primary care settings. The feasibility study took place in 37 local mainstream schools. Fifty children (aged 5-15 years) in mainstream school settings with a diagnosis of ASD were entered into the trial. For each child, an associated teacher and parent was also recruited. The intervention was a goal-setting session followed by a manualised toolkit (including a training session) for creating Social Stories™ for use with school-aged children. The comparator treatment was a goal-setting session followed by an attention control. Both arms received treatment as usual. Outcomes tested as part of the feasibility study included child- and proxy-completed questionnaires for mental health, quality of life and goal-based outcome measures. Adults additionally completed behaviour diaries and the parental stress index. The review found that the research into social stories is predominantly based in the USA, carried out in under-12-year-olds and using single-case designs. Most studies either did not follow established Social Story criteria or did not report if they did. The assessment of effectiveness presents a largely positive picture but is limited by methodological issues. There were no adequate RCTs and insufficient information to assess a number of important sources of potential bias in most studies. A manualised intervention was produced using an iterative process between user focus groups and a writing team, and assessed in the feasibility study. All 50 participant groups were recruited within the study time frame. Two outcome measures, the Social Responsiveness Scale-2 and the custom-made goal-based measure, showed high levels of completion rates and appeared to be capturing social and behaviour skills targeted by the use of Social Stories. Detailed recommendations for a full trial are provided. Blinding of participants was not feasible. Treatment fidelity was not assessed because of low levels of story return rates. The study showed that a fully powered RCT is feasible with an extended geographical footprint. A large amount of data and information has helped to inform the design of this RCT, which will be the subject of a future research grant application. Future work could focus on developing an appropriate blinded outcome measure for this population. This study is registered as PROSPERO CRD42011001440. Current Controlled Trials ISRCTN96286707. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 6. See the NIHR Journals Library website for further project information.

The reliability and stability of visual working memory capacity.

PubMed

Xu, Z; Adam, K C S; Fang, X; Vogel, E K

2018-04-01

Because of the central role of working memory capacity in cognition, many studies have used short measures of working memory capacity to examine its relationship to other domains. Here, we measured the reliability and stability of visual working memory capacity, measured using a single-probe change detection task. In Experiment 1, the participants (N = 135) completed a large number of trials of a change detection task (540 in total, 180 each of set sizes 4, 6, and 8). With large numbers of both trials and participants, reliability estimates were high (α > .9). We then used an iterative down-sampling procedure to create a look-up table for expected reliability in experiments with small sample sizes. In Experiment 2, the participants (N = 79) completed 31 sessions of single-probe change detection. The first 30 sessions took place over 30 consecutive days, and the last session took place 30 days later. This unprecedented number of sessions allowed us to examine the effects of practice on stability and internal reliability. Even after much practice, individual differences were stable over time (average between-session r = .76).

Lonoctocog Alfa: A Review in Haemophilia A.

PubMed

Al-Salama, Zaina T; Scott, Lesley J

2017-10-01

Lonoctocog alfa (rVIII-SingleChain; Afstyla ® ) is a novel single-chain recombinant factor VIII (FVIII) molecule, with a truncated B-domain and the heavy and light chains covalently linked to form a stable and homogenous drug that binds with high affinity to von Willebrand factor (VWF). Intravenous lonoctocog alfa is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in several countries worldwide. In two pivotal, multicentre trials, lonoctocog alfa was effective in the treatment of bleeding episodes and as prophylaxis, including for perioperative management in adults, adolescents and children. In terms of haemostatic efficacy in controlling bleeding episodes, overall treatment and investigator-assessed success rates were high across all age groups, with the majority of these bleeds controlled with a single injection of lonoctocog alfa. Low median spontaneous, overall and traumatic annualized bleeding rates were evident with prophylactic lonoctocog alfa regimens in both trials. Lonoctocog alfa was generally well-tolerated, with very low rates of injection-site reactions. No previously treated patient experienced an anaphylactic reaction or developed an inhibitor. In conclusion, lonoctocog alfa is an effective and generally well-tolerated alternative to conventional FVIII products for the treatment and prophylaxis of bleeding, including in the surgical setting, in adults, adolescents and children with haemophilia A.

Clinical Trial Design for HIV Prevention Research: Determining Standards of Prevention.

PubMed

Dawson, Liza; Zwerski, Sheryl

2015-06-01

This article seeks to advance ethical dialogue on choosing standards of prevention in clinical trials testing improved biomedical prevention methods for HIV. The stakes in this area of research are high, given the continued high rates of infection in many countries and the budget limitations that have constrained efforts to expand treatment for all who are currently HIV-infected. New prevention methods are still needed; at the same time, some existing prevention and treatment interventions have been proven effective but are not yet widely available in the countries where they most urgently needed. The ethical tensions in this field of clinical research are well known and have been the subject of extensive debate. There is no single clinical trial design that can optimize all the ethically important goals and commitments involved in research. Several recent articles have described the current ethical difficulties in designing HIV prevention trials, especially in resource limited settings; however, there is no consensus on how to handle clinical trial design decisions, and existing international ethical guidelines offer conflicting advice. This article acknowledges these deep ethical dilemmas and moves beyond a simple descriptive approach to advance an organized method for considering what clinical trial designs will be ethically acceptable for HIV prevention trials, balancing the relevant criteria and providing justification for specific design decisions. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Who is the research subject in cluster randomized trials in health research?

PubMed Central

2011-01-01

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently. We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met. PMID:21791064

IVF or IUI as first-line treatment in unexplained subfertility: the conundrum of treatment selection markers.

PubMed

Tjon-Kon-Fat, R I; Tajik, P; Zafarmand, M H; Bensdorp, A J; Bossuyt, P M M; Oosterhuis, G J E; van Golde, R; Repping, S; Lambers, M D A; Slappendel, E; Perquin, D; Pelinck, M J; Gianotten, J; Maas, J W M; Eijkemans, M J C; van der Veen, F; Mol, B W; van Wely, M

2017-05-01

Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)? We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility. A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI. We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples). We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1. None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10). Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations. We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples. The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest. The trial was registered at the Dutch trial registry (NTR939). © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Primaquine or other 8-aminoquinoline for reducing Plasmodium falciparum transmission

PubMed Central

Graves, Patricia M; Gelband, Hellen; Garner, Paul

2015-01-01

Background Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium falciparum gametocytes are sensitive to the drug primaquine (PQ) and other 8-aminoquinolines (8AQ); these drugs could prevent parasite transmission from infected people to mosquitoes, and consequently reduce the incidence of malaria. However, PQ will not directly benefit the individual, and could be harmful to those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In 2010, The World Health Organization (WHO) recommended a single dose of PQ at 0.75 mg/kg, alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination. In 2013 the WHO revised this to 0.25 mg/kg due to concerns about safety. Objectives To assess whether giving PQ or an alternative 8AQ alongside treatment for P. falciparum malaria reduces malaria transmission, and to estimate the frequency of severe or haematological adverse events when PQ is given for this purpose. Search methods We searched the following databases up to 10 Feb 2014 for trials: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'malaria*', 'falciparum', and 'primaquine' as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs comparing PQ (or alternative 8AQ) given as a single dose or short course alongside treatment for P. falciparum malaria with malaria treatment given without PQ/8AQ in adults or children. Data collection and analysis Two authors independently screened all abstracts, applied inclusion criteria, and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, as well as secondary outcomes of asexual clearance time and recrudescence. We stratified by whether the malaria treatment regimen included an artemisinin derivative or not; by PQ dose category (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg); and by PQ schedules. We used the GRADE approach to assess evidence quality. Main results We included 17 RCTs and one quasi-RCT. Eight studies tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining ten trials either did not report on whether they tested (8), or reported that they did not test (2). Nine trials included study arms with artemisinin-based malaria treatment regimens, and eleven included study arms with non-artemisinin-based treatments. Only two trials evaluated PQ given at low doses (0.25 mg/kg in one and 0.1 mg/kg in the other). PQ with artemisinin-based treatments: No trials evaluated effects on malaria transmission directly (incidence, prevalence, or entomological inoculation rate), and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two thirds with high dose PQ category (RR 0.29, 95% CI 0.22 to 0.37, seven trials, 1380 participants, high quality evidence), and with medium dose PQ category (RR 0.34, 95% CI 0.19 to 0.59, two trials, 269 participants, high quality evidence), but the trial evaluating low dose PQ category (0.1 mg/kg) did not demonstrate an effect (RR 0.67, 95% CI 0.44 to 1.02, one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline, and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on malaria transmission directly. Two small trials from the same laboratory evaluated infectiousness to mosquitoes, and report that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by around half with high dose PQ category (RR 0.44, 95% CI 0.27 to 0.70, three trials, 206 participants, high quality evidence), and by around a third with medium dose category (RR 0.62, 0.50 to 0.76, two trials, 283 participants, high quality evidence), but the single trial using low dose PQ category did not demonstrate a difference between groups (one trial, 59 participants, very low quality evidence). Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (n = 112) preclude a definite conclusion. Authors' conclusions In individual patients, PQ added to malaria treatments reduces gametocyte prevalence when given in doses greater than 0.4 mg/kg. Whether this translates into preventing people transmitting malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community malaria transmission either in low-endemic settings approaching elimination, or in highly-endemic settings where many people are infected but have no symptoms and are unlikely to be treated. For the currently recommended low dose regimen, there is little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved. Most trials excluded people with G6PD deficiency, and thus there is little reliable evidence from controlled trials of the safety of PQ in single dose or short course. PLAIN LANGUAGE SUMMARY A single dose of primaquine added to malaria treatment to prevent malaria transmission We conducted a review of the effects of adding a single dose (or short course) of primaquine to malaria treatment with the aim of reducing the transmission of malaria. We included 17 randomized controlled trials and one quasi-randomized controlled trial. What is primaquine and how might it reduce transmission Primaquine is an antimalarial drug which does not cure malaria illness, but is known to kill the gametocyte stage of the malaria parasite which infects mosquitoes when they bite humans. Primaquine is also known to have potentially serious side effects in people with an enzyme deficiency common in many malaria endemic settings (glucose-6-phosphate dehydrogenase (G6PD) deficiency). In these people, high doses of primaquine given over several days sometimes destroys red blood cells, causing anaemia and, in some cases, possibly life-threatening effects. The World Health Organization (WHO) recommends adding a single dose of primaquine to malaria treatment with the intention of reducing malaria transmission and to contribute to malaria elimination. This recommendation was made in 2010, but in 2013 the WHO amended its recommendation from a dose of 0.75 mg/kg to 0.25 mg/kg due to concerns about safety, and indirect evidence suggesting this was as effective as the higher dose.This review examines the evidence of benefits and harms of using primaquine in this way, and looks for evidence that primaquine will reduce malaria transmission in communities. What the research says We did not find any studies that tested whether primaquine added to malaria treatment reduces the community transmission of malaria. When added to current treatments for malaria (artemisinin-based combination therapy), we found no studies evaluating the effects of primaquine on the number of mosquitoes infected. However, primaquine does reduce the duration of infectiousness (the period that gametocytes are detected circulating in the blood) when given at doses of 0.4 mg/kg or above (high quality evidence). We only found one study using 0.1 mg/kg but this study did not conclusively show that primaquine was still effective at this dose (low quality evidence). When added to older treatments for malaria, two studies showed that primaquine at doses of 0.75 mg/kg reduced the number of mosquitoes infected after biting humans (low quality evidence). Doses above 0.4 mg/kg reduced the duration of detectable gametocytes (high quality evidence), but in a single study of the currently recommended 0.25 mg/kg no effect was demonstrated (very low quality evidence). Some studies excluded patients with G6PD deficiency, some included them, and some did not comment. Overall the safety of PQ given as a single dose was poorly evaluated across all studies, so these data do not demonstrate whether the drug is safe or potentially harmful at this dosing level. PMID:25693791

Primaquine or other 8-aminoquinoline for reducing P. falciparum transmission

PubMed Central

Graves, Patricia M; Gelband, Hellen; Garner, Paul

2014-01-01

Background Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium falciparum gametocytes are sensitive to the drug primaquine (PQ) and other 8-aminoquinolines (8AQ); these drugs could prevent parasite transmission from infected people to mosquitoes, and consequently reduce the incidence of malaria. However, PQ will not directly benefit the individual, and could be harmful to those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In 2010, The World Health Organization (WHO) recommended a single dose of PQ at 0.75 mg/kg, alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination. In 2013 the WHO revised this to 0.25 mg/kg due to concerns about safety. Objectives To assess whether giving PQ or an alternative 8AQ alongside treatment for P. falciparum malaria reduces malaria transmission, and to estimate the frequency of severe or haematological adverse events when PQ is given for this purpose. Search methods We searched the following databases up to 10 Feb 2014 for trials: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'malaria*', 'falciparum', and 'primaquine' as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Selection criteria Randomized controlled trials (RCTs) or quasi-RCTs comparing PQ (or alternative 8AQ) given as a single dose or short course alongside treatment for P. falciparum malaria with malaria treatment given without PQ/8AQ in adults or children. Data collection and analysis Two authors independently screened all abstracts, applied inclusion criteria, and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, as well as secondary outcomes of asexual clearance time and recrudescence. We stratified by whether the malaria treatment regimen included an artemisinin derivative or not; by PQ dose category (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg); and by PQ schedules. We used the GRADE approach to assess evidence quality. Main results We included 17 RCTs and one quasi-RCT. Eight studies tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining ten trials either did not report on whether they tested (8), or reported that they did not test (2). Nine trials included study arms with artemisinin-based malaria treatment regimens, and eleven included study arms with non-artemisinin-based treatments. Only two trials evaluated PQ given at low doses (0.25 mg/kg in one and 0.1 mg/kg in the other). PQ with artemisinin-based treatments: No trials evaluated effects on malaria transmission directly (incidence, prevalence, or entomological inoculation rate), and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two thirds with high dose PQ category (RR 0.29, 95% CI 0.22 to 0.37, seven trials, 1380 participants, high quality evidence), and with medium dose PQ category (RR 0.34, 95% CI 0.19 to 0.59, two trials, 269 participants, high quality evidence), but the trial evaluating low dose PQ category (0.1 mg/kg) did not demonstrate an effect (RR 0.67, 95% CI 0.44 to 1.02, one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline, and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on malaria transmission directly. Two small trials from the same laboratory evaluated infectiousness to mosquitoes, and report that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by around half with high dose PQ category (RR 0.44, 95% CI 0.27 to 0.70, three trials, 206 participants, high quality evidence), and by around a third with medium dose category (RR 0.62, 0.50 to 0.76, two trials, 283 participants, high quality evidence), but the single trial using low dose PQ category did not demonstrate a difference between groups (one trial, 59 participants, very low quality evidence). Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis. Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (n = 112) preclude a definite conclusion. Authors' conclusions In individual patients, PQ added to malaria treatments reduces gametocyte prevalence when given in doses greater than 0.4 mg/kg. Whether this translates into preventing people transmitting malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community malaria transmission either in low-endemic settings approaching elimination, or in highly-endemic settings where many people are infected but have no symptoms and are unlikely to be treated. For the currently recommended low dose regimen, there is little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved. Most trials excluded people with G6PD deficiency, and thus there is little reliable evidence from controlled trials of the safety of PQ in single dose or short course. PLAIN LANGUAGE SUMMARY A single dose of primaquine added to malaria treatment to prevent malaria transmission We conducted a review of the effects of adding a single dose (or short course) of primaquine to malaria treatment with the aim of reducing the transmission of malaria. We included 17 randomized controlled trials and one quasi-randomized controlled trial. What is primaquine and how might it reduce transmission Primaquine is an antimalarial drug which does not cure malaria illness, but is known to kill the gametocyte stage of the malaria parasite which infects mosquitoes when they bite humans. Primaquine is also known to have potentially serious side effects in people with an enzyme deficiency common in many malaria endemic settings (glucose-6-phosphate dehydrogenase (G6PD) deficiency). In these people, high doses of primaquine given over several days sometimes destroys red blood cells, causing anaemia and, in some cases, possibly life-threatening effects. The World Health Organization (WHO) recommends adding a single dose of primaquine to malaria treatment with the intention of reducing malaria transmission and to contribute to malaria elimination. This recommendation was made in 2010, but in 2013 the WHO amended its recommendation from a dose of 0.75 mg/kg to 0.25 mg/kg due to concerns about safety, and indirect evidence suggesting this was as effective as the higher dose.This review examines the evidence of benefits and harms of using primaquine in this way, and looks for evidence that primaquine will reduce malaria transmission in communities. What the research says We did not find any studies that tested whether primaquine added to malaria treatment reduces the community transmission of malaria. When added to current treatments for malaria (artemisinin-based combination therapy), we found no studies evaluating the effects of primaquine on the number of mosquitoes infected. However, primaquine does reduce the duration of infectiousness (the period that gametocytes are detected circulating in the blood) when given at doses of 0.4 mg/kg or above (high quality evidence). We only found one study using 0.1 mg/kg but this study did not conclusively show that primaquine was still effective at this dose (low quality evidence). When added to older treatments for malaria, two studies showed that primaquine at doses of 0.75 mg/kg reduced the number of mosquitoes infected after biting humans (low quality evidence). Doses above 0.4 mg/kg reduced the duration of detectable gametocytes (high quality evidence), but in a single study of the currently recommended 0.25 mg/kg no effect was demonstrated (very low quality evidence). Some studies excluded patients with G6PD deficiency, some included them, and some did not comment. Overall the safety of PQ given as a single dose was poorly evaluated across all studies, so these data do not demonstrate whether the drug is safe or potentially harmful at this dosing level. PMID:24979199

Da Vinci single site© surgical platform in clinical practice: a systematic review.

PubMed

Morelli, Luca; Guadagni, Simone; Di Franco, Gregorio; Palmeri, Matteo; Di Candio, Giulio; Mosca, Franco

2016-12-01

The Da Vinci single-site© surgical platform (DVSSP) is a set of single-site instruments and accessories specifically dedicated to robot-assisted single-site surgery. The PubMed database from inception to June 2015 was searched for English literature on the clinical use of DVSSP in general surgery, urology and gynecology. Twenty-nine articles involving the clinical application of DVSSP were identified; 15 articles on general surgery (561 procedures), four articles on urology (48 procedures) and 10 articles on gynecology (212 procedures). All studies have proven the safety and feasibility of the use of DVSSP. The principal reported advantage is the restoration of intra-abdominal triangulation, while the main reported limitation is the lack of the endowrist. Da Vinci systems have proven to be valuable assets in single-site surgery, owing to the combination of robot use with the dedicated single-incision platform. However, case-control or prospective trials are warranted to draw more definitive conc lusions. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Working memory component processes: isolating BOLD signal changes.

PubMed

Motes, Michael A; Rypma, Bart

2010-01-15

The chronology of the component processes subserving working memory (WM) and hemodynamic response lags has hindered the use of fMRI for exploring neural substrates of WM. In the present study, however, participants completed full trials that involved encoding two or six letters, maintaining the memory set over a delay, and then deciding whether a probe was in the memory set or not. Additionally, they completed encode-only, encode-and-maintain, and encode-and-decide partial trials intermixed with the full trials. The inclusion of partial trials allowed for the isolation of BOLD signal changes to the different trial periods. The results showed that only lateral and medial prefrontal cortex regions differentially responded to the 2- and 6-letter memory sets over the trial periods, showing greater activation to 6-letter sets during the encode and maintain trial periods. Thus, the data showed the differential involvement of PFC in the encoding and maintenance of supra- and sub-capacity memory sets and show the efficacy of using fMRI partial trial methods to study WM component processes.

Working Memory Component Processes: Isolating BOLD Signal-Changes

PubMed Central

Motes, Michael A.; Rypma, Bart

2009-01-01

The chronology of the component processes subserving working memory (WM) and hemodynamic response lags have hindered the use of fMRI for exploring neural substrates of WM. In the present study, however, participants completed full trials that involved encoding two or six letters, maintaining the memory-set over a delay, and then deciding whether a probe was in the memory-set or not. Additionally, they completed encode only, encode and maintain, and encode and decide partial-trials intermixed with the full-trials. The inclusion of partial-trials allowed for the isolation of BOLD signal-changes to the different trial-periods. The results showed that only lateral and medial prefrontal cortex regions differentially responded to the 2- and 6-letter memory-sets over the trial-periods, showing greater activation to 6-letter sets during the encode and maintain trial-periods. Thus, the data showed the differential involvement of PFC in the encoding and maintenance of supra- and sub-capacity memory-sets and show the efficacy of using fMRI partial-trial methods to study WM component processes. PMID:19732840

Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials.

PubMed

Weisman, Alanna; Bai, Johnny-Wei; Cardinez, Marina; Kramer, Caroline K; Perkins, Bruce A

2017-07-01

Closed-loop artificial pancreas systems have been in development for several years, including assessment in numerous varied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance. We did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcutaneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3·9-10 mmol/L or 3·9-8 mmol/L, depending on the study), assessed by random-effects meta-analysis. This study is registered with PROSPERO, number 2015:CRD42015026854. We identified 984 reports; after exclusions, 27 comparisons from 24 studies (23 crossover and one parallel design) including a total of 585 participants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hormone (insulin and glucagon), two comparisons assessed both dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hormone artificial pancreas systems. Time in target was 12·59% higher with artificial pancreas systems (95% CI 9·02-16·16; p<0·0001), from a weighted mean of 58·21% for conventional pump therapy (I 2 =84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19·52% [95% CI 15·12-23·91] vs 11·06% [6·94 to 15·18]; p=0·006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the comparator. Single-hormone studies had higher heterogeneity than dual-hormone studies (I 2 79% vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the intervention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies. Artificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and technical factors. None. Copyright © 2017 Elsevier Ltd. All rights reserved.

Improving Exercise Performance with an Accelerometer-Based Smartphone App: A Randomized Controlled Trial.

PubMed

Bittel, Daniel C; Bittel, Adam J; Williams, Christine; Elazzazi, Ashraf

2017-05-01

Proper exercise form is critical for the safety and efficacy of therapeutic exercise. This research examines if a novel smartphone application, designed to monitor and provide real-time corrections during resistance training, can reduce performance errors and elicit a motor learning response. Forty-two participants aged 18 to 65 years were randomly assigned to treatment and control groups. Both groups were tested for the number of movement errors made during a 10-repetition set completed at baseline, immediately after, and 1 to 2 weeks after a single training session of knee extensions. The treatment group trained with real-time, smartphone-generated feedback, whereas the control subjects did not. Group performance (number of errors) was compared across test sets using a 2-factor mixed-model analysis of variance. No differences were observed between groups for age, sex, or resistance training experience. There was a significant interaction between test set and group. The treatment group demonstrated fewer errors on posttests 1 and 2 compared with pretest (P < 0.05). There was no reduction in the number of errors on any posttest for control subjects. Smartphone apps, such as the one used in this study, may enhance patient supervision, safety, and exercise efficacy across rehabilitation settings. A single training session with the app promoted motor learning and improved exercise performance.

European Marketing Authorizations Granted Based on a Single Pivotal Clinical Trial: The Rule or the Exception?

PubMed

Morant, Anne Vinther; Vestergaard, Henrik Tang

2018-07-01

A minimum of two positive, adequate, and well-controlled clinical trials has historically been the gold standard for providing substantial evidence to support regulatory approval of a new medicine. Nevertheless, the present analysis of European Marketing Authorizations granted between 2012 and 2016 showed that 45% of new active substances were approved based on a single pivotal clinical trial. For therapeutic areas such as oncology and cardiovascular diseases, approvals based on a single pivotal trial are the rule rather than the exception, whereas new medicines within the nervous system area were generally supported by two or more pivotal trials. While overall similar trends have been observed in the US, the recent US Food and Drug Administration approvals of nervous system medicines based on a single pivotal trial suggest that a case-by-case scientific evaluation of the totality of evidence is increasingly applied to facilitate faster access of new medicines to patients suffering from serious diseases. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Strategies to improve recruitment to randomised trials.

PubMed

Treweek, Shaun; Pitkethly, Marie; Cook, Jonathan; Fraser, Cynthia; Mitchell, Elizabeth; Sullivan, Frank; Jackson, Catherine; Taskila, Tyna K; Gardner, Heidi

2018-02-22

Recruiting participants to trials can be extremely difficult. Identifying strategies that improve trial recruitment would benefit both trialists and health research. To quantify the effects of strategies for improving recruitment of participants to randomised trials. A secondary objective is to assess the evidence for the effect of the research setting (e.g. primary care versus secondary care) on recruitment. We searched the Cochrane Methodology Review Group Specialised Register (CMR) in the Cochrane Library (July 2012, searched 11 February 2015); MEDLINE and MEDLINE In Process (OVID) (1946 to 10 February 2015); Embase (OVID) (1996 to 2015 Week 06); Science Citation Index & Social Science Citation Index (ISI) (2009 to 11 February 2015) and ERIC (EBSCO) (2009 to 11 February 2015). Randomised and quasi-randomised trials of methods to increase recruitment to randomised trials. This includes non-healthcare studies and studies recruiting to hypothetical trials. We excluded studies aiming to increase response rates to questionnaires or trial retention and those evaluating incentives and disincentives for clinicians to recruit participants. We extracted data on: the method evaluated; country in which the study was carried out; nature of the population; nature of the study setting; nature of the study to be recruited into; randomisation or quasi-randomisation method; and numbers and proportions in each intervention group. We used a risk difference to estimate the absolute improvement and the 95% confidence interval (CI) to describe the effect in individual trials. We assessed heterogeneity between trial results. We used GRADE to judge the certainty we had in the evidence coming from each comparison. We identified 68 eligible trials (24 new to this update) with more than 74,000 participants. There were 63 studies involving interventions aimed directly at trial participants, while five evaluated interventions aimed at people recruiting participants. All studies were in health care.We found 72 comparisons, but just three are supported by high-certainty evidence according to GRADE.1. Open trials rather than blinded, placebo trials. The absolute improvement was 10% (95% CI 7% to 13%).2. Telephone reminders to people who do not respond to a postal invitation. The absolute improvement was 6% (95% CI 3% to 9%). This result applies to trials that have low underlying recruitment. We are less certain for trials that start out with moderately good recruitment (i.e. over 10%).3. Using a particular, bespoke, user-testing approach to develop participant information leaflets. This method involved spending a lot of time working with the target population for recruitment to decide on the content, format and appearance of the participant information leaflet. This made little or no difference to recruitment: absolute improvement was 1% (95% CI -1% to 3%).We had moderate-certainty evidence for eight other comparisons; our confidence was reduced for most of these because the results came from a single study. Three of the methods were changes to trial management, three were changes to how potential participants received information, one was aimed at recruiters, and the last was a test of financial incentives. All of these comparisons would benefit from other researchers replicating the evaluation. There were no evaluations in paediatric trials.We had much less confidence in the other 61 comparisons because the studies had design flaws, were single studies, had very uncertain results or were hypothetical (mock) trials rather than real ones. The literature on interventions to improve recruitment to trials has plenty of variety but little depth. Only 3 of 72 comparisons are supported by high-certainty evidence according to GRADE: having an open trial and using telephone reminders to non-responders to postal interventions both increase recruitment; a specialised way of developing participant information leaflets had little or no effect. The methodology research community should improve the evidence base by replicating evaluations of existing strategies, rather than developing and testing new ones.

A review of the patterns of docetaxel use for hormone-resistant prostate cancer at the Princess Margaret Hospital.

PubMed

Chin, S N; Wang, L; Moore, M; Sridhar, S S

2010-04-01

Based on the TAX 327 phase III trial, docetaxel-based chemotherapy is the standard first-line treatment for hormone-resistant prostate cancer (HRPC); however, there is some heterogeneity in the use of this agent in routine clinical practice. The aim of the present study was to examine the patterns of docetaxel use in routine clinical practice at our institution and to compare them with docetaxel use in the TAX 327 clinical trial. We conducted a retrospective chart review of HRPC patients treated with first-line docetaxel between 2005 and 2007 at the Princess Margaret Hospital. In the first-line setting, 88 patients with HRPC received docetaxel. The main reasons for initiating docetaxel were rising prostate-specific antigen (PSA, 98%) and progressive symptoms (77%). The PSA response rate was 67%; median time to response was 1.5 months, and duration of response was 6.8 months. Median survival was 15.9 months (95% confidence interval: 12.4 to 20.5 months). Patients received a median of 7 cycles of treatment, and the main toxicities were fatigue (35%) and neuropathy (24%). Post docetaxel, 36 patients received second-line treatment with a 22% response rate. In routine clinical practice, HRPC patients received docetaxel mainly because of symptomatic disease progression. Overall response rates and toxicities were comparable to those in the TAX 327 trial. However, our patients received a median of only 7 cycles of treatment versus the 9.5 administered on trial, and survival was slightly shorter in our single-institution study. A larger prospective multicentre analysis, including performance status and quality-of-life parameters, may be warranted to determine if docetaxel performs as well in routine clinical practice as it does in the clinical trial setting.

Emerging Therapies in Metastatic Prostate Cancer.

PubMed

Sonnenburg, Daniel W; Morgans, Alicia K

2018-04-11

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

On the role of verbalization during task set selection: switching or serial order control?

PubMed

Bryck, Richard L; Mayr, Ulrich

2005-06-01

Recent task-switching work in which paper-and-pencil administered single-task lists were compared with task-alternation lists has demonstrated large increases in task-switch costs with concurrent articulatory suppression (AS), implicating a crucial role for verbalization during switching (Baddeley, Chincotta, & Adlam, 2001; Emerson & Miyake, 2003). Experiment 1 replicated this result, using computerized assessment, albeit with much smaller effect sizes than in the original reports. In Experiment 2, AS interference was reduced when a sequential cue (spatial location) that indicated the current position in the sequence of task alternations was given. Finally, in Experiment 3, switch trials and no-switch trials were compared within a block of alternating runs of two tasks. Again, AS interference was obtained mainly when the endogenous sequencing demand was high, and it was comparable for no-switch and switch trials. These results suggest that verbalization may be critical for endogenous maintenance and updating of a sequential plan, rather than exclusively for the actual switching process.

Clinical Trial Principles and Endpoint Definitions for Paravalvular Leaks in Surgical Prosthesis: An Expert Statement.

PubMed

Ruiz, Carlos E; Hahn, Rebecca T; Berrebi, Alain; Borer, Jeffrey S; Cutlip, Donald E; Fontana, Greg; Gerosa, Gino; Ibrahim, Reda; Jelnin, Vladimir; Jilaihawi, Hasan; Jolicoeur, E Marc; Kliger, Chad; Kronzon, Itzhak; Leipsic, Jonathon; Maisano, Francesco; Millan, Xavier; Nataf, Patrick; O'Gara, Patrick T; Pibarot, Philippe; Ramee, Stephen R; Rihal, Charanjit S; Rodes-Cabau, Josep; Sorajja, Paul; Suri, Rakesh; Swain, Julie A; Turi, Zoltan G; Tuzcu, E Murat; Weissman, Neil J; Zamorano, Jose L; Serruys, Patrick W; Leon, Martin B

2017-04-25

The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted. Copyright © 2017 American College of Cardiology Foundation and European Society of Cardiology. Published by Elsevier Inc. All rights reserved.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329

Bridging the gap between research-supported interventions and everyday social work practice: a new approach.

PubMed

Rubin, Allen

2014-07-01

This article describes a rationale for a focus on case studies that would provide a database of single-group pre-post mean effect sizes that could be analyzed to identify which service provision characteristics are associated with more desirable outcomes when interventions supported by randomized clinical trials are adapted in everyday practice settings. In addition, meta-analyses are proposed that would provide benchmarks that agency practitioners could compare with their mean effect size to inform their decisions about whether to continue, modify, or replace existing efforts to adopt or adapt a specific research-supported treatment. Social workers should be at the forefront of the recommended studies in light of the profession's emphasis on applied research in real-world settings and the prominence of social work practitioners in such settings.

Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation

PubMed Central

Bensdorp, A J; Tjon-Kon-Fat, R I; Bossuyt, P M M; Koks, C A M; Oosterhuis, G J E; Hoek, A; Hompes, P G A; Broekmans, F J M; Verhoeve, H R; de Bruin, J P; van Golde, R; Repping, S; Cohlen, B J; Lambers, M D A; van Bommel, P F; Slappendel, E; Perquin, D; Smeenk, J M; Pelinck, M J; Gianotten, J; Hoozemans, D A; Maas, J W M; Eijkemans, M J C; van der Veen, F; Mol, B W J

2015-01-01

Objectives To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child. Design Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial. Setting 17 centres in the Netherlands. Participants Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility. Interventions Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation. Main outcome measures The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality Results 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation). Conclusions In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates. Trial registration Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939. PMID:25576320

Setting Single or Multiple Goals for Diet and Physical Activity Behaviors Improves Cardiovascular Disease Risk Factors in Adults With Type 2 Diabetes: A Pragmatic Pilot Randomized Trial.

PubMed

Swoboda, Christine M; Miller, Carla K; Wills, Celia E

2016-08-01

The purpose of this study was to evaluate a 4-month telephone-based goal-setting and decision support intervention among adults with type 2 diabetes mellitus (T2DM) and multiple risk factors for cardiovascular disease (CVD). A randomized pretest-posttest control group design was employed. Overweight or obese adults aged 40 to 75 years with T2DM and ≥1 additional CVD risk factor were provided with individualized CVD risk information. At baseline and each biweekly telephone call, the multiple-goal group self-selected both diet- and physical activity-related goals, the single goal group set a single goal, and the control group received information about community health resources. Dietary intake was assessed via a food frequency questionnaire, physical activity via questionnaire, and A1C and blood lipids via fasting fingerstick sample. Between-group differences for clinical (ie, A1C, blood pressure, and blood lipids), physical activity, and dietary variables were evaluated using Kruskal-Wallis, Mann-Whitney U, analysis of variance, and t tests. From pre- to postintervention, the single-goal group demonstrated significant improvement in systolic blood pressure and intake of servings of fruits, vegetables, and refined grains (all P < .05). The multiple-goal group reported significant reduction in percent energy from total, saturated, monounsaturated, and trans fat intake and significant increase in leisure time walking (all P < .05). A multiple-goal approach over 4 months can improve dietary and physical activity outcomes, while a single-goal approach may facilitate improvement in one behavioral domain. Additional research is needed to evaluate maintenance of the achieved changes. © 2016 The Author(s).

UVB phototherapy in an outpatient setting or at home: a pragmatic randomised single-blind trial designed to settle the discussion. The PLUTO study.

PubMed

Koek, Mayke B G; Buskens, Erik; Steegmans, Paul H A; van Weelden, Huib; Bruijnzeel-Koomen, Carla A F M; Sigurdsson, Vigfús

2006-08-01

Home ultraviolet B (UVB) treatment is a much-debated treatment, especially with regard to effectiveness, safety and side effects. However, it is increasingly being prescribed, especially in the Netherlands. Despite ongoing discussions, no randomised research has been performed, and only two studies actually compare two groups of patients. Thus, firm evidence to support or discourage the use of home UVB phototherapy has not yet been obtained. This is the goal of the present study, the PLUTO study (Dutch acronym for "national trial on home UVB phototherapy for psoriasis"). We designed a pragmatic randomised single-blind multi-centre trial. This trial is designed to evaluate the impact of home UVB treatment versus UVB phototherapy in a hospital outpatient clinic as to effectiveness, quality of life and cost-effectiveness. In total 196 patients with psoriasis who were clinically eligible for UVB phototherapy were included. Normally 85% of the patients treated with UVB show a relevant clinical response. With a power of 80% and a 0.05 significance level it will be possible to detect a reduction in effectiveness of 15%. Effectiveness will be determined by calculating differences in the Psoriasis Area and Severity Index (PASI) and the Self Administered PASI (SAPASI) scores. Quality of life is measured using several validated generic questionnaires and a disease-specific questionnaire. Other outcome measures include costs, side effects, dosimetry, concomitant use of medication and patient satisfaction. Patients are followed throughout the therapy and for 12 months thereafter. The study is no longer recruiting patients, and is expected to report in 2006. In the field of home UVB phototherapy this trial is the first randomised parallel group study. As such, this trial addresses the weaknesses encountered in previous studies. The pragmatic design ensures that the results can be well generalised to the target population. Because, in addition to effectiveness, aspects such as quality of life and cost-effectiveness are also taken into consideration, this study will produce valuable evidence to either support or discourage prescription of home UVB phototherapy. Current controlled trials/Nederlands Trial register: ISRCTN83025173. Clinicaltrials.gov: NCT00150930.

Effect of Frequent or Extended Hemodialysis on Cardiovascular Parameters: A Meta-analysis

PubMed Central

Susantitaphong, Paweena; Koulouridis, Ioannis; Balk, Ethan M.; Madias, Nicolaos E.; Jaber, Bertrand L.

2012-01-01

Background Increased left ventricular (LV) mass is a risk factor for cardiovascular mortality in patients with chronic kidney failure. More frequent or extended hemodialysis (HD) has been hypothesized to have a beneficial effect on LV mass. Study Design Meta-analysis. Setting & Population MEDLINE literature search (inception-April 2011), Cochrane Central Register of Controlled Trials and ClinicalTrials.gov using the search terms “short daily HD”, “daily HD”, “quotidian HD”, “frequent HD”, “intensive HD”, “nocturnal HD”, and “home HD”. Selection Criteria for Studies Single-arm cohort studies (with pre- and post-study evaluations) and randomized controlled trials examining the effect of frequent or extended HD on cardiac morphology and function, and blood pressure parameters. Studies of hemofiltration, hemodiafiltration and peritoneal dialysis were excluded. Intervention Frequent (2–8 hours,> thrice weekly) or extended (>4 hours, thrice weekly) HD as compared with conventional (≤ 4 hours, thrice weekly) HD. Outcomes Absolute changes in cardiac morphology and function, including LV mass index (LVMI) (primary), and blood pressure parameters (secondary). Results We identified 38 single-arm studies, 5 crossover trials and 3 randomized controlled trials. By meta-analysis of 23 study arms, frequent or extended HD significantly reduced LVMI from baseline (−31.2 g/m2, 95% CI, −39.8 to −22.5; P<0.001).The 3 randomized trials found a less pronounced net reduction in LVMI (−7.0 g/m2; 95% CI, −10.2 to −3.7; P<0.001). LV ejection fraction improved by 6.7% (95% CI, 1.6 to 11.9; P=0.01). Other cardiac morphological parameters displayed similar improvements. There were also significant decreases in systolic, diastolic, and mean blood pressure, and mean number of anti-hypertensive medications. Limitations Paucity of randomized controlled trials. Conclusions Conversion from conventional to frequent or extended HD is associated with an improvement in cardiac morphology and function, including LVMI and LV ejection fraction, respectively, and in several blood pressure parameters, which collectively might confer long-term cardiovascular benefit. Trials with long-term clinical outcomes are needed. PMID:22370022

The t-CWT: a new ERP detection and quantification method based on the continuous wavelet transform and Student's t-statistics.

PubMed

Bostanov, Vladimir; Kotchoubey, Boris

2006-12-01

This study was aimed at developing a method for extraction and assessment of event-related brain potentials (ERP) from single-trials. This method should be applicable in the assessment of single persons' ERPs and should be able to handle both single ERP components and whole waveforms. We adopted a recently developed ERP feature extraction method, the t-CWT, for the purposes of hypothesis testing in the statistical assessment of ERPs. The t-CWT is based on the continuous wavelet transform (CWT) and Student's t-statistics. The method was tested in two ERP paradigms, oddball and semantic priming, by assessing individual-participant data on a single-trial basis, and testing the significance of selected ERP components, P300 and N400, as well as of whole ERP waveforms. The t-CWT was also compared to other univariate and multivariate ERP assessment methods: peak picking, area computation, discrete wavelet transform (DWT) and principal component analysis (PCA). The t-CWT produced better results than all of the other assessment methods it was compared with. The t-CWT can be used as a reliable and powerful method for ERP-component detection and testing of statistical hypotheses concerning both single ERP components and whole waveforms extracted from either single persons' or group data. The t-CWT is the first such method based explicitly on the criteria of maximal statistical difference between two average ERPs in the time-frequency domain and is particularly suitable for ERP assessment of individual data (e.g. in clinical settings), but also for the investigation of small and/or novel ERP effects from group data.

Prediction of successful memory encoding based on single-trial rhinal and hippocampal phase information.

PubMed

Höhne, Marlene; Jahanbekam, Amirhossein; Bauckhage, Christian; Axmacher, Nikolai; Fell, Juergen

2016-10-01

Mediotemporal EEG characteristics are closely related to long-term memory formation. It has been reported that rhinal and hippocampal EEG measures reflecting the stability of phases across trials are better suited to distinguish subsequently remembered from forgotten trials than event-related potentials or amplitude-based measures. Theoretical models suggest that the phase of EEG oscillations reflects neural excitability and influences cellular plasticity. However, while previous studies have shown that the stability of phase values across trials is indeed a relevant predictor of subsequent memory performance, the effect of absolute single-trial phase values has been little explored. Here, we reanalyzed intracranial EEG recordings from the mediotemporal lobe of 27 epilepsy patients performing a continuous word recognition paradigm. Two-class classification using a support vector machine was performed to predict subsequently remembered vs. forgotten trials based on individually selected frequencies and time points. We demonstrate that it is possible to successfully predict single-trial memory formation in the majority of patients (23 out of 27) based on only three single-trial phase values given by a rhinal phase, a hippocampal phase, and a rhinal-hippocampal phase difference. Overall classification accuracy across all subjects was 69.2% choosing frequencies from the range between 0.5 and 50Hz and time points from the interval between -0.5s and 2s. For 19 patients, above chance prediction of subsequent memory was possible even when choosing only time points from the prestimulus interval (overall accuracy: 65.2%). Furthermore, prediction accuracies based on single-trial phase surpassed those based on single-trial power. Our results confirm the functional relevance of mediotemporal EEG phase for long-term memory operations and suggest that phase information may be utilized for memory enhancement applications based on deep brain stimulation. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of complex community-based childhood obesity prevention interventions.

PubMed

Karacabeyli, D; Allender, S; Pinkney, S; Amed, S

2018-05-16

Multi-setting, multi-component community-based interventions have shown promise in preventing childhood obesity; however, evaluation of these complex interventions remains a challenge. The objective of the study is to systematically review published methodological approaches to outcome evaluation for multi-setting community-based childhood obesity prevention interventions and synthesize a set of pragmatic recommendations. MEDLINE, CINAHL and PsycINFO were searched from inception to 6 July 2017. Papers were included if the intervention targeted children ≤18 years, engaged at least two community sectors and described their outcome evaluation methodology. A single reviewer conducted title and abstract scans, full article review and data abstraction. Directed content analysis was performed by three reviewers to identify prevailing themes. Thirty-three studies were included, and of these, 26 employed a quasi-experimental design; the remaining were randomized control trials. Body mass index was the most commonly measured outcome, followed by health behaviour change and psychosocial outcomes. Six themes emerged, highlighting advantages and disadvantages of active vs. passive consent, quasi-experimental vs. randomized control trials, longitudinal vs. repeat cross-sectional designs and the roles of process evaluation and methodological flexibility in evaluating complex interventions. Selection of study designs and outcome measures compatible with community infrastructure, accompanied by process evaluation, may facilitate successful outcome evaluation. © 2018 World Obesity Federation.

Rationale and design of the SMaRT trial: A randomised, prospective, parallel, non-blinded, one-centre trial to evaluate the use of magnetic resonance imaging in acute setting in patients presenting with suspected scaphoid fracture.

PubMed

Rua, Tiago; Vijayanathan, Sanjay; Parkin, David; Goh, Vicky; McCrone, Paul; Gidwani, Sam

2018-04-01

Background Wrist injury is a common presentation to the Emergency Department in the United Kingdom. Among these injuries, the scaphoid is the most common fractured carpal bone. However, given the limited ability of conventional radiography to accurately diagnose a suspected scaphoid fracture on presentation, its diagnosis and management remain challenging. Despite the vast clinical evidence supporting the superior accuracy of magnetic resonance imaging, there is little to no evidence around the real-world clinical and economic impact of immediate magnetic resonance imaging in the management of suspected scaphoid fractures. Methods Review of design and implementation challenges associated with the identification and subsequent recruitment of eligible patients, implementation of a novel clinical pathway in an acute setting, rationale behind the primary and secondary outcomes selected and measurement of the primary outcome. Results The Scaphoid Magnetic Resonance Imaging in Trauma trial is a single-site prospective, randomised, non-blinded, parallel design trial that aims to evaluate the use of immediate magnetic resonance imaging in the management of patients presenting to the acute setting with suspected scaphoid fractures. The primary outcome is the total 3-month cost per patient associated with the diagnosis and treatment of suspected scaphoid fractures. It is hypothesised that the immediate use of magnetic resonance imaging, a more accurate but expensive imaging modality, in patients with negative findings in the initial four-view radiography, will reduce the overall National Health Service costs by promoting definitive care and avoiding unnecessary diagnostic and treatment procedures. Other rationale design considerations in the recruitment, randomisation, data acquisition and intervention implementation are also discussed. Several of these challenges derive from real-world operational issues associated with the provision of magnetic resonance imaging in an intrinsically complex acute setting. Staff engagement during the trial's planning phase, combined with an extensive training programme rolled out prior to the trial's launch, were essential to raise staff awareness and engagement. Given the acute nature of the clinical condition, the latter was deemed essential as the eligibility assessment, recruitment, randomisation and treatment allocation processes all need to happen in a very tight time frame. Limitations Findings from the Scaphoid Magnetic Resonance Imaging in Trauma trial might not be generalisable to other National Health Service hospitals, foreign healthcare systems nor patient presentations outside normal magnetic resonance imaging working hours. Conclusion The Scaphoid Magnetic Resonance Imaging in Trauma trial was designed to evaluate the costs, patient satisfaction and clinical outcomes around the management of suspected scaphoid fractures and ultimately provide solid evidence on which to base the United Kingdom and international clinical practice. This article discusses the steps considered in the design of this novel trial, with particular emphasis on the issues and lessons learned during the planning and implementation stages.

Effectiveness of a multimodal standard nursing program on health-related quality of life in Chinese mainland female patients with breast cancer: protocol for a single-blind cluster randomized controlled trial.

PubMed

Zhou, Kaina; Wang, Duolao; He, Xiaole; Huo, Lanting; An, Jinghua; Li, Minjie; Wang, Wen; Li, Xiaomei

2016-08-31

Breast cancer and its treatment-related adverse effects are harmful to physical, psychological, and social functioning, leading to health-related quality of life (HRQoL) impairment in patients. Many programs have been used with this population for HRQoL improvement; however, few studies have considered the physical, psychological, and social health domains comprehensively, and few have constructed multimodal standard nursing interventions based on specific theories. The purpose of this trial is to examine the effect of a health belief model (HBM)-based multimodal standard nursing program (MSNP) on HRQoL in female patients with breast cancer. This is a two-arm single-blind cluster randomized controlled trial (cRCT) in clinical settings. Twelve tertiary hospitals will be randomly selected from the 24 tertiary hospitals in Xi'an, China, and allocated to the intervention arm and control arm using a computer-generated random numbers table. Inpatient female patients with breast cancer from each hospital will receive either MSNP plus routine nursing care immediately after recruitment (intervention arm), or only routine nursing care (control arm). The intervention will be conducted by trained nurses for 12 months. All recruited female patients with breast cancer, participating clinical staff, and trained data collectors from the 12 hospitals will be blind with respect to group allocation. Patients of the control arm will not be offered any information about the MSNP during the study period to prevent bias. The primary outcome is HRQoL measured through the Functional Assessment of Cancer Therapy-Breast version 4.0 at 12 months. Secondary outcomes include pain, fatigue, sleep, breast cancer-related lymphedema, and upper limb function, which are evaluated by a visual analogue scale, the circumference method, and the Constant-Murley Score. This trial will provide important evidence on the effectiveness of multimodal nursing interventions delivered by nurses in clinical settings. Study findings will inform strategies for scaling up comprehensive standard intervention programs on health management in the population of female patients with breast cancer. Chictr.org.cn ChiCTR-IOR-16008253 (April 9, 2016).

Review and Analysis of Publication Trends over Three Decades in Three High Impact Medicine Journals.

PubMed

Ivanov, Alexander; Kaczkowska, Beata A; Khan, Saadat A; Ho, Jean; Tavakol, Morteza; Prasad, Ashok; Bhumireddy, Geetha; Beall, Allan F; Klem, Igor; Mehta, Parag; Briggs, William M; Sacchi, Terrence J; Heitner, John F

2017-01-01

Over the past three decades, industry sponsored research expanded in the United States. Financial incentives can lead to potential conflicts of interest (COI) resulting in underreporting of negative study results. We hypothesized that over the three decades, there would be an increase in: a) reporting of conflict of interest and source of funding; b) percentage of randomized control trials c) number of patients per study and d) industry funding. Original articles published in three calendar years (1988, 1998, and 2008) in The Lancet, New England Journal of Medicine and Journal of American Medical Association were collected. Studies were reviewed and investigational design categorized as prospective and retrospective clinical trials. Prospective trials were categorized into randomized or non-randomized and single-center or multi-center trials. Retrospective trials were categorized as registries, meta-analyses and other studies, mostly comprising of case reports or series. Study outcomes were categorized as positive or negative depending on whether the pre-specified hypothesis was met. Financial disclosures were researched for financial relationships and profit status, and accordingly categorized as government, non-profit or industry sponsored. Studies were assessed for reporting COI. 1,671 original articles were included in this analysis. Total number of published studies decreased by 17% from 1988 to 2008. Over 20 year period, the proportion of prospective randomized trials increased from 22 to 46% (p < 0.0001); whereas the proportion of prospective non-randomized trials decreased from 59% to 27% (p < 0.001). There was an increase in the percentage of prospective randomized multi-center trials from 11% to 41% (p < 0.001). Conversely, there was a reduction in non-randomized single-center trials from 47% to 10% (p < 0.001). Proportion of government funded studies remained constant, whereas industry funded studies more than doubled (17% to 40%; p < 0.0001). The number of studies with negative results more than doubled (10% to 22%; p<0.0001). While lack of funding disclosure decreased from 35% to 7%, COI reporting increased from 2% to 84% (p < 0.0001). Improved reporting of COI, clarity in financial sponsorship, increased publication of negative results in the setting of larger and better designed clinical trials represents a positive step forward in the scientific publications, despite the higher percentage of industry funded studies.

Bibliography of Mock Trial Materials.

ERIC Educational Resources Information Center

National Inst. for Citizen Education in the Law, Washington, DC.

This catalog lists general articles on mock trials, information for arranging mock trial competitions, mock trial problem sets, and video tapes. The problem sets contain introductory material, applicable law, statements of facts, witness statements, and documents. The cases include issues in family, consumer, criminal, and immigration law. Several…

Somatosensory spatial attention modulates amplitudes, latencies, and latency jitter of laser-evoked brain potentials.

PubMed

Franz, Marcel; Nickel, Moritz M; Ritter, Alexander; Miltner, Wolfgang H R; Weiss, Thomas

2015-04-01

Several studies provided evidence that the amplitudes of laser-evoked potentials (LEPs) are modulated by attention. However, previous reports were based on across-trial averaging of LEP responses at the expense of losing information about intertrial variability related to attentional modulation. The aim of this study was to investigate the effects of somatosensory spatial attention on single-trial parameters (i.e., amplitudes, latencies, and latency jitter) of LEP components (N2 and P2). Twelve subjects participated in a sustained spatial attention paradigm while noxious laser stimuli (left hand) and noxious electrical stimuli (right hand) were sequentially delivered to the dorsum of the respective hand with nonnoxious air puffs randomly interspersed within the sequence of noxious stimuli. Participants were instructed to mentally count all stimuli (i.e., noxious and nonnoxious) applied to the attended location. Laser stimuli, presented to the attended hand (ALS), elicited larger single-trial amplitudes of the N2 component compared with unattended laser stimuli (ULS). In contrast, single-trial amplitudes of the P2 component were not significantly affected by spatial attention. Single-trial latencies of the N2 and P2 were significantly smaller for ALS vs. ULS. Additionally, the across-trial latency jitter of the N2 component was reduced for ALS. Conversely, the latency jitter of the P2 component was smaller for ULS compared with ALS. With the use of single-trial analysis, the study provided new insights into brain dynamics of LEPs related to spatial attention. Our results indicate that single-trial parameters of LEP components are differentially modulated by spatial attention. Copyright © 2015 the American Physiological Society.

Single-Trial Normalization for Event-Related Spectral Decomposition Reduces Sensitivity to Noisy Trials

PubMed Central

Grandchamp, Romain; Delorme, Arnaud

2011-01-01

In electroencephalography, the classical event-related potential model often proves to be a limited method to study complex brain dynamics. For this reason, spectral techniques adapted from signal processing such as event-related spectral perturbation (ERSP) – and its variant event-related synchronization and event-related desynchronization – have been used over the past 20 years. They represent average spectral changes in response to a stimulus. These spectral methods do not have strong consensus for comparing pre- and post-stimulus activity. When computing ERSP, pre-stimulus baseline removal is usually performed after averaging the spectral estimate of multiple trials. Correcting the baseline of each single-trial prior to averaging spectral estimates is an alternative baseline correction method. However, we show that this method leads to positively skewed post-stimulus ERSP values. We eventually present new single-trial-based ERSP baseline correction methods that perform trial normalization or centering prior to applying classical baseline correction methods. We show that single-trial correction methods minimize the contribution of artifactual data trials with high-amplitude spectral estimates and are robust to outliers when performing statistical inference testing. We then characterize these methods in terms of their time–frequency responses and behavior compared to classical ERSP methods. PMID:21994498

Goal-setting, self-efficacy, and memory performance in older and younger adults.

PubMed

West, R L; Thorn, R M

2001-01-01

Research in field and laboratory settings has shown that goals lead to improved self-efficacy and performance, especially when individuals also receive positive feedback. The present study extended goal-setting theory to examine self-set goals and feedback in relation to younger and older adults' memory performance and self-efficacy. Following a baseline recall trial, participants completed three shopping list recall trials. Half of the participants were instructed to set goals for the three experimental trials, and half in each goal condition received performance feedback after each trial. Young adults' self-efficacy, clustering, and recall exceeded that of older adults. Goal setting increased self-efficacy for younger but not older adults, and it did not affect performance. Younger adults and participants in the feedback condition increased their goals across trials, as did participants for whom feedback indicated success. These data provide a first look at the motivational impact of feedback and self-set recall goals in memory aging. Additional study is needed to understand the interactive effects of type of feedback, memory task difficulty, and type of goal setting at different ages.

How attention influences perceptual decision making: Single-trial EEG correlates of drift-diffusion model parameters

PubMed Central

Nunez, Michael D.; Vandekerckhove, Joachim; Srinivasan, Ramesh

2016-01-01

Perceptual decision making can be accounted for by drift-diffusion models, a class of decision-making models that assume a stochastic accumulation of evidence on each trial. Fitting response time and accuracy to a drift-diffusion model produces evidence accumulation rate and non-decision time parameter estimates that reflect cognitive processes. Our goal is to elucidate the effect of attention on visual decision making. In this study, we show that measures of attention obtained from simultaneous EEG recordings can explain per-trial evidence accumulation rates and perceptual preprocessing times during a visual decision making task. Models assuming linear relationships between diffusion model parameters and EEG measures as external inputs were fit in a single step in a hierarchical Bayesian framework. The EEG measures were features of the evoked potential (EP) to the onset of a masking noise and the onset of a task-relevant signal stimulus. Single-trial evoked EEG responses, P200s to the onsets of visual noise and N200s to the onsets of visual signal, explain single-trial evidence accumulation and preprocessing times. Within-trial evidence accumulation variance was not found to be influenced by attention to the signal or noise. Single-trial measures of attention lead to better out-of-sample predictions of accuracy and correct reaction time distributions for individual subjects. PMID:28435173

How attention influences perceptual decision making: Single-trial EEG correlates of drift-diffusion model parameters.

PubMed

Nunez, Michael D; Vandekerckhove, Joachim; Srinivasan, Ramesh

2017-02-01

Perceptual decision making can be accounted for by drift-diffusion models, a class of decision-making models that assume a stochastic accumulation of evidence on each trial. Fitting response time and accuracy to a drift-diffusion model produces evidence accumulation rate and non-decision time parameter estimates that reflect cognitive processes. Our goal is to elucidate the effect of attention on visual decision making. In this study, we show that measures of attention obtained from simultaneous EEG recordings can explain per-trial evidence accumulation rates and perceptual preprocessing times during a visual decision making task. Models assuming linear relationships between diffusion model parameters and EEG measures as external inputs were fit in a single step in a hierarchical Bayesian framework. The EEG measures were features of the evoked potential (EP) to the onset of a masking noise and the onset of a task-relevant signal stimulus. Single-trial evoked EEG responses, P200s to the onsets of visual noise and N200s to the onsets of visual signal, explain single-trial evidence accumulation and preprocessing times. Within-trial evidence accumulation variance was not found to be influenced by attention to the signal or noise. Single-trial measures of attention lead to better out-of-sample predictions of accuracy and correct reaction time distributions for individual subjects.

Extended fault inversion with random slipmaps: A resolution test for the 2012 Mw 7.6 Nicoya, Costa Rica earthquake from a Popperian inversion strategy.

