Benefits and challenges of using the cohort multiple randomised controlled trial design for testing an intervention for depression.

PubMed

Viksveen, Petter; Relton, Clare; Nicholl, Jon

2017-07-06

Trials which test the effectiveness of interventions compared with the status quo frequently encounter challenges. The cohort multiple randomised controlled trial (cmRCT) design is an innovative approach to the design and conduct of pragmatic trials which seeks to address some of these challenges. In this article, we report our experiences with the first completed randomised controlled trial (RCT) using the cmRCT design. This trial-the Depression in South Yorkshire (DEPSY) trial-involved comparison of treatment as usual (TAU) with TAU plus the offer of an intervention for people with self-reported long-term moderate to severe depression. In the trial, we used an existing large population-based cohort: the Yorkshire Health Study. We discuss our experiences with recruitment, attrition, crossover, data analysis, generalisability of results, and cost. The main challenges in using the cmRCT design were the high crossover to the control group and the lower questionnaire response rate among patients who refused the offer of treatment. However, the design did help facilitate efficient and complete recruitment of the trial population as well as analysable data that were generalisable to the population of interest. Attrition rates were also smaller than those reported in other depression trials. This first completed full trial using the cmRCT design testing an intervention for self-reported depression was associated with a number of important benefits. Further research is required to compare the acceptability and cost effectiveness of standard pragmatic RCT design with the cmRCT design. ISRCTN registry: ISRCTN02484593 . Registered on 7 Jan 2013.

Planning multi-arm screening studies within the context of a drug development program

PubMed Central

Wason, James M S; Jaki, Thomas; Stallard, Nigel

2013-01-01

Screening trials are small trials used to decide whether an intervention is sufficiently promising to warrant a large confirmatory trial. Previous literature examined the situation where treatments are tested sequentially until one is considered sufficiently promising to take forward to a confirmatory trial. An important consideration for sponsors of clinical trials is how screening trials should be planned to maximize the efficiency of the drug development process. It has been found previously that small screening trials are generally the most efficient. In this paper we consider the design of screening trials in which multiple new treatments are tested simultaneously. We derive analytic formulae for the expected number of patients until a successful treatment is found, and propose methodology to search for the optimal number of treatments, and optimal sample size per treatment. We compare designs in which only the best treatment proceeds to a confirmatory trial and designs in which multiple treatments may proceed to a multi-arm confirmatory trial. We find that inclusion of a large number of treatments in the screening trial is optimal when only one treatment can proceed, and a smaller number of treatments is optimal when more than one can proceed. The designs we investigate are compared on a real-life set of screening designs. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23529936

Verbal Learning and Memory Functions in Adolescents with Reading Disabilities

ERIC Educational Resources Information Center

Oyler, James D.; Obrzut, John E.; Asbjornsen, Arve E.

2012-01-01

The authors of this current study compared the memory performance of adolescent students with specific reading disabilities (RD) with that of typical adolescent readers on a newly developed verbal learning test, the "Bergen-Tucson Verbal Learning Test" (BTVLT). This multiple trial test was designed to measure memory acquisition,…

Multiplicity: discussion points from the Statisticians in the Pharmaceutical Industry multiplicity expert group.

PubMed

Phillips, Alan; Fletcher, Chrissie; Atkinson, Gary; Channon, Eddie; Douiri, Abdel; Jaki, Thomas; Maca, Jeff; Morgan, David; Roger, James Henry; Terrill, Paul

2013-01-01

In May 2012, the Committee of Health and Medicinal Products issued a concept paper on the need to review the points to consider document on multiplicity issues in clinical trials. In preparation for the release of the updated guidance document, Statisticians in the Pharmaceutical Industry held a one-day expert group meeting in January 2013. Topics debated included multiplicity and the drug development process, the usefulness and limitations of newly developed strategies to deal with multiplicity, multiplicity issues arising from interim decisions and multiregional development, and the need for simultaneous confidence intervals (CIs) corresponding to multiple test procedures. A clear message from the meeting was that multiplicity adjustments need to be considered when the intention is to make a formal statement about efficacy or safety based on hypothesis tests. Statisticians have a key role when designing studies to assess what adjustment really means in the context of the research being conducted. More thought during the planning phase needs to be given to multiplicity adjustments for secondary endpoints given these are increasing in importance in differentiating products in the market place. No consensus was reached on the role of simultaneous CIs in the context of superiority trials. It was argued that unadjusted intervals should be employed as the primary purpose of the intervals is estimation, while the purpose of hypothesis testing is to formally establish an effect. The opposing view was that CIs should correspond to the test decision whenever possible. Copyright © 2013 John Wiley & Sons, Ltd.

Race-Related Cognitive Test Bias in the ACTIVE Study: A MIMIC Model Approach

PubMed Central

Aiken Morgan, Adrienne T.; Marsiske, Michael; Dzierzewski, Joseph; Jones, Richard N.; Whitfield, Keith E.; Johnson, Kathy E.; Cresci, Mary K.

2010-01-01

The present study investigated evidence for race-related test bias in cognitive measures used in the baseline assessment of the ACTIVE clinical trial. Test bias against African Americans has been documented in both cognitive aging and early lifespan studies. Despite significant mean performance differences, Multiple Indicators Multiple Causes (MIMIC) models suggested most differences were at the construct level. There was little evidence that specific measures put either group at particular advantage or disadvantage and little evidence of cognitive test bias in this sample. Small group differences in education, cognitive status, and health suggest positive selection may have attenuated possible biases. PMID:20845121

Improving Clinical Trial Efficiency: Thinking outside the Box.

PubMed

Mandrekar, Sumithra J; Dahlberg, Suzanne E; Simon, Richard

2015-01-01

Clinical trial design strategies have evolved over the past few years as a means to accelerate the drug development process so that the right therapies can be delivered to the right patients. Basket, umbrella, and adaptive enrichment strategies represent a class of novel designs for testing targeted therapeutics in oncology. Umbrella trials include a central infrastructure for screening and identification of patients, and focus on a single tumor type or histology with multiple subtrials, each testing a targeted therapy within a molecularly defined subset. Basket trial designs offer the possibility to include multiple molecularly defined subpopulations, often across histology or tumor types, but included in one cohesive design to evaluate the targeted therapy in question. Adaptive enrichment designs offer the potential to enrich for patients with a particular molecular feature that is predictive of benefit for the test treatment based on accumulating evidence from the trial. This review will aim to discuss the fundamentals of these design strategies, the underlying statistical framework, the logistical barriers of implementation, and, ultimately, the interpretation of the trial results. New statistical approaches, extensive multidisciplinary collaboration, and state of the art data capture technologies are needed to implement these strategies in practice. Logistical challenges to implementation arising from centralized assay testing, requirement of multiple specimens, multidisciplinary collaboration, and infrastructure requirements will also be discussed. This review will present these concepts in the context of the National Cancer Institute's precision medicine initiative trials: MATCH, ALCHEMIST, Lung MAP, as well as other trials such as FOCUS4.

Smoking Cessation and Reduction in Schizophrenia (SCARIS) with e-cigarette: study protocol for a randomized control trial

PubMed Central

2014-01-01

Background It is well established in studies across several countries that tobacco smoking is more prevalent among schizophrenic patients than the general population. Electronic cigarettes are becoming increasingly popular with smokers worldwide. To date there are no large randomized trials of electronic cigarettes in schizophrenic smokers. A well-designed trial is needed to compare efficacy and safety of these products in this special population. Methods/Design Intervention: We have designed a randomized controlled trial investigating the efficacy and safety of electronic cigarette. The trial will take the form of a prospective 12-month randomized clinical study to evaluate smoking reduction, smoking abstinence and adverse events in schizophrenic smokers not intending to quit. We will also monitor quality of life, neurocognitive functioning and measure participants’ perception and satisfaction of the product. Outcome measures: A ≥50% reduction in the number of cigarettes/day from baseline, will be calculated at each study visit (“reducers”). Abstinence from smoking will be calculated at each study visit (“quitters”). Smokers who leave the study protocol before its completion and will carry out the Early Termination Visit or who will not satisfy the criteria of “reducers” and “quitters” will be defined “non responders”. Statistical analysis: The differences of continuous variables between the three groups will be evaluated with the Kruskal-Wallis Test, followed by the Dunn multiple comparison test. The differences between the three groups for normally distributed data will be evaluated with ANOVA test one way, followed by the Newman-Keuls multiple comparison test. The normality of the distribution will be evaluated with the Kolmogorov-Smirnov test. Any correlations between the variables under evaluation will be assessed by Spearman r correlation. To compare qualitative data will be used the Chi-square test. Discussion The main strengths of the SCARIS study are the following: it’s the first large RCT on schizophrenic patient, involving in and outpatient, evaluating the effect of a three-arm study design, and a long term of follow-up (52-weeks). The goal is to propose an effective intervention to reduce the risk of tobacco smoking, as a complementary tool to treat tobacco addiction in schizophrenia. Trial registration ClinicalTrials.gov, NCT01979796. PMID:24655473

Bayesian adaptive phase II screening design for combination trials.

PubMed

Cai, Chunyan; Yuan, Ying; Johnson, Valen E

2013-01-01

Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments. The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial.

Dispersion of Response Times Reveals Cognitive Dynamics

ERIC Educational Resources Information Center

Holden, John G.; Van Orden, Guy C.; Turvey, Michael T.

2009-01-01

Trial-to-trial variation in word-pronunciation times exhibits 1/f scaling. One explanation is that human performances are consequent on multiplicative interactions among interdependent processes-interaction dominant dynamics. This article describes simulated distributions of pronunciation times in a further test for multiplicative interactions and…

Design and analysis of three-arm trials with negative binomially distributed endpoints.

PubMed

Mütze, Tobias; Munk, Axel; Friede, Tim

2016-02-20

A three-arm clinical trial design with an experimental treatment, an active control, and a placebo control, commonly referred to as the gold standard design, enables testing of non-inferiority or superiority of the experimental treatment compared with the active control. In this paper, we propose methods for designing and analyzing three-arm trials with negative binomially distributed endpoints. In particular, we develop a Wald-type test with a restricted maximum-likelihood variance estimator for testing non-inferiority or superiority. For this test, sample size and power formulas as well as optimal sample size allocations will be derived. The performance of the proposed test will be assessed in an extensive simulation study with regard to type I error rate, power, sample size, and sample size allocation. For the purpose of comparison, Wald-type statistics with a sample variance estimator and an unrestricted maximum-likelihood estimator are included in the simulation study. We found that the proposed Wald-type test with a restricted variance estimator performed well across the considered scenarios and is therefore recommended for application in clinical trials. The methods proposed are motivated and illustrated by a recent clinical trial in multiple sclerosis. The R package ThreeArmedTrials, which implements the methods discussed in this paper, is available on CRAN. Copyright © 2015 John Wiley & Sons, Ltd.

Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success?