NASA Astrophysics Data System (ADS)

Ángel López Comino, José; Stich, Daniel; Ferreira, Ana M. G.; Morales Soto, José

2015-04-01

The inversion of seismic data for extended fault slip distributions provides us detailed models of earthquake sources. The validity of the solutions depends on the fit between observed and synthetic seismograms generated with the source model. However, there may exist more than one model that fit the data in a similar way, leading to a multiplicity of solutions. This underdetermined problem has been analyzed and studied by several authors, who agree that inverting for a single best model may become overly dependent on the details of the procedure. We have addressed this resolution problem by using a global search that scans the solutions domain using random slipmaps, applying a Popperian inversion strategy that involves the generation of a representative set of slip distributions. The proposed technique solves the forward problem for a large set of models calculating their corresponding synthetic seismograms. Then, we propose to perform extended fault inversion through falsification, that is, falsify inappropriate trial models that do not reproduce the data within a reasonable level of mismodelling. The remainder of surviving trial models forms our set of coequal solutions. Thereby the ambiguities that might exist can be detected by taking a look at the solutions, allowing for an efficient assessment of the resolution. The solution set may contain only members with similar slip distributions, or else uncover some fundamental ambiguity like, for example, different patterns of main slip patches or different patterns of rupture propagation. For a feasibility study, the proposed resolution test has been evaluated using teleseismic body wave recordings from the September 5th 2012 Nicoya, Costa Rica earthquake. Note that the inversion strategy can be applied to any type of seismic, geodetic or tsunami data for which we can handle the forward problem. A 2D von Karman distribution is used to describe the spectrum of heterogeneity in slipmaps, and we generate possible models by spectral synthesis for random phase, keeping the rake angle, rupture velocity and slip velocity function fixed. The 2012 Nicoya earthquake turns out to be relatively well constrained from 50 teleseismic waveforms. The solution set contains 252 out of 10.000 trial models with normalized L1-fit within 5 percent from the global minimum. The set includes only similar solutions -a single centred slip patch- with minor differences. Uncertainties are related to the details of the slip maximum, including the amount of peak slip (2m to 3.5m), as well as the characteristics of peripheral slip below 1 m. Synthetic tests suggest that slip patterns like Nicoya may be a fortunate case, while it may be more difficult to unambiguously reconstruct more distributed slip from teleseismic data.

A randomized controlled trial of physical activity with individual goal-setting and volunteer mentors to overcome sedentary lifestyle in older adults at risk of cognitive decline: the INDIGO trial protocol.

PubMed

Cox, Kay L; Cyarto, Elizabeth V; Etherton-Beer, Christopher; Ellis, Kathryn A; Alfonso, Helman; Clare, Linda; Liew, Danny; Ames, David; Flicker, Leon; Almeida, Osvaldo P; LoGiudice, Dina; Lautenschlager, Nicola T

2017-09-13

Increasing physical activity (PA) effectively in those who are inactive is challenging. For those who have subjective memory complaints (SMC) or mild cognitive impairment (MCI) this is a greater challenge necessitating the need for more engaging and innovative approaches. The primary aim of this trial is to determine whether a home-based 6-month PA intervention with individual goal-setting and peer mentors (GM-PA) can significantly increase PA levels in insufficiently active older adults at increased risk of developing Alzheimer's disease (AD). Community living 60-80 year olds with SMC or MCI who do not engage in more than 60 min per week of moderate intensity PA will be recruited from memory clinics and the community via media advertisements to participate in this randomized, single-blind controlled trial. All participants will receive an individually tailored home-based PA program of 150 min of moderate intensity walking/week for 6 months. The intervention group will undertake individual goal-setting and behavioral education workshops with mentor support via telephone (GM-PA). Those randomized to the control group will have standard education workshops and Physical Activity Liaison (PAL) contact via telephone (CO-PA). Increase in PA is the primary outcome, fitness, cognitive, personality, demographic and clinical parameters will be measured and a health economic analysis performed. A saliva sample will be collected for APOE e4 genotyping. All participants will have a goal-setting interview to determine their PA goals. Active volunteers aged 50-85 years will be recruited from the community randomized and trained to provide peer support as mentors (intervention group) or PALS (control group) for the 6-month intervention. Mentors and PALS will have PA, exercise self-efficacy and mentoring self-efficacy measured. Participants in both groups are asked to attend 3 workshops in 6 months. At the first workshop, they will meet their allocated Mentor or PAL who will deliver their respective programs and support via 6 telephone calls during the intervention. If the GM-PA program is successful in increasing the PA levels of the target group it will potentially provide another strategy and community resource that can be translated into practice. Australia New Zealand Clinical Trials Registry ACTRN12613001181796 . (29/10/2013) retrospectively registered.

Maximally reliable spatial filtering of steady state visual evoked potentials.

PubMed

Dmochowski, Jacek P; Greaves, Alex S; Norcia, Anthony M

2015-04-01

Due to their high signal-to-noise ratio (SNR) and robustness to artifacts, steady state visual evoked potentials (SSVEPs) are a popular technique for studying neural processing in the human visual system. SSVEPs are conventionally analyzed at individual electrodes or linear combinations of electrodes which maximize some variant of the SNR. Here we exploit the fundamental assumption of evoked responses--reproducibility across trials--to develop a technique that extracts a small number of high SNR, maximally reliable SSVEP components. This novel spatial filtering method operates on an array of Fourier coefficients and projects the data into a low-dimensional space in which the trial-to-trial spectral covariance is maximized. When applied to two sample data sets, the resulting technique recovers physiologically plausible components (i.e., the recovered topographies match the lead fields of the underlying sources) while drastically reducing the dimensionality of the data (i.e., more than 90% of the trial-to-trial reliability is captured in the first four components). Moreover, the proposed technique achieves a higher SNR than that of the single-best electrode or the Principal Components. We provide a freely-available MATLAB implementation of the proposed technique, herein termed "Reliable Components Analysis". Copyright © 2015 Elsevier Inc. All rights reserved.

Haphazard reporting of deaths in clinical trials: a review of cases of ClinicalTrials.gov records and matched publications–a cross-sectional study

PubMed Central

Earley, Amy; Lau, Joseph; Uhlig,, Katrin

2013-01-01

Context A participant death is a serious event in a clinical trial and needs to be unambiguously and publicly reported. Objective To examine (1) how often and how numbers of deaths are reported in ClinicalTrials.gov records; (2) how often total deaths can be determined per arm within a ClinicalTrials.gov results record and its corresponding publication and (3) whether counts may be discordant. Design Registry-based study of clinical trial results reporting. Setting ClinicalTrials.gov results database searched in July 2011 and matched PubMed publications. Selection criteria A random sample of ClinicalTrials.gov results records. Detailed review of records with a single corresponding publication. Main outcome measure ClinicalTrials.gov records reporting number of deaths under participant flow, primary or secondary outcome or serious adverse events. Consistency in reporting of number of deaths between ClinicalTrials.gov records and corresponding publications. Results In 500 randomly selected ClinicalTrials.gov records, only 123 records (25%) reported a number for deaths. Reporting of deaths across data modules for participant flow, primary or secondary outcomes and serious adverse events was variable. In a sample of 27 pairs of ClinicalTrials.gov records with number of deaths and corresponding publications, total deaths per arm could only be determined in 56% (15/27 pairs) but were discordant in 19% (5/27). In 27 pairs of ClinicalTrials.gov records without any information on number of deaths, 48% (13/27) were discordant since the publications reported absence of deaths in 33% (9/27) and positive death numbers in 15% (4/27). Conclusions Deaths are variably reported in ClinicalTrials.gov records. A reliable total number of deaths per arm cannot always be determined with certainty or can be discordant with number reported in corresponding trial publications. This highlights a need for unambiguous and complete reporting of the number of deaths in trial registries and publications. PMID:23335556

Web-Based Decision Aid to Assist Help-Seeking Choices for Young People Who Self-Harm: Outcomes From a Randomized Controlled Feasibility Trial

PubMed Central

Patel, Krisna; French, Rebecca S; Henderson, Claire; Ougrin, Dennis; Slade, Mike; Moran, Paul

2018-01-01

Background Adolescents who self-harm are often unsure how or where to get help. We developed a Web-based personalized decision aid (DA) designed to support young people in decision making about seeking help for their self-harm. Objective The aim of this study was to evaluate the feasibility and acceptability of the DA intervention and the randomized controlled trial (RCT) in a school setting. Methods We conducted a two-group, single blind, randomized controlled feasibility trial in a school setting. Participants aged 12 to 18 years who reported self-harm in the past 12 months were randomized to either a Web-based DA or to general information about mood and feelings. Feasibility of recruitment, randomization, and follow-up rates were assessed, as was acceptability of the intervention and study procedures. Descriptive data were collected on outcome measures examining decision making and help-seeking behavior. Qualitative interviews were conducted with young people, parents or carers, and staff and subjected to thematic analysis to explore their views of the DA and study processes. Results Parental consent was a significant barrier to young people participating in the trial, with only 17.87% (208/1164) of parents or guardians who were contacted for consent responding to study invitations. Where parental consent was obtained, we were able to recruit 81.7% (170/208) of young people into the study. Of those young people screened, 13.5% (23/170) had self-harmed in the past year. Ten participants were randomized to receiving the DA, and 13 were randomized to the control group. Four-week follow-up assessments were completed with all participants. The DA had good acceptability, but qualitative interviews suggested that a DA that addressed broader mental health problems such as depression, anxiety, and self-harm may be more beneficial. Conclusions A broad-based mental health DA addressing a wide range of psychosocial problems may be useful for young people. The requirement for parental consent is a key barrier to intervention research on self-harm in the school setting. Adaptations to the research design and the intervention are needed before generalizable research about DAs can be successfully conducted in a school setting. Trial Registration International Standard Randomized Controlled Trial registry: ISRCTN11230559; http://www.isrctn.com/ISRCTN11230559 (Archived by WebCite at http://www.webcitation.org/6wqErsYWG) PMID:29382626

77 FR 48611 - Rules of Practice for Trials Before the Patent Trial and Appeal Board and Judicial Review of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-14

... consolidated set of rules relating to Board trial practice for inter partes review, post-grant review, the... rules relating to Board trial practice for inter partes review, post- grant review, the transitional...), to provide a consolidated set of rules relating to Board trial practice for inter partes review, post...

Choice of Moisturiser for Eczema Treatment (COMET): feasibility study of a randomised controlled parallel group trial in children recruited from primary care

PubMed Central

Ridd, Matthew J; Garfield, Kirsty; Gaunt, Daisy M; Redmond, Niamh M; Powell, Kingsley; Wilson, Victoria; Guy, Richard H; Ball, Nicola; Shaw, Lindsay; Purdy, Sarah; Metcalfe, Chris

2016-01-01

Objectives To determine the feasibility of a randomised controlled trial of ‘leave on’ emollients for children with eczema. Design Single-centre, pragmatic, 4-arm, observer-blinded, parallel, randomised feasibility trial. Setting General practices in the UK. Participants Children with eczema aged 1 month to <5 years. Outcome measures Primary outcome—proportion of parents who reported use of the allocated study emollient every day for the duration of follow-up (12 weeks). Other feasibility outcomes—participant recruitment and retention, data collection and completeness and blinding of observers to allocation. Interventions Aveeno lotion, Diprobase cream, Doublebase gel, Hydromol ointment. Results 197 children were recruited—107 by self-referral (mainly via practice mail-outs) and 90 by inconsultation (clinician consenting and randomising) pathways. Participants recruited inconsultation were younger, had more severe Patient-Oriented Eczema Measure scores and were more likely to withdraw than self-referrals. Parents of 20 (10%) of all the randomised participants reported using the allocated emollient daily for 84 days. The use of other non-study emollients was common. Completeness of data collected by parent-held daily diaries and at monthly study visits was good. Daily diaries were liked (81%) but mainly completed on paper rather than via electronic (‘app’) form. Major costs drivers were general practitioner consultations and eczema-related prescriptions. Observer unblinding was infrequent, and occurred at the baseline or first follow-up visit through accidental disclosure. Conclusions It is feasible in a primary care setting to recruit and randomise young children with eczema to emollients, follow them up and collect relevant trial data, while keeping observers blinded to their allocation. However, reported use of emollients (study and others) has design implications for future trials. Trial registration number ISRCTN21828118/EudraCT2013-003001-26. PMID:27852708

Critical periods after stroke study: translating animal stroke recovery experiments into a clinical trial

PubMed Central

Dromerick, Alexander W.; Edwardson, Matthew A.; Edwards, Dorothy F.; Giannetti, Margot L.; Barth, Jessica; Brady, Kathaleen P.; Chan, Evan; Tan, Ming T.; Tamboli, Irfan; Chia, Ruth; Orquiza, Michael; Padilla, Robert M.; Cheema, Amrita K.; Mapstone, Mark E.; Fiandaca, Massimo S.; Federoff, Howard J.; Newport, Elissa L.

2015-01-01

Introduction: Seven hundred ninety-five thousand Americans will have a stroke this year, and half will have a chronic hemiparesis. Substantial animal literature suggests that the mammalian brain has much potential to recover from acute injury using mechanisms of neuroplasticity, and that these mechanisms can be accessed using training paradigms and neurotransmitter manipulation. However, most of these findings have not been tested or confirmed in the rehabilitation setting, in large part because of the challenges in translating a conceptually straightforward laboratory experiment into a meaningful and rigorous clinical trial in humans. Through presentation of methods for a Phase II trial, we discuss these issues and describe our approach. Methods: In rodents there is compelling evidence for timing effects in rehabilitation; motor training delivered at certain times after stroke may be more effective than the same training delivered earlier or later, suggesting that there is a critical or sensitive period for strongest rehabilitation training effects. If analogous critical/sensitive periods can be identified after human stroke, then existing clinical resources can be better utilized to promote recovery. The Critical Periods after Stroke Study (CPASS) is a phase II randomized, controlled trial designed to explore whether such a sensitive period exists. We will randomize 64 persons to receive an additional 20 h of upper extremity therapy either immediately upon rehab admission, 2–3 months after stroke onset, 6 months after onset, or to an observation-only control group. The primary outcome measure will be the Action Research Arm Test (ARAT) at 1 year. Blood will be drawn at up to 3 time points for later biomarker studies. Conclusion: CPASS is an example of the translation of rodent motor recovery experiments into the clinical setting; data obtained from this single site randomized controlled trial will be used to finalize the design of a Phase III trial. PMID:25972803

Parametric models to relate spike train and LFP dynamics with neural information processing.

PubMed

Banerjee, Arpan; Dean, Heather L; Pesaran, Bijan

2012-01-01

Spike trains and local field potentials (LFPs) resulting from extracellular current flows provide a substrate for neural information processing. Understanding the neural code from simultaneous spike-field recordings and subsequent decoding of information processing events will have widespread applications. One way to demonstrate an understanding of the neural code, with particular advantages for the development of applications, is to formulate a parametric statistical model of neural activity and its covariates. Here, we propose a set of parametric spike-field models (unified models) that can be used with existing decoding algorithms to reveal the timing of task or stimulus specific processing. Our proposed unified modeling framework captures the effects of two important features of information processing: time-varying stimulus-driven inputs and ongoing background activity that occurs even in the absence of environmental inputs. We have applied this framework for decoding neural latencies in simulated and experimentally recorded spike-field sessions obtained from the lateral intraparietal area (LIP) of awake, behaving monkeys performing cued look-and-reach movements to spatial targets. Using both simulated and experimental data, we find that estimates of trial-by-trial parameters are not significantly affected by the presence of ongoing background activity. However, including background activity in the unified model improves goodness of fit for predicting individual spiking events. Uncovering the relationship between the model parameters and the timing of movements offers new ways to test hypotheses about the relationship between neural activity and behavior. We obtained significant spike-field onset time correlations from single trials using a previously published data set where significantly strong correlation was only obtained through trial averaging. We also found that unified models extracted a stronger relationship between neural response latency and trial-by-trial behavioral performance than existing models of neural information processing. Our results highlight the utility of the unified modeling framework for characterizing spike-LFP recordings obtained during behavioral performance.

User and Provider Acceptability of Intermittent Screening and Treatment and Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine to Prevent Malaria in Pregnancy in Western Kenya.

PubMed

Hill, Jenny; Hoyt, Jenna; Achieng, Florence; Ouma, Peter; L'lanziva, Anne; Kariuki, Simon; Desai, Meghna; Webster, Jayne

2016-01-01

The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) alongside long-lasting insecticide-treated nets (LLIN) and case management for reducing the risks associated with malaria in pregnancy in areas of moderate-to-high transmission in sub-Saharan Africa. Due to increasing Plasmodium falciparum resistance to SP, the search for alternative drugs or strategies to control malaria in pregnancy is a priority. We assessed the acceptability among pregnant women and health providers of intermittent screening and treatment (ISTp) and IPTp with dihydroartemisinin-piperaquine (DP) as alternative strategies in the context of an un-blinded clinical trial. Qualitative data were collected through ten focus group discussions with women participating in a randomized controlled trial to evaluate ISTp or IPTp with DP (multi-day regimen) versus IPTp with SP (single dose) in western Kenya. Individual in-depth interviews were conducted with 26 health providers working in the trial facilities and trial staff. Women appreciated the advantages of being tested with a rapid diagnostic test (RDT) at every ANC visit (although a few women disliked finger pricks) and accepted that they would not receive any antimalarial when tested RDT-negative. There were differences in women's experiences of the efficacy of antimalarials between the trial arms, with more women in the IPTp-SP arm reporting they had experienced malaria episodes. Side effects were experienced among women taking DP and SP. Although women and trial staff reported adherence to the full DP regimen within the trial, health providers were not confident that women would adhere to multi-day regimens in non-trial settings. Health providers recognized the advantages of ISTp in reducing unnecessary exposure to drugs, but lacked confidence in the reliability of RDTs compared to microscopy. Our findings indicate that, within a trial context, ISTp-DP and IPTp-DP were generally acceptable among both users and providers and were regarded as potentially valuable alternatives to IPTp-SP. Several challenges were identified the most important of which was concerns with achieving adherence to DP in non-trial settings, requiring operational feasibility studies in routine health systems. Policy adoption of ISTp with RDTs would require a major shift in thinking among health providers due to lack of confidence in RDTs.

Effects of cognitive stimulation therapy Japanese version (CST-J) for people with dementia: a single-blind, controlled clinical trial

PubMed Central

Yamanaka, Katsuo; Kawano, Yoshiyuki; Noguchi, Dai; Nakaaki, Shutaro; Watanabe, Norio; Amano, Takashi; Spector, Aimee

2013-01-01

Objectives Cognitive stimulation therapy (CST) has shown to have significant benefits in improving the cognitive function and quality of life (QOL) in people with mild-to-moderate dementia in a UK randomized controlled trial (RCT). We developed and examined the Japanese version of group CST (CST-J) in a single-blind, controlled clinical trial. Method CST-J consisting of 14 sessions was administered to a treatment group (n = 26) twice a week for 7 weeks. The treatment group was compared with a control group (n = 30). Based on single-blindness, cognition was evaluated by a researcher, and QOL and mood were rated by the participants themselves. Additionally, QOL and mood of participants were rated by care workers who were not blind but who observed them most directly in their daily life (important for social validity). Results A linear mixed model was used for analyses of cognition and QOL. There were significant improvements in cognition [COGNISTAT (Neurobehavioral Cognitive Status Examination) and MMSE (Mini-Mental State Examination)] for the treatment group compared with the control group (p < 0.01). Regarding QOL, the EQ-5D was significant (p = 0.019) and the QoL-AD (Quality of Life – Alzheimer's Disease) showed a positive trend (p = 0.06) when rated by care workers, although not when rated by the participants themselves. Using a nonparametrical analysis, there were significant improvements in the face scale for mood when rated by both the participants (p < 0.01) and the care workers (p = 0.017). Conclusion The CST-J shows promising improvements in cognition, mood, and aspects of QOL for people with dementia in Japanese care settings. A large RCT is now needed. PMID:23550665

Classification of single-trial auditory events using dry-wireless EEG during real and motion simulated flight.

PubMed

Callan, Daniel E; Durantin, Gautier; Terzibas, Cengiz

2015-01-01

Application of neuro-augmentation technology based on dry-wireless EEG may be considerably beneficial for aviation and space operations because of the inherent dangers involved. In this study we evaluate classification performance of perceptual events using a dry-wireless EEG system during motion platform based flight simulation and actual flight in an open cockpit biplane to determine if the system can be used in the presence of considerable environmental and physiological artifacts. A passive task involving 200 random auditory presentations of a chirp sound was used for evaluation. The advantage of this auditory task is that it does not interfere with the perceptual motor processes involved with piloting the plane. Classification was based on identifying the presentation of a chirp sound vs. silent periods. Evaluation of Independent component analysis (ICA) and Kalman filtering to enhance classification performance by extracting brain activity related to the auditory event from other non-task related brain activity and artifacts was assessed. The results of permutation testing revealed that single trial classification of presence or absence of an auditory event was significantly above chance for all conditions on a novel test set. The best performance could be achieved with both ICA and Kalman filtering relative to no processing: Platform Off (83.4% vs. 78.3%), Platform On (73.1% vs. 71.6%), Biplane Engine Off (81.1% vs. 77.4%), and Biplane Engine On (79.2% vs. 66.1%). This experiment demonstrates that dry-wireless EEG can be used in environments with considerable vibration, wind, acoustic noise, and physiological artifacts and achieve good single trial classification performance that is necessary for future successful application of neuro-augmentation technology based on brain-machine interfaces.

Low Efficacy of Single-Dose Albendazole and Mebendazole against Hookworm and Effect on Concomitant Helminth Infection in Lao PDR

PubMed Central

Soukhathammavong, Phonepasong Ayé; Sayasone, Somphou; Phongluxa, Khampheng; Xayaseng, Vilavanh; Utzinger, Jürg; Vounatsou, Penelope; Hatz, Christoph; Akkhavong, Kongsap; Keiser, Jennifer; Odermatt, Peter

2012-01-01

Background Albendazole and mebendazole are increasingly deployed for preventive chemotherapy targeting soil-transmitted helminth (STH) infections. We assessed the efficacy of single oral doses of albendazole (400 mg) and mebendazole (500 mg) for the treatment of hookworm infection in school-aged children in Lao PDR. Since Opisthorchis viverrini is co-endemic in our study setting, the effect of the two drugs could also be determined against this liver fluke. Methodology We conducted a randomized, open-label, two-arm trial. In total, 200 children infected with hookworm (determined by quadruplicate Kato-Katz thick smears derived from two stool samples) were randomly assigned to albendazole (n = 100) and mebendazole (n = 100). Cure rate (CR; percentage of children who became egg-negative after treatment), and egg reduction rate (ERR; reduction in the geometric mean fecal egg count at treatment follow-up compared to baseline) at 21–23 days posttreatment were used as primary outcome measures. Adverse events were monitored 3 hours post treatment. Principal Findings Single-dose albendazole and mebendazole resulted in CRs of 36.0% and 17.6% (odds ratio: 0.4; 95% confidence interval: 0.2–0.8; P = 0.01), and ERRs of 86.7% and 76.3%, respectively. In children co-infected with O. viverrini, albendazole and mebendazole showed low CRs (33.3% and 24.2%, respectively) and moderate ERRs (82.1% and 78.2%, respectively). Conclusions/Significance Both albendazole and mebendazole showed disappointing CRs against hookworm, but albendazole cured infection and reduced intensity of infection with a higher efficacy than mebendazole. Single-dose administrations showed an effect against O. viverrini, and hence it will be interesting to monitor potential ancillary benefits of a preventive chemotherapy strategy that targets STHs in areas where opisthorchiasis is co-endemic. Clinical Trial Registration Current Controlled Trials ISRCTN29126001 PMID:22235353

Involving patients in setting priorities for healthcare improvement: a cluster randomized trial.

PubMed

Boivin, Antoine; Lehoux, Pascale; Lacombe, Réal; Burgers, Jako; Grol, Richard

2014-02-20

Patients are increasingly seen as active partners in healthcare. While patient involvement in individual clinical decisions has been extensively studied, no trial has assessed how patients can effectively be involved in collective healthcare decisions affecting the population. The goal of this study was to test the impact of involving patients in setting healthcare improvement priorities for chronic care at the community level. Cluster randomized controlled trial. Local communities were randomized in intervention (priority setting with patient involvement) and control sites (no patient involvement). Communities in a canadian region were required to set priorities for improving chronic disease management in primary care, from a list of 37 validated quality indicators. Patients were consulted in writing, before participating in face-to-face deliberation with professionals. Professionals established priorities among themselves, without patient involvement. A total of 172 individuals from six communities participated in the study, including 83 chronic disease patients, and 89 health professionals. The primary outcome was the level of agreement between patients' and professionals' priorities. Secondary outcomes included professionals' intention to use the selected quality indicators, and the costs of patient involvement. Priorities established with patients were more aligned with core generic components of the Medical Home and Chronic Care Model, including: access to primary care, self-care support, patient participation in clinical decisions, and partnership with community organizations (p < 0.01). Priorities established by professionals alone placed more emphasis on the technical quality of single disease management. The involvement intervention fostered mutual influence between patients and professionals, which resulted in a 41% increase in agreement on common priorities (95%CI: +12% to +58%, p < 0.01). Professionals' intention to use the selected quality indicators was similar in intervention and control sites. Patient involvement increased the costs of the prioritization process by 17%, and required 10% more time to reach consensus on common priorities. Patient involvement can change priorities driving healthcare improvement at the population level. Future research should test the generalizability of these findings to other contexts, and assess its impact on patient care. The Netherlands National Trial Register #NTR2496.

Reliability of Single-Leg Balance and Landing Tests in Rugby Union; Prospect of Using Postural Control to Monitor Fatigue.

PubMed

Troester, Jordan C; Jasmin, Jason G; Duffield, Rob

2018-06-01

The present study examined the inter-trial (within test) and inter-test (between test) reliability of single-leg balance and single-leg landing measures performed on a force plate in professional rugby union players using commercially available software (SpartaMARS, Menlo Park, USA). Twenty-four players undertook test - re-test measures on two occasions (7 days apart) on the first training day of two respective pre-season weeks following 48h rest and similar weekly training loads. Two 20s single-leg balance trials were performed on a force plate with eyes closed. Three single-leg landing trials were performed by jumping off two feet and landing on one foot in the middle of a force plate 1m from the starting position. Single-leg balance results demonstrated acceptable inter-trial reliability (ICC = 0.60-0.81, CV = 11-13%) for sway velocity, anterior-posterior sway velocity, and mediolateral sway velocity variables. Acceptable inter-test reliability (ICC = 0.61-0.89, CV = 7-13%) was evident for all variables except mediolateral sway velocity on the dominant leg (ICC = 0.41, CV = 15%). Single-leg landing results only demonstrated acceptable inter-trial reliability for force based measures of relative peak landing force and impulse (ICC = 0.54-0.72, CV = 9-15%). Inter-test results indicate improved reliability through the averaging of three trials with force based measures again demonstrating acceptable reliability (ICC = 0.58-0.71, CV = 7-14%). Of the variables investigated here, total sway velocity and relative landing impulse are the most reliable measures of single-leg balance and landing performance, respectively. These measures should be considered for monitoring potential changes in postural control in professional rugby union.

Decision-theoretic designs for a series of trials with correlated treatment effects using the Sarmanov multivariate beta-binomial distribution.

PubMed

Hee, Siew Wan; Parsons, Nicholas; Stallard, Nigel

2018-03-01

The motivation for the work in this article is the setting in which a number of treatments are available for evaluation in phase II clinical trials and where it may be infeasible to try them concurrently because the intended population is small. This paper introduces an extension of previous work on decision-theoretic designs for a series of phase II trials. The program encompasses a series of sequential phase II trials with interim decision making and a single two-arm phase III trial. The design is based on a hybrid approach where the final analysis of the phase III data is based on a classical frequentist hypothesis test, whereas the trials are designed using a Bayesian decision-theoretic approach in which the unknown treatment effect is assumed to follow a known prior distribution. In addition, as treatments are intended for the same population it is not unrealistic to consider treatment effects to be correlated. Thus, the prior distribution will reflect this. Data from a randomized trial of severe arthritis of the hip are used to test the application of the design. We show that the design on average requires fewer patients in phase II than when the correlation is ignored. Correspondingly, the time required to recommend an efficacious treatment for phase III is quicker. © 2017 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeted therapy for localized non-small-cell lung cancer: a review

PubMed Central

Paleiron, Nicolas; Bylicki, Olivier; André, Michel; Rivière, Emilie; Grassin, Frederic; Robinet, Gilles; Chouaïd, Christos

2016-01-01

Targeted therapies have markedly improved the management of patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy in localized NSCLC is less well established. The aim of this review is to analyze trials of targeted therapies in localized NSCLC. In patients with wild-type EGFR, tyrosine kinase inhibitors have shown no efficacy in Phase III trials. Few data are available for EGFR-mutated localized NSCLC, as routine biological profiling is not recommended. Available studies are small, often retrospectives, and/or conducted in a single-center making it difficult to draw firm conclusions. Ongoing prospective Phase III trials are comparing adjuvant tyrosine kinase inhibitor administration versus adjuvant chemotherapy. By analogy with the indication of bevacizumab in advanced NSCLC, use of antiangiogenic agents in the perioperative setting is currently restricted to nonsquamous NSCLC. Several trials of adjuvant or neoadjuvant bevacizumab are planned or ongoing, but for the moment there is no evidence of efficacy. Data on perioperative use of biomarkers in early-stage NSCLC come mainly from small, retrospective, uncontrolled studies. Assessment of customized adjuvant or neoadjuvant therapy in localized NSCLC (with or without oncogenic driver mutations) is a major challenge. PMID:27462164

Phase-II trials in osteosarcoma recurrences: A systematic review of past experience.

PubMed

Omer, Natacha; Le Deley, Marie-Cécile; Piperno-Neumann, Sophie; Marec-Berard, Perrine; Italiano, Antoine; Corradini, Nadège; Bellera, Carine; Brugières, Laurence; Gaspar, Nathalie

2017-04-01

The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. To study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Systematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point. Copyright © 2017 Elsevier Ltd. All rights reserved.

Foraging enrichment for stabled horses: effects on behaviour and selection.

PubMed

Goodwin, D; Davidson, H P B; Harris, P

2002-11-01

The restricted access to pasture experienced by many competition horses has been linked to the exhibition of stereotypic and redirected behaviour patterns. It has been suggested that racehorses provided with more than one source of forage are less likely to perform these patterns; however, the reasons for this are currently unclear. To investigate this in 4 replicated trials, up to 12 horses were introduced into each of 2 identical stables containing a single forage, or 6 forages for 5 min. To detect novelty effects, in the first and third trials the single forage was hay. In the second and fourth, it was the preferred forage from the preceding trial. Trials were videotaped and 12 mutually exclusive behaviour patterns compared. When hay was presented as the single forage (Trials 1 and 3), all recorded behaviour patterns were significantly different between stables; e.g. during Trial 3 in the 'Single' stable, horses looked over the stable door more frequently (P<0.001), moved for longer (P<0.001), foraged on straw bedding longer (P<0.001), and exhibited behaviour indicative of motivation to search for alternative resources (P<0.001) more frequently. When a previously preferred forage was presented as the single forage (Trials 2 and 4) behaviour was also significantly different between stables, e.g in Trial 4 horses looked out over the stable door more frequently (P<0.005) and foraged for longer in their straw bedding (P<0.005). Further study is required to determine whether these effects persist over longer periods. However, these trials indicate that enrichment of the stable environment through provision of multiple forages may have welfare benefits for horses, in reducing straw consumption and facilitating the expression of highly motivated foraging behaviour.

Economic evaluation of adult rehabilitation: a systematic review and meta-analysis of randomized controlled trials in a variety of settings.

PubMed

Brusco, Natasha Kareem; Taylor, Nicholas F; Watts, Jennifer J; Shields, Nora

2014-01-01

To report if there is a difference in costs from a societal perspective between adults receiving rehabilitation in an inpatient rehabilitation setting versus an alternative setting. If there are cost differences, to report whether opting for the least expensive program setting adversely affects patient outcomes. Electronic databases from the earliest possible date until May 2011. All languages were included. Multiple reviewers identified randomized controlled trials with a full economic evaluation that compared adult inpatient rehabilitation with an alternative. There were 29 included trials with 6746 participants. Multiple observers extracted data independently. Trial appraisal included a risk of bias assessment and a checklist to report the strength of the economic evaluation. Results were synthesized using standardized mean differences (SMDs) and meta-analyses for the primary outcome of cost. The Grading of Recommendations Assessment, Development, and Evaluation was applied to assess for risk of bias across studies for meta-analyses. There was high-quality evidence that cost was significantly reduced for rehabilitation in the home versus inpatient rehabilitation in a meta-analysis of 732 patients poststroke (pooled SMD [δ]=-.28; 95% confidence interval [CI], -.47 to -.09), without compromise to patient outcomes. Results of individual trials in other patient groups (orthopedic, rheumatoid arthritis, and geriatric) receiving rehabilitation in the home or community were generally consistent with the meta-analysis. There was moderate quality evidence that cost was significantly reduced for inpatient rehabilitation (stroke unit) versus general acute care in a meta-analysis of 463 patients poststroke (δ=.31; 95% CI, .15-.48), with improvement to patient outcomes. These results were not replicated in 2 individual trials with a geriatric and a mixed cohort, where costs did not differ between general acute care and inpatient rehabilitation. Three of the 4 individual trials, inclusive of a stroke or orthopedic population, reported less cost for an intensive inpatient rehabilitation program compared with usual inpatient rehabilitation. Sensitivity analysis included a health service perspective and varied inflation rates with no change to the significant findings of the meta-analyses. Based on this systematic review and meta-analyses, a single rehabilitation service may not provide health economic benefits for all patient groups and situations. For some patients, inpatient rehabilitation may be the most cost-effective method of providing rehabilitation; yet, for other patients, rehabilitation in the home or community may be the most cost-effective model of care. To achieve cost-effective outcomes, the ideal combination of rehabilitation services and patient inclusion criteria, as well as further data for nonstroke populations, warrants further research. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

STI in remote communities: improved and enhanced primary health care (STRIVE) study protocol: a cluster randomised controlled trial comparing ‘usual practice’ STI care to enhanced care in remote primary health care services in Australia

PubMed Central

2013-01-01

Background Despite two decades of interventions, rates of sexually transmissible infections (STI) in remote Australian Aboriginal communities remain unacceptably high. Routine notifications data from 2011 indicate rates of chlamydia and gonorrhoea among Aboriginal people in remote settings were 8 and 61 times higher respectively than in the non-Indigenous population. Methods/design STRIVE is a stepped-wedge cluster randomised trial designed to compare a sexual health quality improvement program (SHQIP) to usual STI clinical care delivered in remote primary health care services. The SHQIP is a multifaceted intervention comprising annual assessments of sexual health service delivery, implementation of a sexual health action plan, six-monthly clinical service activity data reports, regular feedback meetings with a regional coordinator, training and financial incentive payments. The trial clusters comprise either a single community or several communities grouped together based on geographic proximity and cultural ties. The primary outcomes are: prevalence of chlamydia, gonorrhoea and trichomonas in Aboriginal residents aged 16–34 years, and performance in clinical management of STIs based on best practice indicators. STRIVE will be conducted over five years comprising one and a half years of trial initiation and community consultation, three years of trial conditions, and a half year of data analysis. The trial was initiated in 68 remote Aboriginal health services in the Northern Territory, Queensland and Western Australia. Discussion STRIVE is the first cluster randomised trial in STI care in remote Aboriginal health services. The trial will provide evidence to inform future culturally appropriate STI clinical care and control strategies in communities with high STI rates. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12610000358044 PMID:24016143

Effects of the GABA(B) receptor agonist baclofen administered orally on normal food intake and intraperitoneally on fat intake in non-deprived rats.

PubMed

Bains, Rasneer S; Ebenezer, Ivor S

2013-01-05

It has been previously reported that the GABA(B) receptor agonist baclofen decreases food intake after oral administration and fat intake after intraperitoneal administration. The aim of the study was to investigate the effects of baclofen (1-4 mg/ kg) administered orally (Experiment 1) on food intake in non-deprived rats (n=6) and intraperitoneally (Experiment 2) on fat intake in non-deprived rats (n=8) that were naïve to baclofen (1st set of trials) and in the same group of rats after they were sub-chronically exposed to baclofen (2nd set of trials). The results from Experiment 1 show that baclofen had no effects on food intake during the 1st set of trials, but the 2 and 4 mg/kg doses significantly increased food consumption during the 2nd set of trials. Baclofen produced sedation during the 1st set of trials, but tolerance occurred to this effect and was not apparent during the 2nd set of trials. These observations suggest that the motor effects may have competed with the hyperphagic effects of baclofen during the 1st set of trials. The data from Experiment 2 show that baclofen had no effects on fat intake during either the 1st or 2nd set of trials. The results of the study thus indicate that orally administrated baclofen increases food intake and intraperitoneal administration has no effect on fat intake in non-deprived rats under the conditions used in this study. These findings may have important implications for research on the use of baclofen in studies concerned with ingestive behaviours. Copyright © 2012 Elsevier B.V. All rights reserved.

Intervention description is not enough: evidence from an in-depth multiple case study on the untold role and impact of context in randomised controlled trials of seven complex interventions

PubMed Central

2012-01-01

Background A number of single case reports have suggested that the context within which intervention studies take place may challenge the assumptions that underpin randomised controlled trials (RCTs). However, the diverse ways in which context may challenge the central tenets of the RCT, and the degree to which this information is known to researchers or subsequently reported, has received much less attention. In this paper, we explore these issues by focusing on seven RCTs of interventions varying in type and degree of complexity, and across diverse contexts. Methods This in-depth multiple case study using interviews, focus groups and documentary analysis was conducted in two phases. In phase one, a RCT of a nurse-led intervention provided a single exploratory case and informed the design, sampling and data collection within the main study. Phase two consisted of a multiple explanatory case study covering a spectrum of trials of different types of complex intervention. A total of eighty-four data sources across the seven trials were accessed. Results We present consistent empirical evidence across all trials to indicate that four key elements of context (personal, organisational, trial and problem context) are crucial to understanding how a complex intervention works and to enable both assessments of internal validity and likely generalisability to other settings. The ways in which context challenged trial operation was often complex, idiosyncratic, and subtle; often falling outside of current trial reporting formats. However, information on such issues appeared to be available via first hand ‘insider accounts’ of each trial suggesting that improved reporting on the role of context is possible. Conclusions Sufficient detail about context needs to be understood and reported in RCTs of complex interventions, in order for the transferability of complex interventions to be assessed. Improved reporting formats that require and encourage the clarification of both general and project-specific threats to the likely internal and external validity need to be developed. In addition, a cultural change is required in which the open and honest reporting of such issues is seen as an indicator of study strength and researcher integrity, rather than a symbol of a poor quality study or investigator ability. PMID:22742939

Comparison of Critical Power and W' Derived From 2 or 3 Maximal Tests.

PubMed

Simpson, Len Parker; Kordi, Mehdi

2017-07-01

Typically, accessing the asymptote (critical power; CP) and curvature constant (W') parameters of the hyperbolic power-duration relationship requires multiple constant-power exhaustive-exercise trials spread over several visits. However, more recently single-visit protocols and personal power meters have been used. This study investigated the practicality of using a 2-trial, single-visit protocol in providing reliable CP and W' estimates. Eight trained cyclists underwent 3- and 12-min maximal-exercise trials in a single session to derive (2-trial) CP and W' estimates. On a separate occasion a 5-min trial was performed, providing a 3rd trial to calculate (3-trial) CP and W'. There were no differences in CP (283 ± 66 vs 282 ± 65 W) or W' (18.72 ± 6.21 vs 18.27 ± 6.29 kJ) obtained from either the 2-trial or 3-trial method, respectively. After 2 familiarization sessions (completing a 3- and a 12-min trial on both occasions), both CP and W' remained reliable over additional separate measurements. The current study demonstrates that after 2 familiarization sessions, reliable CP and W' parameters can be obtained from trained cyclists using only 2 maximal-exercise trials. These results offer practitioners a practical, time-efficient solution for incorporating power-duration testing into applied athlete support.

Single-Trial Regression Elucidates the Role of Prefrontal Theta Oscillations in Response Conflict

PubMed Central

Cohen, Michael X; Cavanagh, James F.

2011-01-01

In most cognitive neuroscience experiments there are many behavioral and experimental dynamics, and many indices of brain activity, that vary from trial to trial. For example, in studies of response conflict, conflict is usually treated as a binary variable (i.e., response conflict exists or does not in any given trial), whereas some evidence and intuition suggests that conflict may vary in intensity from trial to trial. Here we demonstrate that single-trial multiple regression of time–frequency electrophysiological activity reveals neural mechanisms of cognitive control that are not apparent in cross-trial averages. We also introduce a novel extension to oscillation phase coherence and synchronization analyses, based on “weighted” phase modulation, that has advantages over standard coherence measures in terms of linking electrophysiological dynamics to trial-varying behavior and experimental variables. After replicating previous response conflict findings using trial-averaged data, we extend these findings using single-trial analytic methods to provide novel evidence for the role of medial frontal–lateral prefrontal theta-band synchronization in conflict-induced response time dynamics, including a role for lateral prefrontal theta-band activity in biasing response times according to perceptual conflict. Given that these methods shed new light on the prefrontal mechanisms of response conflict, they are also likely to be useful for investigating other neurocognitive processes. PMID:21713190

Robot-assisted single-site compared with laparoscopic single-incision cholecystectomy for benign gallbladder disease: protocol for a randomized controlled trial.

PubMed

Grochola, Lukasz Filip; Soll, Christopher; Zehnder, Adrian; Wyss, Roland; Herzog, Pascal; Breitenstein, Stefan

2017-02-09

Recent advances in robotic technology suggest that the utilization of the da Vinci Single-Site™ platform for cholecystectomy is safe, feasible and results in a shorter learning curve compared to conventional single-incision laparoscopic cholecystectomy. Moreover, the robot-assisted technology has been shown to reduce the surgeon's stress load compared to standard single-incision laparoscopy in an experimental setup, suggesting an important advantage of the da Vinci platform. However, the above-mentioned observations are based solely on case series, case reports and experimental data, as high-quality clinical trials to demonstrate the benefits of the da Vinci Single-Site™ cholecystectomy have not been performed to date. This study addresses the question whether robot-assisted Single-Site™ cholecystectomy provides significant benefits over single-incision laparoscopic cholecystectomy in terms of surgeon's stress load, while matching the standards of the conventional single-incision approach with regard to peri- and postoperative outcomes. It is designed as a single centre, single-blinded randomized controlled trial, which compares both surgical approaches with the primary endpoint surgeon's physical and mental stress load at the time of surgery. In addition, the study aims to assess secondary endpoints such as operating time, conversion rates, additional trocar placement, intra-operative blood loss, length of hospital stay, costs of procedure, health-related quality of life, cosmesis and complications. Patients as well as ward staff are blinded until the 1 st postoperative year. Sample size calculation based on the results of a previously published experimental setup utilizing an estimated effect size of surgeon's comfort of 0.8 (power of 0.8, alpha-error level of 0.05, error margin of 10-15%) resulted in a number of 30 randomized patients per arm. The study is the first randomized controlled trial that compares the da Vinci Single Site™ platform to conventional laparoscopic approaches in cholecystectomy, one of the most frequently performed operations in general surgery. This trial is registered at clinicaltrials.gov (trial number: NCT02485392 ). Registered February 19, 2015.

Single-trial detection of visual evoked potentials by common spatial patterns and wavelet filtering for brain-computer interface.

PubMed

Tu, Yiheng; Huang, Gan; Hung, Yeung Sam; Hu, Li; Hu, Yong; Zhang, Zhiguo

2013-01-01

Event-related potentials (ERPs) are widely used in brain-computer interface (BCI) systems as input signals conveying a subject's intention. A fast and reliable single-trial ERP detection method can be used to develop a BCI system with both high speed and high accuracy. However, most of single-trial ERP detection methods are developed for offline EEG analysis and thus have a high computational complexity and need manual operations. Therefore, they are not applicable to practical BCI systems, which require a low-complexity and automatic ERP detection method. This work presents a joint spatial-time-frequency filter that combines common spatial patterns (CSP) and wavelet filtering (WF) for improving the signal-to-noise (SNR) of visual evoked potentials (VEP), which can lead to a single-trial ERP-based BCI.

Blockchain technology for improving clinical research quality.

PubMed

Benchoufi, Mehdi; Ravaud, Philippe

2017-07-19

Reproducibility, data sharing, personal data privacy concerns and patient enrolment in clinical trials are huge medical challenges for contemporary clinical research. A new technology, Blockchain, may be a key to addressing these challenges and should draw the attention of the whole clinical research community.Blockchain brings the Internet to its definitive decentralisation goal. The core principle of Blockchain is that any service relying on trusted third parties can be built in a transparent, decentralised, secure "trustless" manner at the top of the Blockchain (in fact, there is trust, but it is hardcoded in the Blockchain protocol via a complex cryptographic algorithm). Therefore, users have a high degree of control over and autonomy and trust of the data and its integrity. Blockchain allows for reaching a substantial level of historicity and inviolability of data for the whole document flow in a clinical trial. Hence, it ensures traceability, prevents a posteriori reconstruction and allows for securely automating the clinical trial through what are called Smart Contracts. At the same time, the technology ensures fine-grained control of the data, its security and its shareable parameters, for a single patient or group of patients or clinical trial stakeholders.In this commentary article, we explore the core functionalities of Blockchain applied to clinical trials and we illustrate concretely its general principle in the context of consent to a trial protocol. Trying to figure out the potential impact of Blockchain implementations in the setting of clinical trials will shed new light on how modern clinical trial methods could evolve and benefit from Blockchain technologies in order to tackle the aforementioned challenges.

The PREEMPT study - evaluating smartphone-assisted n-of-1 trials in patients with chronic pain: study protocol for a randomized controlled trial.

PubMed

Barr, Colin; Marois, Maria; Sim, Ida; Schmid, Christopher H; Wilsey, Barth; Ward, Deborah; Duan, Naihua; Hays, Ron D; Selsky, Joshua; Servadio, Joseph; Schwartz, Marc; Dsouza, Clyde; Dhammi, Navjot; Holt, Zachary; Baquero, Victor; MacDonald, Scott; Jerant, Anthony; Sprinkle, Ron; Kravitz, Richard L

2015-02-27

Chronic pain is prevalent, costly, and clinically vexatious. Clinicians typically use a trial-and-error approach to treatment selection. Repeated crossover trials in a single patient (n-of-1 trials) may provide greater therapeutic precision. N-of-1 trials are the most direct way to estimate individual treatment effects and are useful in comparing the effectiveness and toxicity of different analgesic regimens. The goal of the PREEMPT study is to test the 'Trialist' mobile health smartphone app, which has been developed to make n-of-1 trials easier to accomplish, and to provide patients and clinicians with tools for individualizing treatments for chronic pain. A randomized controlled trial is being conducted to test the feasibility and effectiveness of the Trialist app. A total of 244 participants will be randomized to either the Trialist app intervention group (122 patients) or a usual care control group (122 patients). Patients assigned to the Trialist app will work with their clinicians to set up an n-of-1 trial comparing two pain regimens, selected from a menu of flexible options. The Trialist app provides treatment reminders and collects data entered daily by the patient on pain levels and treatment side effects. Upon completion of the n-of-1 trial, patients review results with their clinicians and develop a long-term treatment plan. The primary study outcome (comparing Trialist to usual care patients) is pain-related interference with daily functioning at 26 weeks. Trialist will allow patients and clinicians to conduct personalized n-of-1 trials. In prior studies, n-of-1 trials have been shown to encourage greater patient involvement with care, which has in turn been associated with better health outcomes. mHealth technology implemented using smartphones may offer an efficient means of facilitating n-of-1 trials so that more patients can benefit from this approach. ClinicalTrials.gov: NCT02116621 , first registered 15 April 2014.

Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010.

PubMed

Califf, Robert M; Zarin, Deborah A; Kramer, Judith M; Sherman, Rachel E; Aberle, Laura H; Tasneem, Asba

2012-05-02

Recent reports highlight gaps between guidelines-based treatment recommendations and evidence from clinical trials that supports those recommendations. Strengthened reporting requirements for studies registered with ClinicalTrials.gov enable a comprehensive evaluation of the national trials portfolio. To examine fundamental characteristics of interventional clinical trials registered in the ClinicalTrials.gov database. A data set comprising 96,346 clinical studies from ClinicalTrials.gov was downloaded on September 27, 2010, and entered into a relational database to analyze aggregate data. Interventional trials were identified and analyses were focused on 3 clinical specialties-cardiovascular, mental health, and oncology-that together encompass the largest number of disability-adjusted life-years lost in the United States. Characteristics of registered clinical trials as reported data elements in the trial registry; how those characteristics have changed over time; differences in characteristics as a function of clinical specialty; and factors associated with use of randomization, blinding, and data monitoring committees (DMCs). The number of registered interventional clinical trials increased from 28,881 (October 2004-September 2007) to 40,970 (October 2007-September 2010), and the number of missing data elements has generally declined. Most interventional trials registered between 2007 and 2010 were small, with 62% enrolling 100 or fewer participants. Many clinical trials were single-center (66%; 24,788/37,520) and funded by organizations other than industry or the National Institutes of Health (NIH) (47%; 17,592/37,520). Heterogeneity in the reported methods by clinical specialty; sponsor type; and the reported use of DMCs, randomization, and blinding was evident. For example, reported use of DMCs was less common in industry-sponsored vs NIH-sponsored trials (adjusted odds ratio [OR], 0.11; 95% CI, 0.09-0.14), earlier-phase vs phase 3 trials (adjusted OR, 0.83; 95% CI, 0.76-0.91), and mental health trials vs those in the other 2 specialties. In similar comparisons, randomization and blinding were less frequently reported in earlier-phase, oncology, and device trials. Clinical trials registered in ClinicalTrials.gov are dominated by small trials and contain significant heterogeneity in methodological approaches, including reported use of randomization, blinding, and DMCs.

The Effects of Test Trial and Processing Level on Immediate and Delayed Retention.

PubMed

Chang, Sau Hou

2017-03-01

The purpose of the present study was to investigate the effects of test trial and processing level on immediate and delayed retention. A 2 × 2 × 2 mixed ANOVAs was used with two between-subject factors of test trial (single test, repeated test) and processing level (shallow, deep), and one within-subject factor of final recall (immediate, delayed). Seventy-six college students were randomly assigned first to the single test (studied the stimulus words three times and took one free-recall test) and the repeated test trials (studied the stimulus words once and took three consecutive free-recall tests), and then to the shallow processing level (asked whether each stimulus word was presented in capital letter or in small letter) and the deep processing level (whether each stimulus word belonged to a particular category) to study forty stimulus words. The immediate test was administered five minutes after the trials, whereas the delayed test was administered one week later. Results showed that single test trial recalled more words than repeated test trial in immediate final free-recall test, participants in deep processing performed better than those in shallow processing in both immediate and delayed retention. However, the dominance of single test trial and deep processing did not happen in delayed retention. Additional study trials did not further enhance the delayed retention of words encoded in deep processing, but did enhance the delayed retention of words encoded in shallow processing.

The Effects of Test Trial and Processing Level on Immediate and Delayed Retention

PubMed Central

Chang, Sau Hou

2017-01-01

The purpose of the present study was to investigate the effects of test trial and processing level on immediate and delayed retention. A 2 × 2 × 2 mixed ANOVAs was used with two between-subject factors of test trial (single test, repeated test) and processing level (shallow, deep), and one within-subject factor of final recall (immediate, delayed). Seventy-six college students were randomly assigned first to the single test (studied the stimulus words three times and took one free-recall test) and the repeated test trials (studied the stimulus words once and took three consecutive free-recall tests), and then to the shallow processing level (asked whether each stimulus word was presented in capital letter or in small letter) and the deep processing level (whether each stimulus word belonged to a particular category) to study forty stimulus words. The immediate test was administered five minutes after the trials, whereas the delayed test was administered one week later. Results showed that single test trial recalled more words than repeated test trial in immediate final free-recall test, participants in deep processing performed better than those in shallow processing in both immediate and delayed retention. However, the dominance of single test trial and deep processing did not happen in delayed retention. Additional study trials did not further enhance the delayed retention of words encoded in deep processing, but did enhance the delayed retention of words encoded in shallow processing. PMID:28344679

Evaluation and comparison of predictive individual-level general surrogates.

PubMed

Gabriel, Erin E; Sachs, Michael C; Halloran, M Elizabeth

2018-07-01

An intermediate response measure that accurately predicts efficacy in a new setting at the individual level could be used both for prediction and personalized medical decisions. In this article, we define a predictive individual-level general surrogate (PIGS), which is an individual-level intermediate response that can be used to accurately predict individual efficacy in a new setting. While methods for evaluating trial-level general surrogates, which are predictors of trial-level efficacy, have been developed previously, few, if any, methods have been developed to evaluate individual-level general surrogates, and no methods have formalized the use of cross-validation to quantify the expected prediction error. Our proposed method uses existing methods of individual-level surrogate evaluation within a given clinical trial setting in combination with cross-validation over a set of clinical trials to evaluate surrogate quality and to estimate the absolute prediction error that is expected in a new trial setting when using a PIGS. Simulations show that our method performs well across a variety of scenarios. We use our method to evaluate and to compare candidate individual-level general surrogates over a set of multi-national trials of a pentavalent rotavirus vaccine.

Single treatments that have lasting effects: some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin.

PubMed

Young, Simon N

2013-03-01

Recent clinical trials suggest that 3 single biological treatments have effects that persist. Based on research showing that the muscles involved in facial expressions can feed back to influence mood, a single trial diminishing glabella frown lines with botulinum toxin demonstrated a significant antidepressant effect for 16 weeks. Based primarily on research with animal models of depression suggesting that glutamate may be involved in depression, the N-methyl-D-aspartate antagonist ketamine has been tested in several trials. A single dose decreased depression for up to a week. The reported effects of the use of mushrooms containing psilocybin by a number of cultures around the world has stimulated several trials showing beneficial effects of a single dose of psilocybin for over a year in healthy people, and for up to 3 months in patients with anxiety disorders who have advanced cancer. This article discusses these studies, their rationale, their possible mechanisms of action, the future clinical research required to establish these therapies and the basic research required to optimize single treatments that have lasting effects.

[Research on the methods for multi-class kernel CSP-based feature extraction].

PubMed

Wang, Jinjia; Zhang, Lingzhi; Hu, Bei

2012-04-01

To relax the presumption of strictly linear patterns in the common spatial patterns (CSP), we studied the kernel CSP (KCSP). A new multi-class KCSP (MKCSP) approach was proposed in this paper, which combines the kernel approach with multi-class CSP technique. In this approach, we used kernel spatial patterns for each class against all others, and extracted signal components specific to one condition from EEG data sets of multiple conditions. Then we performed classification using the Logistic linear classifier. Brain computer interface (BCI) competition III_3a was used in the experiment. Through the experiment, it can be proved that this approach could decompose the raw EEG singles into spatial patterns extracted from multi-class of single trial EEG, and could obtain good classification results.

Reliability analysis of a sensitive and independent stabilometry parameter set

PubMed Central

Nagymáté, Gergely; Orlovits, Zsanett

2018-01-01

Recent studies have suggested reduced independent and sensitive parameter sets for stabilometry measurements based on correlation and variance analyses. However, the reliability of these recommended parameter sets has not been studied in the literature or not in every stance type used in stabilometry assessments, for example, single leg stances. The goal of this study is to evaluate the test-retest reliability of different time-based and frequency-based parameters that are calculated from the center of pressure (CoP) during bipedal and single leg stance for 30- and 60-second measurement intervals. Thirty healthy subjects performed repeated standing trials in a bipedal stance with eyes open and eyes closed conditions and in a single leg stance with eyes open for 60 seconds. A force distribution measuring plate was used to record the CoP. The reliability of the CoP parameters was characterized by using the intraclass correlation coefficient (ICC), standard error of measurement (SEM), minimal detectable change (MDC), coefficient of variation (CV) and CV compliance rate (CVCR). Based on the ICC, SEM and MDC results, many parameters yielded fair to good reliability values, while the CoP path length yielded the highest reliability (smallest ICC > 0.67 (0.54–0.79), largest SEM% = 19.2%). Usually, frequency type parameters and extreme value parameters yielded poor reliability values. There were differences in the reliability of the maximum CoP velocity (better with 30 seconds) and mean power frequency (better with 60 seconds) parameters between the different sampling intervals. PMID:29664938

Reliability analysis of a sensitive and independent stabilometry parameter set.

PubMed

Nagymáté, Gergely; Orlovits, Zsanett; Kiss, Rita M

2018-01-01

Recent studies have suggested reduced independent and sensitive parameter sets for stabilometry measurements based on correlation and variance analyses. However, the reliability of these recommended parameter sets has not been studied in the literature or not in every stance type used in stabilometry assessments, for example, single leg stances. The goal of this study is to evaluate the test-retest reliability of different time-based and frequency-based parameters that are calculated from the center of pressure (CoP) during bipedal and single leg stance for 30- and 60-second measurement intervals. Thirty healthy subjects performed repeated standing trials in a bipedal stance with eyes open and eyes closed conditions and in a single leg stance with eyes open for 60 seconds. A force distribution measuring plate was used to record the CoP. The reliability of the CoP parameters was characterized by using the intraclass correlation coefficient (ICC), standard error of measurement (SEM), minimal detectable change (MDC), coefficient of variation (CV) and CV compliance rate (CVCR). Based on the ICC, SEM and MDC results, many parameters yielded fair to good reliability values, while the CoP path length yielded the highest reliability (smallest ICC > 0.67 (0.54-0.79), largest SEM% = 19.2%). Usually, frequency type parameters and extreme value parameters yielded poor reliability values. There were differences in the reliability of the maximum CoP velocity (better with 30 seconds) and mean power frequency (better with 60 seconds) parameters between the different sampling intervals.

Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study.

PubMed

Blackwood, Bronagh; Ringrow, Suzanne; Clarke, Mike; Marshall, John; Rose, Louise; Williamson, Paula; McAuley, Danny

2015-08-20

Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children. We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes. The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

Duration of treatment for asymptomatic bacteriuria during pregnancy.

PubMed

Villar, J; Lydon-Rochelle, M T; Gülmezoglu, A M; Roganti, A

2000-01-01

A Cochrane systematic review has shown that drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis and reduces the risk of preterm delivery. However, it is not clear whether single dose therapy is as effective as longer conventional antibiotic treatment. The objective of this review was to assess the effects of different durations of treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and the reference lists of articles. Randomised and quasi-randomised trials comparing antimicrobial therapeutic regimens that differed in duration (particularly comparing single dose with longer duration regimens) in pregnant women diagnosed with asymptomatic bacteriuria. Trial quality was assessed and data were extracted independently by the reviewers. Eight studies involving over 400 women were included. All were comparisons of single dose treatment with four to seven day treatments. The trials were generally of poor quality. No difference in 'no-cure' rate was detected between single dose and short course (4-7 day) treatment for asymptomatic bacteriuria in pregnant women (relative risk 1.13, 95% confidence interval 0.82 to 1.54) as well as in the recurrent asymptomtic bacteriuria (relative risk 1.08, 95% confidence interval 0.70 to 1.66). However these results showed significant heterogeneity. No differences were detected for preterm births and pyelonephritis although sample size of trials was small. Longer duration treatment was associated with an increase in reports of adverse effects (relative risk 0.53, 95% confidence interval 0.31 to 0.91). There is not enough evidence to evaluate whether single dose or longer duration doses are more effective in treating asymptomatic bacteriuria in pregnant women. Because single dose has lower cost and increases compliance, this comparison should be explored in a properly sized randomized controlled trial.

Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance.

PubMed

Taylor-Robinson, David C; Maayan, Nicola; Soares-Weiser, Karla; Donegan, Sarah; Garner, Paul

2012-11-14

The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. The WHO state this will improve nutritional status, haemoglobin, and cognition and thus will improve health, intellect, and school attendance. Consequently, it is claimed that school performance will improve, child mortality will decline, and economic productivity will increase. Given the important health and societal benefits attributed to this intervention, we sought to determine whether they are based on reliable evidence. To summarize the effects of giving deworming drugs to children to treat soil-transmitted intestinal worms (nematode geohelminths) on weight, haemoglobin, and cognition; and the evidence of impact on physical well being, school attendance, school performance, and mortality. In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, EMBASE, LILACS, mRCT, and reference lists, and registers of ongoing and completed trials. We selected randomized controlled trials (RCTs) and quasi-RCTs comparing deworming drugs for geohelminth worms with placebo or no treatment in children aged 16 years or less, reporting on weight, haemoglobin, and formal test of intellectual development. In cluster-RCTs treating communities or schools, we also sought data on school attendance, school performance, and mortality. We included trials that included health education with deworming. At least two authors independently assessed the trials, evaluated risk of bias, and extracted data. Continuous data were analysed using the mean difference (MD) with 95% confidence intervals (CI). Where data were missing, we contacted trial authors. We used GRADE to assess evidence quality, and this is reflected in the wording we used: high quality ("deworming improves...."); moderate quality ("deworming probably improves..."); low quality ("deworming may improve...."); and very low quality ("we don't know if deworming improves...."). We identified 42 trials, including eight cluster trials, that met the inclusion criteria. Excluding one trial where data are awaited, the 41 trials include 65,168 participants.Screening then treatingFor children known to be infected with worms (by screening), a single dose of deworming drugs may increase weight (0.58 kg, 95% CI 0.40 to 0.76, three trials, 139 participants; low quality evidence) and may increase haemoglobin (0.37 g/dL, 95% CI 0.1 to 0.64, two trials, 108 participants; low quality evidence), but we do not know if there is an effect on cognitive functioning (two trials, very low quality evidence).Single dose deworming for all childrenIn trials treating all children, a single dose of deworming drugs gave mixed effects on weight, with no effects evident in seven trials, but large effects in two (nine trials, 3058 participants, very low quality evidence). The two trials with a positive effect were from the same very high prevalence setting and may not be easily generalised elsewhere. Single dose deworming probably made little or no effect on haemoglobin (mean difference (MD) 0.06 g/dL, 95% CI -0.06 to 0.17, three trials, 1005 participants; moderate evidence), and may have little or no effect on cognition (two trials, low quality evidence).Mulitple dose deworming for all childrenOver the first year of follow up, multiple doses of deworming drugs given to all children may have little or no effect on weight (MD 0.06 kg, 95% CI -0.17 to 0.30; seven trials, 2460 participants; low quality evidence); haemoglobin, (mean 0.01 g/dL lower; 95% CI 0.14 lower to 0.13 higher; four trials, 807 participants; low quality evidence); cognition (three trials, 30,571 participants, low quality evidence); or school attendance (4% higher attendance; 95% CI -6 to 14; two trials, 30,243 participants; low quality evidence);For time periods beyond a year, there were five trials with weight measures. One cluster-RCT of 3712 children in a low prevalence area showed a large effect (average gain of 0.98 kg), whilst the other four trials did not show an effect, including a cluster-RCT of 27,995 children in a moderate prevalence area (five trials, 37,306 participants; low quality evidence). For height, we are uncertain whether there is an effect of deworming (-0.26 cm; 95% CI -0.84 to 0.31, three trials, 6652 participants; very low quality evidence). Deworming may have little or no effect on haemoglobin (0.00 g/dL, 95%CI -0.08 to 0.08, two trials, 1365 participants, low quality evidence); cognition (two trials, 3720 participants; moderate quality evidence). For school attendance, we are uncertain if there is an effect (mean attendance 5% higher, 95% CI -0.5 to 10.5, approximately 20,000 participants, very low quality evidence).Stratified analysis to seek subgroup effects into low, medium and high helminth endemicity areas did not demonstrate any pattern of effect. In a sensitivity analysis that only included trials with adequate allocation concealment, we detected no significant effects for any primary outcomes.One million children were randomized in a deworming trial from India with mortality as the primary outcome. This was completed in 2005 but the authors have not published the results. Screening children for intestinal helminths and then treating infected children appears promising, but the evidence base is small. Routine deworming drugs given to school children has been more extensively investigated, and has not shown benefit on weight in most studies, except for substantial weight changes in three trials conducted 15 years ago or more. Two of these trials were carried out in the same high prevalence setting. For haemoglobin and cognition, community deworming seems to have little or no effect, and the evidence in relation to school attendance, and school performance is generally poor, with no obvious or consistent effect. Our interpretation of this data is that it is probably misleading to justify contemporary deworming programmes based on evidence of consistent benefit on nutrition, haemoglobin, school attendance or school performance as there is simply insufficient reliable information to know whether this is so.

Multiple Vaccinations: Friend or Foe

PubMed Central

Church, Sarah E.; Jensen, Shawn M.; Twitty, Chris; Bahjat, Keith; Hu, Hong-Ming; Urba, Walter J.; Fox, Bernard A.

2013-01-01

Few immunotherapists would accept the concept of a single vaccination inducing a therapeutic anti-cancer immune response in a patient with advanced cancer. But what is the evidence to support the “more-is-better” approach of multiple vaccinations? Since we are unaware of trials comparing the effect of a single vaccine versus multiple vaccinations on patient outcome, we considered that an anti-cancer immune response might provide a surrogate measure of the effectiveness of vaccination strategies. Since few large trials include immunological monitoring, the majority of information is gleaned from smaller trials in which an evaluation of immune responses to vaccine or tumor, before and at one or more times following the first vaccine was performed. In some studies there is convincing evidence that repeated administration of a specific vaccine can augment the immune response to antigens contained in the vaccine. In other settings multiple vaccinations can significantly reduce the immune response to one or more targets. Results from three large adjuvant vaccine studies support the potential detrimental effect of multiple vaccinations as clinical outcomes in the control arms were significantly better than that for treatment groups. Recent research has provided insights into mechanisms that are likely responsible for the reduced responses in the studies noted above, but supporting evidence from clinical specimens is generally lacking. Interpretation of these results is further complicated by the possibility that the dominant immune response may evolve to recognize epitopes not present in the vaccine. Nonetheless, the FDA-approval of the first therapeutic cancer vaccine and recent developments from preclinical models and clinical trials provide a substantial basis for optimism and a critical evaluation of cancer vaccine strategies. PMID:21952289

A Multiinstitutional Phase 2 Trial of Pazopanib Monotherapy in Advanced Anaplastic Thyroid Cancer

PubMed Central

Suman, Vera J.; Menefee, Michael E.; Smallridge, Robert C.; Molina, Julian R.; Maples, William J.; Karlin, Nina J.; Traynor, Anne M.; Kumar, Priya; Goh, Boon Cher; Lim, Wan-Teck; Bossou, Ayoko R.; Isham, Crescent R.; Webster, Kevin P.; Kukla, Andrea K.; Bieber, Carolyn; Burton, Jill K.; Harris, Pamela; Erlichman, Charles

2012-01-01

Context/Objectives: Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC). Design/Setting/Patients/Interventions/Outcome Measures: Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response. Results: Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45–77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease. Conclusions: Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC. PMID:22774206

A systematic review of the quality of homeopathic clinical trials

PubMed Central

Jonas, Wayne B; Anderson, Rachel L; Crawford, Cindy C; Lyons, John S

2001-01-01

Background While a number of reviews of homeopathic clinical trials have been done, all have used methods dependent on allopathic diagnostic classifications foreign to homeopathic practice. In addition, no review has used established and validated quality criteria allowing direct comparison of the allopathic and homeopathic literature. Methods In a systematic review, we compared the quality of clinical-trial research in homeopathy to a sample of research on conventional therapies using a validated and system-neutral approach. All clinical trials on homeopathic treatments with parallel treatment groups published between 1945–1995 in English were selected. All were evaluated with an established set of 33 validity criteria previously validated on a broad range of health interventions across differing medical systems. Criteria covered statistical conclusion, internal, construct and external validity. Reliability of criteria application is greater than 0.95. Results 59 studies met the inclusion criteria. Of these, 79% were from peer-reviewed journals, 29% used a placebo control, 51% used random assignment, and 86% failed to consider potentially confounding variables. The main validity problems were in measurement where 96% did not report the proportion of subjects screened, and 64% did not report attrition rate. 17% of subjects dropped out in studies where this was reported. There was practically no replication of or overlap in the conditions studied and most studies were relatively small and done at a single-site. Compared to research on conventional therapies the overall quality of studies in homeopathy was worse and only slightly improved in more recent years. Conclusions Clinical homeopathic research is clearly in its infancy with most studies using poor sampling and measurement techniques, few subjects, single sites and no replication. Many of these problems are correctable even within a "holistic" paradigm given sufficient research expertise, support and methods. PMID:11801202

Mechanisms underlying flexible adaptation of cognitive control: behavioral and neuroimaging evidence in a flanker task.

PubMed

Zurawska Vel Grajewska, Blandyna; Sim, Eun-Jin; Hoenig, Klaus; Herrnberger, Bärbel; Kiefer, Markus

2011-11-03

Cognitive control can be adapted flexibly according to the conflict level in a given situation. In the Eriksen flanker task, interference evoked by flankers is larger in conditions with a higher, rather than a lower proportion of compatible trials. Such compatibility ratio effects also occur for stimuli presented at two spatial locations suggesting that different cognitive control settings can be simultaneously maintained. However, the conditions and the neural correlates of this flexible adaptation of cognitive control are only poorly understood. In the present study, we further elucidated the mechanisms underlying the simultaneous maintenance of two cognitive control settings. In behavioral experiments, stimuli were presented centrally above and below fixation and hence processed by both hemispheres or lateralized to stimulate hemispheres differentially. The different compatibility ratio at two stimulus locations had a differential influence on the flanker effect in both experiments. In an fMRI experiment, blocks with an identical compatibility ratio at two central spatial locations elicited stronger activity in a network of prefrontal and parietal brain areas, which are known to be involved in conflict resolution and cognitive control, as compared with blocks with a different compatibility ratio at the same spatial locations. This demonstrates that the simultaneous maintenance of two conflicting control settings vs. one single setting does not recruit additional neural circuits suggesting the involvement of one single cognitive control system. Instead a crosstalk between multiple control settings renders adaptation of cognitive control more efficient when only one uniform rather than two different control settings has to be simultaneously maintained. Copyright © 2011 Elsevier B.V. All rights reserved.

Achieving Consensus on Total Joint Replacement Trial Outcome Reporting Using the OMERACT Filter: Endorsement of the Final Core Domain Set for Total Hip and Total Knee Replacement Trials for Endstage Arthritis.

PubMed

Singh, Jasvinder A; Dowsey, Michelle M; Dohm, Michael; Goodman, Susan M; Leong, Amye L; Scholte Voshaar, Marieke M J H; Choong, Peter F

2017-11-01

Discussion and endorsement of the OMERACT total joint replacement (TJR) core domain set for total hip replacement (THR) and total knee replacement (TKR) for endstage arthritis; and next steps for selection of instruments. The OMERACT TJR working group met at the 2016 meeting at Whistler, British Columbia, Canada. We summarized the previous systematic reviews, the preliminary OMERACT TJR core domain set and results from previous surveys. We discussed preliminary core domains for TJR clinical trials, made modifications, and identified challenges with domain measurement. Working group participants (n = 26) reviewed, clarified, and endorsed each of the inner and middle circle domains and added a range of motion domain to the research agenda. TJR were limited to THR and TKR but included all endstage hip and knee arthritis refractory to medical treatment. Participants overwhelmingly endorsed identification and evaluation of top instruments mapping to the core domains (100%) and use of subscales of validated multidimensional instruments to measure core domains for the TJR clinical trial core measurement set (92%). An OMERACT core domain set for hip/knee TJR trials has been defined and we are selecting instruments to develop the TJR clinical trial core measurement set to serve as a common foundation for harmonizing measures in TJR clinical trials.

The effects of dehydration, moderate alcohol consumption, and rehydration on cognitive functions.

PubMed

Irwin, Christopher; Leveritt, Michael; Shum, David; Desbrow, Ben

2013-05-01

This study investigated the impact of mild-moderate dehydration on alcohol-induced deteriorations in cognitive functions. Sixteen healthy males participated in a single-blind, placebo-controlled cross-over design study involving 4 experimental trials (separated by ≥7 d). In each trial, participants were dehydrated by 2.5% body mass through exercise. After 1 h recovery in a thermo-neutral environment (22 ± 2 °C, 60-70% relative humidity) 4 tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered to the participants (test 1). In two of the trials, participants were provided with water equivalent to either 50% or 150% body mass loss and given salt (NaCl) capsules (50 mmol/L). A set volume of alcohol or placebo was then consumed in each trial, incorporating the conditions: dehydration-placebo (DP), dehydration-alcohol (DA), partial rehydration-alcohol (PA), and full rehydration-alcohol (FA). The same 4 CANTAB tasks were then re-administered (test 2). Subjective ratings of mood and estimates of alcohol intoxication and driving impairment were also recorded in each trial. Alcohol consumption caused deterioration on 3 of the 4 CANTAB measures (viz., choice reaction time, executive function and response inhibition). This reduction in performance was exacerbated when participants were dehydrated compared to trials where full rehydration occurred. Subjective ratings of impairment and intoxication were not significantly different between any of the trials where alcohol was consumed; however ratings for alcohol trials were significantly higher than in the placebo trial. These findings suggest that rehydration after exercise that causes fluid loss can attenuate alcohol-related deterioration of cognitive functions. This may pose implications for post match fluid replacement if a moderate amount of alcohol is also consumed. Copyright © 2013 Elsevier Inc. All rights reserved.

A centralized informatics infrastructure for the National Institute on Drug Abuse Clinical Trials Network.

PubMed

Pan, Jeng-Jong; Nahm, Meredith; Wakim, Paul; Cushing, Carol; Poole, Lori; Tai, Betty; Pieper, Carl F

2009-02-01

Clinical trial networks (CTNs) were created to provide a sustaining infrastructure for the conduct of multisite clinical trials. As such, they must withstand changes in membership. Centralization of infrastructure including knowledge management, portfolio management, information management, process automation, work policies, and procedures in clinical research networks facilitates consistency and ultimately research. In 2005, the National Institute on Drug Abuse (NIDA) CTN transitioned from a distributed data management model to a centralized informatics infrastructure to support the network's trial activities and administration. We describe the centralized informatics infrastructure and discuss our challenges to inform others considering such an endeavor. During the migration of a clinical trial network from a decentralized to a centralized data center model, descriptive data were captured and are presented here to assess the impact of centralization. We present the framework for the informatics infrastructure and evaluative metrics. The network has decreased the time from last patient-last visit to database lock from an average of 7.6 months to 2.8 months. The average database error rate decreased from 0.8% to 0.2%, with a corresponding decrease in the interquartile range from 0.04%-1.0% before centralization to 0.01-0.27% after centralization. Centralization has provided the CTN with integrated trial status reporting and the first standards-based public data share. A preliminary cost-benefit analysis showed a 50% reduction in data management cost per study participant over the life of a trial. A single clinical trial network comprising addiction researchers and community treatment programs was assessed. The findings may not be applicable to other research settings. The identified informatics components provide the information and infrastructure needed for our clinical trial network. Post centralization data management operations are more efficient and less costly, with higher data quality.

Laser in Glaucoma and Ocular Hypertension (LiGHT) trial. A multicentre, randomised controlled trial: design and methodology.

PubMed

Gazzard, Gus; Konstantakopoulou, Evgenia; Garway-Heath, David; Barton, Keith; Wormald, Richard; Morris, Stephen; Hunter, Rachael; Rubin, Gary; Buszewicz, Marta; Ambler, Gareth; Bunce, Catey

2018-05-01

The Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial aims to establish whether initial treatment with selective laser trabeculoplasty (SLT) is superior to initial treatment with topical medication for primary open-angle glaucoma (POAG) or ocular hypertension (OHT). The LiGHT Trial is a prospective, unmasked, multicentre, pragmatic, randomised controlled trial. 718 previously untreated patients with POAG or OHT were recruited at six collaborating centres in the UK between 2012 and 2014. The trial comprises two treatment arms: initial SLT followed by conventional medical therapy as required, and medical therapy without laser therapy. Randomisation was provided online by a web-based randomisation service. Participants will be monitored for 3 years, according to routine clinical practice. The target intraocular pressure (IOP) was set at baseline according to an algorithm, based on disease severity and lifetime risk of loss of vision at recruitment, and subsequently adjusted on the basis of IOP control, optic disc and visual field. The primary outcome measure is health-related quality of life (HRQL) (EQ-5D five-level). Secondary outcomes are treatment pathway cost and cost-effectiveness, Glaucoma Utility Index, Glaucoma Symptom Scale, Glaucoma Quality of Life, objective measures of pathway effectiveness, visual function and safety profiles and concordance. A single main analysis will be performed at the end of the trial on an intention-to-treat basis. The LiGHT Trial is a multicentre, pragmatic, randomised clinical trial that will provide valuable data on the relative HRQL, clinical effectiveness and cost-effectiveness of SLT and topical IOP-lowering medication. ISRCTN32038223, Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Systematic Review of Knowledge Translation Strategies to Promote Research Uptake in Child Health Settings.

PubMed

Albrecht, Lauren; Archibald, Mandy; Snelgrove-Clarke, Erna; Scott, Shannon D

2016-01-01

Strategies to assist evidence-based decision-making for healthcare professionals are crucial to ensure high quality patient care and outcomes. The goal of this systematic review was to identify and synthesize the evidence on knowledge translation interventions aimed at putting explicit research evidence into child health practice. A comprehensive search of thirteen electronic databases was conducted, restricted by date (1985-2011) and language (English). Articles were included if: 1) studies were randomized controlled trials (RCT), controlled clinical trials (CCT), or controlled before-and-after (CBA) studies; 2) target population was child health professionals; 3) interventions implemented research in child health practice; and 4) outcomes were measured at the professional/process, patient, or economic level. Two reviewers independently extracted data and assessed methodological quality. Study data were aggregated and analyzed using evidence tables. Twenty-one studies (13 RCT, 2 CCT, 6 CBA) were included. The studies employed single (n=9) and multiple interventions (n=12). The methodological quality of the included studies was largely moderate (n=8) or weak (n=11). Of the studies with moderate to strong methodological quality ratings, three demonstrated consistent, positive effect(s) on the primary outcome(s); effective knowledge translation interventions were two single, non-educational interventions and one multiple, educational intervention. This multidisciplinary systematic review in child health setting identified effective knowledge translation strategies assessed by the most rigorous research designs. Given the overall poor quality of the research literature, specific recommendations were made to improve knowledge translation efforts in child health. Copyright © 2016 Elsevier Inc. All rights reserved.

Single-visit or multiple-visit root canal treatment: systematic review, meta-analysis and trial sequential analysis

PubMed Central

Schwendicke, Falk; Göstemeyer, Gerd

2017-01-01

Objectives Single-visit root canal treatment has some advantages over conventional multivisit treatment, but might increase the risk of complications. We systematically evaluated the risk of complications after single-visit or multiple-visit root canal treatment using meta-analysis and trial-sequential analysis. Data Controlled trials comparing single-visit versus multiple-visit root canal treatment of permanent teeth were included. Trials needed to assess the risk of long-term complications (pain, infection, new/persisting/increasing periapical lesions ≥1 year after treatment), short-term pain or flare-up (acute exacerbation of initiation or continuation of root canal treatment). Sources Electronic databases (PubMed, EMBASE, Cochrane Central) were screened, random-effects meta-analyses performed and trial-sequential analysis used to control for risk of random errors. Evidence was graded according to GRADE. Study selection 29 trials (4341 patients) were included, all but 6 showing high risk of bias. Based on 10 trials (1257 teeth), risk of complications was not significantly different in single-visit versus multiple-visit treatment (risk ratio (RR) 1.00 (95% CI 0.75 to 1.35); weak evidence). Based on 20 studies (3008 teeth), risk of pain did not significantly differ between treatments (RR 0.99 (95% CI 0.76 to 1.30); moderate evidence). Risk of flare-up was recorded by 8 studies (1110 teeth) and was significantly higher after single-visit versus multiple-visit treatment (RR 2.13 (95% CI 1.16 to 3.89); very weak evidence). Trial-sequential analysis revealed that firm evidence for benefit, harm or futility was not reached for any of the outcomes. Conclusions There is insufficient evidence to rule out whether important differences between both strategies exist. Clinical significance Dentists can provide root canal treatment in 1 or multiple visits. Given the possibly increased risk of flare-ups, multiple-visit treatment might be preferred for certain teeth (eg, those with periapical lesions). PMID:28148534

Duration of treatment for asymptomatic bacteriuria during pregnancy.

PubMed

Widmer, Mariana; Gülmezoglu, A Metin; Mignini, Luciano; Roganti, Ariel

2011-12-07

A Cochrane systematic review has shown that drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis and reduces the risk of preterm delivery. However, it is not clear whether single-dose therapy is as effective as longer conventional antibiotic treatment. To assess the effects of different durations of treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2011) and reference lists of identified articles. Randomized and quasi-randomized trials comparing antimicrobial therapeutic regimens that differed in duration (particularly comparing single dose with longer duration regimens) in pregnant women diagnosed with asymptomatic bacteriuria. We assessed trial quality and extracted data independently. We included 13 studies, involving 1622 women. All were comparisons of single-dose treatment with four- to seven-day treatments. The trials were generally of limited quality. The 'no cure rate' for asymptomatic bacteriuria in pregnant women was slightly higher for the single-dose than for the short-course treatment; however, these results were not statistically significant and showed heterogeneity. When comparing the trials that used the same antibiotic in both treatment and control groups with the trials that used different antibiotics in both groups, the 'no cure rate' risk ratio was similar. There was no statistically significant difference in the recurrence of asymptomatic bacteriuria rate between treatment and control groups. Slight differences were detected for preterm births and pyelonephritis although, apart from one trial, the sample size of the trials was inadequate. Single-dose treatment was associated with a decrease in reports of 'any side-effects' . Single-dose regimen of antibiotics may be less effective than the seven-day regimen. Women with asymptomatic bacteriuria in pregnancy should be treated by the standard regimen of antibiotics until more data become available testing seven-day compared with three- or five-day regimens.

Cognitive workload modulation through degraded visual stimuli: a single-trial EEG study

NASA Astrophysics Data System (ADS)

Yu, K.; Prasad, I.; Mir, H.; Thakor, N.; Al-Nashash, H.

2015-08-01

Objective. Our experiments explored the effect of visual stimuli degradation on cognitive workload. Approach. We investigated the subjective assessment, event-related potentials (ERPs) as well as electroencephalogram (EEG) as measures of cognitive workload. Main results. These experiments confirm that degradation of visual stimuli increases cognitive workload as assessed by subjective NASA task load index and confirmed by the observed P300 amplitude attenuation. Furthermore, the single-trial multi-level classification using features extracted from ERPs and EEG is found to be promising. Specifically, the adopted single-trial oscillatory EEG/ERP detection method achieved an average accuracy of 85% for discriminating 4 workload levels. Additionally, we found from the spatial patterns obtained from EEG signals that the frontal parts carry information that can be used for differentiating workload levels. Significance. Our results show that visual stimuli can modulate cognitive workload, and the modulation can be measured by the single trial EEG/ERP detection method.

Randomized Clinical Trial of Virtual Reality Simulation Training for Transvaginal Gynecologic Ultrasound Skills.

PubMed

Chao, Coline; Chalouhi, Gihad E; Bouhanna, Philippe; Ville, Yves; Dommergues, Marc

2015-09-01

To compare the impact of virtual reality simulation training and theoretical teaching on the ability of inexperienced trainees to produce adequate virtual transvaginal ultrasound images. We conducted a randomized controlled trial with parallel groups. Participants included inexperienced residents starting a training program in Paris. The intervention consisted of 40 minutes of virtual reality simulation training using a haptic transvaginal simulator versus 40 minutes of conventional teaching including a conference with slides and videos and answers to the students' questions. The outcome was a 19-point image quality score calculated from a set of 4 images (sagittal and coronal views of the uterus and left and right ovaries) produced by trainees immediately after the intervention, using the same simulator on which a new virtual patient had been uploaded. Experts assessed the outcome on stored images, presented in a random order, 2 months after the trial was completed. They were blinded to group assignment. The hypothesis was an improved outcome in the intervention group. Randomization was 1 to 1. The mean score was significantly greater in the simulation group (n = 16; mean score, 12; SEM, 0.8) than the control group (n = 18; mean score, 9; SEM, 1.0; P= .0302). The quality of virtual vaginal images produced by inexperienced trainees was greater immediately after a single virtual reality simulation training session than after a single theoretical teaching session. © 2015 by the American Institute of Ultrasound in Medicine.

One-to-one dietary interventions undertaken in a dental setting to change dietary behaviour.

PubMed

Harris, Rebecca; Gamboa, Ana; Dailey, Yvonne; Ashcroft, Angela

2012-03-14

The dental care setting is an appropriate place to deliver dietary assessment and advice as part of patient management. However, we do not know whether this is effective in changing dietary behaviour. To assess the effectiveness of one-to-one dietary interventions for all ages carried out in a dental care setting in changing dietary behaviour. The effectiveness of these interventions in the subsequent changing of oral and general health is also assessed. The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 24 January 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE via OVID (1950 to 24 January 2012), EMBASE via OVID (1980 to 24 January 2012), CINAHL via EBSCO (1982 to 24 January 2012), PsycINFO via OVID (1967 to 24 January 2012), and Web of Science (1945 to 12 April 2011). We also undertook an electronic search of key conference proceedings (IADR and ORCA between 2000 and 13 July 2011). Reference lists of relevant articles, thesis publications (Dissertations Abstracts Online 1861 to 2011) were searched. The authors of eligible trials were contacted to identify any unpublished work. Randomised controlled trials assessing the effectiveness of one-to-one dietary interventions delivered in a dental care setting. Abstract screening, eligibility screening and data extraction decisions were all carried out independently and in duplicate by two review authors. Consensus between the two opinions was achieved by discussion, or involvement of a third review author. Five studies met the criteria for inclusion in the review. Two of these were multi-intervention studies where the dietary intervention was one component of a wider programme of prevention, but where data on dietary behaviour change were reported. One of the single intervention studies was concerned with dental caries prevention. The other two concerned general health outcomes. There were no studies concerned with dietary change aimed at preventing tooth erosion. In four out of the five included studies a significant change in dietary behaviour was found for at least one of the primary outcome variables. There is some evidence that one-to-one dietary interventions in the dental setting can change behaviour, although the evidence is greater for interventions aiming to change fruit/vegetable and alcohol consumption than for those aiming to change dietary sugar consumption. There is a need for more studies, particularly in the dental practice setting, as well as greater methodological rigour in the design, statistical analysis and reporting of such studies.

Identifying a maximum tolerated contour in two-dimensional dose-finding

PubMed Central

Wages, Nolan A.

2016-01-01

The majority of Phase I methods for multi-agent trials have focused on identifying a single maximum tolerated dose combination (MTDC) among those being investigated. Some published methods in the area have been based on the notion that there is no unique MTDC, and that the set of dose combinations with acceptable toxicity forms an equivalence contour in two dimensions. Therefore, it may be of interest to find multiple MTDC's for further testing for efficacy in a Phase II setting. In this paper, we present a new dose-finding method that extends the continual reassessment method to account for the location of multiple MTDC's. Operating characteristics are demonstrated through simulation studies, and are compared to existing methodology. Some brief discussion of implementation and available software is also provided. PMID:26910586

Accounting for selection and correlation in the analysis of two-stage genome-wide association studies.

PubMed

Robertson, David S; Prevost, A Toby; Bowden, Jack

2016-10-01

The problem of selection bias has long been recognized in the analysis of two-stage trials, where promising candidates are selected in stage 1 for confirmatory analysis in stage 2. To efficiently correct for bias, uniformly minimum variance conditionally unbiased estimators (UMVCUEs) have been proposed for a wide variety of trial settings, but where the population parameter estimates are assumed to be independent. We relax this assumption and derive the UMVCUE in the multivariate normal setting with an arbitrary known covariance structure. One area of application is the estimation of odds ratios (ORs) when combining a genome-wide scan with a replication study. Our framework explicitly accounts for correlated single nucleotide polymorphisms, as might occur due to linkage disequilibrium. We illustrate our approach on the measurement of the association between 11 genetic variants and the risk of Crohn's disease, as reported in Parkes and others (2007. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Gen. 39: (7), 830-832.), and show that the estimated ORs can vary substantially if both selection and correlation are taken into account. © The Author 2016. Published by Oxford University Press.

Infusional 5-FU for advanced colorectal cancer.

PubMed

Lokich, J

1995-01-01

5-Fluorouracil (5-FU) has been studied over the past two decades in five prospective randomized trials comparing bolus with infusional schedules. Response rates and time to progression are improved with infusional schedules and survival as determined by the proportion of patients alive at 2 years is also superior for infusional administration. Biochemical modulation of infusional 5-FU by leucovorin or interferon does not increase the therapeutic effect (in contrast to the modulation of bolus delivery) but does effect the toxicity profile adversely. Time modulation of infusional 5-FU has been reported to improve response rates, and survival over constant or flat infusion and additional studies are ongoing. A proposed experimental design for a comparative trial in advanced colon cancer is presented to address the questions of the optimal infusion duration; the role of dose intensity; and the role of chronomodulation. The application of infusional 5-FU into the adjuvant setting seems to be a reasonable step, and such trials have been initiated in both the United States and the United Kingdom. Bolus single agent 5-FU should be abandoned as a treatment option for colon cancer.

Spotlight on olaparib in the treatment of BRCA-mutated ovarian cancer: design, development and place in therapy.

PubMed

Lorusso, Domenica; Tripodi, Elisa; Maltese, Giuseppa; Lepori, Stefano; Sabatucci, Ilaria; Bogani, Giorgio; Raspagliesi, Francesco

2018-01-01

Epithelial ovarian cancer is the sixth most common cancer among women worldwide and the first cause of death among gynecological malignancies. Most of the patients present recurrent disease and unfortunately cannot be cured. The unsatisfactory results obtained with salvage chemotherapy have elicited investigators to search for novel biological agents capable of achieving a better control of the disease. In the setting of homologous recombination deficiency, the DNA errors that occur cannot be accurately repaired, and the treatment with poly(ADP-ribose) polymerase (PARP) inhibition results in definitive cell death in a process called synthetic lethality. As a result of two positive clinical trials, Olaparib was approved in 2014 by U.S. Food and Drug Administration and European Medicines Agency as the first-in-class PARP inhibitor. Olaparib is effective and well tolerated in homologous recombination deficient patients. Several studies with Olaparib have been conducted in the recurrent setting either as maintenance in platinum-responsive patients or as a single agent. Ongoing trials are focused on the use of olaparib as maintenance in the first-line ovarian cancer setting alone or in combination with antiangiogenic agents. Future perspectives will probably investigate the association of olaparib with novel agents as check-point inhibitors and PI3K-AKT inhibitors. The PARP inhibitor era is just at the beginning.

Proof of concept and dose estimation with binary responses under model uncertainty.

PubMed

Klingenberg, B

2009-01-30

This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of lifestyle diet and exercise interventions for osteoarthritis.

PubMed

Messier, S P; Callahan, L F; Golightly, Y M; Keefe, F J

2015-05-01

The objective was to develop a set of "best practices" for use as a primer for those interested in entering the clinical trials field for lifestyle diet and/or exercise interventions in osteoarthritis (OA), and as a set of recommendations for experienced clinical trials investigators. A subcommittee of the non-pharmacologic therapies committee of the OARSI Clinical Trials Working Group was selected by the Steering Committee to develop a set of recommended principles for non-pharmacologic diet/exercise OA randomized clinical trials. Topics were identified for inclusion by co-authors and reviewed by the subcommittee. Resources included authors' expert opinions, traditional search methods including MEDLINE (via PubMed), and previously published guidelines. Suggested steps and considerations for study methods (e.g., recruitment and enrollment of participants, study design, intervention and assessment methods) were recommended. The recommendations set forth in this paper provide a guide from which a research group can design a lifestyle diet/exercise randomized clinical trial in patients with OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Anterior medial prefrontal cortex exhibits activation during task preparation but deactivation during task execution.

PubMed

Koshino, Hideya; Minamoto, Takehiro; Ikeda, Takashi; Osaka, Mariko; Otsuka, Yuki; Osaka, Naoyuki

2011-01-01

The anterior prefrontal cortex (PFC) exhibits activation during some cognitive tasks, including episodic memory, reasoning, attention, multitasking, task sets, decision making, mentalizing, and processing of self-referenced information. However, the medial part of anterior PFC is part of the default mode network (DMN), which shows deactivation during various goal-directed cognitive tasks compared to a resting baseline. One possible factor for this pattern is that activity in the anterior medial PFC (MPFC) is affected by dynamic allocation of attentional resources depending on task demands. We investigated this possibility using an event related fMRI with a face working memory task. Sixteen students participated in a single fMRI session. They were asked to form a task set to remember the faces (Face memory condition) or to ignore them (No face memory condition), then they were given 6 seconds of preparation period before the onset of the face stimuli. During this 6-second period, four single digits were presented one at a time at the center of the display, and participants were asked to add them and to remember the final answer. When participants formed a task set to remember faces, the anterior MPFC exhibited activation during a task preparation period but deactivation during a task execution period within a single trial. The results suggest that the anterior MPFC plays a role in task set formation but is not involved in execution of the face working memory task. Therefore, when attentional resources are allocated to other brain regions during task execution, the anterior MPFC shows deactivation. The results suggest that activation and deactivation in the anterior MPFC are affected by dynamic allocation of processing resources across different phases of processing.

Anterior Medial Prefrontal Cortex Exhibits Activation during Task Preparation but Deactivation during Task Execution

PubMed Central

Koshino, Hideya; Minamoto, Takehiro; Ikeda, Takashi; Osaka, Mariko; Otsuka, Yuki; Osaka, Naoyuki

2011-01-01

Background The anterior prefrontal cortex (PFC) exhibits activation during some cognitive tasks, including episodic memory, reasoning, attention, multitasking, task sets, decision making, mentalizing, and processing of self-referenced information. However, the medial part of anterior PFC is part of the default mode network (DMN), which shows deactivation during various goal-directed cognitive tasks compared to a resting baseline. One possible factor for this pattern is that activity in the anterior medial PFC (MPFC) is affected by dynamic allocation of attentional resources depending on task demands. We investigated this possibility using an event related fMRI with a face working memory task. Methodology/Principal Findings Sixteen students participated in a single fMRI session. They were asked to form a task set to remember the faces (Face memory condition) or to ignore them (No face memory condition), then they were given 6 seconds of preparation period before the onset of the face stimuli. During this 6-second period, four single digits were presented one at a time at the center of the display, and participants were asked to add them and to remember the final answer. When participants formed a task set to remember faces, the anterior MPFC exhibited activation during a task preparation period but deactivation during a task execution period within a single trial. Conclusions/Significance The results suggest that the anterior MPFC plays a role in task set formation but is not involved in execution of the face working memory task. Therefore, when attentional resources are allocated to other brain regions during task execution, the anterior MPFC shows deactivation. The results suggest that activation and deactivation in the anterior MPFC are affected by dynamic allocation of processing resources across different phases of processing. PMID:21829668

Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure

PubMed Central

Palumbo, Paul; Lindsey, Jane C.; Hughes, Michael D.; Cotton, Mark F.; Bobat, Raziya; Meyers, Tammy; Bwakura-Dangarembizi, Mutsawashe; Chi, Benjamin H.; Musoke, Philippa; Kamthunzi, Portia; Schimana, Werner; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne M.; Jean-Philippe, Patrick; Violari, Avy

2010-01-01

BACKGROUND Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. RESULTS A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P = 0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.) PMID:20942667

Selectivity of N170 for visual words in the right hemisphere: Evidence from single-trial analysis.

PubMed

Yang, Hang; Zhao, Jing; Gaspar, Carl M; Chen, Wei; Tan, Yufei; Weng, Xuchu

2017-08-01

Neuroimaging and neuropsychological studies have identified the involvement of the right posterior region in the processing of visual words. Interestingly, in contrast, ERP studies of the N170 typically demonstrate selectivity for words more strikingly over the left hemisphere. Why is right hemisphere selectivity for words during the N170 epoch typically not observed, despite the clear involvement of this region in word processing? One possibility is that amplitude differences measured on averaged ERPs in previous studies may have been obscured by variation in peak latency across trials. This study examined this possibility by using single-trial analysis. Results show that words evoked greater single-trial N170s than control stimuli in the right hemisphere. Additionally, we observed larger trial-to-trial variability on N170 peak latency for words as compared to control stimuli over the right hemisphere. Results demonstrate that, in contrast to much of the prior literature, the N170 can be selective to words over the right hemisphere. This discrepancy is explained in terms of variability in trial-to-trial peak latency for responses to words over the right hemisphere. © 2017 Society for Psychophysiological Research.

Feasibility study of the effects of art as a creative engagement intervention during stroke rehabilitation on improvement of psychosocial outcomes: study protocol for a single blind randomized controlled trial: the ACES study.

PubMed

Morris, Jacqui H; Kelly, Chris; Toma, Madalina; Kroll, Thilo; Joice, Sara; Mead, Gillian; Donnan, Peter; Williams, Brian

2014-09-28

Benefits of art participation after stroke are becoming increasingly recognized. Qualitative studies suggest that participation in visual arts creative engagement interventions (CEIs) during rehabilitation after stroke may improve mood, self-esteem, hope and some aspects of physical recovery. This study examines the feasibility of undertaking a randomized controlled trial of a CEI delivered by artists within in-patient stroke rehabilitation to test effectiveness. This trial is a two arm, single-blind, randomized controlled feasibility trial within in-patient stroke rehabilitation. We will recruit 80 patients receiving stroke rehabilitation in two stroke units in a health board area of Scotland (40 patients in each arm). Intervention arm participants will receive a visual-arts based CEI facilitated by experienced artists. Artists will follow an intervention protocol with specific components that enable participants to set, achieve and review artistic goals. Participants will receive up to eight intervention sessions, four within a group and four one-to-one with the artist. Control group participants will receive usual care only.Data collection will occur at baseline, post-intervention and three-month follow-up. Stroke-related health status is the primary outcome; mood, self-esteem, self-efficacy, perceived recovery control and hope are secondary outcomes. Semi-structured interviews will be conducted with purposively selected patients, artists and healthcare staff to elicit views and experiences of the intervention and feasibility and acceptability of trial processes. Recruitment rates, retention rates and patient preference for art participation will also be collected. Data will indicate, with confidence intervals, the proportion of patients choosing or refusing participation in the CEI and will allow calculation of recruitment rates for a future definitive trial. Summary data will indicate potential variability, magnitude and direction of difference between groups. Findings will inform sample size calculations for a definitive trial. Thematic analysis of qualitative data will be managed using the Framework Approach. Framework is an analytical approach for qualitative data, commonly used in policy and medical research. If shown to demonstrate effects, this intervention has the potential to address aspects of stroke recovery previously. Not routinely addressed in rehabilitation. Registered with Clinical Trials.Gov: NCT02085226 on 6th March 2014.

Single-use instruments, cutting blocks, and trials increase efficiency in the operating room during total knee arthroplasty: a prospective comparison of navigated and non-navigated cases.

PubMed

Mont, Michael A; McElroy, Mark J; Johnson, Aaron J; Pivec, Robert

2013-08-01

The purpose of this prospective controlled trial was to determine if efficiency increases could be achieved in non-navigated and navigated total knee arthroplasties by replacing traditional saws, cutting blocks, and trials with specialized saws and single-use cutting blocks and trials. Various timing metrics during total knee arthroplasty, including operating room preparation times and specific intra-operative times, were measured in 400 procedures performed by eight different surgeons at 6 institutions. Efficiency increases were the result of statistically significant reductions in combined instrument setup and cleanup times as well as in adjusted surgical episode times in navigated total knee arthroplasties. Single-use instruments show promising benefits, but adequate patient follow-up is needed to confirm safety and efficacy before they can be widely adopted. Nevertheless, the authors believe that the use of single-use instruments, cutting guides, and trial implants for total knee arthroplasty will play an increasing role in improving operating room efficiency. Copyright © 2013 Elsevier Inc. All rights reserved.

Slope-based and geometric encoding of a goal location by the terrestrial toad (Rhinella arenarum).

PubMed

Sotelo, María Inés; Bingman, Verner P; Muzio, Rubén N

2017-11-01

The current study was designed to test for the ability of terrestrial toads, Rhinella arenarum , to use slope as source of spatial information to locate a goal, and investigate the relative importance of slope and geometric information for goal localization. Toads were trained to locate a single, water-reward goal location in a corner of a rectangular arena placed on an incline. Once the toads learned the task, 3 types of probe trials were carried out to determine the relative use of slope and geometric information for goal localization. The probe trials revealed that the toads were able to independently use slope, and as previously reported, geometry to locate the goal. However, the boundary geometry of the experimental arena was found to be preferentially used by the toads when geometric and slope information were set in conflict. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Development of outcome measures for large-vessel vasculitis for use in clinical trials: opportunities, challenges, and research agenda.

PubMed

Direskeneli, Haner; Aydin, Sibel Z; Kermani, Tanaz A; Matteson, Eric L; Boers, Maarten; Herlyn, Karen; Luqmani, Raashid A; Neogi, Tuhina; Seo, Philip; Suppiah, Ravi; Tomasson, Gunnar; Merkel, Peter A

2011-07-01

Giant cell (GCA) and Takayasu's arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development.

Development of Outcome Measures for Large-vessel Vasculitis for Use in Clinical Trials: Opportunities, Challenges, and Research Agenda

PubMed Central

DIRESKENELI, HANER; AYDIN, SIBEL Z.; KERMANI, TANAZ A.; MATTESON, ERIC L.; BOERS, MAARTEN; HERLYN, KAREN; LUQMANI, RAASHID A.; NEOGI, TUHINA; SEO, PHILIP; SUPPIAH, RAVI; TOMASSON, GUNNAR; MERKEL, PETER A.

2013-01-01

Giant cell (GCA) and Takayasu’s arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development. PMID:21724719

Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: Effect of availability of exception from informed consent

PubMed Central

Yamal, Jose-Miguel; Robertson, Claudia S.; Rubin, M. Laura; Benoit, Julia S.; Hannay, H. Julia; Tilley, Barbara C.

2014-01-01

Background The Final Rule regulations were developed to allow exception from informed consent (EFIC) to enable clinical trial research in emergency settings where major barriers exist for informed consent. There is little known evidence of the effect of the Final Rule in minority enrollment in clinical trials, particularly in traumatic brain injury (TBI) trials. A clinical trial funded by the National Institute of Neurological Disorders and Stroke was conducted to study the effects of erythropoietin on cerebral vascular dysfunction and anemia in subjects with TBI. There were periods of time when EFIC was and was not available for enrollment into the study. Purpose To explore the effect of EFIC availability on TBI trial enrollment of minority versus non-minority subjects. Methods Minority status of screened (n=289) and enrolled (n=191) TBI subjects was determined for this study. We tested for the presence of a minority and EFIC availability interaction in a multiple logistic regression model after controlling for EFIC and minority group main effects and other covariates. Results An interaction between the availability of EFIC minority and non-minority enrollment was not detected (odds ratio: 1.22; 95% confidence interval: 0.29–5.16). Limitations Our study was conducted at a single site and the confidence interval for the EFIC and minority interaction term was wide. Therefore, a small interaction effect cannot be ruled out. Conclusions EFIC increased the odds of being enrolled regardless of minority status. PMID:24686108

Defining a clinically meaningful effect for the design and interpretation of randomized controlled trials.

PubMed

Keefe, Richard S E; Kraemer, Helena C; Epstein, Robert S; Frank, Ellen; Haynes, Ginger; Laughren, Thomas P; McNulty, James; Reed, Shelby D; Sanchez, Juan; Leon, Andrew C

2013-05-01

This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.

Spontaneous Fluctuations in Sensory Processing Predict Within-Subject Reaction Time Variability.

PubMed

Ribeiro, Maria J; Paiva, Joana S; Castelo-Branco, Miguel

2016-01-01

When engaged in a repetitive task our performance fluctuates from trial-to-trial. In particular, inter-trial reaction time variability has been the subject of considerable research. It has been claimed to be a strong biomarker of attention deficits, increases with frontal dysfunction, and predicts age-related cognitive decline. Thus, rather than being just a consequence of noise in the system, it appears to be under the control of a mechanism that breaks down under certain pathological conditions. Although the underlying mechanism is still an open question, consensual hypotheses are emerging regarding the neural correlates of reaction time inter-trial intra-individual variability. Sensory processing, in particular, has been shown to covary with reaction time, yet the spatio-temporal profile of the moment-to-moment variability in sensory processing is still poorly characterized. The goal of this study was to characterize the intra-individual variability in the time course of single-trial visual evoked potentials and its relationship with inter-trial reaction time variability. For this, we chose to take advantage of the high temporal resolution of the electroencephalogram (EEG) acquired while participants were engaged in a 2-choice reaction time task. We studied the link between single trial event-related potentials (ERPs) and reaction time using two different analyses: (1) time point by time point correlation analyses thereby identifying time windows of interest; and (2) correlation analyses between single trial measures of peak latency and amplitude and reaction time. To improve extraction of single trial ERP measures related with activation of the visual cortex, we used an independent component analysis (ICA) procedure. Our ERP analysis revealed a relationship between the N1 visual evoked potential and reaction time. The earliest time point presenting a significant correlation of its respective amplitude with reaction time occurred 175 ms after stimulus onset, just after the onset of the N1 peak. Interestingly, single trial N1 latency correlated significantly with reaction time, while N1 amplitude did not. In conclusion, our findings suggest that inter-trial variability in the timing of extrastriate visual processing contributes to reaction time variability.

Spontaneous Fluctuations in Sensory Processing Predict Within-Subject Reaction Time Variability

PubMed Central

Ribeiro, Maria J.; Paiva, Joana S.; Castelo-Branco, Miguel

2016-01-01

When engaged in a repetitive task our performance fluctuates from trial-to-trial. In particular, inter-trial reaction time variability has been the subject of considerable research. It has been claimed to be a strong biomarker of attention deficits, increases with frontal dysfunction, and predicts age-related cognitive decline. Thus, rather than being just a consequence of noise in the system, it appears to be under the control of a mechanism that breaks down under certain pathological conditions. Although the underlying mechanism is still an open question, consensual hypotheses are emerging regarding the neural correlates of reaction time inter-trial intra-individual variability. Sensory processing, in particular, has been shown to covary with reaction time, yet the spatio-temporal profile of the moment-to-moment variability in sensory processing is still poorly characterized. The goal of this study was to characterize the intra-individual variability in the time course of single-trial visual evoked potentials and its relationship with inter-trial reaction time variability. For this, we chose to take advantage of the high temporal resolution of the electroencephalogram (EEG) acquired while participants were engaged in a 2-choice reaction time task. We studied the link between single trial event-related potentials (ERPs) and reaction time using two different analyses: (1) time point by time point correlation analyses thereby identifying time windows of interest; and (2) correlation analyses between single trial measures of peak latency and amplitude and reaction time. To improve extraction of single trial ERP measures related with activation of the visual cortex, we used an independent component analysis (ICA) procedure. Our ERP analysis revealed a relationship between the N1 visual evoked potential and reaction time. The earliest time point presenting a significant correlation of its respective amplitude with reaction time occurred 175 ms after stimulus onset, just after the onset of the N1 peak. Interestingly, single trial N1 latency correlated significantly with reaction time, while N1 amplitude did not. In conclusion, our findings suggest that inter-trial variability in the timing of extrastriate visual processing contributes to reaction time variability. PMID:27242470

Familias Unidas for high risk adolescents: Study design of a cultural adaptation and randomized controlled trial of a U.S. drug and sexual risk behavior intervention in Ecuador.

PubMed

Jacobs, Petra; Estrada, Yannine A; Tapia, Maria I; Quevedo Terán, Ana M; Condo Tamayo, Cecilia; Albán García, Mónica; Valenzuela Triviño, Gilda M; Pantin, Hilda; Velazquez, Maria R; Horigian, Viviana E; Alonso, Elizabeth; Prado, Guillermo

2016-03-01

Developing, testing and implementing evidence-based prevention interventions are important in decreasing substance use and sexual risk behavior among adolescents. This process requires research expertise, infrastructure, resources and decades of research testing, which might not always be feasible for low resource countries. Adapting and testing interventions proven to be efficacious in similar cultures might circumvent the time and costs of implementing evidence-based interventions in new settings. This paper describes the two-phase study, including training and development of the research infrastructure in the Ecuadorian university necessary to implement a randomized controlled trial. Familias Unidas is a multilevel parent-centered intervention designed in the U.S. to prevent drug use and sexual risk behaviors in Hispanic adolescents. The current study consisted of Phase 1 feasibility study (n=38) which adapted the intervention and study procedures within a single-site school setting in an area with a high prevalence of drug use and unprotected sexual behavior among adolescents in Ecuador, and Phase 2 randomized controlled trial of the adapted intervention in two public high schools with a target population of families with adolescents from 12 to 14 years old. The trial is currently in Phase 2. Study recruitment was completed with 239 parent-youth dyads enrolling. The intervention phase and the first follow-up assessment have been completed. The second and third follow-up assessments will be completed in 2016. This project has the potential of benefitting a large population of families in areas of Ecuador that are disproportionally affected by drug trafficking and its consequences. MSP-DIS-2015-0055-0, Ministry of Public Health (MSP), Quito, Ecuador. Copyright © 2016 Elsevier Inc. All rights reserved.

Rationale and design of a home-based trial using wearable sensors to detect asymptomatic atrial fibrillation in a targeted population: The mHealth Screening To Prevent Strokes (mSToPS) trial.

PubMed

Steinhubl, Steven R; Mehta, Rajesh R; Ebner, Gail S; Ballesteros, Marissa M; Waalen, Jill; Steinberg, Gregory; Van Crocker, Percy; Felicione, Elise; Carter, Chureen T; Edmonds, Shawn; Honcz, Joseph P; Miralles, Gines Diego; Talantov, Dimitri; Sarich, Troy C; Topol, Eric J

2016-05-01

Efficient methods for screening populations for undiagnosed atrial fibrillation (AF) are needed to reduce its associated mortality, morbidity, and costs. The use of digital technologies, including wearable sensors and large health record data sets allowing for targeted outreach toward individuals at increased risk for AF, might allow for unprecedented opportunities for effective, economical screening. The trial's primary objective is to determine, in a real-world setting, whether using wearable sensors in a risk-targeted screening population can diagnose asymptomatic AF more effectively than routine care. Additional key objectives include (1) exploring 2 rhythm-monitoring strategies-electrocardiogram-based and exploratory pulse wave-based-for detection of new AF, and (2) comparing long-term clinical and resource outcomes among groups. In all, 2,100 Aetna members will be randomized 1:1 to either immediate or delayed monitoring, in which a wearable patch will capture a single-lead electrocardiogram during the first and last 2 weeks of a 4-month period beginning immediately or 4 months after enrollment, respectively. An observational, risk factor-matched control group (n = 4,000) will be developed from members who did not receive an invitation to participate. The primary end point is the incidence of new AF in the immediate- vs delayed-monitoring arms at the end of the 4-month monitoring period. Additional efficacy and safety end points will be captured at 1 and 3 years. The results of this digital medicine trial might benefit a substantial proportion of the population by helping identify and refine screening methods for undiagnosed AF. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.

PubMed

Clark, Amy S; Karasic, Thomas B; DeMichele, Angela; Vaughn, David J; O'Hara, Mark; Perini, Rodolfo; Zhang, Paul; Lal, Priti; Feldman, Michael; Gallagher, Maryann; O'Dwyer, Peter J

2016-02-01

Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings. Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.

Effectiveness and economic evaluation of self-help educational materials for the prevention of smoking relapse: randomised controlled trial.

PubMed

Blyth, Annie; Maskrey, Vivienne; Notley, Caitlin; Barton, Garry R; Brown, Tracey J; Aveyard, Paul; Holland, Richard; Bachmann, Max O; Sutton, Stephen; Leonardi-Bee, Jo; Brandon, Thomas H; Song, Fujian

2015-07-01

Most people who quit smoking successfully for a short period will return to smoking again in 12 months. A previous exploratory meta-analysis indicated that self-help booklets may be effective for smoking relapse prevention in unaided quitters. This study aimed to evaluate the effectiveness of a set of self-help educational booklets to prevent smoking relapse in people who had stopped smoking with the aid of behavioural support. This is an open, randomised controlled trial and qualitative process evaluation. Trial participants were randomly allocated to one of two groups, using a simple randomisation process without attempts to stratify by participant characteristics. The participant allocation was 'concealed' because the recruitment of quitters occurred before the random allocation. Short-term quitters were recruited from NHS Stop Smoking Clinics, and self-help educational materials were posted to study participants at home. A total of 1407 carbon monoxide (CO)-validated quitters at 4 weeks after quit date in NHS Stop Smoking Clinics. The trial excluded pregnant women and quitters who were not able to read the educational materials in English. Participants in the experimental group (n = 703) received a set of eight revised Forever Free booklets, and participants in the control group (n = 704) received a single leaflet that is currently given to NHS patients. Follow-up telephone interviews were conducted 3 and 12 months after quit date. The primary outcome was prolonged, CO-verified abstinence from months 4 to 12 during which time no more than five cigarettes were smoked. The secondary outcomes included self-reported abstinence during the previous 7 days at 3 and 12 months, CO-verified abstinence at 12 months, costs (NHS and NHS and participant medication costs perspectives) and quality-adjusted life-years. Logistic regression analyses were conducted to investigate effect-modifying variables. A simultaneous qualitative process evaluation was conducted to help interpret the trial results. Data from 1404 participants were used for the final analysis, after excluding three participants who died before the 12-month follow-up. The proportion with prolonged abstinence from months 4 to 12 after quit date was 36.9% in the intervention group and 38.6% in the control group. There was no statistically significant difference between the groups (odds ratio 0.93, 95% confidence interval 0.75 to 1.15; p = 0.509). There were no statistically significant differences between the groups in secondary smoking outcomes. People who reported knowing risky situations for relapse and using strategies to handle urges to smoke were less likely to relapse. However, there were no differences between the groups in the proportion of participants who reported that they knew any more about coping skills, and no differences in reported use of strategies to cope with urges to smoke between the trial groups. The qualitative study found that some quitters considered self-help booklets unhelpful for smoking relapse prevention, although positive feedback by participants was common. Among quitters who had stopped smoking with the aid of intensive behavioural support, there was no significant difference in the likelihood of smoking relapse between those who subsequently received a set of eight revised Forever Free booklets and those who received a single leaflet. Although many people had suboptimal strategies to prevent relapse and most relapsed, the Forever Free booklets proved an ineffective medium for teaching them the skills to prevent relapse. Further research should focus on interventions that may increase the use of coping skills when required. Current Controlled Trials ISRCTN36980856.