PubMed

Chan, John K; Ueda, Stefanie M; Sugiyama, Valerie E; Stave, Christopher D; Shin, Jacob Y; Monk, Bradley J; Sikic, Branimir I; Osann, Kathryn; Kapp, Daniel S

2008-03-20

To identify the characteristics of phase II studies that predict for subsequent "positive" phase III trials (those that reached the proposed primary end points of study or those wherein the study drug was superior to the standard regimen investigating targeted agents in advanced tumors. We identified all phase III clinical trials of targeted therapies against advanced cancers published from 1985 to 2005. Characteristics of the preceding phase II studies were reviewed to identify predictive factors for success of the subsequent phase III trial. Data were analyzed using the chi(2) test and logistic regression models. Of 351 phase II studies, 167 (47.6%) subsequent phase III trials were positive and 184 (52.4%) negative. Phase II studies from multiple rather than single institutions were more likely to precede a successful trial (60.4% v 39.4%; P < .001). Positive phase II results were more likely to lead to a successful phase III trial (50.8% v 22.5%; P = .003). The percentage of successful trials from pharmaceutical companies was significantly higher compared with academic, cooperative groups, and research institutes (89.5% v 44.2%, 45.2%, and 46.3%, respectively; P = .002). On multivariate analysis, these factors and shorter time interval between publication of phase II results and III study publication were independent predictive factors for a positive phase III trial. In phase II studies of targeted agents, multiple- versus single-institution participation, positive phase II trial, pharmaceutical company-based trials, and shorter time period between publication of phase II to phase III trial were independent predictive factors of success in a phase III trial. Investigators should be cognizant of these factors in phase II studies before designing phase III trials.

Children with multiple sclerosis should not become therapeutic hostages

PubMed Central

Rose, Klaus; Müller, Thomas

2016-01-01

Background: Both the United States (US) Food and Drug Administration (FDA) and the European Union (EU) European Medicines Agency (EMA) order pediatric clinical trials as a condition for approval of new compounds. We evaluate clinical value and likelihood of sufficient recruitment for pediatric multiple sclerosis (pMS) studies and discuss US and EU pediatric legislation with pMS as a paradigm. Methods: We analyzed pMS clinical trials requested by the FDA and the EMA and industry-sponsored pMS studies registered on www.clinicaltrials.gov and www.clinicaltrialsregister.eu. Results: The FDA demands four and the EMA 15 pMS trials Conclusions: pMS is rare. Neither FDA nor EMA prioritize compounds for potential benefit in pMS. The EMA in particular orders multiple pMS studies, which will probably not recruit enough patients. Therefore, it is likely that the pMS trial outcomes will not be relevant for evidence-based medicine analyses, clinical practice and a pMS label for the respective drug. EMA requests for multiple pediatric studies have been described in metastasized adolescent melanoma, another very rare pediatric disease. The terms ‘ghost studies’ and ‘therapeutic hostages’ have been proposed for such trials and children whose parents are lured into permitting study participation. Clinical studies are not ethical if the probability is high that they will not provide reasonable outcomes. For now, pMS clinicians will have to continue to use new MS drugs in children off-label. They might consider a more proactive international coordinating role in prioritizing and testing new MS compounds in children. PMID:27582894

A study to assess whether fixed-width beam walking provides sufficient challenge to assess balance ability across lower limb prosthesis users.

PubMed

Sawers, Andrew; Hafner, Brian J

2018-04-01

To evaluate the feasibility of fixed-width beam walking for assessing balance in lower limb prosthesis users. Cross-sectional. Laboratory. Lower limb prosthesis users. Participants attempted 10 walking trials on three fixed-width beams (18.6, 8.60, and 4.01 wide; 5.5 m long; 3.8 cm high). Beam-walking performance was quantified using the distance walked to balance failure. Heuristic rules applied to each participant's beam-walking distance to classify each beam as "too easy," "too hard," or "appropriately challenging" and determine whether any single beam provided an appropriate challenge to all participants. The number of trials needed to achieve stable beam-walking performance was quantified for appropriately challenging beams by identifying the last inflection point in the slope of each participant's trial-by-trial cumulative performance record. In all, 30 unilateral lower limb prosthesis users participated in the study. Each of the fixed-width beams was either too easy or too hard for at least 33% of the sample. Thus, no single beam was appropriately challenging for all participants. Beam-walking performance was stable by trial 8 for all participants and by trial 6 for 90% of participants. There was no significant difference in the number of trials needed to achieve stable performance among beams ( P = 0.74). Results suggest that a clinical beam-walking test would require multiple beams to evaluate balance across a range of lower limb prosthesis users, emphasizing the need for adaptive or progressively challenging balance tests. While the administrative burden of a multiple-beam balance test may limit clinical feasibility, alternatives to ease this administrative burden are proposed.

Reliability and Concurrent Validity of the Narrow Path Walking Test in Persons With Multiple Sclerosis.

PubMed

Rosenblum, Uri; Melzer, Itshak

2017-01-01

About 90% of people with multiple sclerosis (PwMS) have gait instability and 50% fall. Reliable and clinically feasible methods of gait instability assessment are needed. The study investigated the reliability and validity of the Narrow Path Walking Test (NPWT) under single-task (ST) and dual-task (DT) conditions for PwMS. Thirty PwMS performed the NPWT on 2 different occasions, a week apart. Number of Steps, Trial Time, Trial Velocity, Step Length, Number of Step Errors, Number of Cognitive Task Errors, and Number of Balance Losses were measured. Intraclass correlation coefficients (ICC2,1) were calculated from the average values of NPWT parameters. Absolute reliability was quantified from standard error of measurement (SEM) and smallest real difference (SRD). Concurrent validity of NPWT with Functional Reach Test, Four Square Step Test (FSST), 12-item Multiple Sclerosis Walking Scale (MSWS-12), and 2 Minute Walking Test (2MWT) was determined using partial correlations. Intraclass correlation coefficients (ICCs) for most NPWT parameters during ST and DT ranged from 0.46-0.94 and 0.55-0.95, respectively. The highest relative reliability was found for Number of Step Errors (ICC = 0.94 and 0.93, for ST and DT, respectively) and Trial Velocity (ICC = 0.83 and 0.86, for ST and DT, respectively). Absolute reliability was high for Number of Step Errors in ST (SEM % = 19.53%) and DT (SEM % = 18.14%) and low for Trial Velocity in ST (SEM % = 6.88%) and DT (SEM % = 7.29%). Significant correlations for Number of Step Errors and Trial Velocity were found with FSST, MSWS-12, and 2MWT. In persons with PwMS performing the NPWT, Number of Step Errors and Trial Velocity were highly reliable parameters. Based on correlations with other measures of gait instability, Number of Step Errors was the most valid parameter of dynamic balance under the conditions of our test.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A159).

Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: implications for multiple sclerosis clinical trials.

PubMed

Benedict, Ralph H B; Smerbeck, Audrey; Parikh, Rajavi; Rodgers, Jonathan; Cadavid, Diego; Erlanger, David

2012-09-01

Cognitive impairment is common in multiple sclerosis (MS), but is seldom assessed in clinical trials investigating the effects of disease-modifying therapies. The Symbol Digit Modalities Test (SDMT) is a particularly promising tool due to its sensitivity and robust correlation with brain magnetic resonance imaging (MRI) and vocational disability. Unfortunately, there are no validated alternate SDMT forms, which are needed to mitigate practice effects. The aim of the study was to assess the reliability and equivalence of SDMT alternate forms. Twenty-five healthy participants completed each of five alternate versions of the SDMT - the standard form, two versions from the Rao Brief Repeatable Battery, and two forms specifically designed for this study. Order effects were controlled using a Latin-square research design. All five versions of the SDMT produced mean values within 3 raw score points of one another. Three forms were very consistent, and not different by conservative statistical tests. The SDMT test-retest reliability using these forms was good to excellent, with all r values exceeding 0.80. For the first time, we find good evidence that at least three alternate versions of the SDMT are of equivalent difficulty in healthy adults. The forms are reliable, and can be implemented in clinical trials emphasizing cognitive outcomes.

People use the memory for past-test heuristic as an explicit cue for judgments of learning.

PubMed

Serra, Michael J; Ariel, Robert

2014-11-01

When people estimate their memory for to-be-learned material over multiple study-test trials, they tend to base their judgments of learning (JOLs) on their test performance for those materials on the previous trial. Their use of this information-known as the memory for past-test (MPT) heuristic-is believed to be responsible for improvements in the relative accuracy (resolution) of people's JOLs across learning trials. Although participants seem to use past-test information as a major basis for their JOLs, little is known about how learners translate this information into a judgment of learning. Toward this end, in two experiments, we examined whether participants factored past-test performance into their JOLs in either an explicit, theory-based way or an implicit way. To do so, we had one group of participants (learners) study paired associates, make JOLs, and take a test on two study-test trials. Other participants (observers) viewed learners' protocols and made JOLs for the learners. Presumably, observers could only use theory-based information to make JOLs for the learners, which allowed us to estimate the contribution of explicit and implicit information to learners' JOLs. Our analyses suggest that all participants factored simple past-test performance into their JOLs in an explicit, theory-based way but that this information made limited contributions to improvements in relative accuracy across trials. In contrast, learners also used other privileged, implicit information about their learning to inform their judgments (that observers had no access to) that allowed them to achieve further improvements in relative accuracy across trials.

Bayesian adaptive phase II screening design for combination trials

PubMed Central

Cai, Chunyan; Yuan, Ying; Johnson, Valen E

2013-01-01

Background Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Methods Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Results Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments. Limitations The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. Conclusions The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial. PMID:23359875

Assessing the criterion validity of four highly abbreviated measures from the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS).

PubMed

Gromisch, Elizabeth S; Zemon, Vance; Holtzer, Roee; Chiaravalloti, Nancy D; DeLuca, John; Beier, Meghan; Farrell, Eileen; Snyder, Stacey; Schairer, Laura C; Glukhovsky, Lisa; Botvinick, Jason; Sloan, Jessica; Picone, Mary Ann; Kim, Sonya; Foley, Frederick W

2016-10-01

Cognitive dysfunction is prevalent in multiple sclerosis. As self-reported cognitive functioning is unreliable, brief objective screening measures are needed. Utilizing widely used full-length neuropsychological tests, this study aimed to establish the criterion validity of highly abbreviated versions of the Brief Visuospatial Memory Test - Revised (BVMT-R), Symbol Digit Modalities Test (SDMT), Delis-Kaplan Executive Function System (D-KEFS) Sorting Test, and Controlled Oral Word Association Test (COWAT) in order to begin developing an MS-specific screening battery. Participants from Holy Name Medical Center and the Kessler Foundation were administered one or more of these four measures. Using test-specific criterion to identify impairment at both -1.5 and -2.0 SD, receiver-operating-characteristic (ROC) analyses of BVMT-R Trial 1, Trial 2, and Trial 1 + 2 raw data (N = 286) were run to calculate the classification accuracy of the abbreviated version, as well as the sensitivity and specificity. The same methods were used for SDMT 30-s and 60-s (N = 321), D-KEFS Sorting Free Card Sort 1 (N = 120), and COWAT letters F and A (N = 298). Using these definitions of impairment, each analysis yielded high classification accuracy (89.3 to 94.3%). BVMT-R Trial 1, SDMT 30-s, D-KEFS Free Card Sort 1, and COWAT F possess good criterion validity in detecting impairment on their respective overall measure, capturing much of the same information as the full version. Along with the first two trials of the California Verbal Learning Test - Second Edition (CVLT-II), these five highly abbreviated measures may be used to develop a brief screening battery.

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.

Physician compensation for industry-sponsored clinical trials in multiple sclerosis influences patient trust.

PubMed

Klein, E; Solomon, A J; Corboy, J; Bernat, J

2016-07-01

Perceived physician financial conflicts of interest of can affect patient trust. Payment to physicians for industry sponsored clinical trials in multiple sclerosis is a relatively new potential source of physician conflict of interest. There is limited available data on how physician payment for trial involvement in multiple sclerosis clinical trials may influence patient trust. To understand how patient trust is influenced by information about physician payment for multiple sclerosis clinical trials. An anonymous online instrument was developed. 597 people with multiple sclerosis participated in the study. The study found that 61% of patients who had not previously participated in a clinical trial estimated that they would have lower levels of trust in their physician if the physician was paid for involvement in their clinical trial. Among former clinical trial participants, 38% self-reported a lower level of trust. Other potential physician-industry relationships, such as industry consulting or giving industry-sponsored talks, also adversely affected trust, though to a lesser extent than physician payment for subject participation in clinical trials. Results of this study demonstrate that physician payment for study participation in multiple sclerosis clinical trials is a potential conflict that can adversely affect patient trust. Copyright © 2016 Elsevier B.V. All rights reserved.

The validity of three tests of temperament in guppies (Poecilia reticulata).

PubMed

Burns, James G

2008-11-01

Differences in temperament (consistent differences among individuals in behavior) can have important effects on fitness-related activities such as dispersal and competition. However, evolutionary ecologists have put limited effort into validating their tests of temperament. This article attempts to validate three standard tests of temperament in guppies: the open-field test, emergence test, and novel-object test. Through multiple reliability trials, and comparison of results between different types of test, this study establishes the confidence that can be placed in these temperament tests. The open-field test is shown to be a good test of boldness and exploratory behavior; the open-field test was reliable when tested in multiple ways. There were problems with the emergence test and novel-object test, which leads one to conclude that the protocols used in this study should not be considered valid tests for this species. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

Awareness and attitudes towards clinical trials among Polish oncological patients who had never participated in a clinical trial.

PubMed

Staniszewska, Anna; Lubiejewska, Adriana; Czerw, Aleksandra; Dąbrowska-Bender, Marta; Duda-Zalewska, Aneta; Olejniczak, Dominik; Juszczyk, Grzegorz; Bujalska-Zadrożny, Magdalena

2018-03-21

Participation in a clinical trial significantly shortens waiting time associated with receiving specialist care. Furthermore, it may be the case that, through clinical trials, subjects can access medicines that are not typically available in Poland. The aim of this study was to determine the opinions of oncological patients about clinical trials. The research has been carried out during the years 2014-2016. A proprietary questionnaire consisting of 10 closed, single and multiple choice questions about awareness and perceptions of clinical trials, and 5 questions concerning demographic information was used. A group of 256 patients with cancer (54% women, 46% men), aged 21-77 years, was surveyed. Respondents were statistically more likely to decide to participate in a clinical trial as oncological patients than the healthy volunteers (Pearson's χ2 test p = 0.00006). The desire to qualify for clinical trials in no way depends on the knowledge of side effects (Pearson's χ2 test p = 0.16796). Our study found that the patients' awareness about clinical trials varied. However, a positive attitude towards research was visible. The main identified barriers to clinical trial participation were fear of possible side effects. Most patients regarded clinical trials as useful, and considered that they are conducted to introduce new treatment/new drug.

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.

The Contributions of Primary and Secondary Memory to Working Memory Capacity: An Individual Differences Analysis of Immediate Free Recall

ERIC Educational Resources Information Center

Unsworth, Nash; Spillers, Gregory J.; Brewer, Gene A.

2010-01-01

The present study tested the dual-component model of working memory capacity (WMC) by examining estimates of primary memory and secondary memory from an immediate free recall task. Participants completed multiple measures of WMC and general intellectual ability as well as multiple trials of an immediate free recall task. It was demonstrated that…

Nutrition Intervention Trials in Linxian, China

Cancer.gov

Randomized controlled trials were launched in 1985 to test the effects of multiple vitamin and mineral interventions on total mortality and total and cause-specific cancer mortality in a rural Chinese population

Sensitivity and specificity of a digit symbol recognition trial in the identification of response bias.

PubMed

Kim, Nancy; Boone, Kyle B; Victor, Tara; Lu, Po; Keatinge, Carolyn; Mitchell, Cary

2010-08-01

Recently published practice standards recommend that multiple effort indicators be interspersed throughout neuropsychological evaluations to assess for response bias, which is most efficiently accomplished through use of effort indicators from standard cognitive tests already included in test batteries. The present study examined the utility of a timed recognition trial added to standard administration of the WAIS-III Digit Symbol subtest in a large sample of "real world" noncredible patients (n=82) as compared with credible neuropsychology clinic patients (n=89). Scores from the recognition trial were more sensitive in identifying poor effort than were standard Digit Symbol scores, and use of an equation incorporating Digit Symbol Age-Corrected Scaled Scores plus accuracy and time scores from the recognition trial was associated with nearly 80% sensitivity at 88.7% specificity. Thus, inclusion of a brief recognition trial to Digit Symbol administration has the potential to provide accurate assessment of response bias.

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.

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.

A data grid for imaging-based clinical trials

NASA Astrophysics Data System (ADS)

Zhou, Zheng; Chao, Sander S.; Lee, Jasper; Liu, Brent; Documet, Jorge; Huang, H. K.

2007-03-01

Clinical trials play a crucial role in testing new drugs or devices in modern medicine. Medical imaging has also become an important tool in clinical trials because images provide a unique and fast diagnosis with visual observation and quantitative assessment. A typical imaging-based clinical trial consists of: 1) A well-defined rigorous clinical trial protocol, 2) a radiology core that has a quality control mechanism, a biostatistics component, and a server for storing and distributing data and analysis results; and 3) many field sites that generate and send image studies to the radiology core. As the number of clinical trials increases, it becomes a challenge for a radiology core servicing multiple trials to have a server robust enough to administrate and quickly distribute information to participating radiologists/clinicians worldwide. The Data Grid can satisfy the aforementioned requirements of imaging based clinical trials. In this paper, we present a Data Grid architecture for imaging-based clinical trials. A Data Grid prototype has been implemented in the Image Processing and Informatics (IPI) Laboratory at the University of Southern California to test and evaluate performance in storing trial images and analysis results for a clinical trial. The implementation methodology and evaluation protocol of the Data Grid are presented.

Testing moderation in network meta-analysis with individual participant data

PubMed Central

Dagne, Getachew A.; Brown, C. Hendricks; Howe, George; Kellam, Sheppard G.; Liu, Lei

2016-01-01

Summary Meta-analytic methods for combining data from multiple intervention trials are commonly used to estimate the effectiveness of an intervention. They can also be extended to study comparative effectiveness, testing which of several alternative interventions is expected to have the strongest effect. This often requires network meta-analysis (NMA), which combines trials involving direct comparison of two interventions within the same trial and indirect comparisons across trials. In this paper, we extend existing network methods for main effects to examining moderator effects, allowing for tests of whether intervention effects vary for different populations or when employed in different contexts. In addition, we study how the use of individual participant data (IPD) may increase the sensitivity of NMA for detecting moderator effects, as compared to aggregate data NMA that employs study-level effect sizes in a meta-regression framework. A new network meta-analysis diagram is proposed. We also develop a generalized multilevel model for NMA that takes into account within- and between-trial heterogeneity, and can include participant-level covariates. Within this framework we present definitions of homogeneity and consistency across trials. A simulation study based on this model is used to assess effects on power to detect both main and moderator effects. Results show that power to detect moderation is substantially greater when applied to IPD as compared to study-level effects. We illustrate the use of this method by applying it to data from a classroom-based randomized study that involved two sub-trials, each comparing interventions that were contrasted with separate control groups. PMID:26841367

Improvements in cognition, quality of life, and physical performance with clinical Pilates in multiple sclerosis: a randomized controlled trial

PubMed Central

Küçük, Fadime; Kara, Bilge; Poyraz, Esra Çoşkuner; İdiman, Egemen

2016-01-01

[Purpose] The aim of this study was to determine the effects of clinical Pilates in multiple sclerosis patients. [Subjects and Methods] Twenty multiple sclerosis patients were enrolled in this study. The participants were divided into two groups as the clinical Pilates and control groups. Cognition (Multiple Sclerosis Functional Composite), balance (Berg Balance Scale), physical performance (timed performance tests, Timed up and go test), tiredness (Modified Fatigue Impact scale), depression (Beck Depression Inventory), and quality of life (Multiple Sclerosis International Quality of Life Questionnaire) were measured before and after treatment in all participants. [Results] There were statistically significant differences in balance, timed performance, tiredness and Multiple Sclerosis Functional Composite tests between before and after treatment in the clinical Pilates group. We also found significant differences in timed performance tests, the Timed up and go test and the Multiple Sclerosis Functional Composite between before and after treatment in the control group. According to the difference analyses, there were significant differences in Multiple Sclerosis Functional Composite and Multiple Sclerosis International Quality of Life Questionnaire scores between the two groups in favor of the clinical Pilates group. There were statistically significant clinical differences in favor of the clinical Pilates group in comparison of measurements between the groups. Clinical Pilates improved cognitive functions and quality of life compared with traditional exercise. [Conclusion] In Multiple Sclerosis treatment, clinical Pilates should be used as a holistic approach by physical therapists. PMID:27134355

Improvements in cognition, quality of life, and physical performance with clinical Pilates in multiple sclerosis: a randomized controlled trial.

PubMed

Küçük, Fadime; Kara, Bilge; Poyraz, Esra Çoşkuner; İdiman, Egemen

2016-03-01

[Purpose] The aim of this study was to determine the effects of clinical Pilates in multiple sclerosis patients. [Subjects and Methods] Twenty multiple sclerosis patients were enrolled in this study. The participants were divided into two groups as the clinical Pilates and control groups. Cognition (Multiple Sclerosis Functional Composite), balance (Berg Balance Scale), physical performance (timed performance tests, Timed up and go test), tiredness (Modified Fatigue Impact scale), depression (Beck Depression Inventory), and quality of life (Multiple Sclerosis International Quality of Life Questionnaire) were measured before and after treatment in all participants. [Results] There were statistically significant differences in balance, timed performance, tiredness and Multiple Sclerosis Functional Composite tests between before and after treatment in the clinical Pilates group. We also found significant differences in timed performance tests, the Timed up and go test and the Multiple Sclerosis Functional Composite between before and after treatment in the control group. According to the difference analyses, there were significant differences in Multiple Sclerosis Functional Composite and Multiple Sclerosis International Quality of Life Questionnaire scores between the two groups in favor of the clinical Pilates group. There were statistically significant clinical differences in favor of the clinical Pilates group in comparison of measurements between the groups. Clinical Pilates improved cognitive functions and quality of life compared with traditional exercise. [Conclusion] In Multiple Sclerosis treatment, clinical Pilates should be used as a holistic approach by physical therapists.

Testing moderation in network meta-analysis with individual participant data.

PubMed

Dagne, Getachew A; Brown, C Hendricks; Howe, George; Kellam, Sheppard G; Liu, Lei

2016-07-10

Meta-analytic methods for combining data from multiple intervention trials are commonly used to estimate the effectiveness of an intervention. They can also be extended to study comparative effectiveness, testing which of several alternative interventions is expected to have the strongest effect. This often requires network meta-analysis (NMA), which combines trials involving direct comparison of two interventions within the same trial and indirect comparisons across trials. In this paper, we extend existing network methods for main effects to examining moderator effects, allowing for tests of whether intervention effects vary for different populations or when employed in different contexts. In addition, we study how the use of individual participant data may increase the sensitivity of NMA for detecting moderator effects, as compared with aggregate data NMA that employs study-level effect sizes in a meta-regression framework. A new NMA diagram is proposed. We also develop a generalized multilevel model for NMA that takes into account within-trial and between-trial heterogeneity and can include participant-level covariates. Within this framework, we present definitions of homogeneity and consistency across trials. A simulation study based on this model is used to assess effects on power to detect both main and moderator effects. Results show that power to detect moderation is substantially greater when applied to individual participant data as compared with study-level effects. We illustrate the use of this method by applying it to data from a classroom-based randomized study that involved two sub-trials, each comparing interventions that were contrasted with separate control groups. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A mixture gatekeeping procedure based on the Hommel test for clinical trial applications.