Single treatments that have lasting effects: some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin

PubMed Central

Young, Simon N.

2013-01-01

Recent clinical trials suggest that 3 single biological treatments have effects that persist. Based on research showing that the muscles involved in facial expressions can feed back to influence mood, a single trial diminishing glabella frown lines with botulinum toxin demonstrated a significant antidepressant effect for 16 weeks. Based primarily on research with animal models of depression suggesting that glutamate may be involved in depression, the N-methyl-d-aspartate antagonist ketamine has been tested in several trials. A single dose decreased depression for up to a week. The reported effects of the use of mushrooms containing psilocybin by a number of cultures around the world has stimulated several trials showing beneficial effects of a single dose of psilocybin for over a year in healthy people, and for up to 3 months in patients with anxiety disorders who have advanced cancer. This article discusses these studies, their rationale, their possible mechanisms of action, the future clinical research required to establish these therapies and the basic research required to optimize single treatments that have lasting effects. PMID:23171696

The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility.

PubMed

Bensdorp, Alexandra J; Slappendel, Els; Koks, Carolien; Oosterhuis, Jur; Hoek, Annemieke; Hompes, Peter; Broekmans, Frank; Verhoeve, Harold; de Bruin, Jan Peter; van Weert, Janne Meije; Traas, Maaike; Maas, Jacques; Beckers, Nicole; Repping, Sjoerd; Mol, Ben W; van der Veen, Fulco; van Wely, Madelon

2009-12-18

Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART.Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate.This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months.Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded.Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. Current Controlled Trials ISRCTN 52843371.

The Ethics of Randomized Controlled Trials in Social Settings: Can Social Trials Be Scientifically Promising and Must There Be Equipoise?

ERIC Educational Resources Information Center

Fives, Allyn; Russell, Daniel W.; Canavan, John; Lyons, Rena; Eaton, Patricia; Devaney, Carmel; Kearns, Norean; O'Brien, Aoife

2015-01-01

In a randomized controlled trial (RCT), treatments are assigned randomly and treatments are withheld from participants. Is it ethically permissible to conduct an RCT in a social setting? This paper addresses two conditions for justifying RCTs: that there should be a state of equipoise and that the trial should be scientifically promising.…

Vowel Imagery Decoding toward Silent Speech BCI Using Extreme Learning Machine with Electroencephalogram

PubMed Central

Kim, Jongin; Park, Hyeong-jun

2016-01-01

The purpose of this study is to classify EEG data on imagined speech in a single trial. We recorded EEG data while five subjects imagined different vowels, /a/, /e/, /i/, /o/, and /u/. We divided each single trial dataset into thirty segments and extracted features (mean, variance, standard deviation, and skewness) from all segments. To reduce the dimension of the feature vector, we applied a feature selection algorithm based on the sparse regression model. These features were classified using a support vector machine with a radial basis function kernel, an extreme learning machine, and two variants of an extreme learning machine with different kernels. Because each single trial consisted of thirty segments, our algorithm decided the label of the single trial by selecting the most frequent output among the outputs of the thirty segments. As a result, we observed that the extreme learning machine and its variants achieved better classification rates than the support vector machine with a radial basis function kernel and linear discrimination analysis. Thus, our results suggested that EEG responses to imagined speech could be successfully classified in a single trial using an extreme learning machine with a radial basis function and linear kernel. This study with classification of imagined speech might contribute to the development of silent speech BCI systems. PMID:28097128

The CONSENSUS study: protocol for a mixed methods study to establish which outcomes should be included in a core outcome set for oropharyngeal cancer

PubMed Central

2014-01-01

Background The incidence of oropharyngeal cancer is increasing in the developed world. This has led to a large rise in research activity and clinical trials in this area, yet there is no consensus on which outcomes should be measured. As a result, the outcomes measured often differ between trials of comparable interventions, making the combination or comparison of results between trials impossible. Outcomes may also be ‘cherry-picked’, such that favourable results are reported, and less favourable results withheld. The development of a minimum outcome reporting standard, known as a core outcome set, goes some way to addressing these problems. Core outcome sets are ideally developed using a patient-centred approach so that the outcomes measured are relevant to patients and clinical practice. Core outcome sets drive up the quality and relevance of research by ensuring that the right outcomes are consistently measured and reported in trials in specific areas of health or healthcare. Methods/Design This is a mixed methods study involving three phases to develop a core outcome set for oropharyngeal cancer clinical trials. Firstly, a systematic review will establish which outcomes are measured in published oropharyngeal cancer randomised controlled trials (RCTs). Secondly, qualitative interviews with patients and carers in the UK and the USA will aim to establish which outcomes are important to these stakeholders. Data from these first two stages will be used to develop a comprehensive list of outcomes to be considered for inclusion in the core outcome set. In the third stage, patients and clinicians will participate in an iterative consensus exercise known as a Delphi study to refine the contents of the core outcome set. This protocol lays out the methodology to be implemented in the CONSENSUS study. Discussion A core outcome set defines a minimum outcome reporting standard for clinical trials in a particular area of health or healthcare. Its consistent implementation in oropharyngeal cancer clinical trials will improve the quality and relevance of research. Trials and registration This study is registered at the National Institute for Health Research (NIHR) Clinical Research Network (CRN) portfolio, ID 13823 (17 January 2013). PMID:24885068

Exercise to prevent falls in older adults: an updated systematic review and meta-analysis.

PubMed

Sherrington, Catherine; Michaleff, Zoe A; Fairhall, Nicola; Paul, Serene S; Tiedemann, Anne; Whitney, Julie; Cumming, Robert G; Herbert, Robert D; Close, Jacqueline C T; Lord, Stephen R

2017-12-01

Previous meta-analyses have found that exercise prevents falls in older people. This study aimed to test whether this effect is still present when new trials are added, and it explores whether characteristics of the trial design, sample or intervention are associated with greater fall prevention effects. Update of a systematic review with random effects meta-analysis and meta-regression. Cochrane Library, CINAHL, MEDLINE, EMBASE, PubMed, PEDro and SafetyLit were searched from January 2010 to January 2016. We included randomised controlled trials that compared fall rates in older people randomised to receive exercise as a single intervention with fall rates in those randomised to a control group. 99 comparisons from 88 trials with 19 478 participants were available for meta-analysis. Overall, exercise reduced the rate of falls in community-dwelling older people by 21% (pooled rate ratio 0.79, 95% CI 0.73 to 0.85, p<0.001, I 2 47%, 69 comparisons) with greater effects seen from exercise programmes that challenged balance and involved more than 3 hours/week of exercise. These variables explained 76% of the between-trial heterogeneity and in combination led to a 39% reduction in falls (incident rate ratio 0.61, 95% CI 0.53 to 0.72, p<0.001). Exercise also had a fall prevention effect in community-dwelling people with Parkinson's disease (pooled rate ratio 0.47, 95% CI 0.30 to 0.73, p=0.001, I 2 65%, 6 comparisons) or cognitive impairment (pooled rate ratio 0.55, 95% CI 0.37 to 0.83, p=0.004, I 2 21%, 3 comparisons). There was no evidence of a fall prevention effect of exercise in residential care settings or among stroke survivors or people recently discharged from hospital. Exercise as a single intervention can prevent falls in community-dwelling older people. Exercise programmes that challenge balance and are of a higher dose have larger effects. The impact of exercise as a single intervention in clinical groups and aged care facility residents requires further investigation, but promising results are evident for people with Parkinson's disease and cognitive impairment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Simulation-based multiprofessional obstetric anaesthesia training conducted in situ versus off-site leads to similar individual and team outcomes: a randomised educational trial

PubMed Central

Sørensen, Jette Led; van der Vleuten, Cees; Rosthøj, Susanne; Østergaard, Doris; LeBlanc, Vicki; Johansen, Marianne; Ekelund, Kim; Starkopf, Liis; Lindschou, Jane; Gluud, Christian; Weikop, Pia; Ottesen, Bent

2015-01-01

Objective To investigate the effect of in situ simulation (ISS) versus off-site simulation (OSS) on knowledge, patient safety attitude, stress, motivation, perceptions of simulation, team performance and organisational impact. Design Investigator-initiated single-centre randomised superiority educational trial. Setting Obstetrics and anaesthesiology departments, Rigshospitalet, University of Copenhagen, Denmark. Participants 100 participants in teams of 10, comprising midwives, specialised midwives, auxiliary nurses, nurse anaesthetists, operating theatre nurses, and consultant doctors and trainees in obstetrics and anaesthesiology. Interventions Two multiprofessional simulations (clinical management of an emergency caesarean section and a postpartum haemorrhage scenario) were conducted in teams of 10 in the ISS versus the OSS setting. Primary outcome Knowledge assessed by a multiple choice question test. Exploratory outcomes Individual outcomes: scores on the Safety Attitudes Questionnaire, stress measurements (State-Trait Anxiety Inventory, cognitive appraisal and salivary cortisol), Intrinsic Motivation Inventory and perceptions of simulations. Team outcome: video assessment of team performance. Organisational impact: suggestions for organisational changes. Results The trial was conducted from April to June 2013. No differences between the two groups were found for the multiple choice question test, patient safety attitude, stress measurements, motivation or the evaluation of the simulations. The participants in the ISS group scored the authenticity of the simulation significantly higher than did the participants in the OSS group. Expert video assessment of team performance showed no differences between the ISS versus the OSS group. The ISS group provided more ideas and suggestions for changes at the organisational level. Conclusions In this randomised trial, no significant differences were found regarding knowledge, patient safety attitude, motivation or stress measurements when comparing ISS versus OSS. Although participant perception of the authenticity of ISS versus OSS differed significantly, there were no differences in other outcomes between the groups except that the ISS group generated more suggestions for organisational changes. Trial registration number NCT01792674. PMID:26443654

Development of Methods for Cross-Sectional HIV Incidence Estimation in a Large, Community Randomized Trial

PubMed Central

Donnell, Deborah; Komárek, Arnošt; Omelka, Marek; Mullis, Caroline E.; Szekeres, Greg; Piwowar-Manning, Estelle; Fiamma, Agnes; Gray, Ronald H.; Lutalo, Tom; Morrison, Charles S.; Salata, Robert A.; Chipato, Tsungai; Celum, Connie; Kahle, Erin M.; Taha, Taha E.; Kumwenda, Newton I.; Karim, Quarraisha Abdool; Naranbhai, Vivek; Lingappa, Jairam R.; Sweat, Michael D.; Coates, Thomas; Eshleman, Susan H.

2013-01-01

Background Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment. Methods and Findings Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept. Conclusions In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation. PMID:24236054

An Objective Measure of Noseband Tightness and Its Measurement Using a Novel Digital Tightness Gauge.

PubMed

Doherty, Orla; Conway, Thomas; Conway, Richard; Murray, Gerard; Casey, Vincent

2017-01-01

Noseband tightness is difficult to assess in horses participating in equestrian sports such as dressage, show jumping and three-day-eventing. There is growing concern that nosebands are commonly tightened to such an extent as to restrict normal equine behaviour and possibly cause injury. In the absence of a clear agreed definition of noseband tightness, a simple model of the equine nose-noseband interface environment was developed in order to guide further studies in this area. The normal force component of the noseband tensile force was identified as the key contributor to sub-noseband tissue compression. The model was used to inform the design of a digital tightness gauge which could reliably measure the normal force component of the noseband tensile force. A digital tightness gauge was developed to measure this parameter under nosebands fitted to bridled horses. Results are presented for field tests using two prototype designs. Prototype version three was used in field trial 1 (n = 15, frontal nasal plane sub-noseband site). Results of this trial were used to develop an ergonomically designed prototype, version 4, which was tested in a second field trial (n = 12, frontal nasal plane and lateral sub-noseband site). Nosebands were set to three tightness settings in each trial as judged by a single rater using an International Society for Equitation Science (ISES) taper gauge. Normal forces in the range 7-95 N were recorded at the frontal nasal plane while a lower range 1-28 N was found at the lateral site for the taper gauge range used in the trials. The digital tightness gauge was found to be simple to use, reliable, and safe and its use did not agitate the animals in any discernable way. A simple six point tightness scale is suggested to aid regulation implementation and the control of noseband tightness using normal force measurement as the objective tightness discriminant.

WHO Parents Skills Training (PST) programme for children with developmental disorders and delays delivered by Family Volunteers in rural Pakistan: study protocol for effectiveness implementation hybrid cluster randomized controlled trial.

PubMed

Hamdani, S U; Akhtar, P; Zill-E-Huma; Nazir, H; Minhas, F A; Sikander, S; Wang, D; Servilli, C; Rahman, A

2017-01-01

Development disorders and delays are recognised as a public health priority and included in the WHO mental health gap action programme (mhGAP). Parents Skills Training (PST) is recommended as a key intervention for such conditions under the WHO mhGAP intervention guide. However, sustainable and scalable delivery of such evidence based interventions remains a challenge. This study aims to evaluate the effectiveness and scaled-up implementation of locally adapted WHO PST programme delivered by family volunteers in rural Pakistan. The study is a two arm single-blind effectiveness implementation-hybrid cluster randomised controlled trial. WHO PST programme will be delivered by 'family volunteers' to the caregivers of children with developmental disorders and delays in community-based settings. The intervention consists of the WHO PST along with the WHO mhGAP intervention for developmental disorders adapted for delivery using the android application on a tablet device. A total of 540 parent-child dyads will be recruited from 30 clusters. The primary outcome is child's functioning, measured by WHO Disability Assessment Schedule - child version (WHODAS-Child) at 6 months post intervention. Secondary outcomes include children's social communication and joint engagement with their caregiver, social emotional well-being, parental health related quality of life, family empowerment and stigmatizing experiences. Mixed method will be used to collect data on implementation outcomes. Trial has been retrospectively registered at ClinicalTrials.gov (NCT02792894). This study addresses implementation challenges in the real world by incorporating evidence-based intervention strategies with social, technological and business innovations. If proven effective, the study will contribute to scaled-up implementation of evidence-based packages for public mental health in low resource settings. Registered with ClinicalTrials.gov as Family Networks (FaNs) for Children with Developmental Disorders and Delays. Identifier: NCT02792894 Registered on 6 July 2016.

Online Early Resilience Intervention for Combat-Related PTSD in Military Primary Healthcare Settings: A Randomized Trial of DESTRESS-PC

DTIC Science & Technology

2009-08-01

Bryant, R, Engel, CC (2004). A therapist-assisted internet self-help program for traumatic stress . Professional Psychology: Research and Practice, 35...Combat-Related PTSD in Military Primary Healthcare Settings: A Randomized Trial of “DESTRESS-PC” PRINCIPAL INVESTIGATOR: Charles Engel...Early Resilience Intervention for Combat-Related PTSD in Military Primary Healthcare Settings: A Randomized Trial of DESTRESS-PC 5b. GRANT NUMBER

Gene therapy for sickle cell disease.

PubMed

Olowoyeye, Abiola; Okwundu, Charles I

2016-11-14

Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. This is an update of a previously published Cochrane Review. The objectives of this review are:to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 15 August 2016. All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. No trials of gene therapy for sickle cell disease were found. No trials of gene therapy for sickle cell disease were reported. No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

Gene therapy for sickle cell disease.

PubMed

Olowoyeye, Abiola; Okwundu, Charles I

2014-10-10

Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. The objectives of this review are:- to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;- to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 21 July 2014. All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. No trials of gene therapy for sickle cell disease were found. No trials of gene therapy for sickle cell disease were reported. No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

Does self-management for return to work increase the effectiveness of vocational rehabilitation for chronic compensated musculoskeletal disorders? - Protocol for a randomised controlled trial

PubMed Central

2010-01-01

Background Musculoskeletal disorders are common and costly disorders to workers compensation and motor accident insurance systems and are a leading contributor to the burden of ill-health. In Australia, vocational rehabilitation is provided to workers to assist them to stay in, or return to work. Self-management training may be an innovative addition to improve health and employment outcomes from vocational rehabilitation. Methods/Design The research plan contains mixed methodology consisting of a single blind randomised controlled trial, an economic evaluation and qualitative research. Participants (n = 366) are volunteers with compensated musculoskeletal disorders of 3 months to 3 years in duration who were working at the time of the injury/onset of the chronic disorder. The trial tests the effectiveness of usual vocational rehabilitation plus the Chronic Disease Self-Management Program (CDSMP) to which two additional and newly-developed modules have been added, against vocational rehabilitation alone (control) The modules added to the CDSMP focus on how to navigate through compensation systems and manage the return to work process, and aim to be relevant to those in a vocational rehabilitation setting. The primary outcome of this study is readiness for return to work which will be evaluated using the Readiness for Return-to-Work scale. Secondary outcomes include return to work status, health efficacy (heiQ™ questionnaire) and general health status (SF-12v2® Health Survey). Measures will be taken at baseline, immediately post-intervention and at 6- and 12- months post-intervention by an independent assessor. An economic evaluation will compare the costs and outcomes between the intervention and control groups in terms of cost-effectiveness and a partial cost-benefit or cost analysis. The impact of the intervention will also be evaluated qualitatively, in terms of its acceptability to stakeholders. Discussion This article describes the protocol for a single blind randomised controlled trial with a one year follow-up. The results will provide evidence for the addition or not of self-management training within vocational rehabilitation for chronic compensated musculoskeletal disorders. Trial Registration Australia and New Zealand Clinical Trials Registry ACTRN12609000843257 PMID:20534168

Web-Based Decision Aid to Assist Help-Seeking Choices for Young People Who Self-Harm: Outcomes From a Randomized Controlled Feasibility Trial.

PubMed

Rowe, Sarah L; Patel, Krisna; French, Rebecca S; Henderson, Claire; Ougrin, Dennis; Slade, Mike; Moran, Paul

2018-01-30

Adolescents who self-harm are often unsure how or where to get help. We developed a Web-based personalized decision aid (DA) designed to support young people in decision making about seeking help for their self-harm. The aim of this study was to evaluate the feasibility and acceptability of the DA intervention and the randomized controlled trial (RCT) in a school setting. We conducted a two-group, single blind, randomized controlled feasibility trial in a school setting. Participants aged 12 to 18 years who reported self-harm in the past 12 months were randomized to either a Web-based DA or to general information about mood and feelings. Feasibility of recruitment, randomization, and follow-up rates were assessed, as was acceptability of the intervention and study procedures. Descriptive data were collected on outcome measures examining decision making and help-seeking behavior. Qualitative interviews were conducted with young people, parents or carers, and staff and subjected to thematic analysis to explore their views of the DA and study processes. Parental consent was a significant barrier to young people participating in the trial, with only 17.87% (208/1164) of parents or guardians who were contacted for consent responding to study invitations. Where parental consent was obtained, we were able to recruit 81.7% (170/208) of young people into the study. Of those young people screened, 13.5% (23/170) had self-harmed in the past year. Ten participants were randomized to receiving the DA, and 13 were randomized to the control group. Four-week follow-up assessments were completed with all participants. The DA had good acceptability, but qualitative interviews suggested that a DA that addressed broader mental health problems such as depression, anxiety, and self-harm may be more beneficial. A broad-based mental health DA addressing a wide range of psychosocial problems may be useful for young people. The requirement for parental consent is a key barrier to intervention research on self-harm in the school setting. Adaptations to the research design and the intervention are needed before generalizable research about DAs can be successfully conducted in a school setting. International Standard Randomized Controlled Trial registry: ISRCTN11230559; http://www.isrctn.com/ISRCTN11230559 (Archived by WebCite at http://www.webcitation.org/6wqErsYWG). ©Sarah L Rowe, Krisna Patel, Rebecca S French, Claire Henderson, Dennis Ougrin, Mike Slade, Paul Moran. Originally published in JMIR Mental Health (http://mental.jmir.org), 30.01.2018.

Qualitative differences in the guidance of attention during single-color and multiple-color visual search: behavioral and electrophysiological evidence.

PubMed

Grubert, Anna; Eimer, Martin

2013-10-01

To find out whether attentional target selection can be effectively guided by top-down task sets for multiple colors, we measured behavioral and ERP markers of attentional target selection in an experiment where participants had to identify color-defined target digits that were accompanied by a single gray distractor object in the opposite visual field. In the One Color task, target color was constant. In the Two Color task, targets could have one of two equally likely colors. Color-guided target selection was less efficient during multiple-color relative to single-color search, and this was reflected by slower response times and delayed N2pc components. Nontarget-color items that were presented in half of all trials captured attention and gained access to working memory when participants searched for two colors, but were excluded from attentional processing in the One Color task. Results demonstrate qualitative differences in the guidance of attentional target selection between single-color and multiple-color visual search. They suggest that top-down attentional control can be applied much more effectively when it is based on a single feature-specific attentional template. PsycINFO Database Record (c) 2013 APA, all rights reserved.

A Review of Escitalopram and Citalopram in Child and Adolescent Depression

PubMed Central

Carandang, Carlo; Jabbal, Rekha; MacBride, Angela; Elbe, Dean

2011-01-01

Objective: To review the basic pharmacology and published literature regarding escitalopram and citalopram in child and adolescent depression. Methods: A literature review was conducted using the search terms: ‘escitalopram’, ‘citalopram’, ‘depression’, ‘randomized controlled trial’, ‘open label trial’ and limits set to: Human trials, English Language and All Child (Age 0–18). Additional articles were identified from reference information and poster presentation data. Results: Three prospective, randomized controlled trials (RCT) were found for escitalopram in pediatric depression, and two RCTs were found for citalopram. One RCT each for escitalopram and citalopram showed superiority over placebo on the primary out come measure. Adverse effects in escitalopram and citalopram trials were generally mild to moderate. Suicidality was not assessed systematically in all RCTs reviewed, but did not appear to be elevated over placebo in escitalopram RCTs. One trial reported numerically higher suicide related events for citalopram compared to placebo (14 vs. 5, p=0.06). Conclusion: At present, escitalopram and citalopram should be considered a second-line option for adolescent depression. The US Food and Drug Administration approval of escitalopram for treatment of adolescent depression was based on a single positive RCT. This is less evidence than typically required for approval of a drug for a new indication. PMID:22114615

A product of independent beta probabilities dose escalation design for dual-agent phase I trials.

PubMed

Mander, Adrian P; Sweeting, Michael J

2015-04-15

Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia.

PubMed

Gökbuget, N; Kelsh, M; Chia, V; Advani, A; Bassan, R; Dombret, H; Doubek, M; Fielding, A K; Giebel, S; Haddad, V; Hoelzer, D; Holland, C; Ifrah, N; Katz, A; Maniar, T; Martinelli, G; Morgades, M; O'Brien, S; Ribera, J-M; Rowe, J M; Stein, A; Topp, M; Wadleigh, M; Kantarjian, H

2016-09-23

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.

Primaquine or other 8-aminoquinoline for reducing P. falciparum transmission.

PubMed

Graves, Patricia M; Gelband, Hellen; Garner, Paul

2014-06-30

Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person's blood. Plasmodium falciparum gametocytes are sensitive to the drug primaquine (PQ) and other 8-aminoquinolines (8AQ); these drugs could prevent parasite transmission from infected people to mosquitoes, and consequently reduce the incidence of malaria. However, PQ will not directly benefit the individual, and could be harmful to those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.In 2010, The World Health Organization (WHO) recommended a single dose of PQ at 0.75 mg/kg, alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination. In 2013 the WHO revised this to 0.25 mg/kg due to concerns about safety. To assess whether giving PQ or an alternative 8AQ alongside treatment for P. falciparum malaria reduces malaria transmission, and to estimate the frequency of severe or haematological adverse events when PQ is given for this purpose. We searched the following databases up to 10 Feb 2014 for trials: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; metaRegister of Controlled Trials (mRCT); and the WHO trials search portal using 'malaria*', 'falciparum', and 'primaquine' as search terms. In addition, we searched conference proceedings and reference lists of included studies, and contacted researchers and organizations. Randomized controlled trials (RCTs) or quasi-RCTs comparing PQ (or alternative 8AQ) given as a single dose or short course alongside treatment for P. falciparum malaria with malaria treatment given without PQ/8AQ in adults or children. Two authors independently screened all abstracts, applied inclusion criteria, and extracted data. We sought evidence of an impact on transmission (community incidence), infectiousness (mosquitoes infected from humans) and potential infectiousness (gametocyte measures). We calculated the area under the curve (AUC) for gametocyte density over time for comparisons for which data were available. We sought data on haematological and other adverse effects, as well as secondary outcomes of asexual clearance time and recrudescence. We stratified by whether the malaria treatment regimen included an artemisinin derivative or not; by PQ dose category (low < 0.4 mg/kg; medium ≥ 0.4 to < 0.6 mg/kg; high ≥ 0.6 mg/kg); and by PQ schedules. We used the GRADE approach to assess evidence quality. We included 17 RCTs and one quasi-RCT. Eight studies tested for G6PD status: six then excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and one included all irrespective of status. The remaining ten trials either did not report on whether they tested (8), or reported that they did not test (2). Nine trials included study arms with artemisinin-based malaria treatment regimens, and eleven included study arms with non-artemisinin-based treatments.Only two trials evaluated PQ given at low doses (0.25 mg/kg in one and 0.1 mg/kg in the other). PQ with artemisinin-based treatments: No trials evaluated effects on malaria transmission directly (incidence, prevalence, or entomological inoculation rate), and none evaluated infectiousness to mosquitoes. For potential infectiousness, the proportion of people with detectable gametocytaemia on day eight was reduced by around two thirds with high dose PQ category (RR 0.29, 95% CI 0.22 to 0.37, seven trials, 1380 participants, high quality evidence), and with medium dose PQ category (RR 0.34, 95% CI 0.19 to 0.59, two trials, 269 participants, high quality evidence), but the trial evaluating low dose PQ category (0.1 mg/kg) did not demonstrate an effect (RR 0.67, 95% CI 0.44 to 1.02, one trial, 223 participants, low quality evidence). Reductions in log(10)AUC estimates for gametocytaemia on days 1 to 43 with medium and high doses ranged from 24.3% to 87.5%. For haemolysis, one trial reported percent change in mean haemoglobin against baseline, and did not detect a difference between the two arms (very low quality evidence). PQ with non-artemisinin treatments: No trials assessed effects on malaria transmission directly. Two small trials from the same laboratory evaluated infectiousness to mosquitoes, and report that infectivity was eliminated on day 8 in 15/15 patients receiving high dose PQ compared to 1/15 in the control group (low quality evidence). For potential infectiousness, the proportion of people with detectable gametocytaemia on day 8 was reduced by around half with high dose PQ category (RR 0.44, 95% CI 0.27 to 0.70, three trials, 206 participants, high quality evidence), and by around a third with medium dose category (RR 0.62, 0.50 to 0.76, two trials, 283 participants, high quality evidence), but the single trial using low dose PQ category did not demonstrate a difference between groups (one trial, 59 participants, very low quality evidence). Reduction in log(10)AUC for gametocytaemia days 1 to 43 were 24.3% and 27.1% for two arms in one trial giving medium dose PQ. No trials systematically sought evidence of haemolysis.Two trials evaluated the 8AQ bulaquine, and suggest the effects may be greater than PQ, but the small number of participants (n = 112) preclude a definite conclusion. In individual patients, PQ added to malaria treatments reduces gametocyte prevalence when given in doses greater than 0.4 mg/kg. Whether this translates into preventing people transmitting malaria to mosquitoes has rarely been tested in controlled trials, but there appeared to be a strong reduction in infectiousness in the two small studies that evaluated this. No included trials evaluated whether this policy has an impact on community malaria transmission either in low-endemic settings approaching elimination, or in highly-endemic settings where many people are infected but have no symptoms and are unlikely to be treated.For the currently recommended low dose regimen, there is little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved.Most trials excluded people with G6PD deficiency, and thus there is little reliable evidence from controlled trials of the safety of PQ in single dose or short course.

A comparative analysis of costs of single and dual rapid HIV and syphilis diagnostics: results from a randomised controlled trial in Colombia

PubMed Central

Obure, Carol Dayo; Gaitan-Duarte, Hernando; Losada Saenz, Ricardo; Gonzalez, Lina; Angel-Muller, Edith; Laverty, Maura; Perez, Freddy

2017-01-01

Background HIV and congenital syphilis are major public health burdens contributing to substantial perinatal morbidity and mortality globally. Although studies have reported on the costs and cost-effectiveness of rapid diagnostic tests (RDTs) for syphilis screening within antenatal care in a number of resource-constrained settings, empirical evidence on country-specific cost and estimates of single RDTs compared with dual RDTs for HIV and syphilis are limited. Methods A cluster randomised controlled study design was used to compare the incremental costs of two testing algorithms: (1) single RDTs for HIV and syphilis and (2) dual RDTs for HIV and syphilis, in 12 health facilities in Bogota and Cali, Colombia. The costs of single HIV and syphilis RDTs and dual HIV and syphilis RDTs were collected from each of the health facilities. The economic costs per woman tested for HIV and syphilis and costs per woman treated for syphilis defined as the total costs required to test and treat one woman for syphilis were estimated. Results A total of 2214 women were tested in the study facilities. Cost per pregnant woman tested and cost per woman treated for syphilis were US$10.26 and US$607.99, respectively in the single RDT arm. For the dual RDTs, the cost per pregnant woman tested for HIV and syphilis and cost per woman treated for syphilis were US$15.89 and US$1859.26, respectively. Overall costs per woman tested for HIV and syphilis and cost per woman treated for syphilis were lower in Cali compared with Bogota across both intervention arms. Staff costs accounted for the largest proportion of costs while treatment costs comprised <1% of the preventive programme. Conclusions Findings show lower average costs for single RDTs compared with dual RDTs with costs sensitive to personnel costs and the scale of output at the health facilities. Trial registration number NCT02454816; results. PMID:28495681

Video-games used in a group setting is feasible and effective to improve indicators of physical activity in individuals with chronic stroke: a randomized controlled trial.

PubMed

Givon, Noa; Zeilig, Gabi; Weingarden, Harold; Rand, Debbie

2016-04-01

To investigate the feasibility of using video-games in a group setting and to compare the effectiveness of video-games as a group intervention to a traditional group intervention for improving physical activity in individuals with chronic stroke. A single-blind randomized controlled trial with evaluations pre and post a 3-month intervention, and at 3-month follow-up. Compliance (session attendance), satisfaction and adverse effects were feasibility measures. Grip strength and gait speed were measures of physical activity. Hip accelerometers quantified steps/day and the Action Research Arm Test assessed the functional ability of the upper extremity. Forty-seven community-dwelling individuals with chronic stroke (29-78 years) were randomly allocated to receive video-game (N=24) or traditional therapy (N=23) in a group setting. There was high treatment compliance for both interventions (video-games-78%, traditional therapy-66%), but satisfaction was rated higher for the video-game (93%) than the traditional therapy (71%) (χ(2)=4.98, P=0.026). Adverse effects were not reported in either group. Significant improvements were demonstrated in both groups for gait speed (F=3.9, P=0.02), grip strength of the weaker (F=6.67, P=0.002) and stronger hands (F=7.5, P=0.001). Daily steps and functional ability of the weaker hand did not increase in either group. Using video-games in a small group setting is feasible, safe and satisfying. Video-games improve indicators of physical activity of individuals with chronic stroke. © The Author(s) 2015.

Hand washing promotion for preventing diarrhoea

PubMed Central

Ejemot-Nwadiaro, Regina I; Ehiri, John E; Arikpo, Dachi; Meremikwu, Martin M; Critchley, Julia A

2015-01-01

Background Diarrhoea accounts for 1.8 million deaths in children in low- and middle-income countries (LMICs). One of the identified strategies to prevent diarrhoea is hand washing. Objectives To assess the effects of hand washing promotion interventions on diarrhoeal episodes in children and adults. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register (27 May 2015); CENTRAL (published in the Cochrane Library 2015, Issue 5); MEDLINE (1966 to 27 May 2015); EMBASE (1974 to 27 May 2015); LILACS (1982 to 27 May 2015); PsycINFO (1967 to 27 May 2015); Science Citation Index and Social Science Citation Index (1981 to 27 May 2015); ERIC (1966 to 27 May 2015); SPECTR (2000 to 27 May 2015); Bibliomap (1990 to 27 May 2015); RoRe, The Grey Literature (2002 to 27 May 2015); World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP), metaRegister of Controlled Trials (mRCT), and reference lists of articles up to 27 May 2015. We also contacted researchers and organizations in the field. Selection criteria Individually randomized controlled trials (RCTs) and cluster-RCTs that compared the effects of hand washing interventions on diarrhoea episodes in children and adults with no intervention. Data collection and analysis Three review authors independently assessed trial eligibility, extracted data, and assessed risk of bias. We stratified the analyses for child day-care centres or schools, community, and hospital-based settings. Where appropriate, incidence rate ratios (IRR) were pooled using the generic inverse variance method and random-effects model with 95% confidence intervals (CIs). We used the GRADE approach to assess the quality of evidence. Main results We included 22 RCTs: 12 trials from child day-care centres or schools in mainly high-income countries (54,006 participants), nine community-based trials in LMICs (15,303 participants), and one hospital-based trial among people with acquired immune deficiency syndrome (AIDS) (148 participants). Hand washing promotion (education activities, sometimes with provision of soap) at child day-care facilities or schools prevents around one-third of diarrhoea episodes in high income countries (rate ratio 0.70; 95% CI 0.58 to 0.85; nine trials, 4664 participants, high quality evidence), and may prevent a similar proportion in LMICs but only two trials from urban Egypt and Kenya have evaluated this (rate ratio 0.66, 95% CI 0.43 to 0.99; two trials, 45,380 participants, low quality evidence). Only three trials reported measures of behaviour change and the methods of data collection were susceptible to bias. In one trial from the USA hand washing behaviour was reported to improve; and in the trial from Kenya that provided free soap, hand washing did not increase, but soap use did (data not pooled; three trials, 1845 participants, low quality evidence). Hand washing promotion among communities in LMICs probably prevents around one-quarter of diarrhoea episodes (rate ratio 0.72, 95% CI 0.62 to 0.83; eight trials, 14,726 participants, moderate quality evidence). However, six of these eight trials were from Asian settings, with only single trials from South America and sub-Saharan Africa. In six trials, soap was provided free alongside hand washing education, and the overall average effect size was larger than in the two trials which did not provide soap (soap provided: rate ratio 0.66, 95% CI 0.56 to 0.78; six trials, 11,422 participants; education only: rate ratio: 0.84, 95% CI 0.67 to 1.05; two trials, 3304 participants). There was increased hand washing at major prompts (before eating/cooking, after visiting the toilet or cleaning the baby's bottom), and increased compliance to hand hygiene procedure (behavioural outcome) in the intervention groups than the control in community trials (data not pooled: three trials, 3490 participants, high quality evidence). Hand washing promotion for the one trial conducted in a hospital among high-risk population showed significant reduction in mean episodes of diarrhoea (1.68 fewer) in the intervention group (Mean difference 1.68, 95% CI 1.93 to 1.43; one trial, 148 participants, moderate quality evidence). There was increase in hand washing frequency, seven times per day in the intervention group versus three times in the control in this hospital trial (one trial, 148 participants, moderate quality evidence). We found no trials evaluating or reporting the effects of hand washing promotions on diarrhoea-related deaths, all-cause-under five mortality, or costs. Authors' conclusions Hand washing promotion probably reduces diarrhoea episodes in both child day-care centres in high-income countries and among communities living in LMICs by about 30%. However, less is known about how to help people maintain hand washing habits in the longer term. PLAIN LANGUAGE SUMMARY Hand washing promotion for preventing diarrhoea Review question This Cochrane Review summarises trials evaluating the effects of promoting hand washing on the incidence of diarrhoea among children and adults in day-care centres, schools, communities, or hospitals. After searching for relevant trials up to 27 May 2015, we included 22 randomized controlled trials conducted in both high-income countries (HICs) and low- and middle-income countries (LMICs). These trials enrolled 69,309 children and 148 adults. How does hand washing prevent diarrhoea and how might hand washing be promoted Diarrhoea causes many deaths in children below five years of age, mostly in LMICs. The organisms causing diarrhoea are transmitted from person to person through food and water contaminated with faeces, or through person-to-person contact. Hand washing after defecation, or after cleaning a baby's bottom, and before preparing and eating food, can therefore reduce the risk of diarrhoea. Hand washing can be promoted through group or individual training on hygiene education, germ-health awareness, use of posters, leaflets, comic books, songs, and drama. What this review says Hand washing promotion at child day-care facilities or schools in HICs probably prevents around 30% of diarrhoea episodes (high quality evidence), and may prevent a similar proportion in schools in LMICs (low quality evidence). Among communities in LMICs hand washing promotion prevents around 28% of diarrhoea episodes (moderate quality evidence). In the only hospital-based trial included in this review, hand washing promotion also had important reduction in the mean episodes of diarrhoea (moderate quality evidence). This is based on only a single trial with few participants and thus there is need for more trials to confirm this. Effects of hand washing promotion on related hand hygiene behaviour changes improved more in the intervention groups than in the control in all the settings (low to high quality evidence). None of the included trials assessed the effect of handwashing promotion on diarrhoeal-related deaths, all-cause under-five mortality, or the cost-effectiveness of hand washing promotions. Conclusion Hand washing promotion in HICs and LMICs settings may reduce incidence of diarrhoea by about 30%. However, less is known about how to help people maintain hand washing habits in the longer term. PMID:26346329

Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies.

PubMed

Kreimer, Aimée R; Herrero, Rolando; Sampson, Joshua N; Porras, Carolina; Lowy, Douglas R; Schiller, John T; Schiffman, Mark; Rodriguez, Ana Cecilia; Chanock, Stephen; Jimenez, Silvia; Schussler, John; Gail, Mitchell H; Safaeian, Mahboobeh; Kemp, Troy J; Cortes, Bernal; Pinto, Ligia A; Hildesheim, Allan; Gonzalez, Paula

2018-01-20

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Published by Elsevier Ltd.

Working memory load-dependent spatio-temporal activity of single-trial P3 response detected with an adaptive wavelet denoiser.

PubMed

Zhang, Qiushi; Yang, Xueqian; Yao, Li; Zhao, Xiaojie

2017-03-27

Working memory (WM) refers to the holding and manipulation of information during cognitive tasks. Its underlying neural mechanisms have been explored through both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Trial-by-trial coupling of simultaneously collected EEG and fMRI signals has become an important and promising approach to study the spatio-temporal dynamics of such cognitive processes. Previous studies have demonstrated a modulation effect of the WM load on both the BOLD response in certain brain areas and the amplitude of P3. However, much remains to be explored regarding the WM load-dependent relationship between the amplitude of ERP components and cortical activities, and the low signal-to-noise ratio (SNR) of the EEG signal still poses a challenge to performing single-trial analyses. In this paper, we investigated the spatio-temporal activities of P3 during an n-back verbal WM task by introducing an adaptive wavelet denoiser into the extraction of single-trial P3 features and using general linear model (GLM) to integrate simultaneously collected EEG and fMRI data. Our results replicated the modulation effect of the WM load on the P3 amplitude. Additionally, the activation of single-trial P3 amplitudes was detected in multiple brain regions, including the insula, the cuneus, the lingual gyrus (LG), and the middle occipital gyrus (MOG). Moreover, we found significant correlations between P3 features and behavioral performance. These findings suggest that the single-trial integration of simultaneous EEG and fMRI signals may provide new insights into classical cognitive functions. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Limited Effects of Set Shifting Training in Healthy Older Adults

PubMed Central

Grönholm-Nyman, Petra; Soveri, Anna; Rinne, Juha O.; Ek, Emilia; Nyholm, Alexandra; Stigsdotter Neely, Anna; Laine, Matti

2017-01-01

Our ability to flexibly shift between tasks or task sets declines in older age. As this decline may have adverse effects on everyday life of elderly people, it is of interest to study whether set shifting ability can be trained, and if training effects generalize to other cognitive tasks. Here, we report a randomized controlled trial where healthy older adults trained set shifting with three different set shifting tasks. The training group (n = 17) performed adaptive set shifting training for 5 weeks with three training sessions a week (45 min/session), while the active control group (n = 16) played three different computer games for the same period. Both groups underwent extensive pre- and post-testing and a 1-year follow-up. Compared to the controls, the training group showed significant improvements on the trained tasks. Evidence for near transfer in the training group was very limited, as it was seen only on overall accuracy on an untrained computerized set shifting task. No far transfer to other cognitive functions was observed. One year later, the training group was still better on the trained tasks but the single near transfer effect had vanished. The results suggest that computerized set shifting training in the elderly shows long-lasting effects on the trained tasks but very little benefit in terms of generalization. PMID:28386226

Micronutrient supplementation in adults with HIV infection.

PubMed

Visser, Marianne E; Durao, Solange; Sinclair, David; Irlam, James H; Siegfried, Nandi

2017-05-18

Micronutrient deficiencies are common among adults living with HIV disease, particularly in low-income settings where the diet may be low in essential vitamins and minerals. Some micronutrients play critical roles in maintenance of the immune system, and routine supplementation could therefore be beneficial. This is an update of a Cochrane Review previously published in 2010. To assess whether micronutrient supplements are effective and safe in reducing mortality and HIV-related morbidity of HIV-positive adults (excluding pregnant women). We performed literature searches from January 2010 to 18 November 2016 for new randomized controlled trials (RCTs) of micronutrient supplements since the previous review included all trials identified from searches prior to 2010. We searched the CENTRAL (the Cochrane Library), Embase, and PubMed databases. Also we checked the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the ClinicalTrials.gov trials registers. We also checked the reference lists of all new included trials. We included RCTs that compared supplements that contained either single, dual, or multiple micronutrients with placebo, no treatment, or other supplements. We excluded studies that were primarily designed to investigate the role of micronutrients for the treatment of HIV-positive participants with metabolic morbidity related to highly active antiretroviral therapy (HAART). Primary outcomes included all-cause mortality, morbidity, and disease progression. Two review authors independently selected trials for inclusion, and appraised trial quality for risk of bias. Where possible, we presented results as risk ratios (RR) for dichotomous variables, as hazard ratios (HRs) for time-to-event data, and as mean differences (MD) for continuous variables, each with 95% confidence intervals (CIs). Since we were often unable to pool the outcome data, we tabulated it for each comparison. We assessed the certainty of the evidence using the GRADE approach. We included 33 trials with 10,325 participants, of which 17 trials were new trials. Ten trials compared a daily multiple micronutrient supplement to placebo in doses up to 20 times the dietary reference intake, and one trial compared a daily standard dose with a high daily dose of multivitamins. Nineteen trials compared supplementation with single or dual micronutrients (such as vitamins A and D, zinc, and selenium) to placebo, and three trials compared different dosages or combinations of micronutrients. Multiple micronutrientsWe conducted analyses across antiretroviral therapy (ART)-naive adults (3 trials, 1448 participants), adults on antiretroviral therapy (ART) (1 trial, 400 participants), and ART-naive adults with concurrent active tuberculosis (3 trials, 1429 participants). Routine multiple micronutrient supplementation may have little or no effect on mortality in adults living with HIV (RR 0.91, 95% CI 0.72 to 1.15; 7 trials, 2897 participants, low certainty evidence).Routine supplementation for up to two years may have little or no effect on the average of mean CD4+ cell count (MD 26.40 cells/mm³, 95% CI -22.91 to 75.70; 6 trials, 1581 participants, low certainty evidence), or the average of mean viral load (MD -0.1 log 10 viral copies, 95% CI -0.26 to 0.06; 4 trials, 840 participants, moderate certainty evidence). One additional trial in ART-naïve adults did report an increase in the time to reach a CD4+ cell count < 250 cells/mm³ after two years of high dose supplementation in Botswana (HR 0.48, 95% CI 0.26 to 0.88; 1 trial, 439 participants). However, the trial authors reported this effect only in the trial arm that received multiple micronutrients plus selenium (not either supplementation alone), which is inconsistent with the findings of other trials that used similar combinations of micronutrients and selenium.In one additional trial that compared high-dose multiple micronutrient supplementation with standard doses in people on ART, peripheral neuropathy was lower with high dose supplements compared to standard dose (incidence rate ratio (IRR) 0.81, 95% CI 0.7 to 0.94; 1 trial, 3418 participants), but the trial was stopped early due to increased adverse events (elevated alanine transaminase (ALT) levels) in the high dose group. Single or dual micronutrientsNone of the trials of single or dual micronutrient supplements were adequately powered to assess for effects on mortality or morbidity outcomes. No clinically significant changes in CD4 cell count (data not pooled, 14 trials, 2370 participants, very low or low certainty evidence) or viral load (data not pooled, seven studies, 1334 participants, very low or low certainty evidence), were reported. Supplementation probably does increase blood concentrations of vitamin D and zinc (data not pooled, vitamin D: 4 trials, 299 participants, zinc: 4 trials, 484 participants, moderate certainty evidence) and may also increase blood concentrations of vitamin A (data not pooled, 3 trials, 495 participants, low certainty evidence), especially in those who are deficient. The analyses of the available trials have not revealed consistent clinically important benefits with routine multiple micronutrient supplementation in people living with HIV. Larger trials might reveal small but important effects.These findings should not be interpreted as a reason to deny micronutrient supplements for people living with HIV where specific deficiencies are found or where the person's diet is insufficient to meet the recommended daily allowance of vitamins and minerals.

Acute effects of a single exercise class on appetite, energy intake and mood. Is there a time of day effect?

PubMed

Maraki, M; Tsofliou, F; Pitsiladis, Y P; Malkova, D; Mutrie, N; Higgins, S

2005-12-01

This study aimed to investigate the acute effects of a single exercise class on appetite sensations, energy intake and mood, and to determine if there was a time of day effect. Twelve healthy, young, normal weight females, who were non-regular exercisers, participated in four trials: morning control, morning exercise, evening control and evening exercise. Exercise trials were a one-hour class of aerobic and muscle conditioning exercise of varying intensities, to music. Control trials were a one-hour rest. Ratings of perceived exertion were significantly greater during the warm-up and muscle conditioning parts of the morning exercise trial compared to those of the evening exercise trial. Although both exercise trials, compared to control trials, produced an increase in appetite sensations, they did not alter energy intake and produced a decrease in 'relative' energy intake. In relation to mood, both exercise trials increased positive affect and decreased negative affect. These results suggest that a single exercise class, representative of that offered by many sports centres, regardless of whether it is performed in the morning or evening produces a short-term negative energy balance and improves mood in normal weight women. However, when this type of exercise was performed in the morning it was perceived to require more effort.

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer

PubMed Central

Bosch, Linda J.W.; Coupé, Veerle M.H.; Mongera, Sandra; Haan, Josien C.; Richman, Susan D.; Koopman, Miriam; Tol, Jolien; de Meyer, Tim; Louwagie, Joost; Dehaspe, Luc; van Grieken, Nicole C.T.; Ylstra, Bauke; Verheul, Henk M.W.; van Engeland, Manon; Nagtegaal, Iris D.; Herman, James G.; Quirke, Philip; Seymour, Matthew T.; Punt, Cornelis J.A.; van Criekinge, Wim; Carvalho, Beatriz; Meijer, Gerrit A.

2017-01-01

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials. PMID:28968978

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer.

PubMed

Bosch, Linda J W; Trooskens, Geert; Snaebjornsson, Petur; Coupé, Veerle M H; Mongera, Sandra; Haan, Josien C; Richman, Susan D; Koopman, Miriam; Tol, Jolien; de Meyer, Tim; Louwagie, Joost; Dehaspe, Luc; van Grieken, Nicole C T; Ylstra, Bauke; Verheul, Henk M W; van Engeland, Manon; Nagtegaal, Iris D; Herman, James G; Quirke, Philip; Seymour, Matthew T; Punt, Cornelis J A; van Criekinge, Wim; Carvalho, Beatriz; Meijer, Gerrit A

2017-09-08

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 ( DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p =0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p =0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p =0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p =0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1 : HR=0.7 (95%CI 0.5-0.9, p =0.01), unmethylated DCR1 : HR=0.8 (95%CI 0.6-1.2, p =0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials.

Single-visit or multiple-visit root canal treatment: systematic review, meta-analysis and trial sequential analysis.

PubMed

Schwendicke, Falk; Göstemeyer, Gerd

2017-02-01

Single-visit root canal treatment has some advantages over conventional multivisit treatment, but might increase the risk of complications. We systematically evaluated the risk of complications after single-visit or multiple-visit root canal treatment using meta-analysis and trial-sequential analysis. Controlled trials comparing single-visit versus multiple-visit root canal treatment of permanent teeth were included. Trials needed to assess the risk of long-term complications (pain, infection, new/persisting/increasing periapical lesions ≥1 year after treatment), short-term pain or flare-up (acute exacerbation of initiation or continuation of root canal treatment). Electronic databases (PubMed, EMBASE, Cochrane Central) were screened, random-effects meta-analyses performed and trial-sequential analysis used to control for risk of random errors. Evidence was graded according to GRADE. 29 trials (4341 patients) were included, all but 6 showing high risk of bias. Based on 10 trials (1257 teeth), risk of complications was not significantly different in single-visit versus multiple-visit treatment (risk ratio (RR) 1.00 (95% CI 0.75 to 1.35); weak evidence). Based on 20 studies (3008 teeth), risk of pain did not significantly differ between treatments (RR 0.99 (95% CI 0.76 to 1.30); moderate evidence). Risk of flare-up was recorded by 8 studies (1110 teeth) and was significantly higher after single-visit versus multiple-visit treatment (RR 2.13 (95% CI 1.16 to 3.89); very weak evidence). Trial-sequential analysis revealed that firm evidence for benefit, harm or futility was not reached for any of the outcomes. There is insufficient evidence to rule out whether important differences between both strategies exist. Dentists can provide root canal treatment in 1 or multiple visits. Given the possibly increased risk of flare-ups, multiple-visit treatment might be preferred for certain teeth (eg, those with periapical lesions). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Auditory proactive interference in monkeys: The role of stimulus set size and intertrial interval

PubMed Central

Bigelow, James; Poremba, Amy

2013-01-01

We conducted two experiments to examine the influence of stimulus set size (the number of stimuli that are used throughout the session) and intertrial interval (ITI, the elapsed time between trials) in auditory short-term memory in monkeys. We used an auditory delayed matching-to-sample task wherein the animals had to indicate whether two sounds separated by a 5-s retention interval were the same (match trials) or different (non-match trials). In Experiment 1, we randomly assigned a stimulus set size of 2, 4, 8, 16, 32, 64, or 192 (trial unique) for each session of 128 trials. Consistent with previous visual studies, overall accuracy was consistently lower when smaller stimulus set sizes were used. Further analyses revealed that these effects were primarily caused by an increase in incorrect “same” responses on non-match trials. In Experiment 2, we held the stimulus set size constant at four for each session and alternately set the ITI at 5, 10, or 20 s. Overall accuracy improved by increasing the ITI from 5 to 10 s, but the 10 and 20 s conditions were the same. As in Experiment 1, the overall decrease in accuracy during the 5-s condition was caused by a greater number of false “match” responses on non-match trials. Taken together, Experiments 1 and 2 show that auditory short-term memory in monkeys is highly susceptible to PI caused by stimulus repetition. Additional analyses from Experiment 1 suggest that monkeys may make same/different judgments based on a familiarity criterion that is adjusted by error-related feedback. PMID:23526232

Drug-resistant tuberculosis clinical trials: proposed core research definitions in adults.

PubMed

Furin, J; Alirol, E; Allen, E; Fielding, K; Merle, C; Abubakar, I; Andersen, J; Davies, G; Dheda, K; Diacon, A; Dooley, K E; Dravnice, G; Eisenach, K; Everitt, D; Ferstenberg, D; Goolam-Mahomed, A; Grobusch, M P; Gupta, R; Harausz, E; Harrington, M; Horsburgh, C R; Lienhardt, C; McNeeley, D; Mitnick, C D; Nachman, S; Nahid, P; Nunn, A J; Phillips, P; Rodriguez, C; Shah, S; Wells, C; Thomas-Nyang'wa, B; du Cros, P

2016-03-01

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

Vaccines for preventing typhoid fever.

PubMed

Milligan, Rachael; Paul, Mical; Richardson, Marty; Neuberger, Ami

2018-05-31

Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are widely available, Ty21a (oral) and Vi polysaccharide (parenteral). Newer typhoid conjugate vaccines are at varying stages of development and use. The World Health Organization has recently recommended a Vi tetanus toxoid (Vi-TT) conjugate vaccine, Typbar-TCV, as the preferred vaccine for all ages. To assess the effects of vaccines for preventing typhoid fever. In February 2018, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and mRCT. We also searched the reference lists of all included trials. Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease) in adults and children. Human challenge studies were not eligible. Two review authors independently applied inclusion criteria and extracted data, and assessed the certainty of the evidence using the GRADE approach. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella enterica serovar Typhi in blood. We calculated risk ratios (RRs) and efficacy (1 - RR as a percentage) with 95% confidence intervals (CIs). In total, 18 RCTs contributed to the quantitative analysis in this review: 13 evaluated efficacy (Ty21a: 5 trials; Vi polysaccharide: 6 trials; Vi-rEPA: 1 trial; Vi-TT: 1 trial), and 9 reported on adverse events. All trials but one took place in typhoid-endemic countries. There was no information on vaccination in adults aged over 55 years of age, pregnant women, or travellers. Only one trial included data on children under two years of age.Ty21a vaccine (oral vaccine, three doses)A three-dose schedule of Ty21a vaccine probably prevents around half of typhoid cases during the first three years after vaccination (cumulative efficacy 2.5 to 3 years: 50%, 95% CI 35% to 61%, 4 trials, 235,239 participants, moderate-certainty evidence). These data include patients aged 3 to 44 years.Compared with placebo, this vaccine probably does not cause more vomiting, diarrhoea, nausea or abdominal pain (2 trials, 2066 participants; moderate-certainty evidence), headache, or rash (1 trial, 1190 participants; moderate-certainty evidence); however, fever (2 trials, 2066 participants; moderate-certainty evidence) is probably more common following vaccination.Vi polysaccharide vaccine (injection, one dose)A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (year 1: 69%, 95% CI 63% to 74%; 3 trials, 99,979 participants; high-certainty evidence). In year 2, trial results were more variable, with the vaccine probably preventing between 45% and 69% of typhoid cases (year 2: 59%, 95% CI 45% to 69%; 4 trials, 194,969 participants; moderate-certainty evidence). These data included participants aged 2 to 55 years of age.The three-year cumulative efficacy of the vaccine may be around 55% (95% CI 30% to 70%; 11,384 participants, 1 trial; low-certainty evidence). These data came from a single trial conducted in South Africa in the 1980s in participants aged 5 to 15 years.Compared with placebo, this vaccine probably did not increase the incidence of fever (3 trials, 132,261 participants; moderate-certainty evidence) or erythema (3 trials, 132,261 participants; low-certainty evidence); however, swelling (3 trials, 1767 participants; moderate-certainty evidence) and pain at the injection site (1 trial, 667 participants; moderate-certainty evidence) were more common in the vaccine group.Vi-rEPA vaccine (two doses)Administration of two doses of the Vi-rEPA vaccine probably prevents between 50% and 96% of typhoid cases during the first two years after vaccination (year 1: 94%, 95% CI 75% to 99%; year 2: 87%, 95% CI 56% to 96%, 1 trial, 12,008 participants; moderate-certainty evidence). These data came from a single trial with children two to five years of age conducted in Vietnam.Compared with placebo, both the first and the second dose of this vaccine increased the risk of fever (1 trial, 12,008 and 11,091 participants, low-certainty evidence) and the second dose increase the incidence of swelling at the injection site (one trial, 11,091 participants, moderate-certainty evidence).Vi-TT vaccine (two doses)We are uncertain of the efficacy of administration of two doses of Vi-TT (PedaTyph) in typhoid cases in children during the first year after vaccination (year 1: 94%, 95% CI -1% to 100%, 1 trial, 1625 participants; very low-certainty evidence). These data come from a single cluster-randomized trial in children aged six months to 12 years and conducted in India. For single dose Vi-TT (Typbar-TCV), we found no efficacy trials evaluating the vaccine with natural exposure.There were no reported serious adverse effects in RCTs of any of the vaccines studied. The licensed Ty21a and Vi polysaccharide vaccines are efficacious in adults and children older than two years in endemic countries. The Vi-rEPA vaccine is just as efficacious, although data is only available for children. The new Vi-TT vaccine (PedaTyph) requires further evaluation to determine if it provides protection against typhoid fever. At the time of writing, there were only efficacy data from a human challenge setting in adults on the Vi-TT vaccine (Tybar), which clearly justify the ongoing field trials to evaluate vaccine efficacy.

Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

PubMed

Mayhew, S D; Mullinger, K J; Ostwald, D; Porcaro, C; Bowtell, R; Bagshaw, A P; Francis, S T

2016-06-01

In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of average responses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial – challenges, enablers and lessons learned

PubMed Central

Anguzu, Ronald; Akun, Pamela R; Ogwang, Rodney; Shour, Abdul Rahman; Sekibira, Rogers; Ningwa, Albert; Nakamya, Phellister; Abbo, Catherine; Mwaka, Amos D; Opar, Bernard; Idro, Richard

2018-01-01

ABSTRACT A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research. PMID:29382251

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial - challenges, enablers and lessons learned.