PubMed

Brechenmacher, Thomas; Xu, Jane; Dmitrienko, Alex; Tamhane, Ajit C

2011-07-01

When conducting clinical trials with hierarchically ordered objectives, it is essential to use multiplicity adjustment methods that control the familywise error rate in the strong sense while taking into account the logical relations among the null hypotheses. This paper proposes a gatekeeping procedure based on the Hommel (1988) test, which offers power advantages compared to other p value-based tests proposed in the literature. A general description of the procedure is given and details are presented on how it can be applied to complex clinical trial designs. Two clinical trial examples are given to illustrate the methodology developed in the paper.

Young Children Are Not Underconfident with Practice: The Benefit of Ignoring a Fallible Memory Heuristic

ERIC Educational Resources Information Center

Lipko, Amanda R.; Dunlosky, John; Lipowski, Stacy L.; Merriman, William E.

2012-01-01

In this study the authors investigated whether children demonstrated the "underconfidence-with-practice" (UWP) effect. This effect is a highly robust metacognitive illusion in which adults become underconfident in their memory performance when asked to predict their memory for the same items across multiple study-test trials. One…

Use of Dried Capillary Blood Sampling for Islet Autoantibody Screening in Relatives: A Feasibility Study.

PubMed

Bingley, Polly J; Rafkin, Lisa E; Matheson, Della; Steck, Andrea K; Yu, Liping; Henderson, Courtney; Beam, Craig A; Boulware, David C

2015-12-01

Islet autoantibody testing provides the basis for assessment of risk of progression to type 1 diabetes. We set out to determine the feasibility and acceptability of dried capillary blood spot-based screening to identify islet autoantibody-positive relatives potentially eligible for inclusion in prevention trials. Dried blood spot (DBS) and venous samples were collected from 229 relatives participating in the TrialNet Pathway to Prevention Study. Both samples were tested for glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies, and venous samples were additionally tested for insulin autoantibodies and islet cell antibodies. We defined multiple autoantibody positive as two or more autoantibodies in venous serum and DBS screen positive if one or more autoantibodies were detected. Participant questionnaires compared the sample collection methods. Of 44 relatives who were multiple autoantibody positive in venous samples, 42 (95.5%) were DBS screen positive, and DBS accurately detected 145 of 147 autoantibody-negative relatives (98.6%). Capillary blood sampling was perceived as more painful than venous blood draw, but 60% of participants would prefer initial screening using home fingerstick with clinic visits only required if autoantibodies were found. Capillary blood sampling could facilitate screening for type 1 diabetes prevention studies.

A Randomized Controlled Trial of Cognitive Behavioral Therapy (CBT) for Adjusting to Multiple Sclerosis (The saMS Trial): Does CBT Work and for Whom Does It Work?

ERIC Educational Resources Information Center

Moss-Morris, Rona; Dennison, Laura; Landau, Sabine; Yardley, Lucy; Silber, Eli; Chalder, Trudie

2013-01-01

Objective: The aims were (a) to test the effectiveness of a nurse-led cognitive behavioral therapy (CBT) program to assist adjustment in the early stages of multiple sclerosis (MS) and (b) to determine moderators of treatment including baseline distress, social support (SS), and treatment preference. Method: Ninety-four ambulatory people with MS…

A unified framework for weighted parametric multiple test procedures.

PubMed

Xi, Dong; Glimm, Ekkehard; Maurer, Willi; Bretz, Frank

2017-09-01

We describe a general framework for weighted parametric multiple test procedures based on the closure principle. We utilize general weighting strategies that can reflect complex study objectives and include many procedures in the literature as special cases. The proposed weighted parametric tests bridge the gap between rejection rules using either adjusted significance levels or adjusted p-values. This connection is made by allowing intersection hypotheses of the underlying closed test procedure to be tested at level smaller than α. This may be also necessary to take certain study situations into account. For such cases we introduce a subclass of exact α-level parametric tests that satisfy the consonance property. When the correlation is known only for certain subsets of the test statistics, a new procedure is proposed to fully utilize this knowledge within each subset. We illustrate the proposed weighted parametric tests using a clinical trial example and conduct a simulation study to investigate its operating characteristics. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Exercising away the blues: can it help multiple sclerosis-related depression?

PubMed

Feinstein, Anthony; Rector, Neil; Motl, Robert

2013-12-01

The present review focuses on exercise as a treatment for depression in multiple sclerosis. While exercise has emerged as a potentially useful treatment in the general psychiatry-depression literature, the findings from a small number of multiple sclerosis-related treatment trials are equivocal. Methodological limitations, including the absence of depression as a primary endpoint, characterize all the studies completed to date. Given that limitations in study design can be rectified, it is time to put exercise to the test once more. Depressed multiple sclerosis patients and those involved in their care are looking for guidance here because the prevailing zeitgeist promotes the benefits of exercise to mood. But first, some clarity is needed.

Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy.

PubMed

Auyeung, S Freda; Long, Qi; Royster, Erica Bruce; Murthy, Smitha; McNutt, Marcia D; Lawson, David; Miller, Andrew; Manatunga, Amita; Musselman, Dominique L

2009-10-01

Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine. Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.

Advances in the behavioural testing and network imaging of rodent recognition memory

PubMed Central

Kinnavane, Lisa; Albasser, Mathieu M.; Aggleton, John P.

2015-01-01

Research into object recognition memory has been galvanised by the introduction of spontaneous preference tests for rodents. The standard task, however, contains a number of inherent shortcomings that reduce its power. Particular issues include the problem that individual trials are time consuming, so limiting the total number of trials in any condition. In addition, the spontaneous nature of the behaviour and the variability between test objects add unwanted noise. To combat these issues, the ‘bow-tie maze’ was introduced. Although still based on the spontaneous preference of novel over familiar stimuli, the ability to give multiple trials within a session without handling the rodents, as well as using the same objects as both novel and familiar samples on different trials, overcomes key limitations in the standard task. Giving multiple trials within a single session also creates new opportunities for functional imaging of object recognition memory. A series of studies are described that examine the expression of the immediate-early gene, c-fos. Object recognition memory is associated with increases in perirhinal cortex and area Te2 c-fos activity. When rats explore novel objects the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to the dentate gyrus and CA3, is engaged. In contrast, when familiar objects are explored the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to CA1, takes precedence. The switch to the perforant pathway (novel stimuli) from the temporoammonic pathway (familiar stimuli) may assist the enhanced associative learning promoted by novel stimuli. PMID:25106740

Memory and other properties of multiple test procedures generated by entangled graphs.

PubMed

Maurer, Willi; Bretz, Frank

2013-05-10

Methods for addressing multiplicity in clinical trials have attracted much attention during the past 20 years. They include the investigation of new classes of multiple test procedures, such as fixed sequence, fallback and gatekeeping procedures. More recently, sequentially rejective graphical test procedures have been introduced to construct and visualize complex multiple test strategies. These methods propagate the local significance level of a rejected null hypothesis to not-yet rejected hypotheses. In the graph defining the test procedure, hypotheses together with their local significance levels are represented by weighted vertices and the propagation rule by weighted directed edges. An algorithm provides the rules for updating the local significance levels and the transition weights after rejecting an individual hypothesis. These graphical procedures have no memory in the sense that the origin of the propagated significance level is ignored in subsequent iterations. However, in some clinical trial applications, memory is desirable to reflect the underlying dependence structure of the study objectives. In such cases, it would allow the further propagation of significance levels to be dependent on their origin and thus reflect the grouped parent-descendant structures of the hypotheses. We will give examples of such situations and show how to induce memory and other properties by convex combination of several individual graphs. The resulting entangled graphs provide an intuitive way to represent the underlying relative importance relationships between the hypotheses, are as easy to perform as the original individual graphs, remain sequentially rejective and control the familywise error rate in the strong sense. Copyright © 2012 John Wiley & Sons, Ltd.

Reliability of surface electromyography activity of gluteal and hamstring muscles during sub-maximal and maximal voluntary isometric contractions.

PubMed

Bussey, Melanie D; Aldabe, Daniela; Adhia, Divya; Mani, Ramakrishnan

2018-04-01

Normalizing to a reference signal is essential when analysing and comparing electromyography signals across or within individuals. However, studies have shown that MVC testing may not be as reliable in persons with acute and chronic pain. The purpose of this study was to compare the test-retest reliability of the muscle activity in the biceps femoris and gluteus maximus between a novel sub-MVC and standard MVC protocols. This study utilized a single individual repeated measures design with 12 participants performing multiple trials of both the sub-MVC and MVC tasks on two separate days. The participant position in the prone leg raise task was standardised with an ultrasonic sensor to improve task precession between trials/days. Day-to-day and trial-to-trial reliability of the maximal muscle activity was examined using ICC and SEM. Day-to-day and trial-to-trial reliability of the EMG activity in the BF and GM were high (0.70-0.89) to very high (≥0.90) for both test procedures. %SEM was <5-10% for both tests on a given day but higher in the day-to-day comparisons. The lower amplitude of the sub-MVC is a likely contributor to increased %SEM (8-13%) in the day-to-day comparison. The findings show that the sub-MVC modified prone double leg raise results in GM and BF EMG measures similar in reliability and precision to the standard MVC tasks. Therefore, the modified prone double leg raise may be a useful substitute for traditional MVC testing for normalizing EMG signals of the BF and GM. Copyright © 2017 Elsevier Ltd. All rights reserved.

Taxonomy for colorectal cancer screening promotion: Lessons from recent randomized controlled trials.

PubMed

Ritvo, Paul; Myers, Ronald E; Serenity, Mardie; Gupta, Samir; Inadomi, John M; Green, Beverly B; Jerant, Anthony; Tinmouth, Jill; Paszat, Lawrence; Pirbaglou, Meysam; Rabeneck, Linda

2017-08-01

To derive a taxonomy for colorectal cancer screening that advances Randomized Controlled Trials (RCTs) and screening uptake. Detailed publication review, multiple interviews with principal investigators (PIs) and collaboration with PIs as co-authors produced a CRCS intervention taxonomy. Semi-structured interview questions with PIs (Drs. Inadomi, Myers, Green, Gupta, Jerant and Ritvo) yielded details about trial conduct. Interview comparisons led to an iterative process informing serial interviews until a consensus was obtained on final taxonomy structure. These taxonomy headings (Engagement Sponsor, Population Targeted, Alternative Screening Tests, Delivery Methods, and Support for Test Performance (EPADS)) were used to compare studies. Exemplary insights emphasized: 1) direct test delivery to patients; 2) linguistic-ethnic matching of staff to minority subjects; and 3) authorization of navigators to schedule or refer for colonoscopies and/or distribute stool blood tests during screening promotion. PIs of key RCTs (2012-2015) derived a CRCS taxonomy useful in detailed examination of CRCS promotion and design of future RCTs. Copyright © 2017 Elsevier Inc. All rights reserved.

A generic minimization random allocation and blinding system on web.