PubMed

Anguzu, Ronald; Akun, Pamela R; Ogwang, Rodney; Shour, Abdul Rahman; Sekibira, Rogers; Ningwa, Albert; Nakamya, Phellister; Abbo, Catherine; Mwaka, Amos D; Opar, Bernard; Idro, Richard

2018-01-01

A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research.

Challenges and impact of conducting vaccine trials in Asia and Africa

PubMed Central

Kochhar, Sonali

2013-01-01

Immunization is one of the most beneficial and cost-effective disease prevention measures. There are global efforts to develop new vaccines for disease control. The vaccine clinical trials must be conducted in the countries where they will be used. This has led to vaccine trials being conducted across Asia and Africa where there is a high burden of infectious diseases. The setup and successful conduct of International standard GCP vaccine trials across trial centers located in resource constrained settings are challenging. The challenges, ethical considerations and impact of the implementation of clinical trials in low-resource settings are highlighted here to help vaccine development programs successfully conduct such trials. PMID:23321645

Probabilistic Common Spatial Patterns for Multichannel EEG Analysis

PubMed Central

Chen, Zhe; Gao, Xiaorong; Li, Yuanqing; Brown, Emery N.; Gao, Shangkai

2015-01-01

Common spatial patterns (CSP) is a well-known spatial filtering algorithm for multichannel electroencephalogram (EEG) analysis. In this paper, we cast the CSP algorithm in a probabilistic modeling setting. Specifically, probabilistic CSP (P-CSP) is proposed as a generic EEG spatio-temporal modeling framework that subsumes the CSP and regularized CSP algorithms. The proposed framework enables us to resolve the overfitting issue of CSP in a principled manner. We derive statistical inference algorithms that can alleviate the issue of local optima. In particular, an efficient algorithm based on eigendecomposition is developed for maximum a posteriori (MAP) estimation in the case of isotropic noise. For more general cases, a variational algorithm is developed for group-wise sparse Bayesian learning for the P-CSP model and for automatically determining the model size. The two proposed algorithms are validated on a simulated data set. Their practical efficacy is also demonstrated by successful applications to single-trial classifications of three motor imagery EEG data sets and by the spatio-temporal pattern analysis of one EEG data set recorded in a Stroop color naming task. PMID:26005228

Revealing the secret life of pre-implantation embryos by time-lapse monitoring: A review

PubMed Central

Faramarzi, Azita; Khalili, Mohammad Ali; Micara, Giulietta; Agha-Rahimi, Azam

2017-01-01

High implantation success following in vitro fertilization cycles are achieved via the transfer of embryos with the highest developmental competence. Multiple pregnancies as a result of the transfer of several embryos per cycle accompany with various complication. Thus, single-embryo transfer (SET) is the preferred practice in assisted reproductive technique (ART) treatment. In order to improve the pregnancy rate for SET, embryologists need reliable biomarkers to aid their selection of embryos with the highest developmental potential. Time-lapse technology is a noninvasive alternative conventional microscopic assessment. It provides uninterrupted and continues the survey of embryo development to transfer day. Today, there are four time-lapse systems that are commercially available for ART centers. In world and Iran, the first time lapse babies were born in 2010 and 2015, respectively, conceived by SET. Here, we review the use of time-lapse monitoring in the observation of embryogenesis as well as its role in SET. Although, the findings from our review support common use of time-lapse monitoring in ART centers; but, future large studies assessing this system in well-designed trials are necessary. PMID:28744520

Energy and traffic light labelling have no impact on parent and child fast food selection.

PubMed

Dodds, Pennie; Wolfenden, Luke; Chapman, Kathy; Wellard, Lyndal; Hughes, Clare; Wiggers, John

2013-10-25

Labelling of food from fast food restaurants at point-of-purchase has been suggested as one strategy to reduce population energy consumption and contribute to reductions in obesity prevalence. The aim of this study was to examine the effects of energy and single traffic light labelling systems on the energy content of child and adult intended food purchases. The study employed a randomised controlled trial design. English speaking parents of children aged between three and 12 years were recruited from an existing research cohort. Participants were mailed one of three hypothetical fast food menus. Menus differed in their labelling technique- either energy labels, single traffic light labels, or a no-label control. Participants then completed a telephone survey which assessed intended food purchases for both adult and child. The primary trial outcome was total energy of intended food purchase. A total of 329 participants completed the follow-up telephone interview. Eighty-two percent of the energy labelling group and 96% of the single traffic light labelling group reported noticing labelling information on their menu. There were no significant differences in total energy of intended purchases of parents, or intended purchases made by parents for children, between the menu labelling groups, or between menu labelling groups by socio-demographic subgroups. This study provided no evidence to suggest that energy labelling or single traffic light labelling alone were effective in reducing the energy of fast food items selected from hypothetical fast food menus for purchase. Additional complementary public health initiatives promoting the consumption of healthier foods identified by labelling, and which target other key drivers of menu item selection in this setting may be required. Copyright © 2013. Published by Elsevier Ltd.

A Machine Learning Approach to Identifying Placebo Responders in Late-Life Depression Trials.

PubMed

Zilcha-Mano, Sigal; Roose, Steven P; Brown, Patrick J; Rutherford, Bret R

2018-01-11

Despite efforts to identify characteristics associated with medication-placebo differences in antidepressant trials, few consistent findings have emerged to guide participant selection in drug development settings and differential therapeutics in clinical practice. Limitations in the methodologies used, particularly searching for a single moderator while treating all other variables as noise, may partially explain the failure to generate consistent results. The present study tested whether interactions between pretreatment patient characteristics, rather than a single-variable solution, may better predict who is most likely to benefit from placebo versus medication. Data were analyzed from 174 patients aged 75 years and older with unipolar depression who were randomly assigned to citalopram or placebo. Model-based recursive partitioning analysis was conducted to identify the most robust significant moderators of placebo versus citalopram response. The greatest signal detection between medication and placebo in favor of medication was among patients with fewer years of education (≤12) who suffered from a longer duration of depression since their first episode (>3.47 years) (B = 2.53, t(32) = 3.01, p = 0.004). Compared with medication, placebo had the greatest response for those who were more educated (>12 years), to the point where placebo almost outperformed medication (B = -0.57, t(96) = -1.90, p = 0.06). Machine learning approaches capable of evaluating the contributions of multiple predictor variables may be a promising methodology for identifying placebo versus medication responders. Duration of depression and education should be considered in the efforts to modulate placebo magnitude in drug development settings and in clinical practice. Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Progress on core outcome sets for critical care research.

PubMed

Blackwood, Bronagh; Marshall, John; Rose, Louise

2015-10-01

Appropriate selection and definition of outcome measures are essential for clinical trials to be maximally informative. Core outcome sets (an agreed, standardized collection of outcomes measured and reported in all trials for a specific clinical area) were developed due to established inconsistencies in trial outcome selection. This review discusses the rationale for, and methods of, core outcome set development, as well as current initiatives in critical care. Recent systematic reviews of reported outcomes and measurement instruments relevant to the critically ill highlight inconsistencies in outcome selection, definition, and measurement, thus establishing the need for core outcome sets. Current critical care initiatives include development of core outcome sets for trials aimed at reducing mechanical ventilation duration; rehabilitation following critical illness; long-term outcomes in acute respiratory failure; and epidemic and pandemic studies of severe acute respiratory infection. Development and utilization of core outcome sets for studies relevant to the critically ill is in its infancy compared to other specialties. Notwithstanding, core outcome set development frameworks and guidelines are available, several sets are in various stages of development, and there is strong support from international investigator-led collaborations including the International Forum for Acute Care Trialists.

Single, double or multiple-injection techniques for non-ultrasound guided axillary brachial plexus block in adults undergoing surgery of the lower arm.

PubMed

Chin, Ki Jinn; Alakkad, Husni; Cubillos, Javier E

2013-08-08

Regional anaesthesia comprising axillary block of the brachial plexus is a common anaesthetic technique for distal upper limb surgery. This is an update of a review first published in 2006 and updated in 2011. To compare the relative effects (benefits and harms) of three injection techniques (single, double and multiple) of axillary block of the brachial plexus for distal upper extremity surgery. We considered these effects primarily in terms of anaesthetic effectiveness; the complication rate (neurological and vascular); and pain and discomfort caused by performance of the block. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and reference lists of trials. We contacted trial authors. The date of the last search was March 2013 (updated from March 2011). We included randomized controlled trials that compared double with single-injection techniques, multiple with single-injection techniques, or multiple with double-injection techniques for axillary block in adults undergoing surgery of the distal upper limb. We excluded trials using ultrasound-guided techniques. Independent study selection, risk of bias assessment and data extraction were performed by at least two investigators. We undertook meta-analysis. The 21 included trials involved a total of 2148 participants who received regional anaesthesia for hand, wrist, forearm or elbow surgery. Risk of bias assessment indicated that trial design and conduct were generally adequate; the most common areas of weakness were in blinding and allocation concealment.Eight trials comparing double versus single injections showed a statistically significant decrease in primary anaesthesia failure (risk ratio (RR 0.51), 95% confidence interval (CI) 0.30 to 0.85). Subgroup analysis by method of nerve location showed that the effect size was greater when neurostimulation was used rather than the transarterial technique.Eight trials comparing multiple with single injections showed a statistically significant decrease in primary anaesthesia failure (RR 0.25, 95% CI 0.14 to 0.44) and of incomplete motor block (RR 0.61, 95% CI 0.39 to 0.96) in the multiple injection group.Eleven trials comparing multiple with double injections showed a statistically significant decrease in primary anaesthesia failure (RR 0.28, 95% CI 0.20 to 0.40) and of incomplete motor block (RR 0.55, 95% CI 0.36 to 0.85) in the multiple injection group.Tourniquet pain was significantly reduced with multiple injections compared with double injections (RR 0.53, 95% CI 0.33 to 0.84). Otherwise there were no statistically significant differences between groups in any of the three comparisons on secondary analgesia failure, complications and patient discomfort. The time for block performance was significantly shorter for single and double injections compared with multiple injections. This review provides evidence that multiple-injection techniques using nerve stimulation for axillary plexus block produce more effective anaesthesia than either double or single-injection techniques. However, there was insufficient evidence for a significant difference in other outcomes, including safety.

Will the EU Clinical Trials Regulation Support the Innovative Industry in Bringing New Medicines Faster to Patients?

PubMed

Atzor, Sabine; Gokhale, Surendra; Doherty, Michael

2013-04-01

A perspective from the innovative industry is provided in this article about the long awaited legal proposal for a Clinical Trial Regulation ("Proposal"), adopted in July 2012. With this Proposal, the European Commission reacted to a call by all stakeholders for more harmonization and streamlining of the provisions for conducting clinical trials in the EU. Discrepant approaches between Member States, a failure to respect legal timelines, and a lack of formal coordination mechanisms within and between Member States have resulted in an increased workload for the industry and contributed to a decline in Europe's attractiveness as a place to carry out research and development. The Proposal introduces a concept whereby the sponsor makes a single submission of the clinical trial application dossier to an EU portal, which is followed by a single assessment based on cooperation between Member States. A possibility for the sponsor to choose a 'reporting Member State' to take the lead on key aspects of the assessment is expected to support excellence building and work sharing of Competent Authorities in the EU. The Proposal respects the fact that certain aspects need to be reviewed nationally. The new process aims to lead to a single decision per clinical trial per concerned Member State. The rules are built on the principle of strict adherence to timelines for authorization. The timelines are ambitious but at the same time competitive, as the process builds in mechanisms that strengthen compliance. The rules have been designed to encourage sponsors to file complete submission packages, since any substantial modification to a trial would lead to delays in its commencement. Sponsors need to streamline their internal processes accordingly. In the end, streamlining is an effort that needs to be accepted by all parties involved. The Proposal does not detail how Member States organize the involvement of different bodies, such as Competent Authorities and Ethics Committees, because according to the EU Treaty, the EU cannot legislate on aspects falling into pure Member State competence. The Proposal, however, establishes the assessment objectives on the basis of Good Clinical Practices set by the International Conference on Harmonisation (ICH) and the Declaration of Helsinki by the World Medical Association. As such, the new legislation is likely to have implications on Member States' internal organization. In addition, Ethics Committees in Europe would benefit from an EU platform for best practice exchange-a concept that would need to be requested by the Council and the European Parliament through the legislative process. A single decision system for the entire EU per clinical trial has been discussed as an option, but such an approach was difficult to achieve while respecting national competencies. In this situation, the Proposal represents an acceptable compromise, provided its proposed mechanisms, processes, and timelines are retained upon implementation. As the Proposal is now on the table for discussion by the 27 Member States' governments and by the European Parliament, co-legislators and stakeholders should be aware that any dilution of these provisions would be detrimental to the objective to ensure patient access and make the conditions for clinical research in Europe attractive and fit for the future.

Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer

PubMed Central

Katz, Matthew H. G.; Shi, Qian; Ahmad, Syed A.; Herman, Joseph M.; Marsh, Robert de W.; Collisson, Eric; Schwartz, Lawrence; Frankel, Wendy; Martin, Robert; Conway, William; Truty, Mark; Kindler, Hedy; Lowy, Andrew M.; Bekaii-Saab, Tanios; Philip, Philip; Talamonti, Mark; Cardin, Dana; LoConte, Noelle; Shen, Perry; Hoffman, John P.; Venook, Alan P.

2016-01-01

IMPORTANCE Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50–76 years]; 55% female). Patients registered between May 29, 2013, and February 7,2014. INTERVENTIONS Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%–83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%–88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01821612 PMID:27275632

The CONSENSUS study: protocol for a mixed methods study to establish which outcomes should be included in a core outcome set for oropharyngeal cancer.

PubMed

Waters, Aoife Mi; Tudur Smith, Catrin; Young, Bridget; Jones, Terry M

2014-05-13

The incidence of oropharyngeal cancer is increasing in the developed world. This has led to a large rise in research activity and clinical trials in this area, yet there is no consensus on which outcomes should be measured. As a result, the outcomes measured often differ between trials of comparable interventions, making the combination or comparison of results between trials impossible. Outcomes may also be 'cherry-picked', such that favourable results are reported, and less favourable results withheld. The development of a minimum outcome reporting standard, known as a core outcome set, goes some way to addressing these problems. Core outcome sets are ideally developed using a patient-centred approach so that the outcomes measured are relevant to patients and clinical practice. Core outcome sets drive up the quality and relevance of research by ensuring that the right outcomes are consistently measured and reported in trials in specific areas of health or healthcare. This is a mixed methods study involving three phases to develop a core outcome set for oropharyngeal cancer clinical trials. Firstly, a systematic review will establish which outcomes are measured in published oropharyngeal cancer randomised controlled trials (RCTs). Secondly, qualitative interviews with patients and carers in the UK and the USA will aim to establish which outcomes are important to these stakeholders. Data from these first two stages will be used to develop a comprehensive list of outcomes to be considered for inclusion in the core outcome set. In the third stage, patients and clinicians will participate in an iterative consensus exercise known as a Delphi study to refine the contents of the core outcome set. This protocol lays out the methodology to be implemented in the CONSENSUS study. A core outcome set defines a minimum outcome reporting standard for clinical trials in a particular area of health or healthcare. Its consistent implementation in oropharyngeal cancer clinical trials will improve the quality and relevance of research. This study is registered at the National Institute for Health Research (NIHR) Clinical Research Network (CRN) portfolio, ID 13823 (17 January 2013).

Randomization Methods in Emergency Setting Trials: A Descriptive Review

ERIC Educational Resources Information Center

Corbett, Mark Stephen; Moe-Byrne, Thirimon; Oddie, Sam; McGuire, William

2016-01-01

Background: Quasi-randomization might expedite recruitment into trials in emergency care settings but may also introduce selection bias. Methods: We searched the Cochrane Library and other databases for systematic reviews of interventions in emergency medicine or urgent care settings. We assessed selection bias (baseline imbalances) in prognostic…

Introducing the Event Related Fixed Interval Area (ERFIA) Multilevel Technique: a Method to Analyze the Complete Epoch of Event-Related Potentials at Single Trial Level

PubMed Central

Vossen, Catherine J.; Vossen, Helen G. M.; Marcus, Marco A. E.; van Os, Jim; Lousberg, Richel

2013-01-01

In analyzing time-locked event-related potentials (ERPs), many studies have focused on specific peaks and their differences between experimental conditions. In theory, each latency point after a stimulus contains potentially meaningful information, regardless of whether it is peak-related. Based on this assumption, we introduce a new concept which allows for flexible investigation of the whole epoch and does not primarily focus on peaks and their corresponding latencies. For each trial, the entire epoch is partitioned into event-related fixed-interval areas under the curve (ERFIAs). These ERFIAs, obtained at single trial level, act as dependent variables in a multilevel random regression analysis. The ERFIA multilevel method was tested in an existing ERP dataset of 85 healthy subjects, who underwent a rating paradigm of 150 painful and non-painful somatosensory electrical stimuli. We modeled the variability of each consecutive ERFIA with a set of predictor variables among which were stimulus intensity and stimulus number. Furthermore, we corrected for latency variations of the P2 (260 ms). With respect to known relationships between stimulus intensity, habituation, and pain-related somatosensory ERP, the ERFIA method generated highly comparable results to those of commonly used methods. Notably, effects on stimulus intensity and habituation were also observed in non-peak-related latency ranges. Further, cortical processing of actual stimulus intensity depended on the intensity of the previous stimulus, which may reflect pain-memory processing. In conclusion, the ERFIA multilevel method is a promising tool that can be used to study event-related cortical processing. PMID:24224018

About the Community Oncology and Prevention Trials Research Group | Division of Cancer Prevention

Cancer.gov

The Community Oncology and Prevention Trials Research Group supports clinical oncology trials in cancer prevention and control in community settings. The group also supports investigator-initiated research projects in supportive, palliative and end-of-life care, and coordinates clinical oncology research projects with other NCI programs to be done in the community setting. |

Sensitivity subgroup analysis based on single-center vs. multi-center trial status when interpreting meta-analyses pooled estimates: the logical way forward.

PubMed

Alexander, Paul E; Bonner, Ashley J; Agarwal, Arnav; Li, Shelly-Anne; Hariharan, Abishek; Izhar, Zain; Bhatnagar, Neera; Alba, Carolina; Akl, Elie A; Fei, Yutong; Guyatt, Gordon H; Beyene, Joseph

2016-06-01

Prior studies regarding whether single-center trial estimates are larger than multi-center are equivocal. We examined the extent to which single-center trials yield systematically larger effects than multi-center trials. We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of randomized controlled trials (RCTs) published during 2012. In this meta-epidemiologic study, for binary variables, we computed the pooled ratio of ORs (RORs), and for continuous outcomes mean difference in standardized mean differences (SMDs), we conducted weighted random-effects meta-regression and random-effects MA modeling. Our primary analyses were restricted to MAs that included at least five RCTs and in which at least 25% of the studies used each of single trial center (SC) and more trial center (MC) designs. We identified 81 MAs for the odds ratio (OR) and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes [RORs: 1.02; 95% confidence interval (CI): 0.83, 1.24; I(2) 20.2%]. Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13; 95% CI: -0.21, -0.05; I(2) 0%). Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses). Copyright © 2015 Elsevier Inc. All rights reserved.

An integrated intervention to reduce intimate partner violence and psychological distress with refugees in low-resource settings: study protocol for the Nguvu cluster randomized trial.

PubMed

Tol, Wietse A; Greene, M Claire; Likindikoki, Samuel; Misinzo, Lusia; Ventevogel, Peter; Bonz, Ann G; Bass, Judith K; Mbwambo, Jessie K K

2017-05-18

Intimate partner violence (IPV) is a critical public health and human rights concern globally, including for refugee women in low-resource settings. Little is known about effective interventions for this population. IPV and psychological distress have a bi-directional relationship, indicating the potential benefit of a structured psychological component as part of efforts to reduce IPV for women currently in violent relationships. This protocol describes a cluster randomized controlled trial aimed at evaluating an 8-session integrated psychological and advocacy intervention (Nguvu) with female adult survivors of past-year IPV displaying moderate to severe psychological distress. Outcomes are reductions in: recurrence of IPV; symptoms of anxiety, depression and post-traumatic stress (primary); and functional impairment (secondary). Hypothesized mediators of the intervention are improvements in social support, coping skills and support seeking. We will recruit 400 participants from existing women's support groups operating within villages in Nyarugusu refugee camp, Tanzania. Women's groups will be randomized to receive the intervention (Nguvu and usual care) or usual care alone. All eligible women will complete a baseline assessment (week 0) followed by a post-treatment (week 9) and a 3-month post-treatment assessment (week 20). The efficacy of the intervention will be determined by between-group differences in the longitudinal trajectories of primary outcomes evaluated using mixed-effects models. Study procedures have been approved by Institutional Review Boards in the United States and Tanzania. This trial will provide evidence on the efficacy of a novel integrated group intervention aimed at secondary prevention of IPV that includes a structured psychological component to address psychological distress. The psychological and advocacy components of the proposed intervention have been shown to be efficacious for their respective outcomes when delivered in isolation; however, administering these approaches through a single, integrated intervention may result in synergistic effects given the interrelated, bidirectional relationship between IPV and mental health. Furthermore, this trial will provide information regarding the feasibility of implementing a structured intervention for IPV and mental health in a protracted humanitarian setting. ISRCTN65771265 , June 27, 2016.

Comparison of different Kalman filter approaches in deriving time varying connectivity from EEG data.

PubMed

Ghumare, Eshwar; Schrooten, Maarten; Vandenberghe, Rik; Dupont, Patrick

2015-08-01

Kalman filter approaches are widely applied to derive time varying effective connectivity from electroencephalographic (EEG) data. For multi-trial data, a classical Kalman filter (CKF) designed for the estimation of single trial data, can be implemented by trial-averaging the data or by averaging single trial estimates. A general linear Kalman filter (GLKF) provides an extension for multi-trial data. In this work, we studied the performance of the different Kalman filtering approaches for different values of signal-to-noise ratio (SNR), number of trials and number of EEG channels. We used a simulated model from which we calculated scalp recordings. From these recordings, we estimated cortical sources. Multivariate autoregressive model parameters and partial directed coherence was calculated for these estimated sources and compared with the ground-truth. The results showed an overall superior performance of GLKF except for low levels of SNR and number of trials.

Genetic and Environmental Pathways in Type 1 Diabetes Complications

DTIC Science & Technology

2010-09-26

setting? In the event that the project identifies a set of strongly predictive biomarkers an appropriate next step would be to approach TrialNet (see...http://www.diabetestrialnet.org). The TrialNet organization is a multi center study with the goal of identifying subjects for T1D prevention and...intervention trials. Children’s Hospital of Pittsburgh (CHP) is already acting as a clinical center for the TrialNet natural history study (Mahon et al

Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

PubMed

Mates, M; Fletcher, G G; Freedman, O C; Eisen, A; Gandhi, S; Trudeau, M E; Dent, S F

2015-03-01

This systematic review addresses the question "What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer?" The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population.

Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline

PubMed Central

Mates, M.; Fletcher, G.G.; Freedman, O.C.; Eisen, A.; Gandhi, S.; Trudeau, M.E.; Dent, S.F.

2015-01-01

Background This systematic review addresses the question “What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)–positive breast cancer?” Methods The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. Results Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). Conclusions Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population. PMID:25848335

Ketamine for Depression: Where Do We Go from Here?

PubMed Central

aan het Rot, Marije; Zarate, Carlos A.; Charney, Dennis S.; Mathew, Sanjay J.

2012-01-01

Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk–benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting. PMID:22705040

Improved participants' understanding of research information in real settings using the SIDCER informed consent form: a randomized-controlled informed consent study nested with eight clinical trials.

PubMed

Koonrungsesomboon, Nut; Tharavanij, Thipaporn; Phiphatpatthamaamphan, Kittichet; Vilaichone, Ratha-Korn; Manuwong, Sudsayam; Curry, Parichat; Siramolpiwat, Sith; Punchaipornpon, Thanachai; Kanitnate, Supakit; Tammachote, Nattapol; Yamprasert, Rodsarin; Chanvimalueng, Waipoj; Kaewkumpai, Ruchirat; Netanong, Soiphet; Kitipawong, Peerapong; Sritipsukho, Paskorn; Karbwang, Juntra

2017-02-01

This study aimed to test the applicability and effectiveness of the principles and informed consent form (ICF) template proposed by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER) across multiple clinical trials involving Thai research participants with various conditions. A single-center, randomized-controlled study nested with eight clinical trials was conducted at Thammasat University Hospital, Thailand. A total of 258 participants from any of the eight clinical trials were enrolled and randomly assigned to read either the SIDCER ICF (n = 130) or the conventional ICF (n = 128) of the respective trial. Their understanding of necessary information was assessed using the post-test questionnaire; they were allowed to consult a given ICF while completing the questionnaire. The primary endpoint was the proportion of the participants who had the post-test score of ≥80%, and the secondary endpoint was the total score of the post-test. The proportion of the participants in the SIDCER ICF group who achieved the primary endpoint was significantly higher than that of the conventional ICF group (60.8 vs. 41.4%, p = 0.002). The total score of the post-test was also significantly higher among the participants who read the SIDCER ICF than those who read the conventional ICF (83.3 vs. 76.0%, p < 0.001). The present study demonstrated that the SIDCER ICF was applicable and effective to improve Thai research participants' understanding of research information in diverse clinical trials. Using the SIDCER ICF methodology, clinical researchers can improve the quality of ICFs for their trials.

Systemic inflammatory responses to maximal versus submaximal lengthening contractions of the elbow flexors.

PubMed

Peake, Jonathan M; Nosaka, Kazunori; Muthalib, Makii; Suzuki, Katsuhiko

2006-01-01

We compared changes in markers of muscle damage and systemic inflammation after submaximal and maximal lengthening muscle contractions of the elbow flexors. Using a cross-over design, 10 healthy young men not involved in resistance training completed a submaximal trial (10 sets of 60 lengthening contractions at 10% maximum isometric strength, 1 min rest between sets), followed by a maximal trial (10 sets of three lengthening contractions at 100% maximum isometric strength, 3 min rest between sets). Lengthening contractions were performed on an isokinetic dynamometer. Opposite arms were used for the submaximal and maximal trials, and the trials were separated by a minimum of two weeks. Blood was sampled before, immediately after, 1 h, 3 h, and 1-4 d after each trial. Total leukocyte and neutrophil numbers, and the serum concentration of soluble tumor necrosis factor-alpha receptor 1 were elevated after both trials (P < 0.01), but there were no differences between the trials. Serum IL-6 concentration was elevated 3 h after the submaximal contractions (P < 0.01). The concentrations of serum tumor necrosis factor-alpha, IL-1 receptor antagonist, IL-10, granulocyte-colony stimulating factor and plasma C-reactive protein remained unchanged following both trials. Maximum isometric strength and range of motion decreased significantly (P < 0.001) after both trials, and were lower from 1-4 days after the maximal contractions compared to the submaximal contractions. Plasma myoglobin concentration and creatine kinase activity, muscle soreness and upper arm circumference all increased after both trials (P < 0.01), but were not significantly different between the trials. Therefore, there were no differences in markers of systemic inflammation, despite evidence of greater muscle damage following maximal versus submaximal lengthening contractions of the elbow flexors.

Intravenous iron isomaltoside 1000 administered by high single-dose infusions or standard medical care for the treatment of fatigue in women after postpartum haemorrhage: study protocol for a randomised controlled trial.

PubMed

Holm, Charlotte; Thomsen, Lars Lykke; Norgaard, Astrid; Langhoff-Roos, Jens

2015-01-14

Postpartum haemorrhage can lead to iron deficiency with and without anaemia, the clinical consequences of which include physical fatigue. Although oral iron is the standard treatment, it is often associated with gastrointestinal side effects and poor compliance. To date, no published randomised controlled studies have compared the clinical efficacy and safety of standard medical care with intravenous administration of iron supplementation after postpartum haemorrhage.The primary objective of this study is to compare the efficacy of an intravenous high single-dose of iron isomaltoside 1000 with standard medical care on physical fatigue in women with postpartum haemorrhage. In a single centre, open-labelled, randomised trial, women with postpartum haemorrhage exceeding 700 mL will be allocated to either a single dose of 1,200 mg of iron isomaltoside 1000 or standard medical care. Healthy parturients with a singleton pregnancy will be included within 48 hours after delivery.Participants will complete structured questionnaires that focus on several dimensions of fatigue and mental health (Multidimensional Fatigue Inventory, Edinburgh Postnatal Depression Scale and the Postpartum Questionnaire), at inclusion and at follow-up visits after three days, one week, three weeks, eight weeks, and 12 weeks postpartum. The primary endpoint is the aggregated change in physical fatigue score within 12 weeks postpartum, as measured by a subscale of the Multidimensional Fatigue Inventory. The primary objective will be considered to have been met if an intravenous high single dose of iron isomaltoside 1000 is shown to be superior to standard medical care in women after postpartum haemorrhage regarding physical fatigue.For claiming superiority, we set the minimal clinically relevant difference between the mean scores at 1.8, and the assumed standard deviation at 4.2. Hence, 87 participants per treatment group are needed in order to demonstrate superiority; to provide an extra margin for missing data and dropouts, 200 women will be included. The study will provide evidence on relevant clinical outcomes beyond biochemical parameters for intravenous iron isomaltoside 1000 compared to standard medical care in women after postpartum haemorrhage. This trial is registered with Clinicaltrials.gov (identifier: NCT01895218) on 26 June 2013.

A cooperative network of trained sites for the conduct of a complex clinical trial: a new concept in multicenter clinical research.

PubMed

Davidson, Robert M; McNeer, J Frederick; Logan, Leanne; Higginbotham, Michael B; Anderson, Jerome; Blackshear, Joseph; Chu, Alan; Hettleman, Bruce; McGrew, Frank; Meesse, Roderick; O'Connor, Christopher; Schneider, Ricky; Wagner, Galen S

2006-02-01

The purpose of this report is to present a model of physicians in full-time clinical practice participating as investigators in multicenter clinical trials, sponsored by a pharmaceutical or medical device company. This gas-exchange substudy was conducted as a pilot study to establish the feasibility of the 10-member EXERcise testing group of the Duke University Cooperative Cardiovascular Society (EXERDUCCS) consortium to perform a complex multicenter trial using cardiopulmonary exercise testing. An active interchange of information was established involving the principal investigator for the substudy, a dedicated full-time project coordinator, a medical director of the overall EXERDUCCS network site, the project coordinator for the sponsor, and all the participating EXERDUCCS investigators and coordinators. The sponsor set as a goal of enrollment of 6 subjects per site, and 8 of the 10 sites met this goal. As a result of the successful enrollment and completion of the study and substudy by the EXERDUCCS sites, the sponsor subsequently increased the payment stipends to the sites to compensate for the extra work and expense incurred. This cooperative experience accomplished several goals: (1) it allowed a complex clinical trial to be successfully completed in a time frame which would not have been possible using only single unconnected sites; (2) it educated the physician-investigators (and their personnel) in exercise cardiopulmonary; and (3) it prepared the sites for future clinical trials involving this methodology.

Comparison between single-diode low-level laser therapy (LLLT) and LED multi-diode (cluster) therapy (LEDT) applications before high-intensity exercise.

PubMed

Leal Junior, Ernesto Cesar Pinto; Lopes-Martins, Rodrigo Alvaro Brandão; Baroni, Bruno Manfredini; De Marchi, Thiago; Rossi, Rafael Paolo; Grosselli, Douglas; Generosi, Rafael Abeche; de Godoi, Vanessa; Basso, Maira; Mancalossi, José Luis; Bjordal, Jan Magnus

2009-08-01

There is anecdotal evidence that low-level laser therapy (LLLT) may affect the development of muscular fatigue, minor muscle damage, and recovery after heavy exercises. Although manufacturers claim that cluster probes (LEDT) maybe more effective than single-diode lasers in clinical settings, there is a lack of head-to-head comparisons in controlled trials. This study was designed to compare the effect of single-diode LLLT and cluster LEDT before heavy exercise. This was a randomized, placebo-controlled, double-blind cross-over study. Young male volleyball players (n = 8) were enrolled and asked to perform three Wingate cycle tests after 4 x 30 sec LLLT or LEDT pretreatment of the rectus femoris muscle with either (1) an active LEDT cluster-probe (660/850 nm, 10/30 mW), (2) a placebo cluster-probe with no output, and (3) a single-diode 810-nm 200-mW laser. The active LEDT group had significantly decreased post-exercise creatine kinase (CK) levels (-18.88 +/- 41.48 U/L), compared to the placebo cluster group (26.88 +/- 15.18 U/L) (p < 0.05) and the active single-diode laser group (43.38 +/- 32.90 U/L) (p < 0.01). None of the pre-exercise LLLT or LEDT protocols enhanced performance on the Wingate tests or reduced post-exercise blood lactate levels. However, a non-significant tendency toward lower post-exercise blood lactate levels in the treated groups should be explored further. In this experimental set-up, only the active LEDT probe decreased post-exercise CK levels after the Wingate cycle test. Neither performance nor blood lactate levels were significantly affected by this protocol of pre-exercise LEDT or LLLT.

A single-center randomized, controlled trial investigating the efficacy of a mHealth ECG technology intervention to improve the detection of atrial fibrillation: the iHEART study protocol.

PubMed

Hickey, Kathleen T; Hauser, Nicole R; Valente, Laura E; Riga, Teresa C; Frulla, Ashton P; Masterson Creber, Ruth; Whang, William; Garan, Hasan; Jia, Haomiao; Sciacca, Robert R; Wang, Daniel Y

2016-07-16

Atrial fibrillation is a major public health problem and is the most common cardiac arrhythmia, affecting an estimated 2.7 million Americans. The true prevalence of atrial fibrillation is likely underestimated because episodes are often sporadic; therefore, it is challenging to detect and record an occurrence in a "real world" setting. To date, mobile health tools that promote earlier detection and treatment of atrial fibrillation and improvement in self-management behaviors and knowledge have not been evaluated. This study will be the first to address the epidemic problem of atrial fibrillation with a novel approach utilizing advancements in mobile health electrocardiogram technology to empower patients to actively engage in their healthcare and to evaluate impact on quality of life and quality-adjusted life years. Furthermore, sending a daily electrocardiogram transmission, coupled with receiving educational and motivational text messages aimed at promoting self-management and a healthy lifestyle may improve the management of chronic cardiovascular conditions (e.g., hypertension, diabetes, heart failure, etc.). Therefore, we are currently conducting a randomized controlled trial to assess the efficacy of a mobile health intervention, iPhone® Helping Evaluate Atrial fibrillation Rhythm through Technology (iHEART) versus usual cardiac care. The iHEART study is a single center, prospective, randomized controlled trial. A total of 300 participants with a recent history of atrial fibrillation will be enrolled. Participants will be randomized 1:1 to receive the iHEART intervention, receiving an iPhone® equipped with an AliveCor® Mobile ECG and accompanying Kardia application and behavioral altering motivational text messages or usual cardiac care for 6 months. This will be the first study to investigate the utility of a mobile health intervention in a "real world" setting. We will evaluate the ability of the iHEART intervention to improve the detection and treatment of recurrent atrial fibrillation and assess the intervention's impact on improving clinical outcomes, quality of life, quality-adjusted life-years and disease-specific knowledge. NCT02731326 ; Verified April 2016.

A highly sensitive search strategy for clinical trials in Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) was developed.

PubMed

Manríquez, Juan J

2008-04-01

Systematic reviews should include as many articles as possible. However, many systematic reviews use only databases with high English language content as sources of trials. Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) is an underused source of trials, and there is not a validated strategy for searching clinical trials to be used in this database. The objective of this study was to develop a sensitive search strategy for clinical trials in LILACS. An analytical survey was performed. Several single and multiple-term search strategies were tested for their ability to retrieve clinical trials in LILACS. Sensitivity, specificity, and accuracy of each single and multiple-term strategy were calculated using the results of a hand-search of 44 Chilean journals as gold standard. After combining the most sensitive, specific, and accurate single and multiple-term search strategy, a strategy with a sensitivity of 97.75% (95% confidence interval [CI]=95.98-99.53) and a specificity of 61.85 (95% CI=61.19-62.51) was obtained. LILACS is a source of trials that could improve systematic reviews. A new highly sensitive search strategy for clinical trials in LILACS has been developed. It is hoped this search strategy will improve and increase the utilization of LILACS in future systematic reviews.

Auditory proactive interference in monkeys: the roles of stimulus set size and intertrial interval.

PubMed

Bigelow, James; Poremba, Amy

2013-09-01

We conducted two experiments to examine the influences of stimulus set size (the number of stimuli that are used throughout the session) and intertrial interval (ITI, the elapsed time between trials) in auditory short-term memory in monkeys. We used an auditory delayed matching-to-sample task wherein the animals had to indicate whether two sounds separated by a 5-s retention interval were the same (match trials) or different (nonmatch trials). In Experiment 1, we randomly assigned stimulus set sizes of 2, 4, 8, 16, 32, 64, or 192 (trial-unique) for each session of 128 trials. Consistent with previous visual studies, overall accuracy was consistently lower when smaller stimulus set sizes were used. Further analyses revealed that these effects were primarily caused by an increase in incorrect "same" responses on nonmatch trials. In Experiment 2, we held the stimulus set size constant at four for each session and alternately set the ITI at 5, 10, or 20 s. Overall accuracy improved when the ITI was increased from 5 to 10 s, but it was the same across the 10- and 20-s conditions. As in Experiment 1, the overall decrease in accuracy during the 5-s condition was caused by a greater number of false "match" responses on nonmatch trials. Taken together, Experiments 1 and 2 showed that auditory short-term memory in monkeys is highly susceptible to proactive interference caused by stimulus repetition. Additional analyses of the data from Experiment 1 suggested that monkeys may make same-different judgments on the basis of a familiarity criterion that is adjusted by error-related feedback.

A record-based analysis of 803 patients treated for depression in psychiatric care.

PubMed

Rytsälä, H J; Melartin, T K; Leskelä, U S; Lestelä-Mielonen, P S; Sokero, T P; Isometsä, E T

2001-09-01

New antidepressants emerged and became widely used during the 1990s. The present study investigated quality-of-care problems in the treatment of depression in a current psychiatric setting. We investigated the treatment received for depression by all 803 inpatients or outpatients with a clinical diagnosis of ICD-10 depressive episode or recurrent depressive disorder in 1996 in the Peijas Medical Care District, which provides psychiatric services for citizens of Vantaa, a city in southern Finland. Most patients (84%) in the sample were found to have received antidepressants, generally in adequate, albeit low, doses. Inadequate antidepressant treatment was common only with tricyclic antidepressants. Most patients received a single antidepressant for extended periods; only 22% had 2 or more antidepressant trials. During the treatment period, disability pension was granted to 19% of those not already pensioned, two thirds (67%) of whom had received only 1 antidepressant trial prior to being granted a pension. The present study supports the emerging perception of improved quality of pharmacotherapy in psychiatric settings, with the exception of treatment with tricyclic antidepressants. Problems of quality of care now appear to be related to the suboptimal intensity and monitoring of the treatment provided. which may eventually result in considerable costs to society due to permanent disability.

Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer

PubMed Central

Advani, Pooja; Cornell, Lauren; Chumsri, Saranya; Moreno-Aspitia, Alvaro

2015-01-01

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. PMID:26451122

Effectiveness of Modular CBT for Child Anxiety in Elementary Schools

ERIC Educational Resources Information Center

Chiu, Angela W.; Langer, David A.; McLeod, Bryce D.; Har, Kim; Drahota, Amy; Galla, Brian M.; Jacobs, Jeffrey; Ifekwunigwe, Muriel; Wood, Jeffrey J.

2013-01-01

Most randomized controlled trials of cognitive-behavioral therapy (CBT) for children with anxiety disorders have evaluated treatment efficacy using recruited samples treated in research settings. Clinical trials in school settings are needed to determine if CBT can be effective when delivered in real world settings. This study evaluated a modular…

Genomic Selection in Multi-environment Crop Trials.

PubMed

Oakey, Helena; Cullis, Brian; Thompson, Robin; Comadran, Jordi; Halpin, Claire; Waugh, Robbie

2016-05-03

Genomic selection in crop breeding introduces modeling challenges not found in animal studies. These include the need to accommodate replicate plants for each line, consider spatial variation in field trials, address line by environment interactions, and capture nonadditive effects. Here, we propose a flexible single-stage genomic selection approach that resolves these issues. Our linear mixed model incorporates spatial variation through environment-specific terms, and also randomization-based design terms. It considers marker, and marker by environment interactions using ridge regression best linear unbiased prediction to extend genomic selection to multiple environments. Since the approach uses the raw data from line replicates, the line genetic variation is partitioned into marker and nonmarker residual genetic variation (i.e., additive and nonadditive effects). This results in a more precise estimate of marker genetic effects. Using barley height data from trials, in 2 different years, of up to 477 cultivars, we demonstrate that our new genomic selection model improves predictions compared to current models. Analyzing single trials revealed improvements in predictive ability of up to 5.7%. For the multiple environment trial (MET) model, combining both year trials improved predictive ability up to 11.4% compared to a single environment analysis. Benefits were significant even when fewer markers were used. Compared to a single-year standard model run with 3490 markers, our partitioned MET model achieved the same predictive ability using between 500 and 1000 markers depending on the trial. Our approach can be used to increase accuracy and confidence in the selection of the best lines for breeding and/or, to reduce costs by using fewer markers. Copyright © 2016 Oakey et al.

A three domain covariance framework for EEG/MEG data.

PubMed

Roś, Beata P; Bijma, Fetsje; de Gunst, Mathisca C M; de Munck, Jan C

2015-10-01

In this paper we introduce a covariance framework for the analysis of single subject EEG and MEG data that takes into account observed temporal stationarity on small time scales and trial-to-trial variations. We formulate a model for the covariance matrix, which is a Kronecker product of three components that correspond to space, time and epochs/trials, and consider maximum likelihood estimation of the unknown parameter values. An iterative algorithm that finds approximations of the maximum likelihood estimates is proposed. Our covariance model is applicable in a variety of cases where spontaneous EEG or MEG acts as source of noise and realistic noise covariance estimates are needed, such as in evoked activity studies, or where the properties of spontaneous EEG or MEG are themselves the topic of interest, like in combined EEG-fMRI experiments in which the correlation between EEG and fMRI signals is investigated. We use a simulation study to assess the performance of the estimator and investigate the influence of different assumptions about the covariance factors on the estimated covariance matrix and on its components. We apply our method to real EEG and MEG data sets. Copyright © 2015 Elsevier Inc. All rights reserved.

Implementation of clinical research trials using web-based and mobile devices: challenges and solutions.

PubMed

Eagleson, Roy; Altamirano-Diaz, Luis; McInnis, Alex; Welisch, Eva; De Jesus, Stefanie; Prapavessis, Harry; Rombeek, Meghan; Seabrook, Jamie A; Park, Teresa; Norozi, Kambiz

2017-03-17

With the increasing implementation of web-based, mobile health interventions in clinical trials, it is crucial for researchers to address the security and privacy concerns of patient information according to high ethical standards. The full process of meeting these standards is often made more complicated due to the use of internet-based technology and smartphones for treatment, telecommunication, and data collection; however, this process is not well-documented in the literature. The Smart Heart Trial is a single-arm feasibility study that is currently assessing the effects of a web-based, mobile lifestyle intervention for overweight and obese children and youth with congenital heart disease in Southwestern Ontario. Participants receive telephone counseling regarding nutrition and fitness; and complete goal-setting activities on a web-based application. This paper provides a detailed overview of the challenges the study faced in meeting the high standards of our Research Ethics Board, specifically regarding patient privacy. We outline our solutions, successes, limitations, and lessons learned to inform future similar studies; and model much needed transparency in ensuring high quality security and protection of patient privacy when using web-based and mobile devices for telecommunication and data collection in clinical research.

Telephone counselling for smoking cessation.

PubMed

Stead, Lindsay F; Hartmann-Boyce, Jamie; Perera, Rafael; Lancaster, Tim

2013-08-12

Telephone services can provide information and support for smokers. Counselling may be provided proactively or offered reactively to callers to smoking cessation helplines. To evaluate the effect of proactive and reactive telephone support via helplines and in other settings to help smokers quit. We searched the Cochrane Tobacco Addiction Group Specialised Register for studies of telephone counselling, using search terms including 'hotlines' or 'quitline' or 'helpline'. Date of the most recent search: May 2013. randomized or quasi-randomised controlled trials in which proactive or reactive telephone counselling to assist smoking cessation was offered to smokers or recent quitters. One author identified and data extracted trials, and a second author checked them. The main outcome measure was the risk ratio for abstinence from smoking after at least six months follow-up. We selected the strictest measure of abstinence, using biochemically validated rates where available. We considered participants lost to follow-up to be continuing smokers. Where trials had more than one arm with a less intensive intervention we used only the most similar intervention without the telephone component as the control group in the primary analysis. We assessed statistical heterogeneity amongst subgroups of clinically comparable studies using the I² statistic. We considered trials recruiting callers to quitlines separately from studies recruiting in other settings. Where appropriate, we pooled studies using a fixed-effect model. We used a meta-regression to investigate the effect of differences in planned number of calls, selection for motivation, and the nature of the control condition (self help only, minimal intervention, pharmacotherapy) in the group of studies recruiting in non-quitline settings. Seventy-seven trials met the inclusion criteria. Some trials were judged to be at risk of bias in some domains but overall we did not judge the results to be at high risk of bias. Among smokers who contacted helplines, quit rates were higher for groups randomized to receive multiple sessions of proactive counselling (nine studies, > 24,000 participants, risk ratio (RR) for cessation at longest follow-up 1.37, 95% confidence interval (CI) 1.26 to 1.50). There was mixed evidence about whether increasing the number of calls altered quit rates but most trials used more than two calls. Three studies comparing different counselling approaches during a single quitline contact did not detect significant differences. Of three studies that tested the provision of access to a hotline two detected a significant benefit and one did not.Telephone counselling not initiated by calls to helplines also increased quitting (51 studies, > 30,000 participants, RR 1.27; 95% CI 1.20 to 1.36). In a meta-regression controlling for other factors the effect was estimated to be slightly larger if more calls were offered, and in trials that specifically recruited smokers motivated to try to quit. The relative extra benefit of counselling was smaller when it was provided in addition to pharmacotherapy (usually nicotine replacement therapy) than when the control group only received self-help material or a brief intervention.A further eight studies were too diverse to contribute to meta-analyses and are discussed separately. Two compared different intensities of counselling, both of which detected a dose response; one of these detected a benefit of multiple counselling sessions over a single call for people prescribed bupropion. The others tested a variety of interventions largely involving offering telephone counselling as part of a referral or systems change and none detected evidence of effect. Proactive telephone counselling aids smokers who seek help from quitlines. Telephone quitlines provide an important route of access to support for smokers, and call-back counselling enhances their usefulness. There is limited evidence about the optimal number of calls. Proactive telephone counselling also helps people who receive it in other settings. There is some evidence of a dose response; one or two brief calls are less likely to provide a measurable benefit. Three or more calls increase the chances of quitting compared to a minimal intervention such as providing standard self-help materials, or brief advice, or compared to pharmacotherapy alone.

Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis.

PubMed

Oulhaj, Abderrahim; El Ghouch, Anouar; Holman, Rury R

2017-01-01

Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease.

Differential Contributions of Ventral and Dorsal Striatum to Early and Late Phases of Cognitive Set Reconfiguration

PubMed Central

Sleezer, Brianna J.; Hayden, Benjamin Y.

2017-01-01

Flexible decision-making, a defining feature of human cognition, is typically thought of as a canonical pFC function. Recent work suggests that the striatum may participate as well; however, its role in this process is not well understood. We recorded activity of neurons in both the ventral (VS) and dorsal (DS) striatum while rhesus macaques performed a version of the Wisconsin Card Sorting Test, a classic test of flexibility. Our version of the task involved a trial-and-error phase before monkeys could identify the correct rule on each block. We observed changes in firing rate in both regions when monkeys switched rules. Specifically, VS neurons demonstrated switch-related activity early in the trial-and-error period when the rule needed to be updated, and a portion of these neurons signaled information about the switch context (i.e., whether the switch was intradimensional or extradimensional). Neurons in both VS and DS demonstrated switch-related activity at the end of the trial-and-error period, immediately before the rule was fully established and maintained, but these signals did not carry any information about switch context. We also observed associative learning signals (i.e., specific responses to options associated with rewards in the presentation period before choice) that followed the same pattern as switch signals (early in VS, later in DS). Taken together, these results endorse the idea that the striatum participates directly in cognitive set reconfiguration and suggest that single neurons in the striatum may contribute to a functional handoff from the VS to the DS during reconfiguration processes. PMID:27417204

Multiple Component Event-Related Potential (mcERP) Estimation

NASA Technical Reports Server (NTRS)

Knuth, K. H.; Clanton, S. T.; Shah, A. S.; Truccolo, W. A.; Ding, M.; Bressler, S. L.; Trejo, L. J.; Schroeder, C. E.; Clancy, Daniel (Technical Monitor)

2002-01-01

We show how model-based estimation of the neural sources responsible for transient neuroelectric signals can be improved by the analysis of single trial data. Previously, we showed that a multiple component event-related potential (mcERP) algorithm can extract the responses of individual sources from recordings of a mixture of multiple, possibly interacting, neural ensembles. McERP also estimated single-trial amplitudes and onset latencies, thus allowing more accurate estimation of ongoing neural activity during an experimental trial. The mcERP algorithm is related to informax independent component analysis (ICA); however, the underlying signal model is more physiologically realistic in that a component is modeled as a stereotypic waveshape varying both in amplitude and onset latency from trial to trial. The result is a model that reflects quantities of interest to the neuroscientist. Here we demonstrate that the mcERP algorithm provides more accurate results than more traditional methods such as factor analysis and the more recent ICA. Whereas factor analysis assumes the sources are orthogonal and ICA assumes the sources are statistically independent, the mcERP algorithm makes no such assumptions thus allowing investigators to examine interactions among components by estimating the properties of single-trial responses.

Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

PubMed Central

Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

2016-01-01

Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a meta-analysis. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 13 randomized controlled trials (RCTs) in the review, which enrolled 5824 participants. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. Overall there is little or no difference detected between FDCs and single-drug formulations for most outcomes reported. We did not detect a difference in treatment failure between FDCs compared with single-drug formulations (RR 1.28, 95% CI 0.82 to 2.00; 3606 participants, seven trials, moderate quality evidence). Relapse may be more frequent in people treated with FDCs compared to single-drug formulations, although the confidence interval (CI) includes no difference (RR 1.28, 95% CI 1.00 to 1.64; 3621 participants, 10 trials, low quality evidence). We did not detect any difference in death between fixed-dose and single-drug formulation groups (RR 0.96, 95% CI 0.67 to 1.39; 4800 participants, 11 trials, moderate quality evidence). When we compared FDCs with single-drug formulations we found little or no difference for sputum smear or culture conversion at the end of treatment (RR 0.99, 95% CI 0.96 to 1.02; 2319 participants, seven trials, high quality evidence), for serious adverse events (RR 1.45, 95% CI 0.90 to 2.33; 3388 participants, six trials, moderate quality evidence), and for adverse events that led to discontinuation of therapy (RR 0.96, 95% CI 0.56 to 1.66; 5530 participants, 13 trials, low quality evidence). We conducted a sensitivity analysis excluding studies at high risk of bias and this did not alter the review findings. Authors' conclusions Fixed-dose combinations and single-drug formulations probably have similar effects for treating people with newly diagnosed pulmonary TB. PLAIN LANGUAGE SUMMARY Fixed-dose combinations for treating pulmonary tuberculosis What are fixed-dose combinations and how might they improve care of people with tuberculosis Tuberculosis (TB) is an important health problem, especially in developing countries. The treatment for pulmonary TB in new patients includes four oral medicines taken for six months, sometimes as fixed-dose combinations (FDCs) that are combined in one tablet, or taken separately as single-drug formulations. The World Health Organization recommends prescribers use fixed-dose combinations to reduce the number of tablets that people take. On the supply side, this might reduce prescribing errors and improve drug supply efficiency; on the patient's side, FDCS simplify treatment and improve adherence. We conducted a review to assess the efficacy, safety, and acceptability of FDCs compared with single-drug formulations for treating people with newly diagnosed pulmonary TB. What the research says We searched for relevant trials up to 20 November 2015, and included 13 randomized controlled trials that enrolled 5824 people. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. There is probably little or no difference in FDCs compared to single-drug formulations for treatment failure (moderate quality evidence); relapse may be more frequent (low quality evidence); and the number of deaths were similar (moderate quality evidence). There is little or no difference in sputum smear or culture conversion (high quality evidence), and no difference was shown for serious adverse events (moderate quality evidence) or adverse events that led to discontinuation of therapy (low quality evidence). Authors' conclusions We concluded that fixed-dose combinations have similar efficacy to single-drug formulations for treating people with newly diagnosed pulmonary TB. PMID:27186634

Effects of Recent Exposure to a Conditioned Stimulus on Extinction of Pavlovian Fear Conditioning

ERIC Educational Resources Information Center

Chan, Wan Yee Macy; Leung, Hiu T.; Westbrook, R. Frederick; McNally, Gavan P.

2010-01-01

In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement…

Neural Prediction of Multidimensional Decisions in Monkey Superior Colliculus

NASA Astrophysics Data System (ADS)

Hasegawa, Ryohei P.; Hasegawa, Yukako T.; Segraves, Mark A.

To examine the function of the superior colliculus (SC) in decision-making processes and the application of its single trial activity for “neural mind reading,” we recorded from SC deep layers while two monkeys performed oculomotor go/no-go tasks. We have recently focused on monitoring single trial activities in single SC neurons, and designed a virtual decision function (VDF) to provide a good estimation of single-dimensional decisions (go/no-go decisions for a cue presented at a specific visual field, a response field of each neuron). In this study, we used two VDFs for multidimensional decisions (go/no-go decisions at two cue locations) with the ensemble activity which was simultaneously recorded from a small group (4 to 6) of neurons at both sides of the SC. VDFs predicted cue locations as well as go/no-go decisions. These results suggest that monitoring of ensemble SC activity had sufficient capacity to predict multidimensional decisions on a trial-by-trial basis, which is an ideal candidate to serve for cognitive brain-machine interfaces (BMI) such as two-dimensional word spellers.

Task-Oriented Training with Computer Games for People with Rheumatoid Arthritis or Hand Osteoarthritis: A Feasibility Randomized Controlled Trial.

PubMed

Srikesavan, Cynthia Swarnalatha; Shay, Barbara; Szturm, Tony

2016-09-13

To examine the feasibility of a clinical trial on a novel, home-based task-oriented training with conventional hand exercises in people with rheumatoid arthritis or hand osteoarthritis. To explore the experiences of participants who completed their respective home exercise programmes. Thirty volunteer participants aged between 30 and 60 years and diagnosed with rheumatoid arthritis or hand osteoarthritis were proposed for a single-center, assessor-blinded, randomized controlled trial ( ClinicalTrials.gov : NCT01635582). Participants received task-oriented training with interactive computer games and objects of daily life or finger mobility and strengthening exercises. Both programmes were home based and were done four sessions per week with 20 minutes each session for 6 weeks. Major feasibility outcomes were number of volunteers screened, randomized, and retained; completion of blinded assessments, exercise training, and home exercise sessions; equipment and data management; and clinical outcomes of hand function. Reaching the recruitment target in 18 months and achieving exercise compliance >80% were set as success criteria. Concurrent with the trial, focus group interviews explored experiences of those participants who completed their respective programmes. After trial initiation, revisions in inclusion criteria were required to promote recruitment. A total of 17 participants were randomized and 15 were retained. Completion of assessments, exercise training, and home exercise sessions; equipment and data collection and management demonstrated excellent feasibility. Both groups improved in hand function outcomes and exercise compliance was above 85%. Participants perceived both programmes as appropriate and acceptable. Participants who completed task-oriented training also agreed that playing different computer games was enjoyable, engaging, and motivating. Findings demonstrate initial evidence on recruitment, feasibility of trial procedures, and acceptability of task-oriented training in people with rheumatoid arthritis or hand osteoarthritis. Since the pilot trial was unsuccessful in participant recruitment, a large trial will not follow.

Acute myeloid leukemia: advancing clinical trials and promising therapeutics

PubMed Central

Daver, Naval; Cortes, Jorge; Kantarjian, Hagop; Ravandi, Farhad

2016-01-01

Recent progress in understanding the biology of acute myeloid leukemia (AML) and the identification of targetable driver mutations, leukemia specific antigens and signal transduction pathways has ushered in a new era of therapy. In many circumstances the response rates with such targeted or antibody-based therapies are superior to those achieved with standard therapy and with decreased toxicity. In this review we discuss novel therapies in AML with a focus on two major areas of unmet need: (1) single agent and combination strategies to improve frontline therapy in elderly patients with AML and (2) molecularly targeted therapies in the frontline and salvage setting in all patients with AML. PMID:26910051

A core outcome set for clinical trials in acute diarrhoea.