PubMed

Cai, Hongwei; Xia, Jielai; Xu, Dezhong; Gao, Donghuai; Yan, Yongping

2006-12-01

Minimization is a dynamic randomization method for clinical trials. Although recommended by many researchers, the utilization of minimization has been seldom reported in randomized trials mainly because of the controversy surrounding the validity of conventional analyses and its complexity in implementation. However, both the statistical and clinical validity of minimization were demonstrated in recent studies. Minimization random allocation system integrated with blinding function that could facilitate the implementation of this method in general clinical trials has not been reported. SYSTEM OVERVIEW: The system is a web-based random allocation system using Pocock and Simon minimization method. It also supports multiple treatment arms within a trial, multiple simultaneous trials, and blinding without further programming. This system was constructed with generic database schema design method, Pocock and Simon minimization method and blinding method. It was coded with Microsoft Visual Basic and Active Server Pages (ASP) programming languages. And all dataset were managed with a Microsoft SQL Server database. Some critical programming codes were also provided. SIMULATIONS AND RESULTS: Two clinical trials were simulated simultaneously to test the system's applicability. Not only balanced groups but also blinded allocation results were achieved in both trials. Practical considerations for minimization method, the benefits, general applicability and drawbacks of the technique implemented in this system are discussed. Promising features of the proposed system are also summarized.

Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH).

PubMed

Polster, Sean P; Cao, Ying; Carroll, Timothy; Flemming, Kelly; Girard, Romuald; Hanley, Daniel; Hobson, Nicholas; Kim, Helen; Koenig, James; Koskimäki, Janne; Lane, Karen; Majersik, Jennifer J; McBee, Nichol; Morrison, Leslie; Shenkar, Robert; Stadnik, Agnieszka; Thompson, Richard E; Zabramski, Joseph; Zeineddine, Hussein A; Awad, Issam A

2018-04-11

Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Accounting for Multiple Births in Neonatal and Perinatal Trials: Systematic Review and Case Study

PubMed Central

Hibbs, Anna Maria; Black, Dennis; Palermo, Lisa; Cnaan, Avital; Luan, Xianqun; Truog, William E; Walsh, Michele C; Ballard, Roberta A

2010-01-01

Objectives To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births. To explore the sensitivity of an actual trial to several analytic approaches to multiples. Methods A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The NO CLD trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using non-clustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses. Results In the systematic review, most studies did not describe the randomization of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (p<0.01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not. Conclusions The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue. PMID:19969305

Accounting for multiple births in neonatal and perinatal trials: systematic review and case study.

PubMed

Hibbs, Anna Maria; Black, Dennis; Palermo, Lisa; Cnaan, Avital; Luan, Xianqun; Truog, William E; Walsh, Michele C; Ballard, Roberta A

2010-02-01

To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births and to explore the sensitivity of an actual trial to several analytic approaches to multiples. A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The Nitric Oxide to Prevent Chronic Lung Disease (NO CLD) trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using nonclustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses. In the systematic review, most studies did not describe the random assignment of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (P < .01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not. The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue. Copyright 2010 Mosby, Inc. All rights reserved.

Use of Vitamins and Dietary Supplements by Patients With Multiple Sclerosis: A Review.

PubMed

Evans, Emily; Piccio, Laura; Cross, Anne H

2018-04-23

Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues. Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations. At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation.

Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe.

PubMed

Blok, E J; Bastiaannet, E; van den Hout, W B; Liefers, G J; Smit, V T H B M; Kroep, J R; van de Velde, C J H

2018-01-01

Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.

PubMed

Chan, Dennis; Binks, Sophie; Nicholas, Jennifer M; Frost, Chris; Cardoso, M Jorge; Ourselin, Sebastien; Wilkie, David; Nicholas, Richard; Chataway, Jeremy

2017-08-01

In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6-7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8-8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2-2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3-4·8; p=0·028). A treatment effect was not noted for any other outcomes. To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Using meta-analysis to inform the design of subsequent studies of diagnostic test accuracy.

PubMed

Hinchliffe, Sally R; Crowther, Michael J; Phillips, Robert S; Sutton, Alex J

2013-06-01

An individual diagnostic accuracy study rarely provides enough information to make conclusive recommendations about the accuracy of a diagnostic test; particularly when the study is small. Meta-analysis methods provide a way of combining information from multiple studies, reducing uncertainty in the result and hopefully providing substantial evidence to underpin reliable clinical decision-making. Very few investigators consider any sample size calculations when designing a new diagnostic accuracy study. However, it is important to consider the number of subjects in a new study in order to achieve a precise measure of accuracy. Sutton et al. have suggested previously that when designing a new therapeutic trial, it could be more beneficial to consider the power of the updated meta-analysis including the new trial rather than of the new trial itself. The methodology involves simulating new studies for a range of sample sizes and estimating the power of the updated meta-analysis with each new study added. Plotting the power values against the range of sample sizes allows the clinician to make an informed decision about the sample size of a new trial. This paper extends this approach from the trial setting and applies it to diagnostic accuracy studies. Several meta-analytic models are considered including bivariate random effects meta-analysis that models the correlation between sensitivity and specificity. Copyright © 2012 John Wiley & Sons, Ltd. Copyright © 2012 John Wiley & Sons, Ltd.

Multi-Aircraft Video - Human/Automation Target Recognition Studies: Video Display Size in Unaided Target Acquisition Involving Multiple Videos

DTIC Science & Technology

2008-04-01

Index ( NASA - TLX : Hart & Staveland, 1988), and a Post-Test Questionnaire. Demographic data/Background Questionnaire. This questionnaire was used...very confident). NASA - TLX . The NASA TLX (Hart & Staveland, 1988) is a subjective workload assessment tool. A multidimensional weighting...completed the NASA - TLX . The test trials were randomized across participants and occurred in a counterbalanced order that took into account video display

Effects of Multiple Contexts and Context Similarity on the Renewal of Extinguished Conditioned Behaviour in an ABA Design with Humans

ERIC Educational Resources Information Center

Balooch, Siavash Bandarian; Neumann, David L.

2011-01-01

The ABA renewal procedure involves pairing a conditional stimulus (CS) and an unconditional stimulus (US) in one context (A), presenting extinction trials of the CS alone in a second context (B), and nonreinforced test trials of the CS in the acquisition context (A). The renewal of extinguished conditioned behaviour is observed during test. The…

Detecting small-study effects and funnel plot asymmetry in meta-analysis of survival data: A comparison of new and existing tests.

PubMed

Debray, Thomas P A; Moons, Karel G M; Riley, Richard D

2018-03-01

Small-study effects are a common threat in systematic reviews and may indicate publication bias. Their existence is often verified by visual inspection of the funnel plot. Formal tests to assess the presence of funnel plot asymmetry typically estimate the association between the reported effect size and their standard error, the total sample size, or the inverse of the total sample size. In this paper, we demonstrate that the application of these tests may be less appropriate in meta-analysis of survival data, where censoring influences statistical significance of the hazard ratio. We subsequently propose 2 new tests that are based on the total number of observed events and adopt a multiplicative variance component. We compare the performance of the various funnel plot asymmetry tests in an extensive simulation study where we varied the true hazard ratio (0.5 to 1), the number of published trials (N=10 to 100), the degree of censoring within trials (0% to 90%), and the mechanism leading to participant dropout (noninformative versus informative). Results demonstrate that previous well-known tests for detecting funnel plot asymmetry suffer from low power or excessive type-I error rates in meta-analysis of survival data, particularly when trials are affected by participant dropout. Because our novel test (adopting estimates of the asymptotic precision as study weights) yields reasonable power and maintains appropriate type-I error rates, we recommend its use to evaluate funnel plot asymmetry in meta-analysis of survival data. The use of funnel plot asymmetry tests should, however, be avoided when there are few trials available for any meta-analysis. © 2017 The Authors. Research Synthesis Methods Published by John Wiley & Sons, Ltd.

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.

Nurse-led immunotreatment DEcision Coaching In people with Multiple Sclerosis (DECIMS) - Feasibility testing, pilot randomised controlled trial and mixed methods process evaluation.

PubMed

Rahn, A C; Köpke, S; Backhus, I; Kasper, J; Anger, K; Untiedt, B; Alegiani, A; Kleiter, I; Mühlhauser, I; Heesen, C

2018-02-01

Treatment decision-making is complex for people with multiple sclerosis. Profound information on available options is virtually not possible in regular neurologist encounters. The "nurse decision coach model" was developed to redistribute health professionals' tasks in supporting immunotreatment decision-making following the principles of informed shared decision-making. To test the feasibility of a decision coaching programme and recruitment strategies to inform the main trial. Feasibility testing and parallel pilot randomised controlled trial, accompanied by a mixed methods process evaluation. Two German multiple sclerosis university centres. People with suspected or relapsing-remitting multiple sclerosis facing immunotreatment decisions on first line drugs were recruited. Randomisation to the intervention (n = 38) or control group (n = 35) was performed on a daily basis. Quantitative and qualitative process data were collected from people with multiple sclerosis, nurses and physicians. We report on the development and piloting of the decision coaching programme. It comprises a training course for multiple sclerosis nurses and the coaching intervention. The intervention consists of up to three structured nurse-led decision coaching sessions, access to an evidence-based online information platform (DECIMS-Wiki) and a final physician consultation. After feasibility testing, a pilot randomised controlled trial was performed. People with multiple sclerosis were randomised to the intervention or control group. The latter had also access to the DECIMS-Wiki, but received otherwise care as usual. Nurses were not blinded to group assignment, while people with multiple sclerosis and physicians were. The primary outcome was 'informed choice' after six months including the sub-dimensions' risk knowledge (after 14 days), attitude concerning immunotreatment (after physician consultation), and treatment uptake (after six months). Quantitative process evaluation data were collected via questionnaires. Qualitative interviews were performed with all nurses and a convenience sample of nine people with multiple sclerosis. 116 people with multiple sclerosis fulfilled the inclusion criteria and 73 (63%) were included. Groups were comparable at baseline. Data of 51 people with multiple sclerosis (70%) were available for the primary endpoint. In the intervention group 15 of 31 (48%) people with multiple sclerosis achieved an informed choice after six months and 6 of 20 (30%) in the control group. Process evaluation data illustrated a positive response towards the coaching programme as well as good acceptance. The pilot-phase showed promising results concerning acceptability and feasibility of the intervention, which was well perceived by people with multiple sclerosis, most nurses and physicians. Delegating parts of the immunotreatment decision-making process to trained nurses has the potential to increase informed choice and participation as well as effectiveness of patient-physician consultations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Use of Dried Capillary Blood Sampling for Islet Autoantibody Screening in Relatives: A Feasibility Study

PubMed Central

Rafkin, Lisa E.; Matheson, Della; Steck, Andrea K.; Yu, Liping; Henderson, Courtney; Beam, Craig A.; Boulware, David C.

2015-01-01

Abstract Background: Islet autoantibody testing provides the basis for assessment of risk of progression to type 1 diabetes. We set out to determine the feasibility and acceptability of dried capillary blood spot–based screening to identify islet autoantibody–positive relatives potentially eligible for inclusion in prevention trials. Materials and Methods: Dried blood spot (DBS) and venous samples were collected from 229 relatives participating in the TrialNet Pathway to Prevention Study. Both samples were tested for glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies, and venous samples were additionally tested for insulin autoantibodies and islet cell antibodies. We defined multiple autoantibody positive as two or more autoantibodies in venous serum and DBS screen positive if one or more autoantibodies were detected. Participant questionnaires compared the sample collection methods. Results: Of 44 relatives who were multiple autoantibody positive in venous samples, 42 (95.5%) were DBS screen positive, and DBS accurately detected 145 of 147 autoantibody-negative relatives (98.6%). Capillary blood sampling was perceived as more painful than venous blood draw, but 60% of participants would prefer initial screening using home fingerstick with clinic visits only required if autoantibodies were found. Conclusions: Capillary blood sampling could facilitate screening for type 1 diabetes prevention studies. PMID:26375197

Cognitive Behavioral Therapy for Anxiety in Children with Autism Spectrum Disorders: A Randomized, Controlled Trial

ERIC Educational Resources Information Center

Wood, Jeffrey J.; Drahota, Amy; Sze, Karen; Har, Kim; Chiu, Angela; Langer, David A.