PubMed

Karas, Jacek; Ashkenazi, Shai; Guarino, Alfredo; Lo Vecchio, Andrea; Shamir, Raanan; Vandenplas, Yvan; Szajewska, Hania

2015-04-01

Core outcome sets are the baseline for what should be measured in clinical research and, thus, should serve as a guide for what should be collected and reported. The Consensus Group on Outcome Measures Made in Pediatric Enteral Nutrition Clinical Trials, established in 2012, agreed that consensus on a core set of outcomes with agreed-upon definitions that should be measured and reported in clinical trials was needed. To achieve this goal, six working groups (WGs) were setup, including WG on acute diarrhoea, whose main goal was to develop a core outcome set for trials in acute diarrhoea. The first step identified how published outcomes related to acute diarrhoea were reported. The second focused on the methodology for determining which outcomes to measure in clinical trials. The third employed a two-phase questionnaire study using the Delphi technique to define clinically important outcomes to clinicians and parents. For therapeutic studies, the five most important outcome measures were diarrhoea duration, degree of dehydration, need for hospitalisation (or duration of hospitalisation for inpatients), the proportion of patients recovered by 48 h and adverse effects. The prophylactic core outcome set included prevention of diarrhoea, prevention of dehydration, prevention of hospitalisation and adverse effects. The outcome sets for therapy and prevention can be recommended for use in future trials of patients with gastroenteritis. Their envisioned goal is to decrease study heterogeneity and to ease the comparability of studies. WG's next step is to determine how to measure the outcomes included in the core set. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Retention of the "first-trial effect" in gait-slip among community-living older adults.

PubMed

Liu, Xuan; Bhatt, Tanvi; Wang, Shuaijie; Yang, Feng; Pai, Yi-Chung Clive

2017-02-01

"First-trial effect" characterizes the rapid adaptive behavior that changes the performance outcome (from fall to non-fall) after merely a single exposure to postural disturbance. The purpose of this study was to investigate how long the first-trial effect could last. Seventy-five (≥ 65 years) community-dwelling older adults, who were protected by an overhead full body harness system, were retested for a single slip 6-12 months after their initial exposure to a single gait-slip. Subjects' body kinematics that was used to compute their proactive (feedforward) and reactive (feedback) control of stability was recorded by an eight-camera motion analysis system. We found the laboratory falls of subjects on their retest slip were significantly lower than that on the novel initial slip, and the reactive stability of these subjects was also significantly improved. However, the proactive stability of subjects remains unchanged between their initial slip and retest slip. The fall rates and stability control had no difference among the 6-, 9-, and 12-month retest groups, which indicated a maximum retention on 12 months after a single slip in the laboratory. These results highlighted the importance of the "first-trial effect" and suggested that perturbation training is effective for fall prevention, with lower trial doses for a long period (up to 1 year). Therefore, single slip training might benefit those older adults who could not tolerate larger doses in reality.

Frontal Theta Links Prediction Errors to Behavioral Adaptation in Reinforcement Learning

PubMed Central

Cavanagh, James F.; Frank, Michael J.; Klein, Theresa J.; Allen, John J.B.

2009-01-01

Investigations into action monitoring have consistently detailed a fronto-central voltage deflection in the Event-Related Potential (ERP) following the presentation of negatively valenced feedback, sometimes termed the Feedback Related Negativity (FRN). The FRN has been proposed to reflect a neural response to prediction errors during reinforcement learning, yet the single trial relationship between neural activity and the quanta of expectation violation remains untested. Although ERP methods are not well suited to single trial analyses, the FRN has been associated with theta band oscillatory perturbations in the medial prefrontal cortex. Medio-frontal theta oscillations have been previously associated with expectation violation and behavioral adaptation and are well suited to single trial analysis. Here, we recorded EEG activity during a probabilistic reinforcement learning task and fit the performance data to an abstract computational model (Q-learning) for calculation of single-trial reward prediction errors. Single-trial theta oscillatory activities following feedback were investigated within the context of expectation (prediction error) and adaptation (subsequent reaction time change). Results indicate that interactive medial and lateral frontal theta activities reflect the degree of negative and positive reward prediction error in the service of behavioral adaptation. These different brain areas use prediction error calculations for different behavioral adaptations: with medial frontal theta reflecting the utilization of prediction errors for reaction time slowing (specifically following errors), but lateral frontal theta reflecting prediction errors leading to working memory-related reaction time speeding for the correct choice. PMID:19969093

Kernel PLS Estimation of Single-trial Event-related Potentials

NASA Technical Reports Server (NTRS)

Rosipal, Roman; Trejo, Leonard J.

2004-01-01

Nonlinear kernel partial least squaes (KPLS) regressior, is a novel smoothing approach to nonparametric regression curve fitting. We have developed a KPLS approach to the estimation of single-trial event related potentials (ERPs). For improved accuracy of estimation, we also developed a local KPLS method for situations in which there exists prior knowledge about the approximate latency of individual ERP components. To assess the utility of the KPLS approach, we compared non-local KPLS and local KPLS smoothing with other nonparametric signal processing and smoothing methods. In particular, we examined wavelet denoising, smoothing splines, and localized smoothing splines. We applied these methods to the estimation of simulated mixtures of human ERPs and ongoing electroencephalogram (EEG) activity using a dipole simulator (BESA). In this scenario we considered ongoing EEG to represent spatially and temporally correlated noise added to the ERPs. This simulation provided a reasonable but simplified model of real-world ERP measurements. For estimation of the simulated single-trial ERPs, local KPLS provided a level of accuracy that was comparable with or better than the other methods. We also applied the local KPLS method to the estimation of human ERPs recorded in an experiment on co,onitive fatigue. For these data, the local KPLS method provided a clear improvement in visualization of single-trial ERPs as well as their averages. The local KPLS method may serve as a new alternative to the estimation of single-trial ERPs and improvement of ERP averages.

Mandibular single-implant overdentures: a review with surgical and prosthodontic perspectives of a novel approach.

PubMed

Alsabeeha, Nabeel; Payne, Alan G T; De Silva, Rohana K; Swain, Michael V

2009-04-01

To review the literature on mandibular single-implant overdentures (opposing complete maxillary dentures), and present surgical and prosthodontic perspectives of a novel approach for this treatment option. An electronic search through the databases of Pubmed, Embase and Medline using the linked key words 'mandibular single implant overdentures' was performed. The search was limited to English language articles published up to August 2008. Hand searches through articles retrieved from the electronic search, peer-reviewed journals and recent conference proceedings were also conducted. A limited number of reports were identified on mandibular single-implant overdentures (opposing maxillary complete dentures). They comprised of case-series reports, short-term prospective trials and current randomized-controlled clinical trials. Different loading protocols with different implant systems have been used, but always with regular diameter implants. Specific anatomical and vascular dangers of the mandibular midline symphysis are identified including a novel surgical approach using a currently available short, wide diameter tapered implant. In addition, the prosthodontic rationale for using a larger attachment system (incorporating a platform switch) for mandibular single-implant overdentures is described. The review reveals that there is a lack of published randomized clinical trials using mandibular single-implant overdentures, opposing maxillary complete dentures. Without the evidence from randomized clinical trials, routine use of this novel approach cannot be recommended, compared with using regular diameter implants and matching attachment systems.

Single Versus Multiple Events Error Potential Detection in a BCI-Controlled Car Game With Continuous and Discrete Feedback.

PubMed

Kreilinger, Alex; Hiebel, Hannah; Müller-Putz, Gernot R

2016-03-01

This work aimed to find and evaluate a new method for detecting errors in continuous brain-computer interface (BCI) applications. Instead of classifying errors on a single-trial basis, the new method was based on multiple events (MEs) analysis to increase the accuracy of error detection. In a BCI-driven car game, based on motor imagery (MI), discrete events were triggered whenever subjects collided with coins and/or barriers. Coins counted as correct events, whereas barriers were errors. This new method, termed ME method, combined and averaged the classification results of single events (SEs) and determined the correctness of MI trials, which consisted of event sequences instead of SEs. The benefit of this method was evaluated in an offline simulation. In an online experiment, the new method was used to detect erroneous MI trials. Such MI trials were discarded and could be repeated by the users. We found that, even with low SE error potential (ErrP) detection rates, feasible accuracies can be achieved when combining MEs to distinguish erroneous from correct MI trials. Online, all subjects reached higher scores with error detection than without, at the cost of longer times needed for completing the game. Findings suggest that ErrP detection may become a reliable tool for monitoring continuous states in BCI applications when combining MEs. This paper demonstrates a novel technique for detecting errors in online continuous BCI applications, which yields promising results even with low single-trial detection rates.

Adapted Behavior Therapy for Persistently Depressed Primary Care Patients: An Open Trial

ERIC Educational Resources Information Center

Uebelacker, Lisa A.; Weisberg, Risa B.; Haggarty, Ryan; Miller, Ivan W.

2009-01-01

Major depressive disorder is commonly treated in primary care settings. Psychotherapy occurring in primary care should take advantage of the unique aspects of the setting and must adapt to the problems and limitations of the setting. In this open trial, the authors used a treatment development model to adapt behavior therapy for primary care…

Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance.

PubMed

Taylor-Robinson, David C; Maayan, Nicola; Soares-Weiser, Karla; Donegan, Sarah; Garner, Paul

2015-07-23

The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. As the intervention is often claimed to have important health, nutrition, and societal effects beyond the removal of worms, we critically evaluated the evidence on benefits. To summarize the effects of giving deworming drugs to children to treat soil-transmitted helminths on weight, haemoglobin, and cognition; and the evidence of impact on physical well-being, school attendance, school performance, and mortality. We searched the Cochrane Infectious Diseases Group Specialized Register (14 April 2015); Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2015, Issue 4); MEDLINE (2000 to 14 April 2015); EMBASE (2000 to 14 April 2015); LILACS (2000 to 14 April 2015); the metaRegister of Controlled Trials (mRCT); and reference lists, and registers of ongoing and completed trials up to 14 April 2015. We included randomized controlled trials (RCTs) and quasi-RCTs comparing deworming drugs for soil-transmitted helminths with placebo or no treatment in children aged 16 years or less, reporting on weight, haemoglobin, and formal tests of intellectual development. We also sought data on school attendance, school performance, and mortality. We included trials that combined health education with deworming programmes. At least two review authors independently assessed the trials, evaluated risk of bias, and extracted data. We analysed continuous data using the mean difference (MD) with 95% confidence intervals (CIs). Where data were missing, we contacted trial authors. We used outcomes at time of longest follow-up. The evidence quality was assessed using GRADE. This edition of the Cochrane Review adds the DEVTA trial from India, and draws on an independent analytical replication of a trial from Kenya. We identified 45 trials, including nine cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 44 trials included a total of 67,672 participants. Eight trials were in children known to be infected, and 37 trials were carried out in endemic areas, including areas of high (15 trials), moderate (12 trials), and low prevalence (10 trials). Treating children known to be infectedTreating children known to be infected with a single dose of deworming drugs (selected by screening, or living in areas where all children are infected) may increase weight gain over the next one to six months (627 participants, five trials, low quality evidence). The effect size varied across trials from an additional 0.2 kg gain to 1.3 kg. There is currently insufficient evidence to know whether treatment has additional effects on haemoglobin (247 participants, two trials, very low quality evidence); school attendance (0 trials); cognitive functioning (103 participants, two trials, very low quality evidence), or physical well-being (280 participants, three trials, very low quality evidence). Community deworming programmesTreating all children living in endemic areas with a dose of deworming drugs probably has little or no effect on average weight gain (MD 0.04 kg less, 95% CI 0.11 kg less to 0.04 kg more; trials 2719 participants, seven trials, moderate quality evidence), even in settings with high prevalence of infection (290 participants, two trials). A single dose also probably has no effect on average haemoglobin (MD 0.06 g/dL, 95% CI -0.05 lower to 0.17 higher; 1005 participants, three trials, moderate quality evidence), or average cognition (1361 participants, two trials, low quality evidence).Similiarly, regularly treating all children in endemic areas with deworming drugs, given every three to six months, may have little or no effect on average weight gain (MD 0.08 kg, 95% CI 0.11 kg less to 0.27 kg more; 38,392 participants, 10 trials, low quality evidence). The effects were variable across trials; one trial from a low prevalence setting carried out in 1995 found an increase in weight, but nine trials carried out since then found no effect, including five from moderate and high prevalence areas.There is also reasonable evidence that regular treatment probably has no effect on average height (MD 0.02 cm higher, 95% CI 0.14 lower to 0.17 cm higher; 7057 participants, seven trials, moderate quality evidence); average haemoglobin (MD 0.02 g/dL lower; 95% CI 0.08 g/dL lower to 0.04 g/dL higher; 3595 participants, seven trials, low quality evidence); formal tests of cognition (32,486 participants, five trials, moderate quality evidence); exam performance (32,659 participants, two trials, moderate quality evidence); or mortality (1,005,135 participants, three trials, low quality evidence). There is very limited evidence assessing an effect on school attendance and the findings are inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 4% lower to 8% higher; 20,243 participants, two trials, very low quality evidence).In a sensitivity analysis that only included trials with adequate allocation concealment, there was no evidence of any effect for the main outcomes. Treating children known to have worm infection may have some nutritional benefits for the individual. However, in mass treatment of all children in endemic areas, there is now substantial evidence that this does not improve average nutritional status, haemoglobin, cognition, school performance, or survival.

Outcome Measures Used in Clinical Trials for Behçet Syndrome: A Systematic Review

PubMed Central

Hatemi, Gulen; Merkel, Peter A.; Hamuryudan, Vedat; Boers, Maarten; Direskeneli, Haner; Aydin, Sibel Z.; Yazici, Hasan

2015-01-01

Behçet syndrome (BS) is a multisystem vasculitis that is most active during young adulthood, causing serious disability and significant impairment in quality of life. Differences in the disease course, severity, and organ involvement between patients, depending on the age at presentation and sex, makes it impossible to determine a single management strategy. The diversity and variability in the outcome measures used in clinical trials in BS makes it difficult to compare the results or inform physicians about the best management strategy for individual patients. There is a large unmet need to determine or develop validated outcome measures for use in clinical trials in BS that are acceptable to researchers and regulatory agencies. We conducted a systematic review to describe the outcomes and outcome measures that have been used in clinical trials in BS. This review revealed the diversity and variability in the outcomes and outcome measures and the lack of standard definitions for most outcomes and rarity of validated outcome tools for disease assessment in BS. This systematic literature review will identify domains and candidate instruments for use in a Delphi exercise, the next step in the development of a core set of outcome measures that are properly validated and widely accepted by the collaboration of researchers from many different regions of the world and from different specialties, including rheumatology, ophthalmology, dermatology, gastroenterology, and neurology. PMID:24488418

Evaluation of web-based annotation of ophthalmic images for multicentric clinical trials.

PubMed

Chalam, K V; Jain, P; Shah, V A; Shah, Gaurav Y

2006-06-01

An Internet browser-based annotation system can be used to identify and describe features in digitalized retinal images, in multicentric clinical trials, in real time. In this web-based annotation system, the user employs a mouse to draw and create annotations on a transparent layer, that encapsulates the observations and interpretations of a specific image. Multiple annotation layers may be overlaid on a single image. These layers may correspond to annotations by different users on the same image or annotations of a temporal sequence of images of a disease process, over a period of time. In addition, geometrical properties of annotated figures may be computed and measured. The annotations are stored in a central repository database on a server, which can be retrieved by multiple users in real time. This system facilitates objective evaluation of digital images and comparison of double-blind readings of digital photographs, with an identifiable audit trail. Annotation of ophthalmic images allowed clinically feasible and useful interpretation to track properties of an area of fundus pathology. This provided an objective method to monitor properties of pathologies over time, an essential component of multicentric clinical trials. The annotation system also allowed users to view stereoscopic images that are stereo pairs. This web-based annotation system is useful and valuable in monitoring patient care, in multicentric clinical trials, telemedicine, teaching and routine clinical settings.

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia

PubMed Central

Gökbuget, N; Kelsh, M; Chia, V; Advani, A; Bassan, R; Dombret, H; Doubek, M; Fielding, A K; Giebel, S; Haddad, V; Hoelzer, D; Holland, C; Ifrah, N; Katz, A; Maniar, T; Martinelli, G; Morgades, M; O'Brien, S; Ribera, J-M; Rowe, J M; Stein, A; Topp, M; Wadleigh, M; Kantarjian, H

2016-01-01

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data. PMID:27662202

Outcome measures used in clinical trials for Behçet syndrome: a systematic review.

PubMed

Hatemi, Gulen; Merkel, Peter A; Hamuryudan, Vedat; Boers, Maarten; Direskeneli, Haner; Aydin, Sibel Z; Yazici, Hasan

2014-03-01

Behçet syndrome (BS) is a multisystem vasculitis that is most active during young adulthood, causing serious disability and significant impairment in quality of life. Differences in the disease course, severity, and organ involvement between patients, depending on the age at presentation and sex, makes it impossible to determine a single management strategy. The diversity and variability in the outcome measures used in clinical trials in BS makes it difficult to compare the results or inform physicians about the best management strategy for individual patients. There is a large unmet need to determine or develop validated outcome measures for use in clinical trials in BS that are acceptable to researchers and regulatory agencies. We conducted a systematic review to describe the outcomes and outcome measures that have been used in clinical trials in BS. This review revealed the diversity and variability in the outcomes and outcome measures and the lack of standard definitions for most outcomes and rarity of validated outcome tools for disease assessment in BS. This systematic literature review will identify domains and candidate instruments for use in a Delphi exercise, the next step in the development of a core set of outcome measures that are properly validated and widely accepted by the collaboration of researchers from many different regions of the world and from different specialties, including rheumatology, ophthalmology, dermatology, gastroenterology, and neurology.

Optimality, sample size, and power calculations for the sequential parallel comparison design.

PubMed

Ivanova, Anastasia; Qaqish, Bahjat; Schoenfeld, David A

2011-10-15

The sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials in therapeutic areas where high-placebo response is a concern. The trial is run in two stages, and subjects are randomized into three groups: (i) placebo in both stages; (ii) placebo in the first stage and drug in the second stage; and (iii) drug in both stages. We consider the case of binary response data (response/no response). In the SPCD, all first-stage and second-stage data from placebo subjects who failed to respond in the first stage of the trial are utilized in the efficacy analysis. We develop 1 and 2 degree of freedom score tests for treatment effect in the SPCD. We give formulae for asymptotic power and for sample size computations and evaluate their accuracy via simulation studies. We compute the optimal allocation ratio between drug and placebo in stage 1 for the SPCD to determine from a theoretical viewpoint whether a single-stage design, a two-stage design with placebo only in the first stage, or a two-stage design is the best design for a given set of response rates. As response rates are not known before the trial, a two-stage approach with allocation to active drug in both stages is a robust design choice. Copyright © 2011 John Wiley & Sons, Ltd.

Recommended Patient-Reported Core Set of Symptoms to Measure in Adult Cancer Treatment Trials

PubMed Central

Mitchell, Sandra A.; Dueck, Amylou C.; Basch, Ethan; Cella, David; Reilly, Carolyn Miller; Minasian, Lori M.; Denicoff, Andrea M.; O’Mara, Ann M.; Fisch, Michael J.; Chauhan, Cynthia; Aaronson, Neil K.; Coens, Corneel; Bruner, Deborah Watkins

2014-01-01

Background The National Cancer Institute’s Symptom Management and Health-Related Quality of Life Steering Committee held a clinical trials planning meeting (September 2011) to identify a core symptom set to be assessed across oncology trials for the purposes of better understanding treatment efficacy and toxicity and to facilitate cross-study comparisons. We report the results of an evidence-synthesis and consensus-building effort that culminated in recommendations for core symptoms to be measured in adult cancer clinical trials that include a patient-reported outcome (PRO). Methods We used a data-driven, consensus-building process. A panel of experts, including patient representatives, conducted a systematic review of the literature (2001–2011) and analyzed six large datasets. Results were reviewed at a multistakeholder meeting, and a final set was derived emphasizing symptom prevalence across diverse cancer populations, impact on health outcomes and quality of life, and attribution to either disease or anticancer treatment. Results We recommend that a core set of 12 symptoms—specifically fatigue, insomnia, pain, anorexia (appetite loss), dyspnea, cognitive problems, anxiety (includes worry), nausea, depression (includes sadness), sensory neuropathy, constipation, and diarrhea—be considered for inclusion in clinical trials where a PRO is measured. Inclusion of symptoms and other patient-reported endpoints should be well justified, hypothesis driven, and meaningful to patients. Conclusions This core set will promote consistent assessment of common and clinically relevant disease- and treatment-related symptoms across cancer trials. As such, it provides a foundation to support data harmonization and continued efforts to enhance measurement of patient-centered outcomes in cancer clinical trials and observational studies. PMID:25006191

Comprehensive simulation-enhanced training curriculum for an advanced minimally invasive procedure: a randomized controlled trial.

PubMed

Zevin, Boris; Dedy, Nicolas J; Bonrath, Esther M; Grantcharov, Teodor P

2017-05-01

There is no comprehensive simulation-enhanced training curriculum to address cognitive, psychomotor, and nontechnical skills for an advanced minimally invasive procedure. 1) To develop and provide evidence of validity for a comprehensive simulation-enhanced training (SET) curriculum for an advanced minimally invasive procedure; (2) to demonstrate transfer of acquired psychomotor skills from a simulation laboratory to live porcine model; and (3) to compare training outcomes of SET curriculum group and chief resident group. University. This prospective single-blinded, randomized, controlled trial allocated 20 intermediate-level surgery residents to receive either conventional training (control) or SET curriculum training (intervention). The SET curriculum consisted of cognitive, psychomotor, and nontechnical training modules. Psychomotor skills in a live anesthetized porcine model in the OR was the primary outcome. Knowledge of advanced minimally invasive and bariatric surgery and nontechnical skills in a simulated OR crisis scenario were the secondary outcomes. Residents in the SET curriculum group went on to perform a laparoscopic jejunojejunostomy in the OR. Cognitive, psychomotor, and nontechnical skills of SET curriculum group were also compared to a group of 12 chief surgery residents. SET curriculum group demonstrated superior psychomotor skills in a live porcine model (56 [47-62] versus 44 [38-53], P<.05) and superior nontechnical skills (41 [38-45] versus 31 [24-40], P<.01) compared with conventional training group. SET curriculum group and conventional training group demonstrated equivalent knowledge (14 [12-15] versus 13 [11-15], P = 0.47). SET curriculum group demonstrated equivalent psychomotor skills in the live porcine model and in the OR in a human patient (56 [47-62] versus 63 [61-68]; P = .21). SET curriculum group demonstrated inferior knowledge (13 [11-15] versus 16 [14-16]; P<.05), equivalent psychomotor skill (63 [61-68] versus 68 [62-74]; P = .50), and superior nontechnical skills (41 [38-45] versus 34 [27-35], P<.01) compared with chief resident group. Completion of the SET curriculum resulted in superior training outcomes, compared with conventional surgery training. Implementation of the SET curriculum can standardize training for an advanced minimally invasive procedure and can ensure that comprehensive proficiency milestones are met before exposure to patient care. Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Reward and uncertainty in exploration programs

NASA Technical Reports Server (NTRS)

Kaufman, G. M.; Bradley, P. G.

1971-01-01

A set of variables which are crucial to the economic outcome of petroleum exploration are discussed. These are treated as random variables; the values they assume indicate the number of successes that occur in a drilling program and determine, for a particular discovery, the unit production cost and net economic return if that reservoir is developed. In specifying the joint probability law for those variables, extreme and probably unrealistic assumptions are made. In particular, the different random variables are assumed to be independently distributed. Using postulated probability functions and specified parameters, values are generated for selected random variables, such as reservoir size. From this set of values the economic magnitudes of interest, net return and unit production cost are computed. This constitutes a single trial, and the procedure is repeated many times. The resulting histograms approximate the probability density functions of the variables which describe the economic outcomes of an exploratory drilling program.

A protocol for evaluating video trackers under real-world conditions.

PubMed

Nawaz, Tahir; Cavallaro, Andrea

2013-04-01

The absence of a commonly adopted performance evaluation framework is hampering advances in the design of effective video trackers. In this paper, we present a single-score evaluation measure and a protocol to objectively compare trackers. The proposed measure evaluates tracking accuracy and failure, and combines them for both summative and formative performance assessment. The proposed protocol is composed of a set of trials that evaluate the robustness of trackers on a range of test scenarios representing several real-world conditions. The protocol is validated on a set of sequences with a diversity of targets (head, vehicle and person) and challenges (occlusions, background clutter, pose changes and scale changes) using six state-of-the-art trackers, highlighting their strengths and weaknesses on more than 187000 frames. The software implementing the protocol and the evaluation results are made available online and new results can be included, thus facilitating the comparison of trackers.

Next-Generation Pathology.

PubMed

Caie, Peter D; Harrison, David J

2016-01-01

The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

The SyBil-AA real-time fMRI neurofeedback study: protocol of a single-blind randomized controlled trial in alcohol use disorder.

PubMed

Gerchen, Martin Fungisai; Kirsch, Martina; Bahs, Nathalie; Halli, Patrick; Gerhardt, Sarah; Schäfer, Axel; Sommer, Wolfgang H; Kiefer, Falk; Kirsch, Peter

2018-01-17

Alcohol Use Disorder is a highly prevalent mental disorder which puts a severe burden on individuals, families, and society. The treatment of Alcohol Use Disorder is challenging and novel and innovative treatment approaches are needed to expand treatment options. A promising neuroscience-based intervention method that allows targeting cortical as well as subcortical brain processes is real-time functional magnetic resonance imaging neurofeedback. However, the efficacy of this technique as an add-on treatment of Alcohol Use Disorder in a clinical setting is hitherto unclear and will be assessed in the Systems Biology of Alcohol Addiction (SyBil-AA) neurofeedback study. N = 100 patients with Alcohol Use Disorder will be randomized to 5 parallel groups in a single-blind fashion and receive real-time functional magnetic resonance imaging neurofeedback while they are presented pictures of alcoholic beverages. The groups will either downregulate the ventral striatum, upregulate the right inferior frontal gyrus, negatively modulate the connectivity between these regions, upregulate, or downregulate the auditory cortex as a control region. After receiving 3 sessions of neurofeedback training within a maximum of 2 weeks, participants will be followed up monthly for a period of 3 months and relapse rates will be assessed as the primary outcome measure. The results of this study will provide insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback training in the treatment of Alcohol Use Disorder as well as in the involved brain systems. This might help to identify predictors of successful neurofeedback treatment which could potentially be useful in developing personalized treatment approaches. The study was retrospectively registered in the German Clinical Trials Register (trial identifier: DRKS00010253 ; WHO Universal Trial Number (UTN): U1111-1181-4218) on May 10th, 2016.

Tribendimidine and albendazole for treating soil-transmitted helminths, Strongyloides stercoralis and Taenia spp.: open-label randomized trial.

PubMed

Steinmann, Peter; Zhou, Xiao-Nong; Du, Zun-Wei; Jiang, Jin-Yong; Xiao, Shu-Hua; Wu, Zhong-Xing; Zhou, Hui; Utzinger, Jürg

2008-01-01

Tribendimidine is an anthelminthic drug with a broad spectrum of activity. In 2004 the drug was approved by Chinese authorities for human use. The efficacy of tribendimidine against soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura) has been established, and new laboratory investigations point to activity against cestodes and Strongyloides ratti. In an open-label randomized trial, the safety and efficacy of a single oral dose of albendazole or tribendimidine (both drugs administered at 200 mg for 5- to 14-year-old children, and 400 mg for individuals > or = 15 years) against soil-transmitted helminths, Strongyloides stercoralis, and Taenia spp. were assessed in a village in Yunnan province, People's Republic of China. The analysis was on a per-protocol basis and the trial is registered with controlled-trials.com (number ISRCTN01779485). Both albendazole and tribendimidine were highly efficacious against A. lumbricoides and, moderately, against hookworm. The efficacy against T. trichiura was low. Among 57 individuals who received tribendimidine, the prevalence of S. stercoralis was reduced from 19.3% to 8.8% (observed cure rate 54.5%, p = 0.107), and that of Taenia spp. from 26.3% to 8.8% (observed cure rate 66.7%, p = 0.014). Similar prevalence reductions were noted among the 66 albendazole recipients. Taking into account "new" infections discovered at treatment evaluation, which were most likely missed pre-treatment due to the lack of sensitivity of available diagnostic approaches, the difference between the drug-specific net Taenia spp. cure rates was highly significant in favor of tribendimidine (p = 0.001). No significant adverse events of either drug were observed. Our results suggest that single-dose oral tribendimidine can be employed in settings with extensive intestinal polyparasitism, and its efficacy against A. lumbricoides and hookworm was confirmed. The promising results obtained with tribendimidine against S. stercoralis and Taenia spp. warrant further investigations. In a next step, multiple-dose schedules should be evaluated.

Multivitamin supplementation in HIV infected adults initiating antiretroviral therapy in Uganda: the protocol for a randomized double blinded placebo controlled efficacy trial.

PubMed

Guwatudde, David; Ezeamama, Amara E; Bagenda, Danstan; Kyeyune, Rachel; Wabwire-Mangen, Fred; Wamani, Henry; Mugusi, Ferdinand; Spiegelman, Donna; Wang, Molin; Manabe, Yukari C; Fawzi, Wafaie W

2012-11-15

Use of multivitamin supplements during the pre-HAART era has been found to reduce viral load, enhance immune response, and generally improve clinical outcomes among HIV-infected adults. However, immune reconstitution is incomplete and significant mortality and opportunistic infections occur in spite of HAART. There is insufficient research information on whether multivitamin supplementation may be beneficial as adjunct therapy for HIV-infected individuals taking HAART. We propose to evaluate the efficacy of a single recommended daily allowance (RDA) of micronutrients (including vitamins B-complex, C, and E) in slowing disease progression among HIV-infected adults receiving HAART in Uganda. We are using a randomized, double-blind, placebo-controlled trial study design. Eligible patients are HIV-positive adults aged at least 18 years, and are randomized to receive either a placebo; or multivitamins that include a single RDA of the following vitamins: 1.4 mg B1, 1.4 mg B2, 1.9 mg B6, 2.6 mcg B12, 18 mg niacin, 70 mg C, 10 mg E, and 0.4 mg folic acid. Participants are followed for up to 18 months with evaluations at baseline, 6, 12 and 18 months. The study is primarily powered to examine the effects on immune reconstitution, weight gain, and quality of life. In addition, we will examine the effects on other secondary outcomes including the risks of development of new or recurrent disease progression event, including all-cause mortality; ARV regimen change from first- to second-line therapy; and other adverse events as indicated by incident peripheral neuropathy, severe anemia, or diarrhea. The conduct of this trial provides an opportunity to evaluate the potential benefits of this affordable adjunct therapy (multivitamin supplementation) among HIV-infected adults receiving HAART in a developing country setting. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01228578.

Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper.

PubMed

Casali, P G; Bruzzi, P; Bogaerts, J; Blay, J-Y

2015-02-01

While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

A Poisson approach to the validation of failure time surrogate endpoints in individual patient data meta-analyses.

PubMed

Rotolo, Federico; Paoletti, Xavier; Burzykowski, Tomasz; Buyse, Marc; Michiels, Stefan

2017-01-01

Surrogate endpoints are often used in clinical trials instead of well-established hard endpoints for practical convenience. The meta-analytic approach relies on two measures of surrogacy: one at the individual level and one at the trial level. In the survival data setting, a two-step model based on copulas is commonly used. We present a new approach which employs a bivariate survival model with an individual random effect shared between the two endpoints and correlated treatment-by-trial interactions. We fit this model using auxiliary mixed Poisson models. We study via simulations the operating characteristics of this mixed Poisson approach as compared to the two-step copula approach. We illustrate the application of the methods on two individual patient data meta-analyses in gastric cancer, in the advanced setting (4069 patients from 20 randomized trials) and in the adjuvant setting (3288 patients from 14 randomized trials).

Selective attention and response set in the Stroop task.

PubMed

Lamers, Martijn J M; Roelofs, Ardi; Rabeling-Keus, Inge M

2010-10-01

Response set membership contributes much to the interference in the color-word Stroop task. This may be due to selective allocation of attention to eligible responses or, alternatively, to greater inhibition of distractors that are not responses. In the present article, we report two experiments that were designed to adjudicate between these accounts. In Experiment 1, membership was manipulated on a trial-by-trial basis by cuing the possible responses for each trial. Response time (RT) was longer for distractors that corresponded to a cued, eligible response than to an ineligible one. This cuing effect was independent of the number of different responses. In Experiment 2, the distractor was cued on half the trials. Cuing the distractor decreased RTs on both incongruent and congruent trials. Vincentile analyses in both experiments revealed that the effects were constant throughout the entire RT distributions. These results suggest that response set effects arise because of selective allocation of attention to eligible responses.

Computerised cognitive-behavioural therapy for depression in adolescents: feasibility results and 4-month outcomes of a UK randomised controlled trial.

PubMed

Wright, Barry; Tindall, Lucy; Littlewood, Elizabeth; Allgar, Victoria; Abeles, Paul; Trépel, Dominic; Ali, Shehzad

2017-01-27

Computer-administered cognitive-behavioural therapy (CCBT) may be a promising treatment for adolescents with depression, particularly due to its increased availability and accessibility. The feasibility of delivering a randomised controlled trial (RCT) comparing a CCBT program (Stressbusters) with an attention control (self-help websites) for adolescent depression was evaluated. Single centre RCT feasibility study. The trial was run within community and clinical settings in York, UK. Adolescents (aged 12-18) with low mood/depression were assessed for eligibility, 91 of whom met the inclusion criteria and were consented and randomised to Stressbusters (n=45) or websites (n=46) using remote computerised single allocation. Those with comorbid physical illness were included but those with psychosis, active suicidality or postnatal depression were not. An eight-session CCBT program (Stressbusters) designed for use with adolescents with low mood/depression was compared with an attention control (accessing low mood self-help websites). Participants completed mood and quality of life measures and a service Use Questionnaire throughout completion of the trial and 4 months post intervention. Measures included the Beck Depression Inventory (BDI) (primary outcome measure), Mood and Feelings Questionnaire (MFQ), Spence Children's Anxiety Scale (SCAS), the EuroQol five dimensions questionnaire (youth) (EQ-5D-Y) and Health Utility Index Mark 2 (HUI-2). Changes in self-reported measures and completion rates were assessed by treatment group. From baseline to 4 months post intervention, BDI scores and MFQ scores decreased for the Stressbusters group but increased in the website group. Quality of life, as measured by the EQ-5D-Y, increased for both groups while costs at 4 months were similar to baseline. Good feasibility outcomes were found, suggesting the trial process to be feasible and acceptable for adolescents with depression. With modifications, a fully powered RCT is achievable to investigate a promising treatment for adolescent depression in a climate where child mental health service resources are limited. ISRCTN31219579. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The effects of the Bowen technique on hamstring flexibility over time: a randomised controlled trial.

PubMed

Marr, Michelle; Baker, Julian; Lambon, Nicky; Perry, Jo

2011-07-01

The hamstring muscles are regularly implicated in recurrent injuries, movement dysfunction and low back pain. Links between limited flexibility and development of neuromusculoskeletal symptoms are frequently reported. The Bowen Technique is used to treat many conditions including lack of flexibility. The study set out to investigate the effect of the Bowen Technique on hamstring flexibility over time. An assessor-blind, prospective, randomised controlled trial was performed on 120 asymptomatic volunteers. Participants were randomly allocated into a control group or Bowen group. Three flexibility measurements occurred over one week, using an active knee extension test. The intervention group received a single Bowen treatment. A repeated measures univariate analysis of variance, across both groups for the three time periods, revealed significant within-subject and between-subject differences for the Bowen group. Continuing increases in flexibility levels were observed over one week. No significant change over time was noted for the control group. Copyright © 2010 Elsevier Ltd. All rights reserved.

Persistently active neurons in human medial frontal and medial temporal lobe support working memory

PubMed Central

Kamiński, J; Sullivan, S; Chung, JM; Ross, IB; Mamelak, AN; Rutishauser, U

2017-01-01

Persistent neural activity is a putative mechanism for the maintenance of working memories. Persistent activity relies on the activity of a distributed network of areas, but the differential contribution of each area remains unclear. We recorded single neurons in the human medial frontal cortex and the medial temporal lobe while subjects held up to three items in memory. We found persistently active neurons in both areas. Persistent activity of hippocampal and amygdala neurons was stimulus-specific, formed stable attractors, and was predictive of memory content. Medial frontal cortex persistent activity, on the other hand, was modulated by memory load and task set but was not stimulus-specific. Trial-by-trial variability in persistent activity in both areas was related to memory strength, because it predicted the speed and accuracy by which stimuli were remembered. This work reveals, in humans, direct evidence for a distributed network of persistently active neurons supporting working memory maintenance. PMID:28218914

Complementary contributions of basolateral amygdala and orbitofrontal cortex to value learning under uncertainty

PubMed Central

Stolyarova, Alexandra; Izquierdo, Alicia

2017-01-01

We make choices based on the values of expected outcomes, informed by previous experience in similar settings. When the outcomes of our decisions consistently violate expectations, new learning is needed to maximize rewards. Yet not every surprising event indicates a meaningful change in the environment. Even when conditions are stable overall, outcomes of a single experience can still be unpredictable due to small fluctuations (i.e., expected uncertainty) in reward or costs. In the present work, we investigate causal contributions of the basolateral amygdala (BLA) and orbitofrontal cortex (OFC) in rats to learning under expected outcome uncertainty in a novel delay-based task that incorporates both predictable fluctuations and directional shifts in outcome values. We demonstrate that OFC is required to accurately represent the distribution of wait times to stabilize choice preferences despite trial-by-trial fluctuations in outcomes, whereas BLA is necessary for the facilitation of learning in response to surprising events. DOI: http://dx.doi.org/10.7554/eLife.27483.001 PMID:28682238

Informatics in radiology: An open-source and open-access cancer biomedical informatics grid annotation and image markup template builder.

PubMed

Mongkolwat, Pattanasak; Channin, David S; Kleper, Vladimir; Rubin, Daniel L

2012-01-01

In a routine clinical environment or clinical trial, a case report form or structured reporting template can be used to quickly generate uniform and consistent reports. Annotation and image markup (AIM), a project supported by the National Cancer Institute's cancer biomedical informatics grid, can be used to collect information for a case report form or structured reporting template. AIM is designed to store, in a single information source, (a) the description of pixel data with use of markups or graphical drawings placed on the image, (b) calculation results (which may or may not be directly related to the markups), and (c) supplemental information. To facilitate the creation of AIM annotations with data entry templates, an AIM template schema and an open-source template creation application were developed to assist clinicians, image researchers, and designers of clinical trials to quickly create a set of data collection items, thereby ultimately making image information more readily accessible.

Informatics in Radiology: An Open-Source and Open-Access Cancer Biomedical Informatics Grid Annotation and Image Markup Template Builder

PubMed Central

Channin, David S.; Rubin, Vladimir Kleper Daniel L.

2012-01-01

In a routine clinical environment or clinical trial, a case report form or structured reporting template can be used to quickly generate uniform and consistent reports. Annotation and Image Markup (AIM), a project supported by the National Cancer Institute’s cancer Biomedical Informatics Grid, can be used to collect information for a case report form or structured reporting template. AIM is designed to store, in a single information source, (a) the description of pixel data with use of markups or graphical drawings placed on the image, (b) calculation results (which may or may not be directly related to the markups), and (c) supplemental information. To facilitate the creation of AIM annotations with data entry templates, an AIM template schema and an open-source template creation application were developed to assist clinicians, image researchers, and designers of clinical trials to quickly create a set of data collection items, thereby ultimately making image information more readily accessible. © RSNA, 2012 PMID:22556315

A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck.

PubMed

Patil, Vijay Maruti; Noronha, Vanita; Joshi, Amit; Muddu, Vamshi Krishna; Dhumal, Sachin; Bhosale, Bharatsingh; Arya, Supreeta; Juvekar, Shashikant; Banavali, Shripad; D'Cruz, Anil; Bhattacharjee, Atanu; Prabhash, Kumar

2015-03-01

Cetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. We conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m(2))] to intravenous single agent cisplatin (IP) (75mg/m(2)) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0-2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. 110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249 days, 95% CI: 222.5-275.5 days) compared to the IP arm (median 152 days, 95% CI: 104.2-199.8 days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). Oral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting. Copyright © 2014 Elsevier Ltd. All rights reserved.

Oxytocin for preventing postpartum haemorrhage (PPH) in non-facility birth settings.

PubMed

Pantoja, Tomas; Abalos, Edgardo; Chapman, Evelina; Vera, Claudio; Serrano, Valentina P

2016-04-14

Postpartum haemorrhage (PPH) is the single leading cause of maternal mortality worldwide. Most of the deaths associated with PPH occur in resource-poor settings where effective methods of prevention and treatment - such as oxytocin - are not accessible because many births still occur at home, or in community settings, far from a health facility. Likewise, most of the evidence supporting oxytocin effectiveness comes from hospital settings in high-income countries, mainly because of the need of well-organised care for its administration and monitoring. Easier methods for oxytocin administration have been developed for use in resource-poor settings, but as far as we know, its effectiveness has not been assessed in a systematic review. To assess the effectiveness and safety of oxytocin provided in non-facility birth settings by any way in the third stage of labour to prevent PPH. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov (12 November 2015), and reference lists of retrieved reports. All published, unpublished or ongoing randomised or quasi-randomised controlled trials comparing the administration of oxytocin with no intervention, or usual/standard care for the management of the third stage of labour in non-facility birth settings were considered for inclusion.Quasi-randomised controlled trials and randomised controlled trials published in abstract form only were eligible for inclusion but none were identified. Cross-over trials were not eligible for inclusion in this review. Two review authors independently assessed studies for eligibility, assessed risk of bias and extracted the data using an agreed data extraction form. Data were checked for accuracy. We included one cluster-randomised trial conducted in four rural districts in Ghana that randomised 28 community health officers (CHOs) (serving 2404 potentially eligible pregnant women) to the intervention group and 26 CHOs (serving 3515 potentially eligible pregnant women) to the control group. Overall, the trial had a high risk of bias. CHOs delivered the intervention in the experimental group (injection of 10 IU (international units) of oxytocin in the thigh one minute following birth using a prefilled, auto-disposable syringe). In the control group, CHOs did not provide this prophylactic injection to the women they observed. CHOs had no midwifery skills and did not in any way manage the birth. All other CHO activities (outcome measurement, data collection, and early treatment and referral when necessary) were identical across the control and oxytocin CHOs.Although only one of the nine cases of severe PPH (blood loss greater or equal to 1000 mL) occurred in the oxytocin group, the effect estimate for this outcome was very imprecise and it is uncertain whether the intervention prevents severe PPH (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.02 to 1.30; 1570 women (very low-quality evidence)). Similarly, because of the lack of cases of severe maternal morbidity (e.g. uterine rupture) and maternal deaths, it was not possible to obtain effect estimates for those outcomes (both very low-quality evidence).Oxytocin compared with the control group decreased the incidence of PPH (> 500 mL) in both our unadjusted (RR 0.48, 95% CI 0.28 to 0.81; 1569 women) and adjusted (RR 0.49, 95% CI 0.27 to 0.90; 1174 women (both low-quality evidence)) analyses. There was little or no difference between the oxytocin and control groups on the rates of transfer or referral of the mother to a healthcare facility (RR 0.72, 95% CI 0.34 to 1.56; 1586 women (low-quality evidence)), stillbirths (RR 1.27, 95% CI 0.67 to 2.40; 2006 infants (low-quality evidence)); andearly infant deaths (0 to three days) (RR 1.03, 95% CI 0.35 to 3.07; 1969 infants (low-quality evidence)). There were no cases of needle-stick injury or any other maternal major or minor adverse event or unanticipated harmful event. There were no cases of oxytocin use during labour.There were no data reported for some of this review's secondary outcomes: manual removal of placenta, maternal anaemia, neonatal death within 28 days, neonatal transfer to health facility for advanced care, breastfeeding rates. Similarly, the women's or the provider's satisfaction with the intervention was not reported. It is uncertain if oxytocin administered by CHO in non-facility settings compared with a control group reduces the incidence of severe PPH (>1000 mL), severe maternal morbidity or maternal deaths. However, the intervention probably decreases the incidence of PPH (> 500 mL).The quality of the one trial included in this review was limited because of the risk of attrition and recruitment biases related to limitations in the follow-up of pregnant women in both arms of the trials and some baseline imbalance on the size of babies at birth. Additionally, there was serious imprecision of the effect estimates for most of the primary outcomes mainly because of the size of the trial, very few or no events and CIs around both relative and absolute estimates of effect that include both appreciable benefit and appreciable harm.Although the trial presented data both for primary and secondary outcomes, it seemed to be underpowered to detect differences in the primary outcomes that are the ones more relevant for making judgments about the potential applicability of the intervention in other settings (especially severe PPH).Therefore, taking into account the extreme setting where the intervention was implemented, the limited role of the CHO in the trial and the lack of power for detecting effects on primary (relevant) outcomes, the applicability of the evidence found seems to be rather limited.Further well-executed and adequately-powered randomised controlled trials assessing the effects of using oxytocin in pre-filled injection devices or other new delivery systems (spray-dried ultrafine formulation of oxytocin) on severe PPH are urgently needed. Likewise, other important outcomes like possible adverse events and acceptability of the intervention by mothers and other community stakeholders should also be assessed.

Combining features from ERP components in single-trial EEG for discriminating four-category visual objects.

PubMed

Wang, Changming; Xiong, Shi; Hu, Xiaoping; Yao, Li; Zhang, Jiacai

2012-10-01

Categorization of images containing visual objects can be successfully recognized using single-trial electroencephalograph (EEG) measured when subjects view images. Previous studies have shown that task-related information contained in event-related potential (ERP) components could discriminate two or three categories of object images. In this study, we investigated whether four categories of objects (human faces, buildings, cats and cars) could be mutually discriminated using single-trial EEG data. Here, the EEG waveforms acquired while subjects were viewing four categories of object images were segmented into several ERP components (P1, N1, P2a and P2b), and then Fisher linear discriminant analysis (Fisher-LDA) was used to classify EEG features extracted from ERP components. Firstly, we compared the classification results using features from single ERP components, and identified that the N1 component achieved the highest classification accuracies. Secondly, we discriminated four categories of objects using combining features from multiple ERP components, and showed that combination of ERP components improved four-category classification accuracies by utilizing the complementarity of discriminative information in ERP components. These findings confirmed that four categories of object images could be discriminated with single-trial EEG and could direct us to select effective EEG features for classifying visual objects.

Building clinical trial capacity to develop a new treatment for multidrug-resistant tuberculosis.

PubMed

Tupasi, Thelma; Gupta, Rajesh; Danilovits, Manfred; Cirule, Andra; Sanchez-Garavito, Epifanio; Xiao, Heping; Cabrera-Rivero, Jose L; Vargas-Vasquez, Dante E; Gao, Mengqiu; Awad, Mohamed; Gentry, Leesa M; Geiter, Lawrence J; Wells, Charles D

2016-02-01

New drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities. We carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis. The programme included: (i) site identification and needs assessment; (ii) achieving International Conference on Harmonization - Good Clinical Practice (ICH-GCP) standards; (iii) establishing trial management; and (iv) increasing knowledge of global and local regulatory issues. Trials were conducted at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America). Eight of the 10 sites in low-resource settings had no experience in conducting the requisite clinical trials. Extensive capacity-building was done in all 10 sites. The programme resulted in improved local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services. Clinical trials designed to generate data for regulatory approval require additional efforts beyond traditional research-capacity strengthening. Such capacity-building approaches provide an opportunity for product development partnerships to improve health systems beyond the direct conduct of the specific trial.

Walking economy is predictably determined by speed, grade, and gravitational load.

PubMed

Ludlow, Lindsay W; Weyand, Peter G

2017-11-01

The metabolic energy that human walking requires can vary by more than 10-fold, depending on the speed, surface gradient, and load carried. Although the mechanical factors determining economy are generally considered to be numerous and complex, we tested a minimum mechanics hypothesis that only three variables are needed for broad, accurate prediction: speed, surface grade, and total gravitational load. We first measured steady-state rates of oxygen uptake in 20 healthy adult subjects during unloaded treadmill trials from 0.4 to 1.6 m/s on six gradients: -6, -3, 0, 3, 6, and 9°. Next, we tested a second set of 20 subjects under three torso-loading conditions (no-load, +18, and +31% body weight) at speeds from 0.6 to 1.4 m/s on the same six gradients. Metabolic rates spanned a 14-fold range from supine rest to the greatest single-trial walking mean (3.1 ± 0.1 to 43.3 ± 0.5 ml O 2 ·kg -body -1 ·min -1 , respectively). As theorized, the walking portion (V̇o 2-walk  =  V̇o 2-gross - V̇o 2-supine-rest ) of the body's gross metabolic rate increased in direct proportion to load and largely in accordance with support force requirements across both speed and grade. Consequently, a single minimum-mechanics equation was derived from the data of 10 unloaded-condition subjects to predict the pooled mass-specific economy (V̇o 2-gross , ml O 2 ·kg -body + load -1 ·min -1 ) of all the remaining loaded and unloaded trials combined ( n = 1,412 trials from 90 speed/grade/load conditions). The accuracy of prediction achieved ( r 2  = 0.99, SEE = 1.06 ml O 2 ·kg -1 ·min -1 ) leads us to conclude that human walking economy is predictably determined by the minimum mechanical requirements present across a broad range of conditions. NEW & NOTEWORTHY Introduced is a "minimum mechanics" model that predicts human walking economy across a broad range of conditions from only three variables: speed, surface grade, and body-plus-load mass. The derivation/validation data set includes steady-state loaded and unloaded walking trials ( n = 3,414) that span a fourfold range of walking speeds on each of six different surface gradients (-6 to +9°). The accuracy of our minimum mechanics model ( r 2  = 0.99; SEE = 1.06 ml O 2 ·kg -1 ·min -1 ) appreciably exceeds that of currently used standards. Copyright © 2017 the American Physiological Society.

Single vs two implant-retained overdentures for edentulous mandibles: a systematic review.

PubMed

Alqutaibi, Ahmed Yaseen; Esposito, Marco; Algabri, Radwan; Alfahad, Adnan; Kaddah, Amal; Farouk, Mohammed; Alsourori, Ali

To compare prosthesis and implant failure, patient satisfaction, prosthetic complications and peri-implant marginal bone loss of mandibular overdentures (IOD) supported by a single or two implants. Manual and electronic database (PubMed and Cochrane) searches were performed to identify randomised controlled trials, without language restriction, comparing single vs two implant supported mandibular overdentures. Two investigators extracted data independently. The Cochrane tool was used for assessing the quality of included studies. Meta-analyses were performed for the included RCTs. Six publications corresponding to four RCTs were identified. Three RCTs (corresponding to five publications) were included and one trial was excluded. Follow-ups in function were 1, 3 and 5 years after loading. All included studies were considered to be at a high risk of bias. The pooled result revealed more prosthesis failures at overdentures supported by two implants at 1 year (three trials) (P = 0.02; Risk Difference: -0.12, 95% CI: -0.22, -0.02), however, there were non-significant differences at 3 years (two trials) (P = 0.22; Risk Difference: -0.32, 95% CI: -0.83, 0.19) and at 5 years (one trial) (P = 0.95; Risk Difference: 0.01, 95% CI: -0.22, 0.24). Regarding implant failures, there were more implant losses in overdentures supported by two implants at 1 year (three trials) (P = 0.02; Risk Difference: -0.12, 95% CI: -0.22, -0.02) and at 5 years (one trial) (P = 0.95; Risk Difference: -0.15, 95% CI: -0.28, -0.02), however, there were non-significant difference at 3 years (two trials) (P = 0.2; Risk Difference: -0.33, 95% CI: -0.84, 0.18). After 5 years in function, meta-analyses revealed that there were non-significant differences regarding overall prosthetic complications when mandibular overdentures supported by a single implant were compared with overdentures supported by two implants (P = 0.43; RD: 0.04, 95% CI: -0.06, 0.15). Mandibular overdentures retained by a single implant have comparable results to those retained by two implants. However, this should be interpreted with caution as all the included studies were considered at a high risk of bias.

Micronutrient supplementation in adults with HIV infection

PubMed Central

Visser, Marianne E; Durao, Solange; Sinclair, David; Irlam, James H; Siegfried, Nandi

2017-01-01

Background Micronutrient deficiencies are common among adults living with HIV disease, particularly in low-income settings where the diet may be low in essential vitamins and minerals. Some micronutrients play critical roles in maintenance of the immune system, and routine supplementation could therefore be beneficial. This is an update of a Cochrane Review previously published in 2010. Objectives To assess whether micronutrient supplements are effective and safe in reducing mortality and HIV-related morbidity of HIV-positive adults (excluding pregnant women). Search methods We performed literature searches from January 2010 to 18 November 2016 for new randomized controlled trials (RCTs) of micronutrient supplements since the previous review included all trials identified from searches prior to 2010. We searched the CENTRAL (the Cochrane Library), Embase, and PubMed databases. Also we checked the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the ClinicalTrials.gov trials registers. We also checked the reference lists of all new included trials. Selection criteria We included RCTs that compared supplements that contained either single, dual, or multiple micronutrients with placebo, no treatment, or other supplements. We excluded studies that were primarily designed to investigate the role of micronutrients for the treatment of HIV-positive participants with metabolic morbidity related to highly active antiretroviral therapy (HAART). Primary outcomes included all-cause mortality, morbidity, and disease progression. Data collection and analysis Two review authors independently selected trials for inclusion, and appraised trial quality for risk of bias. Where possible, we presented results as risk ratios (RR) for dichotomous variables, as hazard ratios (HRs) for time-to-event data, and as mean differences (MD) for continuous variables, each with 95% confidence intervals (CIs). Since we were often unable to pool the outcome data, we tabulated it for each comparison. We assessed the certainty of the evidence using the GRADE approach. Main results We included 33 trials with 10,325 participants, of which 17 trials were new trials. Ten trials compared a daily multiple micronutrient supplement to placebo in doses up to 20 times the dietary reference intake, and one trial compared a daily standard dose with a high daily dose of multivitamins. Nineteen trials compared supplementation with single or dual micronutrients (such as vitamins A and D, zinc, and selenium) to placebo, and three trials compared different dosages or combinations of micronutrients. Multiple micronutrients We conducted analyses across antiretroviral therapy (ART)-naive adults (3 trials, 1448 participants), adults on antiretroviral therapy (ART) (1 trial, 400 participants), and ART-naive adults with concurrent active tuberculosis (3 trials, 1429 participants). Routine multiple micronutrient supplementation may have little or no effect on mortality in adults living with HIV (RR 0.91, 95% CI 0.72 to 1.15; 7 trials, 2897 participants, low certainty evidence). Routine supplementation for up to two years may have little or no effect on the average of mean CD4+ cell count (MD 26.40 cells/mm³, 95% CI −22.91 to 75.70; 6 trials, 1581 participants, low certainty evidence), or the average of mean viral load (MD −0.1 log10viral copies, 95% CI −0.26 to 0.06; 4 trials, 840 participants, moderate certainty evidence). One additional trial in ART-naïve adults did report an increase in the time to reach a CD4+ cell count < 250 cells/mm³ after two years of high dose supplementation in Botswana (HR 0.48, 95% CI 0.26 to 0.88; 1 trial, 439 participants). However, the trial authors reported this effect only in the trial arm that received multiple micronutrients plus selenium (not either supplementation alone), which is inconsistent with the findings of other trials that used similar combinations of micronutrients and selenium. In one additional trial that compared high-dose multiple micronutrient supplementation with standard doses in people on ART, peripheral neuropathy was lower with high dose supplements compared to standard dose (incidence rate ratio (IRR) 0.81, 95% CI 0.7 to 0.94; 1 trial, 3418 participants), but the trial was stopped early due to increased adverse events (elevated alanine transaminase (ALT) levels) in the high dose group. Single or dual micronutrients None of the trials of single or dual micronutrient supplements were adequately powered to assess for effects on mortality or morbidity outcomes. No clinically significant changes in CD4 cell count (data not pooled, 14 trials, 2370 participants, very low or low certainty evidence) or viral load (data not pooled, seven studies, 1334 participants, very low or low certainty evidence), were reported. Supplementation probably does increase blood concentrations of vitamin D and zinc (data not pooled, vitamin D: 4 trials, 299 participants, zinc: 4 trials, 484 participants, moderate certainty evidence) and may also increase blood concentrations of vitamin A (data not pooled, 3 trials, 495 participants, low certainty evidence), especially in those who are deficient. Authors' conclusions The analyses of the available trials have not revealed consistent clinically important benefits with routine multiple micronutrient supplementation in people living with HIV. Larger trials might reveal small but important effects. These findings should not be interpreted as a reason to deny micronutrient supplements for people living with HIV where specific deficiencies are found or where the person's diet is insufficient to meet the recommended daily allowance of vitamins and minerals. Micronutrient supplements for non-pregnant adults with HIV infection Cochrane researchers conducted a review of the effects of micronutrient supplements for people living with HIV. This is an update of a Cochrane Review previously published in 2010. After searching for relevant trials up to 18 November 2016, the review authors included 33 trials. Thirteen of these trials included people not on HIV treatment and were conducted in Thailand, Peru, and eight African countries. Nineteen trials included people on HIV treatment and were conducted in North America, Europe, Brazil, Singapore, Thailand, Botswana, and Uganda. One trial from China did not state whether people living with HIV were on treatment or not. Some trials looked at the effects of taking supplements with multiple micronutrients whereas others looked at supplementation with single vitamins or minerals. What are micronutrient supplements and how might they help people living with HIV? Micronutrient supplements contain vitamins or minerals, or both, that are essential to good health. Many of these vitamins play important roles in maintaining the human immune system, which helps to fight off infections. Infection with HIV causes a progressive destruction of the immune system, which leaves people vulnerable to frequent infections. Many people living with HIV, especially in low-income countries, are also undernourished and many consume diets deficient that these essential micronutrients. Supplementation could therefore help people living with HIV to stay healthy for longer by strengthening their immune system or assisting recovery from infections. What the research says Multiple micronutrients Providing a daily supplement that contains multiple vitamins and minerals may have little or no effect on reducing deaths in people living with HIV, whether they are taking antiretroviral drugs or not (low certainty evidence). Daily supplements may have little or no effect on HIV disease progression as measured by CD4 cell count (low certainty evidence) or HIV viral load (low or moderate certainty evidence). Single or dual micronutrients We do not know whether supplements that contain single vitamins or minerals reduce deaths (very low certainty evidence) or slow disease progression (very low/low certainty evidence) in people living with HIV. Supplementation with vitamin A, D, zinc, or selenium may improve the level of each vitamin in a person's blood, especially those with low levels before supplementation (low/moderate certainty evidence). These findings do not mean that an adequate dietary intake for people living with HIV is not important. It is also not a reason to deny micronutrient supplements for those in whom a deficiency has been clinically demonstrated, or who are unlikely to meet the recommended daily allowance of vitamins and minerals. PMID:28518221

Antiviral therapeutics for the treatment of Ebola virus infection.