2009-01-01

Background: Children with autism spectrum disorders often present with comorbid anxiety disorders that cause significant functional impairment. This study tested a modular cognitive behavioral therapy (CBT) program for children with this profile. A standard CBT program was augmented with multiple treatment components designed to accommodate or…

The DIAN-TU Next Generation Alzheimer’s prevention trial: adaptive design and disease progression model

PubMed Central

Bateman, Randall J.; Benzinger, Tammie L.; Berry, Scott; Clifford, David B.; Duggan, Cynthia; Fagan, Anne M.; Fanning, Kathleen; Farlow, Martin R.; Hassenstab, Jason; McDade, Eric M.; Mills, Susan; Paumier, Katrina; Quintana, Melanie; Salloway, Stephen P.; Santacruz, Anna; Schneider, Lon S.; Wang, Guoqiao; Xiong, Chengjie

2016-01-01

INTRODUCTION The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer’s disease in autosomal dominant Alzheimer’s disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation Prevention Trial (NexGen). METHODS In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the NIH, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen trial. RESULTS Our expanded trials toolbox consists of a Disease Progression Model for ADAD, primary endpoint DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD. PMID:27583651

Patent foramen ovale closure with GORE HELEX or CARDIOFORM Septal Occluder vs. antiplatelet therapy for reduction of recurrent stroke or new brain infarct in patients with prior cryptogenic stroke: Design of the randomized Gore REDUCE Clinical Study.

PubMed

Kasner, Scott E; Thomassen, Lars; Søndergaard, Lars; Rhodes, John F; Larsen, Coby C; Jacobson, Joth

2017-12-01

Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus patent foramen ovale closure (with GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Subjects will be prospectively followed for up to five years. Neuroimaging is required for all subjects at baseline and at two years or study exit. Study outcomes The two co-primary endpoints for the study are freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization and incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct) through 24 months. The primary analyses are an unadjusted log-rank test and a binomial test of subject-based proportions, respectively, both on the intent-to-treat population, with adjustment for testing multiplicity. Discussion The REDUCE trial aims to target a patient population with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent clinical ischemic stroke or new silent brain infarct; the neuroimaging data will provide an opportunity to further support the proof of concept. The main results are anticipated in 2017. Registration Clinical trial registration-URL: http://clinicaltrials.gov/show/NCT00738894.

Robust inference from multiple test statistics via permutations: a better alternative to the single test statistic approach for randomized trials.

PubMed

Ganju, Jitendra; Yu, Xinxin; Ma, Guoguang Julie

2013-01-01

Formal inference in randomized clinical trials is based on controlling the type I error rate associated with a single pre-specified statistic. The deficiency of using just one method of analysis is that it depends on assumptions that may not be met. For robust inference, we propose pre-specifying multiple test statistics and relying on the minimum p-value for testing the null hypothesis of no treatment effect. The null hypothesis associated with the various test statistics is that the treatment groups are indistinguishable. The critical value for hypothesis testing comes from permutation distributions. Rejection of the null hypothesis when the smallest p-value is less than the critical value controls the type I error rate at its designated value. Even if one of the candidate test statistics has low power, the adverse effect on the power of the minimum p-value statistic is not much. Its use is illustrated with examples. We conclude that it is better to rely on the minimum p-value rather than a single statistic particularly when that single statistic is the logrank test, because of the cost and complexity of many survival trials. Copyright © 2013 John Wiley & Sons, Ltd.

Clinical Pharmacology Quality Assurance (CPQA) Program: Models for Longitudinal Analysis of Antiretroviral (ARV) Proficiency Testing for International Laboratories

PubMed Central

DiFrancesco, Robin; Rosenkranz, Susan L.; Taylor, Charlene R.; Pande, Poonam G.; Siminski, Suzanne M.; Jenny, Richard W.; Morse, Gene D.

2013-01-01

Among National Institutes of Health (NIH) HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals (ARV). Drug assay data are, in turn, entered into study-specific datasets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semi-annual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance (CPQA) program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1)assess the precision and accuracy of concentrations reported by individual CPLs; (2)determine factors associated with round-specific and long-term assay accuracy, precision and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21)drug concentration results reported for clinical trial samples by multiple CPLs).Using the CLIA acceptance of meeting criteria for ≥2/3 consecutive rounds, all ten laboratories that participated in three or more rounds per analyte maintained CLIA proficiency. Significant associations were present between magnitude of error and CPL (Kruskal Wallis [KW]p<0.001), and ARV (KW p<0.001). PMID:24052065

Clinical pharmacology quality assurance program: models for longitudinal analysis of antiretroviral proficiency testing for international laboratories.

PubMed

DiFrancesco, Robin; Rosenkranz, Susan L; Taylor, Charlene R; Pande, Poonam G; Siminski, Suzanne M; Jenny, Richard W; Morse, Gene D

2013-10-01

Among National Institutes of Health HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals. Drug assay data are, in turn, entered into study-specific data sets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis, and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semiannual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1) assess the precision and accuracy of concentrations reported by individual CPLs and (2) determine factors associated with round-specific and long-term assay accuracy, precision, and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21) drug concentration results reported for clinical trial samples by multiple CPLs). Using the Clinical Laboratory Improvement Act acceptance of meeting criteria for ≥2/3 consecutive rounds, all 10 laboratories that participated in 3 or more rounds per analyte maintained Clinical Laboratory Improvement Act proficiency. Significant associations were present between magnitude of error and CPL (Kruskal-Wallis P < 0.001) and antiretroviral (Kruskal-Wallis P < 0.001).

Vision and vision-related outcome measures in multiple sclerosis

PubMed Central

Balcer, Laura J.; Miller, David H.; Reingold, Stephen C.

2015-01-01

Visual impairment is a key manifestation of multiple sclerosis. Acute optic neuritis is a common, often presenting manifestation, but visual deficits and structural loss of retinal axonal and neuronal integrity can occur even without a history of optic neuritis. Interest in vision in multiple sclerosis is growing, partially in response to the development of sensitive visual function tests, structural markers such as optical coherence tomography and magnetic resonance imaging, and quality of life measures that give clinical meaning to the structure-function correlations that are unique to the afferent visual pathway. Abnormal eye movements also are common in multiple sclerosis, but quantitative assessment methods that can be applied in practice and clinical trials are not readily available. We summarize here a comprehensive literature search and the discussion at a recent international meeting of investigators involved in the development and study of visual outcomes in multiple sclerosis, which had, as its overriding goals, to review the state of the field and identify areas for future research. We review data and principles to help us understand the importance of vision as a model for outcomes assessment in clinical practice and therapeutic trials in multiple sclerosis. PMID:25433914

Patient perspectives on physician conflict of interest in industry-sponsored clinical trials for multiple sclerosis therapeutics.

PubMed

Solomon, Andrew J; Klein, Eran P; Corboy, John R; Bernat, James L

2015-10-01

Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician-industry conflicts of interest created by clinical trials and how such disclosures may influence study participation An anonymous online instrument was developed. 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients' decisions to participate in these studies. Findings from this study support a call for uniform guidelines regarding disclosure of physician-industry relationships to prospective research participants for industry-sponsored clinical trials. © The Author(s), 2015.

Reproducibility of a silicone-based test food to masticatory performance evaluation by different sieve methods.

PubMed

Sánchez-Ayala, Alfonso; Vilanova, Larissa Soares Reis; Costa, Marina Abrantes; Farias-Neto, Arcelino

2014-01-01

The aim of this study was to evaluate the reproducibility of the condensation silicone Optosil Comfort® as an artificial test food for masticatory performance evaluation. Twenty dentate subjects with mean age of 23.3±0.7 years were selected. Masticatory performance was evaluated using the simple (MPI), the double (IME) and the multiple sieve methods. Trials were carried out five times by three examiners: three times by the first, and once by the second and third examiners. Friedman's test was used to find the differences among time trials. Reproducibility was determined by the intra-class correlation (ICC) test (α=0.05). No differences among time trials were found, except for MPI-4 mm (p=0.022) from the first examiner results. The intra-examiner reproducibility (ICC) of almost all data was high (ICC≥0.92, p<0.001), being moderate only for MPI-0.50 mm (ICC=0.89, p<0.001). The inter-examiner reproducibility was high (ICC>0.93, p<0.001) for all results. For the multiple sieve method, the average mean of absolute difference from repeated measurements were lower than 1 mm. This trend was observed only from MPI-0.50 to MPI-1.4 for the single sieve method, and from IME-0.71/0.50 to IME-1.40/1.00 for the double sieve method. The results suggest that regardless of the method used, the reproducibility of Optosil Comfort® is high.

Incorporating Multiple Secondary Targets into Learning Trials for Individuals with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Nottingham, Casey L.; Vladescu, Jason C.; Kodak, Tiffany; Kisamore, April N.

2017-01-01

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary…

Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies

PubMed Central

Lewis, Alan S.; van Schalkwyk, Gerrit I.; Bloch, Michael H.

2017-01-01

Cognitive dysfunction in schizophrenia (SCZ) and Alzheimer’s disease (AD) is a major driver of functional disability but is largely unresponsive to current therapeutics. Animal models of cognitive dysfunction relevant to both disorders suggest the α7 nicotinic acetylcholine receptor (nAChR) may be a promising drug development target, with multiple clinical trials subsequently testing this hypothesis in individuals with SCZ and AD. However, the translational value of rodent cognitive tasks for predicting the overall efficacy of this therapeutic target in clinical trials is unknown. To compare effect sizes between rodent and human studies, we searched PubMed and the Cochrane Library for all randomized, placebo-controlled trials of compounds with pharmacological activity at the α7 nAChR for treatment of cognitive dysfunction in SCZ and AD and identified 18 studies comprising 2670 subjects treated with eight different compounds acting as full or partial agonists. Cognitive outcomes were standardized, and random-effects meta-analyses revealed no statistically significant effects of α7 nAChR agonists on overall cognition or any of eight cognitive subdomains when all doses were included (Range of all cognitive outcomes: Cohen’s d = −0.077 to 0.12, negative favoring drug). In contrast, analysis of 29 rodent studies testing the same α7 agonists revealed large effect sizes in multiple commonly used preclinical behavioral tests of cognition (Range: d = −1.18 to −0.73). Our results suggest that targeting the α7 nAChR with agonists is not a robust treatment for cognitive dysfunction in SCZ or AD and necessitate a better understanding of the translational gap for therapeutics targeting the α7 nAChR. PMID:28065843

The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

PubMed Central

Seymour, Lesley; Ivy, S. Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

2010-01-01

The optimal design of phase II studies continues to be the subject of vigorous debate, especially with regards to studies of newer molecularly targeted agents. The observations that many new therapeutics ‘fail’ in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials further emphasizes the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force(CTD-TF)of the NCI Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on Phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations regarding aspects of phase II trial design which are the subject of frequent debate such as endpoints(response vs. progression free survival), randomization(single arm designs vs. randomization), inclusion of biomarkers, biomarker based patient enrichment strategies, and statistical design(e.g. two stage designs vs. multiple-group adaptive designs). While these recommendations in general encourage the use of progression-free survival as the primary endpoint, the use of randomization, the inclusion of biomarkers and the incorporation of newer designs, we acknowledge that objective response as an endpoint, and single arm designs, remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on the characteristic specific to the situation. PMID:20215557

Evaluation of Evidence of Statistical Support and Corroboration of Subgroup Claims in Randomized Clinical Trials.