PubMed

Cardile, Anthony P; Downey, Lydia G; Wiseman, Perry D; Warren, Travis K; Bavari, Sina

2016-10-01

There have been significant developments in Ebola virus therapeutics. While the efficacy of several products was evaluated in the recent West Africa outbreak, a licensed treatment for EBOV disease remains elusive. Factors that negatively impacted the execution of clinical trials included an overall lack of world readiness to conduct clinical trials in an outbreak setting, ethical concerns limiting implementation of the randomized controlled trials in an outbreak setting, and a decline in case numbers by the time resources were mobilized to conduct clinical trials. We summarize relevant therapeutics that underwent clinical trials during the West Africa outbreak and highlight promising candidates under advanced development. Published by Elsevier Ltd.

Associative Interference and Recognition Memory.

ERIC Educational Resources Information Center

Underwood, Benton J.; And Others

Three experiments tested the generality of the conclusion that associative unlearning is minimal in the A-B, A-D paradigm. In Experiment 1, single-trial study of A-D, following single-trial study of A-B, did not produce retroactive inhibition in the recognition of A-B. In Experiment 2, A-B was acquired by associative matching. The interpolated…

Are multiple-trial experiments appropriate for eyewitness identification studies? Accuracy, choosing, and confidence across trials.

PubMed

Mansour, J K; Beaudry, J L; Lindsay, R C L

2017-12-01

Eyewitness identification experiments typically involve a single trial: A participant views an event and subsequently makes a lineup decision. As compared to this single-trial paradigm, multiple-trial designs are more efficient, but significantly reduce ecological validity and may affect the strategies that participants use to make lineup decisions. We examined the effects of a number of forensically relevant variables (i.e., memory strength, type of disguise, degree of disguise, and lineup type) on eyewitness accuracy, choosing, and confidence across 12 target-present and 12 target-absent lineup trials (N = 349; 8,376 lineup decisions). The rates of correct rejections and choosing (across both target-present and target-absent lineups) did not vary across the 24 trials, as reflected by main effects or interactions with trial number. Trial number had a significant but trivial quadratic effect on correct identifications (OR = 0.99) and interacted significantly, but again trivially, with disguise type (OR = 1.00). Trial number did not significantly influence participants' confidence in correct identifications, confidence in correct rejections, or confidence in target-absent selections. Thus, multiple-trial designs appear to have minimal effects on eyewitness accuracy, choosing, and confidence. Researchers should thus consider using multiple-trial designs for conducting eyewitness identification experiments.

Protein Supplementation to Augment the Effects of High Intensity Resistance Training in Untrained Middle-Aged Males: The Randomized Controlled PUSH Trial.

PubMed

Wittke, Andreas; von Stengel, Simon; Hettchen, Michael; Fröhlich, Michael; Giessing, Jürgen; Lell, Michael; Scharf, Michael; Bebenek, Michael; Kohl, Matthias; Kemmler, Wolfgang

2017-01-01

High intensity (resistance exercise) training (HIT) defined as a "single set resistance exercise to muscular failure" is an efficient exercise method that allows people with low time budgets to realize an adequate training stimulus. Although there is an ongoing discussion, recent meta-analysis suggests the significant superiority of multiple set (MST) methods for body composition and strength parameters. The aim of this study is to determine whether additional protein supplementation may increase the effect of a HIT-protocol on body composition and strength to an equal MST-level. One hundred and twenty untrained males 30-50 years old were randomly allocated to three groups: (a) HIT, (b) HIT and protein supplementation (HIT&P), and (c) waiting-control (CG) and (after cross-over) high volume/high-intensity-training (HVHIT). HIT was defined as "single set to failure protocol" while HVHIT consistently applied two equal sets. Protein supplementation provided an overall intake of 1.5-1.7 g/kg/d/body mass. Primary study endpoint was lean body mass (LBM). LBM significantly improved in all exercise groups ( p ≤ 0.043); however only HIT&P and HVHIT differ significantly from control ( p ≤ 0.002). HIT diverges significantly from HIT&P ( p = 0.017) and nonsignificantly from HVHIT ( p = 0.059), while no differences were observed for HIT&P versus HVHIT ( p = 0.691). In conclusion, moderate to high protein supplementation significantly increases the effects of a HIT-protocol on LBM in middle-aged untrained males.

Reconciling the influence of task-set switching and motor inhibition processes on stop signal after-effects.

PubMed

Anguera, Joaquin A; Lyman, Kyle; Zanto, Theodore P; Bollinger, Jacob; Gazzaley, Adam

2013-01-01

Executive response functions can be affected by preceding events, even if they are no longer associated with the current task at hand. For example, studies utilizing the stop signal task have reported slower response times to "GO" stimuli when the preceding trial involved the presentation of a "STOP" signal. However, the neural mechanisms that underlie this behavioral after-effect are unclear. To address this, behavioral and electroencephalography (EEG) measures were examined in 18 young adults (18-30 years) on "GO" trials following a previously "Successful Inhibition" trial (pSI), a previously "Failed Inhibition" trial (pFI), and a previous "GO" trial (pGO). Like previous research, slower response times were observed during both pSI and pFI trials (i.e., "GO" trials that were preceded by a successful and unsuccessful inhibition trial, respectively) compared to pGO trials (i.e., "GO" trials that were preceded by another "GO" trial). Interestingly, response time slowing was greater during pSI trials compared to pFI trials, suggesting executive control is influenced by both task set switching and persisting motor inhibition processes. Follow-up behavioral analyses indicated that these effects resulted from between-trial control adjustments rather than repetition priming effects. Analyses of inter-electrode coherence (IEC) and inter-trial coherence (ITC) indicated that both pSI and pFI trials showed greater phase synchrony during the inter-trial interval compared to pGO trials. Unlike the IEC findings, differential ITC was present within the beta and alpha frequency bands in line with the observed behavior (pSI > pFI > pGO), suggestive of more consistent phase synchrony involving motor inhibition processes during the ITI at a regional level. These findings suggest that between-trial control adjustments involved with task-set switching and motor inhibition processes influence subsequent performance, providing new insights into the dynamic nature of executive control.

Effects of Gait Self-Efficacy and Lower-Extremity Physical Function on Dual-Task Performance in Older Adults

PubMed Central

Banducci, Sarah E.; Daugherty, Ana M.; Fanning, Jason; Awick, Elizabeth A.; Porter, Gwenndolyn C.; Burzynska, Agnieszka; Shen, Sa; Kramer, Arthur F.; McAuley, Edward

2017-01-01

Objectives. Despite evidence of self-efficacy and physical function's influences on functional limitations in older adults, few studies have examined relationships in the context of complex, real-world tasks. The present study tested the roles of self-efficacy and physical function in predicting older adults' street-crossing performance in single- and dual-task simulations. Methods. Lower-extremity physical function, gait self-efficacy, and street-crossing success ratio were assessed in 195 older adults (60–79 years old) at baseline of a randomized exercise trial. During the street-crossing task, participants walked on a self-propelled treadmill in a virtual reality environment. Participants crossed the street without distraction (single-task trials) and conversed on a cell phone (dual-task trials). Structural equation modeling was used to test hypothesized associations independent of demographic and clinical covariates. Results. Street-crossing performance was better on single-task trials when compared with dual-task trials. Direct effects of self-efficacy and physical function on success ratio were observed in dual-task trials only. The total effect of self-efficacy was significant in both conditions. The indirect path through physical function was evident in the dual-task condition only. Conclusion. Physical function can predict older adults' performance on high fidelity simulations of complex, real-world tasks. Perceptions of function (i.e., self-efficacy) may play an even greater role. The trial is registered with United States National Institutes of Health ClinicalTrials.gov (ID: NCT01472744; Fit & Active Seniors Trial). PMID:28255557

Evaluating the design and reporting of pragmatic trials in osteoarthritis research.

PubMed

Ali, Shabana Amanda; Kloseck, Marita; Lee, Karen; Walsh, Kathleen Ellen; MacDermid, Joy C; Fitzsimmons, Deborah

2018-01-01

Among the challenges in health research is translating interventions from controlled experimental settings to clinical and community settings where chronic disease is managed daily. Pragmatic trials offer a method for testing interventions in real-world settings but are seldom used in OA research. The aim of this study was to evaluate the literature on pragmatic trials in OA research up to August 2016 in order to identify strengths and weaknesses in the design and reporting of these trials. We used established guidelines to assess the degree to which 61 OA studies complied with pragmatic trial design and reporting. We assessed design according to the pragmatic-explanatory continuum indicator summary and reporting according to the pragmatic trials extension of the CONsolidated Standards of Reporting Trials guidelines. None of the pragmatic trials met all 11 criteria evaluated and most of the trials met between 5 and 8 of the criteria. Criteria most often unmet pertained to practitioner expertise (by requiring specialists) and criteria most often met pertained to primary outcome analysis (by using intention-to-treat analysis). Our results suggest a lack of highly pragmatic trials in OA research. We identify this as a point of opportunity to improve research translation, since optimizing the design and reporting of pragmatic trials can facilitate implementation of evidence-based interventions for OA care. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Neratinib for the treatment of HER2-positive early stage breast cancer.

PubMed

Echavarria, Isabel; López-Tarruella, Sara; Márquez-Rodas, Iván; Jerez, Yolanda; Martin, Miguel

2017-08-01

Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.

Human striatal activation during adjustment of the response criterion in visual word recognition.

PubMed

Kuchinke, Lars; Hofmann, Markus J; Jacobs, Arthur M; Frühholz, Sascha; Tamm, Sascha; Herrmann, Manfred

2011-02-01

Results of recent computational modelling studies suggest that a general function of the striatum in human cognition is related to shifting decision criteria in selection processes. We used functional magnetic resonance imaging (fMRI) in 21 healthy subjects to examine the hemodynamic responses when subjects shift their response criterion on a trial-by-trial basis in the lexical decision paradigm. Trial-by-trial criterion setting is obtained when subjects respond faster in trials following a word trial than in trials following nonword trials - irrespective of the lexicality of the current trial. Since selection demands are equally high in the current trials, we expected to observe neural activations that are related to response criterion shifting. The behavioural data show sequential effects with faster responses in trials following word trials compared to trials following nonword trials, suggesting that subjects shifted their response criterion on a trial-by-trial basis. The neural responses revealed a signal increase in the striatum only in trials following word trials. This striatal activation is therefore likely to be related to response criterion setting. It demonstrates a role of the striatum in shifting decision criteria in visual word recognition, which cannot be attributed to pure error-related processing or the selection of a preferred response. Copyright © 2010 Elsevier Inc. All rights reserved.

Single dental implant retained mandibular complete dentures – influence of the loading protocol: study protocol for a randomized controlled trial

PubMed Central

2014-01-01

Background Over the years, there has been a strong consensus in dentistry that at least two implants are required to retain a complete mandibular denture. It has been shown in several clinical trials that one single median implant can retain a mandibular overdenture sufficiently well for up to 5 years without implant failures, when delayed loading was used. However, other trials have reported conflicting results with in part considerable failure rates when immediate loading was applied. Therefore it is the purpose of the current randomized clinical trial to test the hypothesis that immediate loading of a single mandibular midline implant with an overdenture will result in a comparable clinical outcome as using the standard protocol of delayed loading. Methods/design This prospective nine-center randomized controlled clinical trial is still ongoing. The final patient will complete the trial in 2016. In total, 180 edentulous patients between 60 and 89 years with sufficient complete dentures will receive one median implant in the edentulous mandible, which will retain the existing complete denture using a ball attachment. Loading of the median implant is either immediately after implant placement (experimental group) or delayed by 3 months of submerged healing at second-stage surgery (control group). Follow-up of patients will be performed for 24 months after implant loading. The primary outcome measure is non-inferiority of implant success rate of the experimental group compared to the control group. The secondary outcome measures encompass clinical, technical and subjective variables. The study was funded by the Deutsche Forschungsgemeinschaft (German research foundation, KE 477/8-1). Discussion This multi-center clinical trial will give information on the ability of a single median implant to retain a complete mandibular denture when immediately loaded. If viable, this treatment option will strongly improve everyday dental practice. Trial registration The trial has been registered at Deutsches Register Klinischer Studien (German register of clinical trials) under DRKS-ID: DRKS00003730 since 23 August 2012. (http://www.germanctr.de). PMID:24884848

Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review.

PubMed

Veena, Sargoor R; Gale, Catharine R; Krishnaveni, Ghattu V; Kehoe, Sarah H; Srinivasan, Krishnamachari; Fall, Caroline Hd

2016-08-12

The mother is the only source of nutrition for fetal growth including brain development. Maternal nutritional status (anthropometry, macro- and micro-nutrients) before and/or during pregnancy is therefore a potential predictor of offspring cognitive function. The relationship of maternal nutrition to offspring cognitive function is unclear. This review aims to assess existing evidence linking maternal nutritional status with offspring cognitive function. Exposures considered were maternal BMI, height and weight, micronutrient status (vitamins D, B12, folate and iron) and macronutrient intakes (carbohydrate, protein and fat). The outcome was any measure of cognitive function in children aged <18 years. We considered observational studies and trials with allocation groups that differed by single nutrients. We searched Medline/PubMed and the Cochrane Library databases and reference lists of retrieved literature. Two reviewers independently extracted data from relevant articles. We used methods recommended by the Centre for Reviews and Dissemination, University of York and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Of 16,143 articles identified, 38 met inclusion criteria. Most studies were observational, and from high-income settings. There were few randomized controlled trials. There was consistent evidence linking maternal obesity with lower cognitive function in children; low maternal BMI has been inadequately studied. Among three studies of maternal vitamin D status, two showed lower cognitive function in children of deficient mothers. One trial of folic acid supplementation showed no effects on the children's cognitive function and evidence from 13 observational studies was mixed. Among seven studies of maternal vitamin B12 status, most showed no association, though two studies in highly deficient populations suggested a possible effect. Four out of six observational studies and two trials (including one in an Iron deficient population) found no association of maternal iron status with offspring cognitive function. One trial of maternal carbohydrate/protein supplementation showed no effects on offspring cognitive function. Current evidence that maternal nutritional status during pregnancy as defined by BMI, single micronutrient studies, or macronutrient intakes influences offspring cognitive function is inconclusive. There is a need for more trials especially in populations with high rates of maternal undernutrition. Registered in PROSPERO CRD42013005702 .

Twelve-Week 24/7 Ambulatory Artificial Pancreas With Weekly Adaptation of Insulin Delivery Settings: Effect on Hemoglobin A1c and Hypoglycemia.

PubMed

Dassau, Eyal; Pinsker, Jordan E; Kudva, Yogish C; Brown, Sue A; Gondhalekar, Ravi; Dalla Man, Chiara; Patek, Steve; Schiavon, Michele; Dadlani, Vikash; Dasanayake, Isuru; Church, Mei Mei; Carter, Rickey E; Bevier, Wendy C; Huyett, Lauren M; Hughes, Jonathan; Anderson, Stacey; Lv, Dayu; Schertz, Elaine; Emory, Emma; McCrady-Spitzer, Shelly K; Jean, Tyler; Bradley, Paige K; Hinshaw, Ling; Laguna Sanz, Alejandro J; Basu, Ananda; Kovatchev, Boris; Cobelli, Claudio; Doyle, Francis J

2017-12-01

Artificial pancreas (AP) systems are best positioned for optimal treatment of type 1 diabetes (T1D) and are currently being tested in outpatient clinical trials. Our consortium developed and tested a novel adaptive AP in an outpatient, single-arm, uncontrolled multicenter clinical trial lasting 12 weeks. Thirty adults with T1D completed a continuous glucose monitor (CGM)-augmented 1-week sensor-augmented pump (SAP) period. After the AP was started, basal insulin delivery settings used by the AP for initialization were adapted weekly, and carbohydrate ratios were adapted every 4 weeks by an algorithm running on a cloud-based server, with automatic data upload from devices. Adaptations were reviewed by expert study clinicians and patients. The primary end point was change in hemoglobin A 1c (HbA 1c ). Outcomes are reported adhering to consensus recommendations on reporting of AP trials. Twenty-nine patients completed the trial. HbA 1c , 7.0 ± 0.8% at the start of AP use, improved to 6.7 ± 0.6% after 12 weeks (-0.3, 95% CI -0.5 to -0.2, P < 0.001). Compared with the SAP run-in, CGM time spent in the hypoglycemic range improved during the day from 5.0 to 1.9% (-3.1, 95% CI -4.1 to -2.1, P < 0.001) and overnight from 4.1 to 1.1% (-3.1, 95% CI -4.2 to -1.9, P < 0.001). Whereas carbohydrate ratios were adapted to a larger extent initially with minimal changes thereafter, basal insulin was adapted throughout. Approximately 10% of adaptation recommendations were manually overridden. There were no protocol-related serious adverse events. Use of our novel adaptive AP yielded significant reductions in HbA 1c and hypoglycemia. © 2017 by the American Diabetes Association.

A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol

PubMed Central

2011-01-01

Background The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. Methods/Design A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. Discussion This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence. Trial Registritation The trial is registered on ClinicalTrials.gov ref: NCT1146496 (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01146496). PMID:22104027

A shared-care model of obesity treatment for 3-10 year old children: protocol for the HopSCOTCH randomised controlled trial.

PubMed

Wake, Melissa; Lycett, Kate; Sabin, Matthew A; Gunn, Jane; Gibbons, Kay; Hutton, Cathy; McCallum, Zoe; York, Elissa; Stringer, Michael; Wittert, Gary

2012-03-28

Despite record rates of childhood obesity, effective evidence-based treatments remain elusive. While prolonged tertiary specialist clinical input has some individual impact, these services are only available to very few children. Effective treatments that are easily accessible for all overweight and obese children in the community are urgently required. General practitioners are logical care providers for obese children but high-quality trials indicate that, even with substantial training and support, general practitioner care alone will not suffice to improve body mass index (BMI) trajectories. HopSCOTCH (the Shared Care Obesity Trial in Children) will determine whether a shared-care model, in which paediatric obesity specialists co-manage obesity with general practitioners, can improve adiposity in obese children. Randomised controlled trial nested within a cross-sectional BMI survey conducted across 22 general practices in Melbourne, Australia. Children aged 3-10 years identified as obese by Centers for Disease Control criteria at their family practice, and randomised to either a shared-care intervention or usual care. A single multidisciplinary obesity clinic appointment at Melbourne's Royal Children's Hospital, followed by regular appointments with the child's general practitioner over a 12 month period. To support both specialist and general practice consultations, web-based shared-care software was developed to record assessment, set goals and actions, provide information to caregivers, facilitate communication between the two professional groups, and jointly track progress. Primary - change in BMI z-score. Secondary - change in percentage fat and waist circumference; health status, body satisfaction and global self-worth. This will be the first efficacy trial of a general-practitioner based, shared-care model of childhood obesity management. If effective, it could greatly improve access to care for obese children. Australian New Zealand Clinical Trials Registry ACTRN12608000055303.

Adding a single low-dose of primaquine (0.25 mg/kg) to artemether-lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania: a randomized, single-blinded clinical trial.

PubMed

Mwaiswelo, Richard; Ngasala, Billy; Jovel, Irina; Aydin-Schmidt, Berit; Gosling, Roland; Premji, Zul; Mmbando, Bruno; Björkman, Anders; Mårtensson, Andreas

2016-08-26

The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged ≥1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection. Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection. The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania. Trial registration number NCT02090036.

A new account of the effect of probability on task switching: ERP evidence following the manipulation of switch probability, cue informativeness and predictability

PubMed Central

Nessler, Doreen; Friedman, David; Johnson, Ray

2012-01-01

This task-switching ERP study of 16 young participants investigated whether increased RT slowing on stay trials and faster RTs on switch trials for frequent than infrequent switching are explained by an activation or preparation account. The activation account proposes that task sets are maintained at a higher baseline activation level for frequent switching, necessitating increased task-set updating, as reflected by a larger and/or longer lasting early parietal positivity. The preparation account assumes advance (pre-cue) switch preparation (i.e., task-set reconfiguration), preceding stay and switch trials for frequent switching, as reflected by pre-cue and post-cue late parietal positivities. By and large, the data support the activation account. However, we also found increased, pre-cue task-set updating on frequent stay trials and pre-cue, task-set reconfiguration prior to predictable, frequent switches. These results lead us to propose an extended activation account to explain the effects of switch probability on the executive processes underlying task-switching behavior. PMID:22820040

Effectiveness of an annular closure device in a "real-world" population: stratification of registry data using screening criteria from a randomized controlled trial.

PubMed

Kuršumović, Adisa; Rath, Stefan A

2018-01-01

Increased focus has been put on the use of "'real-world" data to support randomized clinical trial (RCT) evidence for clinical decision-making. The objective of this study was to assess the performance of an annular closure device (ACD) after stratifying a consecutive series of "real-world" patients by the screening criteria of an ongoing RCT. This was a single-center registry analysis of 164 subjects who underwent limited discectomy combined with ACD for symptomatic lumbar disc herniation. Patients were stratified into two groups using the selection criteria of a pivotal RCT on the same device: Trial (met inclusion; n=44) or non-Trial (did not meet inclusion; n=120). Patient-reported outcomes, including Oswestry Disability Index (ODI) and visual analog scale (VAS) for leg and back pain, and adverse events were collected from baseline to last follow-up (mean: Trial - 15.6 months; non-Trial - 14.6 months). Statistical analyses were performed with significance set at p <0.05. Patient-reported outcomes were not significantly different between groups at last ( p ≥0.15) and clinical success (≥15-point improvement in ODI score; ≥20-point improvement in VAS scores) was achieved in both the groups. Three non-Trial (2.5%) and three Trial (6.8%) patients experienced symptomatic reherniation ( p =0.34). Rates of reoperation, ACD mesh dislocation/separation, and other radiographic findings were similar between groups ( p =1.00). Outcomes with the ACD appeared advantageous in both the groups, particularly in comparison with historical reherniation rates reported in the same high-risk, large annular defect population. Stratification of this "real-world" series on the basis of RCT screening criteria did not result in significant between-group differences. These findings suggest that the efficacy of the ACD extends beyond the strictly defined patient population being studied in the RCT of this device. Furthermore, reducing the reherniation rate following lumbar discectomy has positive clinical and economic implications.

Could CT screening for lung cancer ever be cost effective in the United Kingdom?

PubMed Central

Whynes, David K

2008-01-01

Background The absence of trial evidence makes it impossible to determine whether or not mass screening for lung cancer would be cost effective and, indeed, whether a clinical trial to investigate the problem would be justified. Attempts have been made to resolve this issue by modelling, although the complex models developed to date have required more real-world data than are currently available. Being founded on unsubstantiated assumptions, they have produced estimates with wide confidence intervals and of uncertain relevance to the United Kingdom. Method I develop a simple, deterministic, model of a screening regimen potentially applicable to the UK. The model includes only a limited number of parameters, for the majority of which, values have already been established in non-trial settings. The component costs of screening are derived from government guidance and from published audits, whilst the values for test parameters are derived from clinical studies. The expected health gains as a result of screening are calculated by combining published survival data for screened and unscreened cohorts with data from Life Tables. When a degree of uncertainty over a parameter value exists, I use a conservative estimate, i.e. one likely to make screening appear less, rather than more, cost effective. Results The incremental cost effectiveness ratio of a single screen amongst a high-risk male population is calculated to be around £14,000 per quality-adjusted life year gained. The average cost of this screening regimen per person screened is around £200. It is possible that, when obtained experimentally in any future trial, parameter values will be found to differ from those previously obtained in non-trial settings. On the basis both of differing assumptions about evaluation conventions and of reasoned speculations as to how test parameters and costs might behave under screening, the model generates cost effectiveness ratios as high as around £20,000 and as low as around £7,000. Conclusion It is evident that eventually being able to identify a cost effective regimen of CT screening for lung cancer in the UK is by no means an unreasonable expectation. PMID:18302756

Clinical and economic benefit of enzymatic debridement of pressure ulcers compared to autolytic debridement with a hydrogel dressing.

PubMed

Waycaster, Curtis; Milne, Catherine T

2013-07-01

The purpose of this study was to determine the cost-effectiveness of enzymatic debridement using collagenase relative to autolytic debridement with a hydrogel dressing for the treatment of pressure ulcers. A 3-stage Markov model was used to determine the expected costs and outcomes of wound care for collagenase and hydrogel dressings. Outcome data used in the analysis were taken from a randomized clinical trial that directly compared collagenase and hydrogel dressings. The primary outcome in the clinical trial was the proportion of patients achieving a closed epithelialized wound. Transition probabilities for the Markov states were estimated from the clinical trial. A 1-year time horizon was used to determine the expected number of closed wound days and the expected costs for the two alternative debridement therapies. Resource utilization was based on the wound care treatment regimen used in the clinical trial. Resource costs were derived from standard cost references and medical supply wholesalers. The economic perspective taken was that of the long-term care facility. No cost discounting was performed due to the short time horizon of the analysis. A deterministic sensitivity analysis was conducted to analyze economic uncertainty. The number of expected wound days for the collagenase and hydrogel cohorts are estimated at 48 and 147, respectively. The expected direct cost per patient for pressure ulcer care was $2003 for collagenase and $5480 for hydrogel debridement. The number of closed wound days was 1.5-times higher for collagenase (317 vs 218 days) than with the hydrogel. The estimated cost/closed wound day was 4-times higher for the hydrogel ($25) vs collagenase ($6). In this Markov model based on a randomized trial of pressure ulcer care in a long-term care setting collagenase debridement was economically dominant over autolytic debridement, yielding better outcomes at a lower total cost. Since it was a single institution study with a small sample size, the results should be interpreted with caution. Specifically, the findings may not necessarily be generalized to other hydrogel dressings, healthcare settings, age groups, or to wounds of other etiologies.

Comparative study of the efficacy of transdermal buprenorphine patches and prolonged-release tramadol tablets for postoperative pain control after spinal fusion surgery: a prospective, randomized controlled non-inferiority trial.

PubMed

Kim, Ho-Joong; Ahn, Hyo Sae; Nam, Yunjin; Chang, Bong-Soon; Lee, Choon-Ki; Yeom, Jin S

2017-11-01

To compare the efficacy of a transdermal buprenorphine patch (5, 10, 15, and 20 μg/h) with that of oral tramadol (150, 200, 250, and 300 mg) for postoperative pain control after single level spinal fusion surgery. The present study (ClinicalTrials.gov, number NCT02416804) was a prospective, randomized controlled non-inferiority trial designed to determine the efficacy of buprenorphine TDS for alleviating postoperative pain following patient controlled analgesia (PCA) in persons underwent a single level posterior lumbar interbody fusion surgery through 1:1 allocation. The primary outcome was the Visual Analog Pain Scale (VAS) score for postoperative back pain at 7 days after surgery. The non-inferior margin of the VAS was set at δ = 1.5 points. The VAS score (primary outcome) for postoperative back pain at 7 days after surgery in the Buprenorphine group was not inferior compared to the Tramadol group. The overall changes in VAS scores for postoperative pain during follow-up assessments over a 2-week period did not differ between both groups. However, the VAS scores for postoperative pain significantly improved with time after surgery in both groups. The patterns of changes in the VAS scores for postoperative pain during the follow-up period were not significantly different between the both groups. The efficacy of buprenorphine TDS was not inferior to that of oral tramadol medication for alleviating postoperative pain in the subacute period from 72 h after surgery, following PCA administration. In addition, adverse events were similar between both groups.

Mental Health Smartphone Apps: Review and Evidence-Based Recommendations for Future Developments.

PubMed

Bakker, David; Kazantzis, Nikolaos; Rickwood, Debra; Rickard, Nikki

2016-03-01

The number of mental health apps (MHapps) developed and now available to smartphone users has increased in recent years. MHapps and other technology-based solutions have the potential to play an important part in the future of mental health care; however, there is no single guide for the development of evidence-based MHapps. Many currently available MHapps lack features that would greatly improve their functionality, or include features that are not optimized. Furthermore, MHapp developers rarely conduct or publish trial-based experimental validation of their apps. Indeed, a previous systematic review revealed a complete lack of trial-based evidence for many of the hundreds of MHapps available. To guide future MHapp development, a set of clear, practical, evidence-based recommendations is presented for MHapp developers to create better, more rigorous apps. A literature review was conducted, scrutinizing research across diverse fields, including mental health interventions, preventative health, mobile health, and mobile app design. Sixteen recommendations were formulated. Evidence for each recommendation is discussed, and guidance on how these recommendations might be integrated into the overall design of an MHapp is offered. Each recommendation is rated on the basis of the strength of associated evidence. It is important to design an MHapp using a behavioral plan and interactive framework that encourages the user to engage with the app; thus, it may not be possible to incorporate all 16 recommendations into a single MHapp. Randomized controlled trials are required to validate future MHapps and the principles upon which they are designed, and to further investigate the recommendations presented in this review. Effective MHapps are required to help prevent mental health problems and to ease the burden on health systems.

Effectiveness of continuous versus single injection femoral nerve block for total knee arthroplasty: A double blinded, randomized trial.

PubMed

Dixit, Varun; Fathima, Samreen; Walsh, Stephen M; Seviciu, Alexandru; Schwendt, Ivan; Spittler, Karl-Heinz; Briggs, Dana

2018-04-26

Effective analgesia following total knee arthroplasty (TKA) is important for maximizing patient satisfaction, early participation in physical therapy and reducing the hospital stay. This trial compared continuous catheter femoral nerve block (cFNB) to single injection femoral nerve block (sFNB) in terms of analgesia, opioid consumption, and participation in physical therapy and associated side effects. This randomized, double blinded trial was conducted in a non-university hospital setting, without major changes to anesthesia or surgical clinical pathways. A total of 85 patients scheduled for primary TKA were randomized to receive either cFNB (n=44) or sFNB (n=41). All patients had FNB with 0.5% ropivacaine bolus followed by subarachnoid block for surgery. Postoperatively, 0.2% ropivacaine infusion was commenced in cFNB group and a sham catheter was taped to the skin in sFNB group. All patients received a structured multimodal analgesia regimen throughout hospital stay. The primary outcomes were peak resting visual analogue scale (VAS) scores and morphine consumption at 48h postoperatively. VAS scores (Mean difference 0.25, 95% Confidence Interval (CI) -0.56 to 1.06; [P=0.196]) and morphine consumption (Mean difference 0.95mg, 95% CI -9.99 to 11.89; [P=0.863]) were not significantly different among patients who received cFNB versus sFNB at 48h. There was no difference in hospital stay (P=0.517) or long-term functional recovery between the two groups (P=0.385). sFNB block provides equal pain relief compared with cFNB, after TKA with no significant difference in opioid consumption, hospital stay, physical therapy outcomes or associated side effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Indocyanine green-augmented diode laser therapy vs. long-pulsed Nd:YAG (1064 nm) laser treatment of telangiectatic leg veins: a randomized controlled trial.

PubMed

Klein, A; Buschmann, M; Babilas, P; Landthaler, M; Bäumler, W

2013-08-01

Telangiectatic leg veins (TLV) represent a common cosmetic problem. Near infrared lasers have been widely used in treatment because of their deeper penetration into the dermis, but with varying degrees of success, particularly because of different vessel diameters. Indocyanine green (ICG)-augmented diode laser treatment (ICG+DL) may present an alternative treatment option. This trial evaluates the efficacy of ICG+DL in the treatment of TLV and compares the safety and efficacy of therapy with the standard treatment, the long-pulsed neodymium-doped yttrium aluminium garnet (Nd:YAG) laser. In a prospective randomized controlled clinical trial, 29 study participants with TLV were treated with a Nd:YAG laser (λem = 1064 nm, 160-240 J cm(-2) , 65-ms pulse duration, 5-mm spot size) and ICG+DL (λem = 810 nm, 60-110 J cm(-2) , 48-87-ms pulse duration, 6-mm spot size; total ICG dose 4 mg kg(-1) ) in a side-by-side comparison in one single treatment setting that included histological examination in four participants. Two blinded investigators and the participants assessed clearance rate, cosmetic appearance and adverse events up to 3 months after treatment. According to both the investigators' and participants' assessment, clearance rates were significantly better after ICG+DL therapy than after Nd:YAG laser treatment (P < 0·05). On a 10-point scale indicating pain during treatment, participants rated ICG+DL therapy to be more painful (6·1 ± 2·0) than Nd:YAG laser (5·4 ± 2·0). ICG+DL therapy represents a new and promising treatment modality for TLV, with high clearance rates and a very good cosmetic outcome after one single treatment session. © 2013 British Association of Dermatologists.

Coordinated within-trial dynamics of low-frequency neural rhythms controls evidence accumulation.

PubMed

Werkle-Bergner, Markus; Grandy, Thomas H; Chicherio, Christian; Schmiedek, Florian; Lövdén, Martin; Lindenberger, Ulman

2014-06-18

Higher cognitive functions, such as human perceptual decision making, require information processing and transmission across wide-spread cortical networks. Temporally synchronized neural firing patterns are advantageous for efficiently representing and transmitting information within and between assemblies. Computational, empirical, and conceptual considerations all lead to the expectation that the informational redundancy of neural firing rates is positively related to their synchronization. Recent theorizing and initial evidence also suggest that the coding of stimulus characteristics and their integration with behavioral goal states require neural interactions across a hierarchy of timescales. However, most studies thus have focused on neural activity in a single frequency range or on a restricted set of brain regions. Here we provide evidence for cooperative spatiotemporal dynamics of slow and fast EEG signals during perceptual decision making at the single-trial level. Participants performed three masked two-choice decision tasks, one each with numerical, verbal, or figural content. Decrements in posterior α power (8-14 Hz) were paralleled by increments in high-frequency (>30 Hz) signal entropy in trials demanding active sensory processing. Simultaneously, frontocentral θ power (4-7 Hz) increased, indicating evidence integration. The coordinated α/θ dynamics were tightly linked to decision speed and remarkably similar across tasks, suggesting a domain-general mechanism. In sum, we demonstrate an inverse association between decision-related changes in widespread low-frequency power and local high-frequency entropy. The cooperation among mechanisms captured by these changes enhances the informational density of neural response patterns and qualifies as a neural coding system in the service of perceptual decision making. Copyright © 2014 the authors 0270-6474/14/348519-10$15.00/0.

Mental Health Smartphone Apps: Review and Evidence-Based Recommendations for Future Developments

PubMed Central

Kazantzis, Nikolaos; Rickwood, Debra; Rickard, Nikki

2016-01-01

Background The number of mental health apps (MHapps) developed and now available to smartphone users has increased in recent years. MHapps and other technology-based solutions have the potential to play an important part in the future of mental health care; however, there is no single guide for the development of evidence-based MHapps. Many currently available MHapps lack features that would greatly improve their functionality, or include features that are not optimized. Furthermore, MHapp developers rarely conduct or publish trial-based experimental validation of their apps. Indeed, a previous systematic review revealed a complete lack of trial-based evidence for many of the hundreds of MHapps available. Objective To guide future MHapp development, a set of clear, practical, evidence-based recommendations is presented for MHapp developers to create better, more rigorous apps. Methods A literature review was conducted, scrutinizing research across diverse fields, including mental health interventions, preventative health, mobile health, and mobile app design. Results Sixteen recommendations were formulated. Evidence for each recommendation is discussed, and guidance on how these recommendations might be integrated into the overall design of an MHapp is offered. Each recommendation is rated on the basis of the strength of associated evidence. It is important to design an MHapp using a behavioral plan and interactive framework that encourages the user to engage with the app; thus, it may not be possible to incorporate all 16 recommendations into a single MHapp. Conclusions Randomized controlled trials are required to validate future MHapps and the principles upon which they are designed, and to further investigate the recommendations presented in this review. Effective MHapps are required to help prevent mental health problems and to ease the burden on health systems. PMID:26932350

Efficacy of a web- and text messaging-based intervention to reduce problem drinking in young people: study protocol of a cluster-randomised controlled trial.

PubMed

Haug, Severin; Kowatsch, Tobias; Castro, Raquel Paz; Filler, Andreas; Schaub, Michael P

2014-08-07

Problem drinking, particularly risky single-occasion drinking is widespread among adolescents and young adults in most Western countries. Mobile phone text messaging allows a proactive and cost-effective delivery of short messages at any time and place and allows the delivery of individualised information at times when young people typically drink alcohol. The main objective of the planned study is to test the efficacy of a combined web- and text messaging-based intervention to reduce problem drinking in young people with heterogeneous educational level. A two-arm cluster-randomised controlled trial with one follow-up assessment after 6 months will be conducted to test the efficacy of the intervention in comparison to assessment only. The fully-automated intervention program will provide an online feedback based on the social norms approach as well as individually tailored mobile phone text messages to stimulate (1) positive outcome expectations to drink within low-risk limits, (2) self-efficacy to resist alcohol and (3) planning processes to translate intentions to resist alcohol into action. Program participants will receive up to two weekly text messages over a time period of 3 months. Study participants will be 934 students from approximately 93 upper secondary and vocational schools in Switzerland. Main outcome criterion will be risky single-occasion drinking in the past 30 days preceding the follow-up assessment. This is the first study testing the efficacy of a combined web- and text messaging-based intervention to reduce problem drinking in young people. Given that this intervention approach proves to be effective, it could be easily implemented in various settings, and it could reach large numbers of young people in a cost-effective way. Current Controlled Trials ISRCTN59944705.

Effects of a tele-prehabilitation program or an in-person prehabilitation program in surgical candidates awaiting total hip or knee arthroplasty: Protocol of a pilot single blind randomized controlled trial.

PubMed

Doiron-Cadrin, Patrick; Kairy, Dahlia; Vendittoli, Pascal-André; Lowry, Véronique; Poitras, Stéphane; Desmeules, François

2016-12-15

The accessibility for total joint arthroplasty often comes up against long wait lists, and may lead to deleterious effects for the awaiting patients. This pilot single blind randomized controlled trial aims to evaluate the impact of a telerehabilitation prehabilitation program before a hip or knee arthroplasty compared to in-person prehabilitation or to usual wait for surgery. Thirty-six patients on a wait list for a total hip or knee arthroplasty will be recruited and randomly assigned to one of three groups. The in-person prehabilitation group (n = 12) will receive a 12-week rehabilitation program (2 sessions/week) including education, exercises of the lower limb and cardiovascular training. Patients in the tele-prehabilitation group (n = 12) will receive the same intervention using a telecommunication software. The control group (n = 12) will be provided with the hospital's usual documentation before surgery. The Lower Extremity Functional Scale (LEFS) will be the primary outcome measure taken at baseline and at 12 weeks. Secondary measures will include self-reported function and quality of life as well as performance tests. A mixed-model, 2-way repeated-measure ANOVA will be used to analyse the effects of the rehabilitation programs. This pilot study is the first to evaluate the feasibility and the impact of a telerehabilitation prehabilitation program for patients awaiting a total joint arthroplasty. The results of this pilot-RCT will set the foundations for further research in the fields of rehabilitation and tele-medicine for patients suffering from lower limb osteoarthritis. ClinicalTrials.gov: NCT02636751.

Espresso Coffee for the Treatment of Somnolence in Parkinson’s Disease: Results of n-of-1 Trials

PubMed Central

Ferreira, Joaquim J.; Mestre, Tiago; Guedes, Leonor Correia; Coelho, Miguel; Rosa, Mário M.; Santos, Ana T.; Barra, Márcio; Sampaio, Cristina; Rascol, Olivier

2016-01-01

There is limited information available concerning the treatment of daytime somnolence associated with Parkinson’s disease (PD); the most frequently applied therapeutic strategies include decreasing the dose of dopamine agonists or adding potential wake-promoting agents. There is recent data from a placebo-controlled trial concluding on a non-significant trend in favor of caffeine. We aimed to evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD. To evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD, we have conducted multiple single-patient (n-of-1) clinical trials comparing regular espresso coffee to decaffeinated coffee in PD patients presenting moderate to severe daytime somnolence defined as an Epworth Sleepiness Scale score >9. Each single-patient (n-of-1) trial included a sequence of three crossovers (two treatment periods separated by two days of washout). Four patients were included in the studies and three completed the three pairs of treatment periods. In two of the four patients, espresso coffee was considered beneficial. This study concludes that multiple single patient trials are feasible in PD and suggests that espresso-coffee may have a beneficial effect on daytime somnolence in some patients. These results cannot be generalized beyond the patients included in these trials. PMID:27014181

Single-trial extraction of cognitive evoked potentials by combination of third-order correlation and wavelet denoising.

PubMed

Zhang, Z; Tian, X

2005-01-01

The application of a recently proposed denoising implementation for obtaining cognitive evoked potentials (CEPs) at the single-trial level is shown. The aim of this investigation is to develop the technique of extracting CEPs by combining both the third-order correlation and the wavelet denoising methods. First, the noisy CEPs was passed through a finite impulse response filter whose impulse response is matched with the shape of the noise-free signal. It was shown that it is possible to estimate the filter impulse response on basis of a select third-order correlation slice (TOCS) of the input noisy CEPs. Second, the output from the third-order correlation filter is decomposed with bi-orthogonal splines at 5 levels. The CEPs is reconstructed by wavelet final approximation a5. We study its performance in simulated data as well as in cognitive evoked potentials of normal rat and Alzheimer's disease (AD) model rat. For the simulated data, the method gives a significantly better reconstruction of the single-trial cognitive evoked potentials responses in comparison with the simulated data. Moreover, with this approach we obtain a significantly better estimation of the amplitudes and latencies of the simulated CEPs. For the real data, the method clearly improves the visualization of single-trial CEPs. This allows the calculation of better averages as well as the study of systematic or unsystematic variations between trials.

Method for enhancing single-trial P300 detection by introducing the complexity degree of image information in rapid serial visual presentation tasks

PubMed Central

Lin, Zhimin; Zeng, Ying; Tong, Li; Zhang, Hangming; Zhang, Chi

2017-01-01

The application of electroencephalogram (EEG) generated by human viewing images is a new thrust in image retrieval technology. A P300 component in the EEG is induced when the subjects see their point of interest in a target image under the rapid serial visual presentation (RSVP) experimental paradigm. We detected the single-trial P300 component to determine whether a subject was interested in an image. In practice, the latency and amplitude of the P300 component may vary in relation to different experimental parameters, such as target probability and stimulus semantics. Thus, we proposed a novel method, Target Recognition using Image Complexity Priori (TRICP) algorithm, in which the image information is introduced in the calculation of the interest score in the RSVP paradigm. The method combines information from the image and EEG to enhance the accuracy of single-trial P300 detection on the basis of traditional single-trial P300 detection algorithm. We defined an image complexity parameter based on the features of the different layers of a convolution neural network (CNN). We used the TRICP algorithm to compute for the complexity of an image to quantify the effect of different complexity images on the P300 components and training specialty classifier according to the image complexity. We compared TRICP with the HDCA algorithm. Results show that TRICP is significantly higher than the HDCA algorithm (Wilcoxon Sign Rank Test, p<0.05). Thus, the proposed method can be used in other and visual task-related single-trial event-related potential detection. PMID:29283998

Mixed response and time-to-event endpoints for multistage single-arm phase II design.

PubMed

Lai, Xin; Zee, Benny Chung-Ying

2015-06-04

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

Vaxchora: A Single-Dose Oral Cholera Vaccine.

PubMed

Cabrera, Adriana; Lepage, Jayne E; Sullivan, Karyn M; Seed, Sheila M

2017-07-01

To review trials evaluating the efficacy and safety of Vaxchora, a reformulated, single-dose, oral, lyophilized Vibrio cholerae CVD 103-HgR vaccine for the prevention of travel-related cholera caused by V cholerae serogroup O1. A literature search was conducted using MEDLINE (1946 to January week 3, 2017) and EMBASE (1996 to 2017 week 3). Keywords included oral cholera vaccine, single-dose, Vaxchora, and CVD 103-HgR. Limits included human, clinical trials published in English since 2010. ClinicalTrials.gov was used as a source for unpublished data. Additional data sources were obtained through bibliographic review of selected articles. Studies that addressed the safety and efficacy of Vaxchora, the reformulated, single-dose oral CVD 103-HgR cholera vaccine, were selected for analysis. Approval of Vaxchora, was based on efficacy of the vaccine in human trials demonstrating 90.3% protection among those challenged with V cholerae 10 days after vaccination and in immunogenicity studies with 90% systemic vibriocidal antibody conversion at 6 months after a single-dose of vaccine. Tolerability was acceptable, with the most common adverse effects reported to be fatigue, headache, and abdominal pain. Vaxchora is the only FDA-approved, single-dose oral vaccine for the prevention of cholera caused by V cholerae serogroup O1 in adult travelers from the United States going to cholera-affected areas. Safety and efficacy has not been established in children, immunocompromised persons, and pregnant or breastfeeding women or those living in cholera-endemic areas.

A P300-based Brain-Computer Interface with Stimuli on Moving Objects: Four-Session Single-Trial and Triple-Trial Tests with a Game-Like Task Design

PubMed Central

Ganin, Ilya P.; Shishkin, Sergei L.; Kaplan, Alexander Y.

2013-01-01

Brain-computer interfaces (BCIs) are tools for controlling computers and other devices without using muscular activity, employing user-controlled variations in signals recorded from the user’s brain. One of the most efficient noninvasive BCIs is based on the P300 wave of the brain’s response to stimuli and is therefore referred to as the P300 BCI. Many modifications of this BCI have been proposed to further improve the BCI’s characteristics or to better adapt the BCI to various applications. However, in the original P300 BCI and in all of its modifications, the spatial positions of stimuli were fixed relative to each other, which can impose constraints on designing applications controlled by this BCI. We designed and tested a P300 BCI with stimuli presented on objects that were freely moving on a screen at a speed of 5.4°/s. Healthy participants practiced a game-like task with this BCI in either single-trial or triple-trial mode within four sessions. At each step, the participants were required to select one of nine moving objects. The mean online accuracy of BCI-based selection was 81% in the triple-trial mode and 65% in the single-trial mode. A relatively high P300 amplitude was observed in response to targets in most participants. Self-rated interest in the task was high and stable over the four sessions (the medians in the 1st/4th sessions were 79/84% and 76/71% in the groups practicing in the single-trial and triple-trial modes, respectively). We conclude that the movement of stimulus positions relative to each other may not prevent the efficient use of the P300 BCI by people controlling their gaze, e.g., in robotic devices and in video games. PMID:24302977

Propose but verify: Fast mapping meets cross-situational word learning

PubMed Central

Trueswell, John C.; Medina, Tamara Nicol; Hafri, Alon; Gleitman, Lila R.

2012-01-01

We report three eyetracking experiments that examine the learning procedure used by adults as they pair novel words and visually presented referents over a sequence of referentially ambiguous trials. Successful learning under such conditions has been argued to be the product of a learning procedure in which participants provisionally pair each novel word with several possible referents and use a statistical-associative learning mechanism to gradually converge on a single mapping across learning instances. We argue here that successful learning in this setting is instead the product of a one-trial procedure in which a single hypothesized word-referent pairing is retained across learning instances, abandoned only if the subsequent instance fails to confirm the pairing – more a ‘fast mapping’ procedure than a gradual statistical one. We provide experimental evidence for this Propose-but-Verify learning procedure via three experiments in which adult participants attempted to learn the meanings of nonce words cross-situationally under varying degrees of referential uncertainty. The findings, using both explicit (referent selection) and implicit (eye movement) measures, show that even in these artificial learning contexts, which are far simpler than those encountered by a language learner in a natural environment, participants do not retain multiple meaning hypotheses across learning instances. As we discuss, these findings challenge ‘gradualist’ accounts of word learning and are consistent with the known rapid course of vocabulary learning in a first language. PMID:23142693

Effects of Data Sampling on Graphical Depictions of Learning

ERIC Educational Resources Information Center

Carey, Mary-Katherine; Bourret, Jason C.

2014-01-01

Continuous and discontinuous data-collection methods were compared in the context of discrete-trial programming. Archival data sets were analyzed using trial sampling (1st 5 trials, 1st 3 trials, and 1st trial only) and session sampling (every other session, every 3rd session, and every 5th session). Results showed that trial sampling…

Assessing sample representativeness in randomized controlled trials: application to the National Institute of Drug Abuse Clinical Trials Network.

PubMed

Susukida, Ryoko; Crum, Rosa M; Stuart, Elizabeth A; Ebnesajjad, Cyrus; Mojtabai, Ramin

2016-07-01

To compare the characteristics of individuals participating in randomized controlled trials (RCTs) of treatments of substance use disorder (SUD) with individuals receiving treatment in usual care settings, and to provide a summary quantitative measure of differences between characteristics of these two groups of individuals using propensity score methods. Design Analyses using data from RCT samples from the National Institute of Drug Abuse Clinical Trials Network (CTN) and target populations of patients drawn from the Treatment Episodes Data Set-Admissions (TEDS-A). Settings Multiple clinical trial sites and nation-wide usual SUD treatment settings in the United States. A total of 3592 individuals from 10 CTN samples and 1 602 226 individuals selected from TEDS-A between 2001 and 2009. Measurements The propensity scores for enrolling in the RCTs were computed based on the following nine observable characteristics: sex, race/ethnicity, age, education, employment status, marital status, admission to treatment through criminal justice, intravenous drug use and the number of prior treatments. Findings The proportion of those with ≥ 12 years of education and the proportion of those who had full-time jobs were significantly higher among RCT samples than among target populations (in seven and nine trials, respectively, at P < 0.001). The pooled difference in the mean propensity scores between the RCTs and the target population was 1.54 standard deviations and was statistically significant at P < 0.001. In the United States, individuals recruited into randomized controlled trials of substance use disorder treatments appear to be very different from individuals receiving treatment in usual care settings. Notably, RCT participants tend to have more years of education and a greater likelihood of full-time work compared with people receiving care in usual care settings. © 2016 Society for the Study of Addiction.

Capecitabine pattern of usage, rate of febrile neutropaenia and treatment related death in asian cancer patients in clinical practice.

PubMed

Phua, Vincent Chee Ee; Wong, Wei Quan; Tan, Pei Lin; Bustam, Anita Zarina; Saad, Marniza; Alip, Adlinda; Wan Ishak, Wan Zamaniah

2015-01-01

Oral capecitabine is increasingly replacing intravenous 5-fluorouracil in many chemotherapy regimens. However, data on the risk of febrile neutropaenia (FN) and treatment related death (TRD) with the drug remain sparse outside of clinical trial settings despite its widespread usage. This study aimed to determine these rates in a large cohort of patients treated in the University of Malaya Medical Centre (UMMC). We reviewed the clinical notes of all patients prescribed with oral capecitabine chemotherapy for any tumour sites in University Malaya Medical Centre (UMMC) from 1st January 2009 till 31st June 2010. Information collected included patient demographics, histopathological features, treatment received including the different chemotherapy regimens and intent of treatment whether the chemotherapy was given for neoadjuvant, concurrent with radiation, adjuvant or palliative intent. The aim of this study is to establish the pattern of usage, FN and TRD rates with capecitabine in clinical practice outside of clinical trial setting. FN is defined as an oral temperature >38.5°or two consecutive readings of >38.0° for 2 hours and an absolute neutrophil count <0.5 x 109/L, or expected to fall below 0.5 x 109/L (de Naurois et al., 2010). Treatment related death was defined as death occurring during or within 30 days of last chemotherapy treatment. Between 1st January 2009 and 30th June 2010, 274 patients were treated with capecitabine chemotherapy in UMMC. The mean age was 58 years (range 22 to 82 years). Capecitabine was used in 14 different tumour sites with the colorectal site predominating with a total of 128 cases (46.7%), followed by breast cancer (35.8%). Capecitabine was most commonly used in the palliative setting accounting for 63.9% of the cases, followed by the adjuvant setting (19.7%). The most common regimen was single agent capecitabine with 129 cases (47.1%). The other common regimens were XELOX (21.5%) and ECX (10.2%). The main result of this study showed an overall FN rate of 2.2% (6/274). The overall TRD rate was 5.1% (14/274). The FN rate for the single agent capecitabine regimen was 1.6% (2/129) and the TRD rate was 5.4% (7/129). All the TRDs were with single agent capecitabine regimen were used for palliative intent. Oral capecitabine is used widely in clinical practice in a myriad of tumour sites and bears a low risk of febrile neutropaenia. However, capecitabine like any other intravenous chemotherapeutic agent carries a significant risk of treatment related death.

Using Single-trial EEG to Predict and Analyze Subsequent Memory

PubMed Central

Noh, Eunho; Herzmann, Grit; Curran, Tim; de Sa, Virginia R.

2013-01-01

We show that it is possible to successfully predict subsequent memory performance based on single-trial EEG activity before and during item presentation in the study phase. Two-class classification was conducted to predict subsequently remembered vs. forgotten trials based on subjects’ responses in the recognition phase. The overall accuracy across 18 subjects was 59.6 % by combining pre- and during-stimulus information. The single-trial classification analysis provides a dimensionality reduction method to project the high-dimensional EEG data onto a discriminative space. These projections revealed novel findings in the pre- and during-stimulus period related to levels of encoding. It was observed that the pre-stimulus information (specifically oscillatory activity between 25–35Hz) −300 to 0 ms before stimulus presentation and during-stimulus alpha (7–12 Hz) information between 1000–1400 ms after stimulus onset distinguished between recollection and familiarity while the during-stimulus alpha information and temporal information between 400–800 ms after stimulus onset mapped these two states to similar values. PMID:24064073

Outpatient 60-hour day-and-night glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or sensor-augmented pump therapy in adults with type 1 diabetes: An open-label, randomised, crossover, controlled trial.

PubMed

Haidar, Ahmad; Messier, Virginie; Legault, Laurent; Ladouceur, Martin; Rabasa-Lhoret, Rémi

2017-05-01

To assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared to the single-hormone (insulin alone) artificial pancreas in outpatient settings during the day and night. In a randomized, three-way, crossover trial we compared the dual-hormone artificial pancreas, the single-hormone artificial pancreas and sensor-augmented pump therapy (control) in 23 adults with type 1 diabetes. Each intervention was applied from 8 AM Day 1 to 8 PM Day 3 (60 hours) in outpatient free-living conditions. The primary outcome was time spent with sensor glucose levels below 4.0 mmol/L. A P value of less than .017 was regarded as significant. The median difference between the dual-hormone system and the single-hormone system was -2.3% (P = .072) for time spent below 4.0 mmol/L, -1.3% (P = .017) for time below 3.5 mmol/L, and -0.7% (P = .031) for time below 3.3 mmol/L. Both systems reduced (P < .017) hypoglycaemia below 4.0, 3.5 and 3.3 mmol/L compared to control therapy, but reductions were larger with the dual-hormone system than with the single-hormone system (medians -4.0% vs -3.4% for 4.0 mmol/L; -2.7% vs -2.2% for 3.5 mmol/L; and -2.2% vs -1.2% for 3.3 mmol/L). There were 34 hypoglycaemic events (<3.0 mmol/L for 20 minutes) with control therapy, 14 with the single-hormone system and 6 with the dual-hormone system. These differences in hypoglycaemia were observed while mean glucose level was low and comparable in all interventions (P = NS). The dual-hormone artificial pancreas had the lowest risk of hypoglycaemia, but the differences were not statistically significant. Larger studies are needed. © 2017 John Wiley & Sons Ltd.

Rapid decrement in the effects of the Ponzo display dissociates action and perception.

PubMed

Whitwell, Robert L; Buckingham, Gavin; Enns, James T; Chouinard, Philippe A; Goodale, Melvyn A

2016-08-01

It has been demonstrated that pictorial illusions have a smaller influence on grasping than they do on perceptual judgments. Yet to date this work has not considered the reduced influence of an illusion as it is measured repeatedly. Here we studied this decrement in the context of a Ponzo illusion to further characterize the dissociation between vision for perception and for action. Participants first manually estimated the lengths of single targets in a Ponzo display with their thumb and index finger, then actually grasped these targets in another series of trials, and then manually estimated the target lengths again in a final set of trials. The results showed that although the perceptual estimates and grasp apertures were equally sensitive to real differences in target length on the initial trials, only the perceptual estimates remained biased by the illusion over repeated measurements. In contrast, the illusion's effect on the grasps decreased rapidly, vanishing entirely after only a few trials. Interestingly, a closer examination of the grasp data revealed that this initial effect was driven largely by undersizing the grip aperture for the display configuration in which the target was positioned between the diverging background lines (i.e., when the targets appeared to be shorter than they really were). This asymmetry between grasping apparently shorter and longer targets suggests that the sensorimotor system may initially treat the edges of the configuration as obstacles to be avoided. This finding highlights the sensorimotor system's ability to rapidly update motor programs through error feedback, manifesting as an immunity to the effects of illusion displays even after only a few trials.

Modulation of Complex-Spike Duration and Probability during Cerebellar Motor Learning in Visually Guided Smooth-Pursuit Eye Movements of Monkeys

PubMed Central

2017-01-01

Abstract Activation of an inferior olivary neuron powerfully excites Purkinje cells via its climbing fiber input and triggers a characteristic high-frequency burst, known as the complex spike (CS). The theory of cerebellar learning postulates that the CS induces long-lasting depression of the strength of synapses from active parallel fibers onto Purkinje cells, and that synaptic depression leads to changes in behavior. Prior reports showed that a CS on one learning trial is linked to a properly timed depression of simple spikes on the subsequent trial, as well as a learned change in pursuit eye movement. Further, the duration of a CS is a graded instruction for single-trial plasticity and behavioral learning. We now show across multiple learning paradigms that both the probability and duration of CS responses are correlated with the magnitudes of neural and behavioral learning in awake behaving monkeys. When the direction of the instruction for learning repeatedly was in the same direction or alternated directions, the duration and probability of CS responses decreased over a learning block along with the magnitude of trial-over-trial neural learning. When the direction of the instruction was randomized, CS duration, CS probability, and neural and behavioral learning remained stable across time. In contrast to depression, potentiation of simple-spike firing rate for ON-direction learning instructions follows a longer time course and plays a larger role as depression wanes. Computational analysis provides a model that accounts fully for the detailed statistics of a complex set of data. PMID:28698888

Determination of the optimal sample size for a clinical trial accounting for the population size.

PubMed

Stallard, Nigel; Miller, Frank; Day, Simon; Hee, Siew Wan; Madan, Jason; Zohar, Sarah; Posch, Martin

2017-07-01

The problem of choosing a sample size for a clinical trial is a very common one. In some settings, such as rare diseases or other small populations, the large sample sizes usually associated with the standard frequentist approach may be infeasible, suggesting that the sample size chosen should reflect the size of the population under consideration. Incorporation of the population size is possible in a decision-theoretic approach either explicitly by assuming that the population size is fixed and known, or implicitly through geometric discounting of the gain from future patients reflecting the expected population size. This paper develops such approaches. Building on previous work, an asymptotic expression is derived for the sample size for single and two-arm clinical trials in the general case of a clinical trial with a primary endpoint with a distribution of one parameter exponential family form that optimizes a utility function that quantifies the cost and gain per patient as a continuous function of this parameter. It is shown that as the size of the population, N, or expected size, N∗ in the case of geometric discounting, becomes large, the optimal trial size is O(N1/2) or O(N∗1/2). The sample size obtained from the asymptotic expression is also compared with the exact optimal sample size in examples with responses with Bernoulli and Poisson distributions, showing that the asymptotic approximations can also be reasonable in relatively small sample sizes. © 2016 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Collaborative Research in Childhood Cancer Survivorship: The Current Landscape

PubMed Central

Bhatia, Smita; Armenian, Saro H.; Armstrong, Gregory T.; van Dulmen-den Broeder, Eline; Hawkins, Michael M.; Kremer, Leontien C.M.; Kuehni, Claudia E.; Olsen, Jørgen H.; Robison, Leslie L.; Hudson, Melissa M.

2015-01-01

Survivors of childhood cancer carry a substantial burden of morbidity and are at increased risk for premature death. Furthermore, clear associations exist between specific therapeutic exposures and the risk for a variety of long-term complications. The entire landscape of health issues encountered for decades after successful completion of treatment is currently being explored in various collaborative research settings. These settings include large population-based or multi-institutional cohorts and single-institution studies. The ascertainment of outcomes has depended on self-reporting, linkage to registries, or clinical assessments. Survivorship research in the cooperative group setting, such as the Children's Oncology Group, has leveraged the clinical trials infrastructure to explore the molecular underpinnings of treatment-related adverse events, and to understand specific complications in the setting of randomized risk-reduction strategies. This review highlights the salient findings from these large collaborative initiatives, emphasizing the need for life-long follow-up of survivors of childhood cancer, and describing the development of several guidelines and efforts toward harmonization. Finally, the review reinforces the need to identify populations at highest risk, facilitating the development of risk prediction models that would allow for targeted interventions across the entire trajectory of survivorship. PMID:26304891

Task-set inertia and memory-consolidation bottleneck in dual tasks.

PubMed

Koch, Iring; Rumiati, Raffaella I

2006-11-01

Three dual-task experiments examined the influence of processing a briefly presented visual object for deferred verbal report on performance in an unrelated auditory-manual reaction time (RT) task. RT was increased at short stimulus-onset asynchronies (SOAs) relative to long SOAs, showing that memory consolidation processes can produce a functional processing bottleneck in dual-task performance. In addition, the experiments manipulated the spatial compatibility of the orientation of the visual object and the side of the speeded manual response. This cross-task compatibility produced relative RT benefits only when the instruction for the visual task emphasized overlap at the level of response codes across the task sets (Experiment 1). However, once the effective task set was in place, it continued to produce cross-task compatibility effects even in single-task situations ("ignore" trials in Experiment 2) and when instructions for the visual task did not explicitly require spatial coding of object orientation (Experiment 3). Taken together, the data suggest a considerable degree of task-set inertia in dual-task performance, which is also reinforced by finding costs of switching task sequences (e.g., AC --> BC vs. BC --> BC) in Experiment 3.

77 FR 6879 - Rules of Practice for Trials Before the Patent Trial and Appeal Board and Judicial Review of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-09

...The United States Patent and Trademark Office (Office or USPTO) proposes new rules of practice to implement the provisions of the Leahy-Smith America Invents Act that provide for trials before the Patent Trial and Appeal Board (Board). The proposed rules would provide a consolidated set of rules relating to Board trial practice for inter partes review, post-grant review, the transitional program for covered business method patents, and derivation proceedings. The proposed rules would also provide a consolidated set of rules to implement the provisions of the Leahy-Smith America Invents Act related to seeking judicial review of Board decisions.

Home telemonitoring of non-invasive ventilation decreases healthcare utilisation in a prospective controlled trial of patients with amyotrophic lateral sclerosis.

PubMed

Pinto, Anabela; Almeida, José Pedro; Pinto, Susana; Pereira, João; Oliveira, António Gouveia; de Carvalho, Mamede

2010-11-01

Non-invasive ventilation (NIV) is an efficient method for treating respiratory failure in patients with amyotrophic lateral sclerosis (ALS). However, it requires a process of adaptation not always achieved due to poor compliance. The role of telemonitoring of NIV is not yet established. To test the advantage of using modem communication in NIV of ALS patients. Prospective, single blinded controlled trial. Population and methods According to their residence, 40 consecutive ventilated ALS patients were assigned to one of two groups: a control group (G1, n=20) in which compliance and ventilator parameter settings were assessed during office visits; or an intervention group (G2, n=20) in which patients received a modem device connected to the ventilator. The number of office and emergency room visits and hospital admissions during the entire span of NIV use and the number of parameter setting changes to achieve full compliance were the primary outcome measurements. Demographic and clinical features were similar between the two groups at admission. No difference in compliance was found between the groups. The incidence of changes in parameter settings throughout the survival period with NIV was lower in G2 (p<0.0001) but it was increased during the initial period needed to achieve full compliance. The number of office or emergency room visits and inhospital admissions was significantly lower in G2 (p<0.0001). Survival showed a trend favouring G2 (p=0.13). This study shows that telemonitoring reduces health care utilisation with probable favourable implications on costs, survival and functional status.

Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran.

PubMed

Lewis, J H; Larrey, D; Olsson, R; Lee, W M; Frison, L; Keisu, M

2008-07-01

Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

Therapist guided internet based cognitive behavioural therapy for body dysmorphic disorder: single blind randomised controlled trial

PubMed Central

Andersson, Erik; Mataix-Cols, David; Lichtenstein, Linn; Alström, Katarina; Andersson, Gerhard; Ljótsson, Brjánn; Rück, Christian

2016-01-01

Objectives To evaluate the efficacy of therapist guided internet based cognitive behavioural therapy (CBT) programme for body dysmorphic disorder (BDD-NET) compared with online supportive therapy. Design A 12 week single blind parallel group randomised controlled trial. Setting Academic medical centre. Participants 94 self referred adult outpatients with a diagnosis of body dysmorphic disorder and a modified Yale-Brown obsessive compulsive scale (BDD-YBOCS) score of ≥20. Concurrent psychotropic drug treatment was permitted if the dose had been stable for at least two months before enrolment and remained unchanged during the trial. Interventions Participants received either BDD-NET (n=47) or supportive therapy (n=47) delivered via the internet for 12 weeks. Main outcome measures The primary outcome was the BDD-YBOCS score after treatment and follow-up (three and six months from baseline) as evaluated by a masked assessor. Responder status was defined as a ≥30% reduction in symptoms on the scale. Secondary outcomes were measures of depression (MADRS-S), global functioning (GAF), clinical global improvement (CGI-I), and quality of life (EQ5D). The six month follow-up time and all outcomes other than BDD-YBOCS and MADRS-S at 3 months were not pre-specified in the registration at clinicaltrials.gov because of an administrative error but were included in the original trial protocol approved by the regional ethics committee before the start of the trial. Results BDD-NET was superior to supportive therapy and was associated with significant improvements in severity of symptoms of body dysmorphic disorder (BDD-YBOCS group difference −7.1 points, 95% confidence interval −9.8 to −4.4), depression (MADRS-S group difference −4.5 points, −7.5 to −1.4), and other secondary measures. At follow-up, 56% of those receiving BDD-NET were classed as responders, compared with 13% receiving supportive therapy. The number needed to treat was 2.34 (1.71 to 4.35). Self reported satisfaction was high. Conclusions CBT can be delivered safely via the internet to patients with body dysmorphic disorder. BDD-NET has the potential to increase access to evidence based psychiatric care for this mental disorder, in line with NICE priority recommendations. It could be particularly useful in a stepped care approach, in which general practitioner or other mental health professionals can offer treatment to people with mild to moderate symptoms at low risk of suicide. Trial registration ClinicalTrials.gov ID: NCT02010619. PMID:26837684

Evaluating Data Abstraction Assistant, a novel software application for data abstraction during systematic reviews: protocol for a randomized controlled trial.

PubMed

Saldanha, Ian J; Schmid, Christopher H; Lau, Joseph; Dickersin, Kay; Berlin, Jesse A; Jap, Jens; Smith, Bryant T; Carini, Simona; Chan, Wiley; De Bruijn, Berry; Wallace, Byron C; Hutfless, Susan M; Sim, Ida; Murad, M Hassan; Walsh, Sandra A; Whamond, Elizabeth J; Li, Tianjing

2016-11-22

Data abstraction, a critical systematic review step, is time-consuming and prone to errors. Current standards for approaches to data abstraction rest on a weak evidence base. We developed the Data Abstraction Assistant (DAA), a novel software application designed to facilitate the abstraction process by allowing users to (1) view study article PDFs juxtaposed to electronic data abstraction forms linked to a data abstraction system, (2) highlight (or "pin") the location of the text in the PDF, and (3) copy relevant text from the PDF into the form. We describe the design of a randomized controlled trial (RCT) that compares the relative effectiveness of (A) DAA-facilitated single abstraction plus verification by a second person, (B) traditional (non-DAA-facilitated) single abstraction plus verification by a second person, and (C) traditional independent dual abstraction plus adjudication to ascertain the accuracy and efficiency of abstraction. This is an online, randomized, three-arm, crossover trial. We will enroll 24 pairs of abstractors (i.e., sample size is 48 participants), each pair comprising one less and one more experienced abstractor. Pairs will be randomized to abstract data from six articles, two under each of the three approaches. Abstractors will complete pre-tested data abstraction forms using the Systematic Review Data Repository (SRDR), an online data abstraction system. The primary outcomes are (1) proportion of data items abstracted that constitute an error (compared with an answer key) and (2) total time taken to complete abstraction (by two abstractors in the pair, including verification and/or adjudication). The DAA trial uses a practical design to test a novel software application as a tool to help improve the accuracy and efficiency of the data abstraction process during systematic reviews. Findings from the DAA trial will provide much-needed evidence to strengthen current recommendations for data abstraction approaches. The trial is registered at National Information Center on Health Services Research and Health Care Technology (NICHSR) under Registration # HSRP20152269: https://wwwcf.nlm.nih.gov/hsr_project/view_hsrproj_record.cfm?NLMUNIQUE_ID=20152269&SEARCH_FOR=Tianjing%20Li . All items from the World Health Organization Trial Registration Data Set are covered at various locations in this protocol. Protocol version and date: This is version 2.0 of the protocol, dated September 6, 2016. As needed, we will communicate any protocol amendments to the Institutional Review Boards (IRBs) of Johns Hopkins Bloomberg School of Public Health (JHBSPH) and Brown University. We also will make appropriate as-needed modifications to the NICHSR website in a timely fashion.

Double gloves: a randomized trial to evaluate a simple strategy to reduce contamination in the operating room.

PubMed

Birnbach, David J; Rosen, Lisa F; Fitzpatrick, Maureen; Carling, Philip; Arheart, Kristopher L; Munoz-Price, L Silvia

2015-04-01

Oral flora, blood-borne pathogens, and bacterial contamination pose a direct risk of infection to patients and health care workers. We conducted a study in a simulated operating room using a newly validated technology to determine whether the use of 2 sets of gloves, with the outer set removed immediately after endotracheal intubation, may reduce this risk. Forty-one anesthesiology residents (PGY 2-4) were enrolled in a study consisting of individual or group simulation sessions. On entry to the simulated operating room, the residents were asked to perform an anesthetic induction and tracheal intubation timed to approximately 6 minutes; they were unaware of the study design. Of the 22 simulation sessions, 11 were conducted with the intubating resident wearing single gloves, and 11 with the intubating resident using double gloves with the outer pair removed after verified intubation. Before the start of the scenario, we coated the lips and inside of the mouth of the mannequin with a fluorescent marking gel as a surrogate pathogen. After the simulation, an observer examined 40 different sites using a handheld ultraviolet light in the operating room to determine the transfer of surrogate pathogens to the patient and the patient's environment. Residents who wore double gloves were instructed by a confederate nurse to remove the outer set immediately after completion of the intubation. Forty sites of potential intraoperative pathogen spread were identified and assigned a score. The difference in the rate of contamination between anesthesiology residents who wore single gloves versus those with double gloves was clinically and statistically significant. The number of sites that were contaminated in the operating room when the intubating resident wore single gloves was 20.3 ± 1.4 (mean ± SE); the number of contaminated sites when residents wore double gloves was 5.0 ± 0.7 (P < 0.001). The results of this study suggest that when an anesthesiologist wears 2 sets of gloves during laryngoscopy and intubation and then removes the outer set immediately after intubation, the contamination of the intraoperative environment is dramatically reduced.

Feasibility, Process, and Outcomes of Cardiovascular Clinical Trial Data Sharing: A Reproduction Analysis of the SMART-AF Trial.

PubMed

Gay, Hawkins C; Baldridge, Abigail S; Huffman, Mark D

2017-12-01

Data sharing is as an expanding initiative for enhancing trust in the clinical research enterprise. To evaluate the feasibility, process, and outcomes of a reproduction analysis of the THERMOCOOL SMARTTOUCH Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation (SMART-AF) trial using shared clinical trial data. A reproduction analysis of the SMART-AF trial was performed using the data sets, data dictionary, case report file, and statistical analysis plan from the original trial accessed through the Yale Open Data Access Project using the SAS Clinical Trials Data Transparency platform. SMART-AF was a multicenter, single-arm trial evaluating the effectiveness and safety of an irrigated, contact force-sensing catheter for ablation of drug refractory, symptomatic paroxysmal atrial fibrillation in 172 participants recruited from 21 sites between June 2011 and December 2011. Analysis of the data was conducted between December 2016 and April 2017. Effectiveness outcomes included freedom from atrial arrhythmias after ablation and proportion of participants without any arrhythmia recurrence over the 12 months of follow-up after a 3-month blanking period. Safety outcomes included major adverse device- or procedure-related events. The SMART AF trial participants' mean age was 58.7 (10.8) years, and 72% were men. The time from initial proposal submission to final analysis was 11 months. Freedom from atrial arrhythmias at 12 months postprocedure was similar compared with the primary study report (74.0%; 95% CI, 66.0-82.0 vs 76.4%; 95% CI, 68.7-84.1). The reproduction analysis success rate was higher than the primary study report (65.8%; 95% CI 56.5-74.2 vs 75.6%; 95% CI, 67.2-82.5). Adverse events were minimal and similar between the 2 analyses, but contact force range or regression models could not be reproduced. The feasibility of a reproduction analysis of the SMART-AF trial was demonstrated through an academic data-sharing platform. Data sharing can be facilitated through incentivizing collaboration, sharing statistical code, and creating more decentralized data sharing platforms with fewer restrictions to data access.

Robust inference for group sequential trials.

PubMed

Ganju, Jitendra; Lin, Yunzhi; Zhou, Kefei

2017-03-01

For ethical reasons, group sequential trials were introduced to allow trials to stop early in the event of extreme results. Endpoints in such trials are usually mortality or irreversible morbidity. For a given endpoint, the norm is to use a single test statistic and to use that same statistic for each analysis. This approach is risky because the test statistic has to be specified before the study is unblinded, and there is loss in power if the assumptions that ensure optimality for each analysis are not met. To minimize the risk of moderate to substantial loss in power due to a suboptimal choice of a statistic, a robust method was developed for nonsequential trials. The concept is analogous to diversification of financial investments to minimize risk. The method is based on combining P values from multiple test statistics for formal inference while controlling the type I error rate at its designated value.This article evaluates the performance of 2 P value combining methods for group sequential trials. The emphasis is on time to event trials although results from less complex trials are also included. The gain or loss in power with the combination method relative to a single statistic is asymmetric in its favor. Depending on the power of each individual test, the combination method can give more power than any single test or give power that is closer to the test with the most power. The versatility of the method is that it can combine P values from different test statistics for analysis at different times. The robustness of results suggests that inference from group sequential trials can be strengthened with the use of combined tests. Copyright © 2017 John Wiley & Sons, Ltd.

Design and Recruitment for a Randomized Controlled Trial of Problem-Solving Therapy to Prevent Depression among Older Adults with Need for Supportive Services.

PubMed

Albert, Steven M; King, Jennifer; Dew, Mary Amanda; Begley, Amy; Anderson, Stewart; Karp, Jordan; Gildengers, Ari; Butters, Meryl; Reynolds, Charles F

2016-01-01

Addressing subthreshold depression (indicated prevention) and vulnerabilities that increase the risk of major depression or anxiety disorders (selective prevention) is important for protecting mental health in old age. The Depression-Agency Based Collaborative (Dep-ABC) is a prevention trial involving older adults recruited from aging services sites (home care agencies, senior housing, senior centers) who meet criteria for subthreshold depression and disability. Therefore, the authors examine the effectiveness of partnerships with aging services sites for recruiting at-risk older adults, the quality of recruitment and acceptability of the Dep-ABC assessment and intervention, and the baseline status of participants. Dep-ABC is a single-blind randomized controlled prevention trial set in aging services settings but with centralized screening, randomization, in-home assessments, and follow-up. Its intervention arm involves six to eight sessions of problem-solving therapy, in which older adults aged 60+ learn to break down problems that affect well-being and develop strategies to address them. We examined participation rates to assess quality of recruitment across sites and level of disability according to service use. Dep-ABC randomized 104 participants, 68.4% of eligible older adults. Screening using self-reported disability successfully netted a sample in which 74% received home care agency services, with remaining participants similarly impaired in structured self-reports of impairment and on observed performance tests. Direct outreach to aging services providers is an effective way to identify older adults with service needs at high risk of major depression. Problem-solving therapy is acceptable to this population and can be added to current services. Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Design of a Cluster-Randomized Controlled Trial of a Diabetes Prevention Program within African-American Churches: The Fit Body and Soul Study

PubMed Central

Williams, Lovoria B.; Sattin, Richard W.; Dias, James; Garvin, Jane T.; Marion, Lucy; Joshua, Thomas; Kriska, Andrea; Kramer, M. Kaye; Echouffo-Tcheugui, Justin B.; Freeman, Arin; Narayan, K.M. Venkat

2013-01-01

Evidence from varied community settings has shown that the Group Lifestyle Balance (GLB) Program and other adaptations of the Diabetes Prevention Program (DPP) intervention are effective in lowering diabetes risk. Most DPP data originated from studies of pre-diabetic whites, with only sparse evidence of the effect of DPP in African Americans (AAs) in community settings. This paper describes the design, methods, baseline characteristics and cost effective measures, of a single-blinded, cluster- randomized trial of a faith-based adaptation of the GLB program, Fit Body and Soul (FBAS). The major aims are to test efficacy and cost utility of FBAS in twenty AA churches. Randomization occurred at the church level and 604 AA overweight/obese (BMI≥25 kg/m2) adults with fasting plasma glucose range from normal to pre-diabetic received either FBAS or a health-education comparison program. FBAS is a group-based, multi-level intervention delivered by trained church health advisors (health professionals from within the church), with the goal of ≥7% weight loss, achieved through increasing physical activity, healthy eating and behavior modification. The primary outcome is weight change at 12-weeks post intervention. Secondary outcomes include hemoglobin A1C, fasting plasma glucose, waist circumference, blood pressure, physical activity level, quality of life measures, and cost-effectiveness. FBAS is the largest known cohort of AAs enrolled in a faith-based DPP translation. Reliance on health professionals from within the church for program implementation and the cost analysis are unique aspects of this trial. The design provides a model for faith-based DPPs and holds promise for program sustainability and widespread dissemination. PMID:23354313

Soil-strain compatibility: the key to effective use of arbuscular mycorrhizal inoculants?

PubMed

Herrera-Peraza, Ricardo A; Hamel, Chantal; Fernández, Félix; Ferrer, Roberto L; Furrazola, Eduardo

2011-04-01

Consistency of response to arbuscular mycorrhizal (AM) inoculation is required for efficient use of AM fungi in plant production. Here, we found that the response triggered in plants by an AM strain depends on the properties of the soil where it is introduced. Two data sets from 130 different experiments assessing the outcome of a total of 548 replicated single inoculation trials conducted either in soils with a history of (1) high input agriculture (HIA; 343 replicated trials) or (2) in more pristine soils from coffee plantations (CA; 205 replicated trials) were examined. Plant response to inoculation with different AM strains in CA soils planted with coffee was related to soil properties associated with soil types. The strains Glomus fasciculatum-like and Glomus etunicatum-like were particularly performant in soil relatively rich in nutrients and organic matter. Paraglomus occultum and Glomus mosseae-like performed best in relatively poor soils, and G. mosseae and Glomus manihotis did best in soils of medium fertility. Acaulospora scrobiculata, Diversispora spurca, G. mosseae-like, G. mosseae and P. occultum stimulated coffee growth best in Chromic, Eutric Alluvial Cambisol, G. fasciculatum-like and G. etunicatum-like in Calcaric Cambisol and G. manihotis, in Chromic, Eutric Cambisols. Acaulospora scrobiculata and Diversispora spurca strains performed best in Chromic Alisols and Rodic Ferralsols. There was no significant relationship between plant response to AM fungal strains and soil properties in the HIA soil data set, may be due to variation induced by the use of different host plant species and to modification of soil properties by a history of intensive production. Consideration of the performance of AM fungal strains in target soil environments may well be the key for efficient management of the AM symbiosis in plant production.

Design and Recruitment for a Randomized Controlled Trial of Problem Solving Therapy to Prevent Depression among Older Adults with Need for Supportive Services

PubMed Central

Albert, Steven M.; King, Jennifer; Dew, Mary Amanda; Begley, Amy; Anderson, Stewart; Karp, Jordan; Gildengers, Ari; Butters, Meryl; Reynolds, Charles F.

2015-01-01

Background Addressing subthreshold depression (indicated prevention) as well as vulnerabilities that increase the risk of major depression or anxiety disorders (selective prevention) is important for protecting mental health in old age. The Depression-Agency Based Collaborative is a prevention trial involving older adults recruited from aging services sites (home care agencies, senior housing senior centers) who meet criteria for subthreshold depression and disability. Objective To examine (i) the effectiveness of partnerships with aging services sites for recruiting at-risk older adults, (ii) the quality of recruitment and acceptability of the Dep-ABC assessment and intervention, and (iii) the baseline status of participants. Methods Dep-ABC is a single-blind randomized controlled prevention trial set in aging services settings but with centralized screening, randomization, in-home assessments, and follow-up. Its intervention arm involves 6–8 sessions of problem-solving therapy, in which older adults aged 60+ learn to break down problems that affect wellbeing and develop strategies to address them. We examined participation rates to assess quality of recruitment across sites and level of disability according to service use. Results Dep-ABC randomized 104 participants, 68.4% of eligible older adults. Screening using self-reported disability successfully netted a sample in which 74% received home care agency services, with remaining participants similarly impaired in structured self-reports of impairment and on observed performance tests. Conclusions Direct outreach to aging services providers is an effective way to identify older adults with service needs at high risk of major depression. Problem solving therapy is acceptable to this population and can be added to current services. PMID:26706911

Transfusion of irradiated red blood cell units with a potassium adsorption filter: A randomized controlled trial.

PubMed

Cid, Joan; Villegas, Vanessa; Carbassé, Gloria; Alba, Cristina; Perea, Dolores; Lozano, Miguel

2016-05-01

The irradiation of red blood cells (RBCs) causes damage of the RBC membrane with increased potassium (K) leak during storage compared with nonirradiated RBC units of similar age. A previous in vitro study showed a mean reduction of K of 94 ± 5% with a potassium adsorption filter (PAF). A prospective, single-center, nonblinded, randomized controlled trial (RCT) was designed to evaluate the safety and efficacy of transfusing irradiated RBC units with the PAF. Patients 18 years of age or older who received irradiated RBC units due to chemotherapy-induced anemia were randomly assigned to receive irradiated RBC units with the PAF (PAF group) or with the standard blood infusion set (control group). Primary outcome measures were safety and efficacy of the PAF (absolute change in hemoglobin [Hb] and K, respectively, in patient's blood values after transfusing the irradiated RBC units with or without the PAF). A total of 63 irradiated RBC units were transfused to 17 patients in the control group, and a total of 56 irradiated RBC units were transfused to 13 patients in the PAF group. The absolute change of Hb (9.3 ± 6.3 g/L vs. 8.1 ± 5.8 g/L; p = 0.3) and the absolute change of K (-0.01 ± 0.4 mmol/L vs. -0.01 ± 0.3 mmol/L; p = 0.2) were comparable between the two groups of the trial. The transfusion of 1 irradiated RBC unit with the PAF was as safe and efficacious as the transfusion of 1 irradiated RBC unit with the standard blood infusion set in patients with chemotherapy-induced anemia. © 2016 AABB.

An automated approach towards detecting complex behaviours in deep brain oscillations.

PubMed

Mace, Michael; Yousif, Nada; Naushahi, Mohammad; Abdullah-Al-Mamun, Khondaker; Wang, Shouyan; Nandi, Dipankar; Vaidyanathan, Ravi

2014-03-15

Extracting event-related potentials (ERPs) from neurological rhythms is of fundamental importance in neuroscience research. Standard ERP techniques typically require the associated ERP waveform to have low variance, be shape and latency invariant and require many repeated trials. Additionally, the non-ERP part of the signal needs to be sampled from an uncorrelated Gaussian process. This limits methods of analysis to quantifying simple behaviours and movements only when multi-trial data-sets are available. We introduce a method for automatically detecting events associated with complex or large-scale behaviours, where the ERP need not conform to the aforementioned requirements. The algorithm is based on the calculation of a detection contour and adaptive threshold. These are combined using logical operations to produce a binary signal indicating the presence (or absence) of an event with the associated detection parameters tuned using a multi-objective genetic algorithm. To validate the proposed methodology, deep brain signals were recorded from implanted electrodes in patients with Parkinson's disease as they participated in a large movement-based behavioural paradigm. The experiment involved bilateral recordings of local field potentials from the sub-thalamic nucleus (STN) and pedunculopontine nucleus (PPN) during an orientation task. After tuning, the algorithm is able to extract events achieving training set sensitivities and specificities of [87.5 ± 6.5, 76.7 ± 12.8, 90.0 ± 4.1] and [92.6 ± 6.3, 86.0 ± 9.0, 29.8 ± 12.3] (mean ± 1 std) for the three subjects, averaged across the four neural sites. Furthermore, the methodology has the potential for utility in real-time applications as only a single-trial ERP is required. Copyright © 2013 Elsevier B.V. All rights reserved.

Does recruitment source moderate treatment effectiveness? A subgroup analysis from the EVIDENT study, a randomised controlled trial of an internet intervention for depressive symptoms.

PubMed

Klein, Jan Philipp; Gamon, Carla; Späth, Christina; Berger, Thomas; Meyer, Björn; Hohagen, Fritz; Hautzinger, Martin; Lutz, Wolfgang; Vettorazzi, Eik; Moritz, Steffen; Schröder, Johanna

2017-07-13

This study aims to examine whether the effects of internet interventions for depression generalise to participants recruited in clinical settings. This study uses subgroup analysis of the results of a randomised, controlled, single-blind trial. The study takes place in five diagnostic centres in Germany. A total of 1013 people with mild to moderate depressive symptoms were recruited from clinical sources as well as internet forums, statutory insurance companies and other sources. This study uses either care-as-usual alone (control) or a 12-week internet intervention (Deprexis) plus usual care (intervention). The primary outcome measure was self-rated depression severity (Patient Health Questionnaire-9) at 3 months and 6 months. Further measures ranged from demographic and clinical parameters to a measure of attitudes towards internet interventions (Attitudes towards Psychological Online Interventions Questionnaire). The recruitment source was only associated with very few of the examined demographic and clinical characteristics. Compared with participants recruited from clinical sources, participants recruited through insurance companies were more likely to be employed. Clinically recruited participants were as severely affected as those from other recruitment sources but more sceptical of internet interventions. The effectiveness of the intervention was not differentially associated with recruitment source (treatment by recruitment source interaction=0.28, p=0.84). Our results support the hypothesis that the intervention we studied is effective across different recruitment sources including clinical settings. ClinicalTrials.gov NCT01636752. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of circuit low-intensity resistance exercise with slow movement on oxygen consumption during and after exercise.

PubMed

Mukaimoto, Takahiro; Ohno, Makoto

2012-01-01

The purpose of this study was to examine oxygen consumption (VO(2)) during and after a single bout of low-intensity resistance exercise with slow movement. Eleven healthy men performed the following three types of circuit resistance exercise on separate days: (1) low-intensity resistance exercise with slow movement: 50% of one-repetition maximum (1-RM) and 4 s each of lifting and lowering phases; (2) high-intensity resistance exercise with normal movement: 80% of 1-RM and 1 s each of lifting and lowering phases; and (3) low-intensity resistance exercise with normal movement: 50% of 1-RM and 1 s each of lifting and lowering phases. These three resistance exercise trials were performed for three sets in a circuit pattern with four exercises, and the participants performed each set until exhaustion. Oxygen consumption was monitored continuously during exercise and for 180 min after exercise. Average VO(2) throughout the exercise session was significantly higher with high- and low-intensity resistance exercise with normal movement than with low-intensity resistance exercise with slow movement (P < 0.05); however, total VO(2) was significantly greater in low-intensity resistance exercise with slow movement than in the other trials. In contrast, there were no significant differences in the total excess post-exercise oxygen consumption among the three exercise trials. The results of this study suggest that low-intensity resistance exercise with slow movement induces much greater energy expenditure than resistance exercise with normal movement of high or low intensity, and is followed by the same total excess post-exercise oxygen consumption for 180 min after exercise.

Influence of single particle orbital sets and configuration selection on multideterminant wavefunctions in quantum Monte Carlo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clay, Raymond C.; Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94550; Morales, Miguel A., E-mail: moralessilva2@llnl.gov

2015-06-21

Multideterminant wavefunctions, while having a long history in quantum chemistry, are increasingly being used in highly accurate quantum Monte Carlo calculations. Since the accuracy of QMC is ultimately limited by the quality of the trial wavefunction, multi-Slater determinants wavefunctions offer an attractive alternative to Slater-Jastrow and more sophisticated wavefunction ansatz for several reasons. They can be efficiently calculated, straightforwardly optimized, and systematically improved by increasing the number of included determinants. In spite of their potential, however, the convergence properties of multi-Slater determinant wavefunctions with respect to orbital set choice and excited determinant selection are poorly understood, which hinders the applicationmore » of these wavefunctions to large systems and solids. In this paper, by performing QMC calculations on the equilibrium and stretched carbon dimer, we find that convergence of the recovered correlation energy with respect to number of determinants can depend quite strongly on basis set and determinant selection methods, especially where there is strong correlation. We demonstrate that properly chosen orbital sets and determinant selection techniques from quantum chemistry methods can dramatically reduce the required number of determinants (and thus the computational cost) to reach a given accuracy, which we argue shows clear need for an automatic QMC-only method for selecting determinants and generating optimal orbital sets.« less

Comparison of the benefits of cochlear implantation versus contra-lateral routing of signal hearing aids in adult patients with single-sided deafness: study protocol for a prospective within-subject longitudinal trial

PubMed Central

2014-01-01

Background Individuals with a unilateral severe-to-profound hearing loss, or single-sided deafness, report difficulty with listening in many everyday situations despite having access to well-preserved acoustic hearing in one ear. The standard of care for single-sided deafness available on the UK National Health Service is a contra-lateral routing of signals hearing aid which transfers sounds from the impaired ear to the non-impaired ear. This hearing aid has been found to improve speech understanding in noise when the signal-to-noise ratio is more favourable at the impaired ear than the non-impaired ear. However, the indiscriminate routing of signals to a single ear can have detrimental effects when interfering sounds are located on the side of the impaired ear. Recent published evidence has suggested that cochlear implantation in individuals with a single-sided deafness can restore access to the binaural cues which underpin the ability to localise sounds and segregate speech from other interfering sounds. Methods/Design The current trial was designed to assess the efficacy of cochlear implantation compared to a contra-lateral routing of signals hearing aid in restoring binaural hearing in adults with acquired single-sided deafness. Patients are assessed at baseline and after receiving a contra-lateral routing of signals hearing aid. A cochlear implant is then provided to those patients who do not receive sufficient benefit from the hearing aid. This within-subject longitudinal design reflects the expected care pathway should cochlear implantation be provided for single-sided deafness on the UK National Health Service. The primary endpoints are measures of binaural hearing at baseline, after provision of a contra-lateral routing of signals hearing aid, and after cochlear implantation. Binaural hearing is assessed in terms of the accuracy with which sounds are localised and speech is perceived in background noise. The trial is also designed to measure the impact of the interventions on hearing- and health-related quality of life. Discussion This multi-centre trial was designed to provide evidence for the efficacy of cochlear implantation compared to the contra-lateral routing of signals. A purpose-built sound presentation system and established measurement techniques will provide reliable and precise measures of binaural hearing. Trial registration Current Controlled Trials http://www.controlled-trials.com/ISRCTN33301739 (05/JUL/2013) PMID:25152694

Theory-based interventions for contraception.

PubMed

Lopez, Laureen M; Tolley, Elizabeth E; Grimes, David A; Chen-Mok, Mario

2011-03-16

The explicit use of theory in research helps expand the knowledge base. Theories and models have been used extensively in HIV-prevention research and in interventions for preventing sexually transmitted infections (STIs). The health behavior field uses many theories or models of change. However, educational interventions addressing contraception often have no stated theoretical base. Review randomized controlled trials (RCTs) that tested a theoretical approach to inform contraceptive choice; encourage contraceptive use; or promote adherence to, or continuation of, a contraceptive regimen. We searched computerized databases for trials that tested a theory-based intervention for improving contraceptive use (MEDLINE, POPLINE, CENTRAL, PsycINFO, EMBASE, ClinicalTrials.gov, and ICTRP). We also wrote to researchers to find other trials. Trials tested a theory-based intervention for improving contraceptive use. We excluded trials focused on high-risk groups and preventing sexually transmitted infections or HIV. Interventions addressed the use of one or more contraceptive methods for contraception. The reports provided evidence that the intervention was based on a specific theory or model. The primary outcomes were pregnancy, contraceptive choice, initiating or changing contraceptive use, contraceptive regimen adherence, and contraception continuation. The primary author evaluated abstracts for eligibility. Two authors extracted data from included studies. We calculated the odds ratio for dichotomous outcomes. No meta-analysis was conducted due to intervention differences. Fourteen RCTs met our inclusion criteria. In 2 of 10 trials with pregnancy or birth data, a theory-based group showed better results. Four of 10 trials with contraceptive use data (other than condoms) showed better outcomes in an experimental group. For condom use, a theory-based group had favorable results in three of eight trials. Social Cognitive Theory was the main theoretical basis for five trials, of which three showed positive results. Two based on other social cognition models had favorable results, as did two of four focused on motivational interviewing. Thirteen trials provided multiple sessions or contacts. Of seven effective interventions, five targeted adolescents, including four with group sessions. Three effective trials had individual sessions. Seven trials were rated as having high or moderate quality; three of those had favorable results. Family planning researchers and practitioners could adapt the effective interventions. Reproductive health needs high-quality research on behavior change, especially for clinical and low-resource settings. More thorough use of single theories would help, as would better reporting on research design and intervention implementation.

Creation of a core outcome set for clinical trials of people with shoulder pain: a study protocol.

PubMed

Gagnier, Joel J; Page, Matthew J; Huang, Hsiaomin; Verhagen, Arianne P; Buchbinder, Rachelle

2017-07-20

The selection of appropriate outcomes or domains is crucial when designing clinical trials, to appreciate the effects of different interventions, pool results, and make valid comparisons between trials. If the findings are to influence policy and practice, then the chosen outcomes need to be relevant and important to key stakeholders, including patients and the public, healthcare professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. Recent reviews of the measurement properties of patient-reported outcome measures for shoulder disorders revealed a large selection of diverse measures, many with questionable validity, reliability, and responsiveness. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set (COS), which should be measured and reported in all trials of shoulder disorders. The purpose of the present project is to develop and disseminate a COS for clinical trials in shoulder disorders. The methods for the COS development will include 3 phases: (1) a comprehensive review of the core domains used in shoulder disorder trials; (2) an international Delphi study involving relevant stakeholders (patients, clinicians, scientists) to define which domains should be core; and (3) an international focus group informed by the evidence identified in phases 1 and 2, to determine which measurement instruments best measure the core domains and identification of any evidence gaps that require further empiric evidence. The aim of the current proposal is to convene several meetings of international experts and patients to develop a COS for clinical trials of shoulder disorders and to develop an implementation strategy to ensure rapid uptake of the core set of outcomes in clinical trials. There would be an expectation that the core set of outcomes would always be collected and reported, but it would not preclude use of additional outcomes in a particular trial.

Outdoor Biology Instructional Strategies Trial Edition. Set II.

ERIC Educational Resources Information Center

Fairwell, Kay, Ed.; And Others

The 24 activities in the Outdoor Biology Instructional Strategies (OBIS) Trial Edition Set II use living organisms such as crabs, birds, crayfish, lichens, and insects to investigate biological interrelationships, organism behavior, and species density to promote greater environmental and sensory awareness. The activities, designed primarily for…

The house mouse (Mus musculus L.) exerts strong differential grain consumption preferences among hard red and white spring wheat (Triticum aestivum L.) varieties in a single-elimination tournament design.

PubMed

Morris, Craig F; Fuerst, E Patrick; McLean, Derek J; Momont, Kathleen; James, Caleb P

2014-11-01

Wheat (Triticum aestivum L.) plays a central role in the health and nutrition of humans. Yet, little is known about possible flavor differences among different varieties. We have developed a model system using the house mouse (Mus musculus L.) to determine feeding preferences as a prelude to extending results to human sensory analysis. Here, we examine the application of a single-elimination tournament design to the analysis of consumption preferences of a set of hard red and hard white spring wheat varieties. A single-elimination tournament design in this case pairs 2 wheat varieties and only 1 of the 2 is advanced to further tests. Preferred varieties were advanced until an overall "winner" was identified; conversely, less desirable varieties were advanced such that an overall "loser" was identified. Hollis and IDO702 were the winner and loser, respectively, for the hard red varieties, and Clear White 515 and WA8123 were the winner and loser, respectively, for the hard white varieties. When using the more powerful protocol of 14 mice and a 4-d trial, differences in mean daily consumption preferences of 2 varieties were separated at P-values as small as 2 × 10(-8) . The single-elimination tournament design is an efficient means of identifying the most and least desirable varieties among a larger set of samples. One application for identifying the 2 extremes in preference within a group of varieties would be to use them as parents of a population to identify quantitative trait loci for preference. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

The Tendril Plot-a novel visual summary of the incidence, significance and temporal aspects of adverse events in clinical trials.

PubMed

Karpefors, Martin; Weatherall, James

2018-03-21

In contrast to efficacy, safety hypotheses of clinical trials are not always pre-specified, and therefore, the safety interpretation work of a trial tends to be more exploratory, often reactive, and the analysis more statistically and graphically challenging. We introduce a new means of visualizing the adverse event data across an entire clinical trial. The approach overcomes some of the current limitations of adverse event analysis and streamlines the way safety data can be explored, interpreted and analyzed. Using a phase II study, we describe and exemplify how the tendril plot effectively summarizes the time-resolved safety profile of two treatment arms in a single plot and how that can provide scientists with a trial safety overview that can support medical decision making. To our knowledge, the tendril plot is the only way to graphically show important treatment differences with preserved temporal information, across an entire clinical trial, in a single view.

Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology.

PubMed

Monsell, Sarah E; Mock, Charles; Fardo, David W; Bertelsen, Sarah; Cairns, Nigel J; Roe, Catherine M; Ellingson, Sally R; Morris, John C; Goate, Alison M; Kukull, Walter A

2017-01-01

The objective was to determine whether symptomatic and asymptomatic persons with Alzheimer disease (AD) neuropathology have different allele counts for single-nucleotide polymorphisms that have been associated with clinical late-onset AD. Data came from the National Alzheimer's Coordinating Center Uniform Data Set and Neuropathology Data Set, and the Alzheimer's Disease Genetics Consortium (ADGC). Participants had low to high AD neuropathologic change. The 22 known/suspected genes associated with late-onset AD were considered. "Symptomatic" was defined as Clinical Dementia Rating global score >0. Sixty-eight asymptomatic and 521 symptomatic participants met inclusion criteria. Single-nucleotide polymorphisms associated with ABCA7 [odds ratio (OR)=1.66; 95% confidence interval (CI), 1.03-2.85] and MAPT (OR=2.18; CI, 1.26-3.77) were associated with symptomatic status. In stratified analyses, loci containing CD2AP (OR=0.35; 95% CI, 0.16-0.74), ZCWPW1 (OR=2.98; 95% CI, 1.34-6.86), and MAPT (OR=3.73, 95% CI, 1.30-11.76) were associated with symptomatic status in APOE e4 carriers. These findings potentially explain some of the variation in whether a person with AD neuropathology expresses symptoms. Understanding why some people remain cognitively normal despite having AD neuropathology could identify pathways to disease heterogeneity and guide treatment trials.

Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection.

PubMed

Pandian, Z; Bhattacharya, S; Ozturk, O; Serour, G I; Templeton, A

2004-10-18

The traditional reliance on the transfer of multiple embryos during in vitro fertilisation (IVF) in order to maximise the chance of pregnancy, has resulted in increasing rates of multiple pregnancies. Women undergoing IVF had a 20 - fold increased risk of twins and 400 - fold increased risk of higher order pregnancies (Martin 1998). The maternal and perinatal morbidity and mortality as well as national health service costs associated with multiple pregnancies is significantly high in comparison with singleton births (Luke 1992; Callahan 1994; Goldfarb 1996). Single embryo transfer is now being considered as an effective means of reducing this iatrogenic complication. This systematic review evaluates the effectiveness of elective two embryo transfer in comparison with single and more than two embryo transfer following IVF and ICSI (intra cytoplasmic sperm injection) treatment. The aim of this review is to determine, whether in couples who undergo IVF/ICSI: (1) the elective transfer of two embryos improves the probability of livebirth compared with: (a) Single embryo transfer, (b) Three embryo transfer or (c) Four embryo transfer.(2) the elective transfer of three embryos improves the probability of livebirth compared with: (a) Single embryo transfer, or (b) Four embryo transfer, We searched the Cochrane Menstrual Disorders and Subfertility Group's trials register (searched June 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003), MEDLINE (1970 to 2003), EMBASE (1985 to 2003) and reference lists of articles. We also handsearched relevant conference proceedings and contacted researchers in the field. Only randomised controlled trials were included. Two reviewers independently assessed eligibility and quality of trials. We found no studies that compared a policy of transferring multiple embryos on one cycle versus a policy of cryo- preservation and transfer of a single embryo over multiple cycles. We also found no trials comparing transfer of two versus three embryos. Three small, poorly reported trials compared transfer of two versus one embryo in a single cycle, and one small, poorly reported trial compared transfer of two versus four embryos in a single cycle. The clinical pregnancy rate per woman/couple associated with two embryo transfer was significantly higher compared to single embryo transfer (OR 2.08, 95% CI 1.24 to 3.50; test for overall effect p = 0.006). The live birth rate per woman/couple associated with two embryo transfer was also significantly higher than that associated with single embryo transfer (OR 1.90, 95% CI 1.12 to 3.22, test for overall effect p=0.02). The multiple pregnancy rate was significantly lower in women who had single embryo transfer (OR 9.97, 95% CI 2.61 to 38.19; p = 0.0008). The effectiveness of double embryo transfer versus four embryo transfer was tested in a single trial. There was no statistically significant differences in the clinical pregnancy rate (OR 0.75, 95% CI 0.26 to 2.16; p=0.6), and multiple pregnancy rates (OR 0.44. 95% CI 0.10 to 1.97; p = 0.28) between the two groups. The livebirth rate in the four embryo transfer group was higher compared to the two embryo transfer group, but the results were not statistically significant (OR 0.35, 95% CI 0.11 to 1.05; p = 0.06). The results of this systematic review suggest that live birth and pregnancy rates following single embryo transfer are lower than those following double embryo transfer as are the chances of multiple pregnancy including twins. As such, it is unlikely that the conclusions are robust enough to catalyse a change in clinical practice. The studies included are limited by their small sample size, so that even large differences might be hidden. Cumulative livebirth rates are seldom reported. The data were inadequate to draw conclusions about single embryo transfer and first frozen single embryo transfer (1FZET) or subsequent single frozen embryo transfers. Until more evidence is available single embryo transfer may not be the preferred choice for all patients undergoing IVF/ICSI. Clinicians may need to individualise protocols for couples based on their risks of multiple pregnancy. A definitive pragmatic, large multi centre randomised controlled trial comparing single embryo versus double embryo transfer in terms of clinical and cost effectiveness as well as acceptability is required. The primary outcome measured should be cumulative livebirth per woman/couple.

A randomized controlled trial of water-based exercise for cardiovascular fitness in individuals with chronic stroke

PubMed Central

Chu, Kelly S; Eng, Janice J; Dawson, Andrew S; Harris, Jocelyn E.; Ozkaplan, Atila; Gylfadóttir, Sif

2011-01-01

Objective To evaluate the effect of an 8-week water-based exercise program (experimental group) over an upper extremity function program (control group) to increase cardiovascular fitness within a community setting for individuals with stroke. Design Single-blind randomized controlled trial Setting Public community centre Participants 12 community-dwelling individuals who have had a stroke with mild to moderate motor deficits; volunteer sample Intervention Experimental and control groups participated in group exercise programs undertaken in one hour sessions, three times per week for 8 weeks. The experimental group undertook chest deep water exercises at targeted heart rates. The control group performed arm and hand exercises while sitting. Main Outcome Measures The primary outcome measure was cardiovascular fitness (VO2max). Secondary measures were maximal workload, muscle strength, gait speed, and the Berg Balance Score. Results The experimental group attained significant improvements over the control group in cardiovascular fitness, maximal workload, gait speed, and paretic lower extremity muscle strength. The relatively short program (8 weeks) of water-based exercise resulted in a large improvement (22%) in cardiovascular fitness in a small group of individuals with stroke with relatively high function. Conclusions A water-based exercise program can be undertaken in the community as a group program and may be an effective means to promote fitness in individuals with stroke. PMID:15179638

Assuring high quality treatment delivery in clinical trials - Results from the Trans-Tasman Radiation Oncology Group (TROG) study 03.04 "RADAR" set-up accuracy study.

PubMed

Haworth, Annette; Kearvell, Rachel; Greer, Peter B; Hooton, Ben; Denham, James W; Lamb, David; Duchesne, Gillian; Murray, Judy; Joseph, David

2009-03-01

A multi-centre clinical trial for prostate cancer patients provided an opportunity to introduce conformal radiotherapy with dose escalation. To verify adequate treatment accuracy prior to patient recruitment, centres submitted details of a set-up accuracy study (SUAS). We report the results of the SUAS, the variation in clinical practice and the strategies used to help centres improve treatment accuracy. The SUAS required each of the 24 participating centres to collect data on at least 10 pelvic patients imaged on a minimum of 20 occasions. Software was provided for data collection and analysis. Support to centres was provided through educational lectures, the trial quality assurance team and an information booklet. Only two centres had recently carried out a SUAS prior to the trial opening. Systematic errors were generally smaller than those previously reported in the literature. The questionnaire identified many differences in patient set-up protocols. As a result of participating in this QA activity more than 65% of centres improved their treatment delivery accuracy. Conducting a pre-trial SUAS has led to improvement in treatment delivery accuracy in many centres. Treatment techniques and set-up accuracy varied greatly, demonstrating a need to ensure an on-going awareness for such studies in future trials and with the introduction of dose escalation or new technologies.

Meeting the Challenge: The National Cancer Institute's Central Institutional Review Board for Multi-Site Research.

PubMed

Massett, Holly A; Hampp, Sharon L; Goldberg, Jacquelyn L; Mooney, Margaret; Parreco, Linda K; Minasian, Lori; Montello, Mike; Mishkin, Grace E; Davis, Catasha; Abrams, Jeffrey S

2018-03-10

The National Institutes of Health (NIH) issued a new policy that requires a single institutional review board (IRB) of record be used for all protocols funded by the NIH that are carried out at more than one site in the United States, effective January 2018. This policy affects several hundred clinical trials opened annually across the NIH. Limited data exist to compare the use of a single IRB to that of multiple local IRBs, so some institutions are resistant to or distrustful of single IRBs. Since 2001, the National Cancer Institute (NCI) has funded a central IRB (CIRB) that provides human patient reviews for its extensive national cancer clinical trials program. This paper presents data to show the adoption, efficiencies gained, and satisfaction of the CIRB among NCI trial networks and reviews key lessons gleaned from 16 years of experience that may be informative for others charged with implementation of the new NIH single-IRB policy.

Thermo-mechanical evaluation of carbon-carbon primary structure for SSTO vehicles

NASA Astrophysics Data System (ADS)

Croop, Harold C.; Lowndes, Holland B.; Hahn, Steven E.; Barthel, Chris A.

1998-01-01

An advanced development program to demonstrate carbon-carbon composite structure for use as primary load carrying structure has entered the experimental validation phase. The component being evaluated is a wing torque box section for a single-stage-to-orbit (SSTO) vehicle. The validation or demonstration component features an advanced carbon-carbon design incorporating 3D woven graphite preforms, integral spars, oxidation inhibited matrix, chemical vapor deposited (CVD) oxidation protection coating, and ceramic matrix composite fasteners. The validation component represents the culmination of a four phase design and fabrication development effort. Extensive developmental testing was performed to verify material properties and integrity of basic design features before committing to fabrication of the full scale box. The wing box component is now being set up for testing in the Air Force Research Laboratory Structural Test Facility at Wright-Patterson Air Force Base, Ohio. One of the important developmental tests performed in support of the design and planned testing of the full scale box was the fabrication and test of a skin/spar trial subcomponent. The trial subcomponent incorporated critical features of the full scale wing box design. This paper discusses the results of the trial subcomponent test which served as a pathfinder for the upcoming full scale box test.

Adherence to Point-of-Use Water Treatment over Short-Term Implementation: Parallel Crossover Trials of Flocculation-Disinfection Sachets in Pakistan and Zambia.

PubMed

Shaheed, A; Rathore, S; Bastable, A; Bruce, J; Cairncross, S; Brown, J

2018-06-05

The health benefits of point-of-use (POU) water treatment can only be realized through high adherence: correct, consistent, and sustained use. We conducted parallel randomized, longitudinal crossover trials measuring short-term adherence to two single-use flocculant-disinfectant sachets in Pakistan and Zambia. In both trials, adherence declined sharply for both products over the eight week surveillance periods, with overall lower adherence to both products in Zambia. There was no significant difference in adherence between the two products. Estimated median daily production of treated water dropped over the crossover period from 2.5 to 1.4 L person -1 day -1 (46% decline) in Pakistan and from 1.4 to 1.1 L person -1 day -1 (21% decline) in Zambia. The percentage of surveillance points with detectable total chlorine in household drinking water declined from 70% to 49% in Pakistan and rose marginally from 28% to 30% in Zambia. The relatively low and decreasing adherence observed in this study suggests that these products would have provided little protection from waterborne disease risk in these settings. Our findings underscore the challenge of achieving high adherence to POU water treatment, even under conditions of short-term adoption with intensive follow-up.

Effectiveness of telerehabilitation programme following surgery in shoulder impingement syndrome (SIS): study protocol for a randomized controlled non-inferiority trial.

PubMed

Pastora-Bernal, Jose-Manuel; Martín-Valero, Rocío; Barón-López, Francisco Javier; García-Gómez, Oscar

2017-02-23

Shoulder pain is common in society, with high prevalence in the general population. Shoulder impingement syndrome (SIS) is the most frequent cause. Patients suffer pain, muscle weakness and loss of movement in the affected joint. Initial treatment is predominantly conservative. The surgical option has high success rates and is often used when conservative strategy fails. Traditional physiotherapy and post-operative exercises are needed for the recovery of joint range, muscle strength, stability and functionality. Telerehabilitation programmes have shown positive results in some orthopaedic conditions after surgery. Customized telerehabilitation intervention programmes should be developed to recover shoulder function after SIS surgery. The objective of this study is to evaluate the feasibility and effectiveness of a telerehabilitation intervention compared with usual care in patients after subacromial decompression surgery. We will compare an intervention group receiving videoconferences and a telerehabilitation programme to a control group receiving traditional physiotherapy intervention in a single-blind, randomized controlled non-inferiority trial study design. Through this study, we will further develop our preliminary data set and practical experience with the telerehabilitation programmes to evaluate their effectiveness and compare this with traditional intervention. We will also explore patient satisfaction and cost-effectiveness. Patient enrolment is ongoing. ClinicalTrials.gov, NCT02909920 . 14 September 2016.

Evaluating the addition of oxaliplatin to single agent fluoropyrimidine in the treatment of locally advanced rectal cancer: a systematic review and meta-analysis.

PubMed

Thavaneswaran, Subotheni; Kok, Peey Sei; Price, Timothy

2017-10-01

Multimodality treatment of patients with locally advanced rectal cancer (LARC) has significantly improved local disease control, however the unaltered overall survival (OS) implicates an inability to further control micrometastases, providing rationale for intensified systemic treatment. A systematic review was conducted to evaluate the efficacy and toxicity of adding oxaliplatin to a fluoropyrimidine (intervention) compared with fluoropyrimidine alone (control) in the treatment of LARC. We searched CENTRAL, Medline Ovid, PubMed and EMBASE databases. Randomised trials comparing the intervention and control delivered either pre- or post-operatively were included. Seven trials involving 4444 patients were identified; five studies evaluated the intervention vs control preoperatively; one study peri-operatively; and one, post-operatively. There was no significant difference in OS with oxaliplatin addition, HR 0.89, 95% CI, 0.75 to 1.06. There was however an improvement in disease free survival, 3-year local and distant recurrence rates (RR) favouring oxaliplatin. Preoperative oxaliplatin improved pathological complete response (pCR), but with a greater toxicity and reduced compliance with radiation. There is no OS benefit with oxaliplatin, despite improved pCR, local and distant RR. Before drawing definitive conclusions, longer follow-up in included trials and availability of published data from other eligible studies, including the induction setting, are needed.