PubMed

Wallach, Joshua D; Sullivan, Patrick G; Trepanowski, John F; Sainani, Kristin L; Steyerberg, Ewout W; Ioannidis, John P A

2017-04-01

Many published randomized clinical trials (RCTs) make claims for subgroup differences. To evaluate how often subgroup claims reported in the abstracts of RCTs are actually supported by statistical evidence (P < .05 from an interaction test) and corroborated by subsequent RCTs and meta-analyses. This meta-epidemiological survey examines data sets of trials with at least 1 subgroup claim, including Subgroup Analysis of Trials Is Rarely Easy (SATIRE) articles and Discontinuation of Randomized Trials (DISCO) articles. We used Scopus (updated July 2016) to search for English-language articles citing each of the eligible index articles with at least 1 subgroup finding in the abstract. Articles with a subgroup claim in the abstract with or without evidence of statistical heterogeneity (P < .05 from an interaction test) in the text and articles attempting to corroborate the subgroup findings. Study characteristics of trials with at least 1 subgroup claim in the abstract were recorded. Two reviewers extracted the data necessary to calculate subgroup-level effect sizes, standard errors, and the P values for interaction. For individual RCTs and meta-analyses that attempted to corroborate the subgroup findings from the index articles, trial characteristics were extracted. Cochran Q test was used to reevaluate heterogeneity with the data from all available trials. The number of subgroup claims in the abstracts of RCTs, the number of subgroup claims in the abstracts of RCTs with statistical support (subgroup findings), and the number of subgroup findings corroborated by subsequent RCTs and meta-analyses. Sixty-four eligible RCTs made a total of 117 subgroup claims in their abstracts. Of these 117 claims, only 46 (39.3%) in 33 articles had evidence of statistically significant heterogeneity from a test for interaction. In addition, out of these 46 subgroup findings, only 16 (34.8%) ensured balance between randomization groups within the subgroups (eg, through stratified randomization), 13 (28.3%) entailed a prespecified subgroup analysis, and 1 (2.2%) was adjusted for multiple testing. Only 5 (10.9%) of the 46 subgroup findings had at least 1 subsequent pure corroboration attempt by a meta-analysis or an RCT. In all 5 cases, the corroboration attempts found no evidence of a statistically significant subgroup effect. In addition, all effect sizes from meta-analyses were attenuated toward the null. A minority of subgroup claims made in the abstracts of RCTs are supported by their own data (ie, a significant interaction effect). For those that have statistical support (P < .05 from an interaction test), most fail to meet other best practices for subgroup tests, including prespecification, stratified randomization, and adjustment for multiple testing. Attempts to corroborate statistically significant subgroup differences are rare; when done, the initially observed subgroup differences are not reproduced.

Incorporating multiple secondary targets into learning trials for individuals with autism spectrum disorder.

PubMed

Nottingham, Casey L; Vladescu, Jason C; Kodak, Tiffany; Kisamore, April N

2017-07-01

The current study examined the outcome of presenting multiple secondary targets in learning trials for individuals with autism spectrum disorder. We compared conditions in which (a) a secondary target was presented in the antecedent and consequence of trials, (b) two secondary targets were presented in the consequence of trials, (c) one secondary target was presented in the consequence of each trial, and (d) no additional targets were presented trials. The participants acquired the majority of secondary targets. Presenting one or multiple secondary targets per trial, regardless of the location of these secondary targets, increased the efficiency of instruction in comparison to a condition with no secondary target. © 2017 Society for the Experimental Analysis of Behavior.

Evaluation of Intervention Fidelity in a Multisite Clinical Trial in Persons With Multiple Sclerosis.

PubMed

Morrison, Janet D; Becker, Heather; Stuifbergen, Alexa K

2017-12-01

Careful consideration of intervention fidelity is critical to establishing the validity and reliability of research findings, yet such reports are often lacking in the research literature. It is imperative that intervention fidelity be methodically evaluated and reported to promote the translation of effective interventions into sound evidence-based practice. The purpose of this article is to explore strategies used to promote intervention fidelity, incorporating examples from a multisite clinical trial, that illustrate the National Institutes of Health Behavior Change Consortium's 5 domains for recommended treatment practices: (1) study design, (2) facilitator training, (3) intervention delivery, (4) intervention receipt, and (5) intervention enactment. A multisite randomized clinical trial testing the efficacy of a computer-assisted cognitive rehabilitation intervention for adults with multiple sclerosis is used to illustrate strategies promoting intervention fidelity. Data derived from audiotapes of intervention classes, audits of computer exercises completed by participants, participant class attendance, and goal attainment scaling suggested relatively high fidelity to the intervention protocol. This study illustrates how to report intervention fidelity in the literature guided by best practice strategies, which may serve to promote fidelity monitoring and reporting in future studies.

Rationale of technical requirements for NRG-BR001: The first NCI-sponsored trial of SBRT for the treatment of multiple metastases.

PubMed

Al-Hallaq, Hania A; Chmura, Steven; Salama, Joseph K; Winter, Kathryn A; Robinson, Clifford G; Pisansky, Thomas M; Borges, Virginia; Lowenstein, Jessica R; McNulty, Susan; Galvin, James M; Followill, David S; Timmerman, Robert D; White, Julia R; Xiao, Ying; Matuszak, Martha M

In 2014, the NRG Oncology Group initiated the first National Cancer Institute-sponsored, phase 1 clinical trial of stereotactic body radiation therapy (SBRT) for the treatment of multiple metastases in multiple organ sites (BR001; NCT02206334). The primary endpoint is to test the safety of SBRT for the treatment of 2 to 4 multiple lesions in several anatomic sites in a multi-institutional setting. Because of the technical challenges inherent to treating multiple lesions as their spatial separation decreases, we present the technical requirements for NRG-BR001 and the rationale for their selection. Patients with controlled primary tumors of breast, non-small cell lung, or prostate are eligible if they have 2 to 4 metastases distributed among 7 extracranial anatomic locations throughout the body. Prescription and organ-at-risk doses were determined by expert consensus. Credentialing requirements include (1) irradiation of the Imaging and Radiation Oncology Core phantom with SBRT, (2) submitting image guided radiation therapy case studies, and (3) planning the benchmark. Guidelines for navigating challenging planning cases including assessing composite dose are discussed. Dosimetric planning to multiple lesions receiving differing doses (45-50 Gy) and fractionation (3-5) while irradiating the same organs at risk is discussed, particularly for metastases in close proximity (≤5 cm). The benchmark case was selected to demonstrate the planning tradeoffs required to satisfy protocol requirements for 2 nearby lesions. Examples of passing benchmark plans exhibited a large variability in plan conformity. NRG-BR001 was developed using expert consensus on multiple issues from the dose fractionation regimen to the minimum image guided radiation therapy guidelines. Credentialing was tied to the task rather than the anatomic site to reduce its burden. Every effort was made to include a variety of delivery methods to reflect current SBRT technology. Although some simplifications were adopted, the successful completion of this trial will inform future designs of both national and institutional trials and would allow immediate clinical adoption of SBRT trials for oligometastases. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Is the NIHSS Certification Process Too Lenient?

PubMed Central

Hills, Nancy K.; Josephson, S. Andrew; Lyden, Patrick D.; Johnston, S. Claiborne

2009-01-01

Background and Purpose The National Institutes of Health Stroke Scale (NIHSS) is a widely used measure of neurological function in clinical trials and patient assessment; inter-rater scoring variability could impact communications and trial power. The manner in which the rater certification test is scored yields multiple correct answers that have changed over time. We examined the range of possible total NIHSS scores from answers given in certification tests by over 7,000 individual raters who were certified. Methods We analyzed the results of all raters who completed one of two standard multiple-patient videotaped certification examinations between 1998 and 2004. The range for the correct score, calculated using NIHSS ‘correct answers’, was determined for each patient. The distribution of scores derived from those who passed the certification test then was examined. Results A total of 6,268 raters scored 5 patients on Test 1; 1,240 scored 6 patients on Test 2. Using a National Stroke Association (NSA) answer key, we found that correct total scores ranged from 2 correct scores to as many as 12 different correct total scores. Among raters who achieved a passing score and were therefore qualified to administer the NIHSS, score distributions were even wider, with 1 certification patient receiving 18 different correct total scores. Conclusions Allowing multiple acceptable answers for questions on the NIHSS certification test introduces scoring variability. It seems reasonable to assume that the wider the range of acceptable answers in the certification test, the greater the variability in the performance of the test in trials and clinical practice by certified examiners. Greater consistency may be achieved by deriving a set of ‘best’ answers through expert consensus on all questions where this is possible, then teaching raters how to derive these answers using a required interactive training module. PMID:19295205

Early Failures Benefit Subsequent Task Performance.

PubMed

Igata, Hideyoshi; Sasaki, Takuya; Ikegaya, Yuji

2016-02-17

Animals navigate using cognitive maps. However, how they adaptively exploit these maps in changing environments is not fully understood. In this study, we investigated the problem-solving behaviors of mice in a complicated maze in which multiple routes with different intersections were available (Test 1). Although all mice eventually settled on the shortest route, mice that initially exhibited more trial-and-error exploration solved the maze more rapidly. We then introduced one or two barriers that obstructed learned routes such that mice had to establish novel roundabout detours (Tests 2/3). Solutions varied among mice but were predictable based on individual early trial-and-error patterns observed in Test 1: mice that had initially explored more extensively found better solutions. Finally, when the barriers were removed (Test 4), all mice reverted to the best solution after active exploration. Thus, early active exploration helps mice to develop optimal strategies.

Validation of science virtual test to assess 8th grade students' critical thinking on living things and environmental sustainability theme

NASA Astrophysics Data System (ADS)

Rusyati, Lilit; Firman, Harry

2017-05-01

This research was motivated by the importance of multiple-choice questions that indicate the elements and sub-elements of critical thinking and implementation of computer-based test. The method used in this research was descriptive research for profiling the validation of science virtual test to measure students' critical thinking in junior high school. The participant is junior high school students of 8th grade (14 years old) while science teacher and expert as the validators. The instrument that used as a tool to capture the necessary data are sheet of an expert judgment, sheet of legibility test, and science virtual test package in multiple choice form with four possible answers. There are four steps to validate science virtual test to measure students' critical thinking on the theme of "Living Things and Environmental Sustainability" in 7th grade Junior High School. These steps are analysis of core competence and basic competence based on curriculum 2013, expert judgment, legibility test and trial test (limited and large trial test). The test item criterion based on trial test are accepted, accepted but need revision, and rejected. The reliability of the test is α = 0.747 that categorized as `high'. It means the test instruments used is reliable and high consistency. The validity of Rxy = 0.63 means that the validity of the instrument was categorized as `high' according to interpretation value of Rxy (correlation).

Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial.

PubMed

Corey-Bloom, Jody; Wolfson, Tanya; Gamst, Anthony; Jin, Shelia; Marcotte, Thomas D; Bentley, Heather; Gouaux, Ben

2012-07-10

Spasticity is a common and poorly controlled symptom of multiple sclerosis. Our objective was to determine the short-term effect of smoked cannabis on this symptom. We conducted a placebo-controlled, crossover trial involving adult patients with multiple sclerosis and spasticity. We recruited participants from a regional clinic or by referral from specialists. We randomly assigned participants to either the intervention (smoked cannabis, once daily for three days) or control (identical placebo cigarettes, once daily for three days). Each participant was assessed daily before and after treatment. After a washout interval of 11 days, participants crossed over to the opposite group. Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale. Our secondary outcomes included patients' perception of pain (as measured using a visual analogue scale), a timed walk and changes in cognitive function (as measured by patient performance on the Paced Auditory Serial Addition Test), in addition to ratings of fatigue. Thirty-seven participants were randomized at the start of the study, 30 of whom completed the trial. Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p < 0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008). Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2). Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003). No serious adverse events occurred during the trial. Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact.

Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial

PubMed Central

Corey-Bloom, Jody; Wolfson, Tanya; Gamst, Anthony; Jin, Shelia; Marcotte, Thomas D.; Bentley, Heather; Gouaux, Ben

2012-01-01

Background: Spasticity is a common and poorly controlled symptom of multiple sclerosis. Our objective was to determine the short-term effect of smoked cannabis on this symptom. Methods: We conducted a placebo-controlled, crossover trial involving adult patients with multiple sclerosis and spasticity. We recruited participants from a regional clinic or by referral from specialists. We randomly assigned participants to either the intervention (smoked cannabis, once daily for three days) or control (identical placebo cigarettes, once daily for three days). Each participant was assessed daily before and after treatment. After a washout interval of 11 days, participants crossed over to the opposite group. Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale. Our secondary outcomes included patients’ perception of pain (as measured using a visual analogue scale), a timed walk and changes in cognitive function (as measured by patient performance on the Paced Auditory Serial Addition Test), in addition to ratings of fatigue. Results: Thirty-seven participants were randomized at the start of the study, 30 of whom completed the trial. Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p < 0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008). Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2). Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003). No serious adverse events occurred during the trial. Interpretation: Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact. PMID:22586334

Pilates exercise training vs. physical therapy for improving walking and balance in people with multiple sclerosis: a randomized controlled trial.

PubMed

Kalron, Alon; Rosenblum, Uri; Frid, Lior; Achiron, Anat

2017-03-01

Evaluate the effects of a Pilates exercise programme on walking and balance in people with multiple sclerosis and compare this exercise approach to conventional physical therapy sessions. Randomized controlled trial. Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. Forty-five people with multiple sclerosis, 29 females, mean age (SD) was 43.2 (11.6) years; mean Expanded Disability Status Scale (S.D) was 4.3 (1.3). Participants received 12 weekly training sessions of either Pilates ( n=22) or standardized physical therapy ( n=23) in an outpatient basis. Spatio-temporal parameters of walking and posturography parameters during static stance. Functional tests included the Time Up and Go Test, 2 and 6-minute walk test, Functional Reach Test, Berg Balance Scale and the Four Square Step Test. In addition, the following self-report forms included the Multiple Sclerosis Walking Scale and Modified Fatigue Impact Scale. At the termination, both groups had significantly increased their walking speed ( P=0.021) and mean step length ( P=0.023). According to the 2-minute and 6-minute walking tests, both groups at the end of the intervention program had increased their walking speed. Mean (SD) increase in the Pilates and physical therapy groups were 39.1 (78.3) and 25.3 (67.2) meters, respectively. There was no effect of group X time in all instrumented and clinical balance and gait measures. Pilates is a possible treatment option for people with multiple sclerosis in order to improve their walking and balance capabilities. However, this approach does not have any significant advantage over standardized physical therapy.

Electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy in multiple myeloma: a feasibility study

PubMed Central

2014-01-01

Background This single-arm study evaluated feasibility, safety, and initial efficacy of electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy (PN) in cancer patients with multiple myeloma. Methods Patients with neuropathy ≥ grade 2 received 20 acupuncture treatments over 9 weeks. Results For the 19 evaluable patients, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity (FACT/GOG/NTX) mean (SD) scores improved significantly between baseline and week 13 (20.8 [9.6] vs 13.2 [8.5], p = 0.0002). Moderate effect size differences began on week 4, with the largest effect size differences found at week 9 for FACT/GOG/NTX scores, worst pain in the last 24 hours, and pain severity (Cohen’s d = 1.43, 1.19, and 1.08, respectively) and continuing through week 13 (Cohen’s d = 0.86, 0.88, and 0.90, respectively). From baseline to week 13, additional significant improvements were seen as follows: postural stability (1.0 [0.6] vs 0.8 [0.4], p = 0.02); coin test (10.0 [7.4] vs 5.6 [1.9], p < 0.0001); button test (96.1 [144.4] vs 54.9 [47.3], p < 0.0001); and walking test (21.6 [10.0] vs 17.2 [7.7], p = 0.0003). No significant changes were seen with NCS. Conclusions Acupuncture may help patients experiencing thalidomide- or bortezomib-induced PN. Larger, randomized, clinical trials are needed. Trial registration ClinicalTrials.gov Identifier: NCT00891618. PMID:24886772

Make Better Choices (MBC): Study design of a randomized controlled trial testing optimal technology-supported change in multiple diet and physical activity risk behaviors

PubMed Central

2010-01-01

Background Suboptimal diet and physical inactivity are prevalent, co-occurring chronic disease risk factors, yet little is known about how to maximize multiple risk behavior change. Make Better Choices, a randomized controlled trial, tests competing hypotheses about the optimal way to promote healthy change in four bundled risk behaviors: high saturated fat intake, low fruit and vegetable intake, low physical activity, and high sedentary leisure screen time. The study aim is to determine which combination of two behavior change goals - one dietary, one activity - yields greatest overall healthy lifestyle change. Methods/Design Adults (n = 200) with poor quality diet and sedentary lifestyle will be recruited and screened for study eligibility. Participants will be trained to record their diet and activities onto a personal data assistant, and use it to complete two weeks of baseline. Those who continue to show all four risk behaviors after baseline recording will be randomized to one of four behavior change prescriptions: 1) increase fruits and vegetables and increase physical activity, 2) decrease saturated fat and increase physical activity, 3) increase fruits and vegetable and decrease saturated fat, or 4) decrease saturated fat and decrease sedentary activity. They will use decision support feedback on the personal digital assistant and receive counseling from a coach to alter their diet and activity during a 3-week prescription period when payment is contingent upon meeting behavior change goals. They will continue recording on an intermittent schedule during a 4.5-month maintenance period when payment is not contingent upon goal attainment. The primary outcome is overall healthy lifestyle change, aggregated across all four risk behaviors. Discussion The Make Better Choices trial tests a disseminable lifestyle intervention supported by handheld technology. Findings will fill a gap in knowledge about optimal goal prescription to facilitate simultaneous diet and activity change. Results will shed light on which goal prescription maximizes healthful lifestyle change. Trial Registration Clinical Trials Gov. Identifier NCT00113672 PMID:20920275

Comparing the effects of whole-body vibration to standard exercise in ambulatory people with Multiple Sclerosis: a randomised controlled feasibility study.

PubMed

Uszynski, Marcin Kacper; Purtill, Helen; Donnelly, Alan; Coote, Susan

2016-07-01

This study aimed firstly to investigate the feasibility of the study protocol and outcome measures, secondly to obtain data in order to inform the power calculations for a larger randomised controlled trial, and finally to investigate if whole-body vibration (WBV) is more effective than the same duration and intensity of standard exercises (EXE) in people with Multiple Sclerosis (PwMS). Randomised controlled feasibility study. Outpatient MS centre. Twenty seven PwMS (age mean (SD) 48.1 (11.2)) with minimal gait impairments. Twelve weeks of WBV or standard EXE, three times weekly. Participants were measured with isokinetic muscle strength, vibration threshold, Timed Up and Go test (TUG), Mini-BESTest (MBT), 6 Minute Walk test (6MWT), Multiple Sclerosis Impact Scale 29 (MSIS 29), Modified Fatigue Impact Scale (MFIS) and Verbal Analogue scale for sensation (VAS) pre and post 12 week intervention. WBV intervention was found feasible with low drop-out rate (11.1%) and high compliance (90%). Data suggest that a sample of 52 in each group would be sufficient to detect a moderate effect size, with 80% power and 5% significance for 6 minute walk test. Large effect sizes in favour of standard exercise were found for vibration threshold at 5th metatarsophalangeal joint and heel (P=0.014, r= 0.5 and P=0.005, r=0.56 respectively). No between group differences were found for muscle strength, balance or gait (P>0.05). Data suggest that the protocol is feasible, there were no adverse effects. A trial including 120 people would be needed to detect an effect on walking endurance. © The Author(s) 2015.

Development of replication-competent viral vectors for HIV vaccine delivery

PubMed Central

Parks, Christopher L.; Picker, Louis J.; King, C. Richter

2014-01-01

Purpose of review Briefly describe some of the replication-competent (RC) vectors being investigated for development of candidate HIV vaccines focusing primarily on technologies that have advanced to testing in macaques or have entered clinical trials. Recent findings RC viral vectors have advanced to the stage were decisions can be made regarding future development of HIV vaccines. The viruses being used as RC vector platforms vary considerably, and their unique attributes make it possible to test multiple vaccine design concepts and also mimic various aspects of an HIV infection. RC viral vectors encoding SIV or HIV proteins can be used to safely immunize macaques, and in some cases, there is evidence of significant vaccine efficacy in challenge protection studies. Several live HIV vaccine vectors are in clinical trials to evaluate immunogenicity, safety, the effect of mucosal delivery, and potential effects of pre-existing immunity. Summary A variety of DNA and RNA viruses are being used to develop RC viral vectors for HIV vaccine delivery. Multiple viral vector platforms have proven to be safe and immunogenic with evidence of efficacy in macaques. Some of the more advanced HIV vaccine prototypes based on vesicular stomatitis virus, vaccinia virus, measles virus, and Sendai virus are in clinical trials. PMID:23925000

Cross-species infection trials reveal cryptic parasite varieties and a putative polymorphism shared among host species.

PubMed

Luijckx, Pepijn; Duneau, David; Andras, Jason P; Ebert, Dieter

2014-02-01

A parasite's host range can have important consequences for ecological and evolutionary processes but can be difficult to infer. Successful infection depends on the outcome of multiple steps and only some steps of the infection process may be critical in determining a parasites host range. To test this hypothesis, we investigated the host range of the bacterium Pasteuria ramosa, a Daphnia parasite, and determined the parasites success in different stages of the infection process. Multiple genotypes of Daphnia pulex, Daphnia longispina and Daphnia magna were tested with four Pasteuria genotypes using infection trials and an assay that determines the ability of the parasite to attach to the hosts esophagus. We find that attachment is not specific to host species but is specific to host genotype. This may suggest that alleles on the locus controlling attachment are shared among different host species that diverged 100 million year. However, in our trials, Pasteuria was never able to reproduce in nonnative host species, suggesting that Pasteuria infecting different host species are different varieties, each with a narrow host range. Our approach highlights the explanatory power of dissecting the steps of the infection process and resolves potentially conflicting reports on parasite host ranges. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Effectiveness of the Comalli Stroop Test as a measure of negative response bias.

PubMed

Arentsen, Timothy J; Boone, Kyle Brauer; Lo, Tracy T Y; Goldberg, Hope E; Cottingham, Maria E; Victor, Tara L; Ziegler, Elizabeth; Zeller, Michelle A

2013-01-01

Practice guidelines recommend the use of multiple performance validity tests (PVTs) to detect noncredible performance during neuropsychological evaluations, and PVTs embedded in standard cognitive tests achieve this goal most efficiently. The present study examined the utility of the Comalli version of the Stroop Test as a measure of response bias in a large sample of "real world" noncredible patients (n = 129) as compared with credible neuropsychology clinic patients (n=233). The credible group performed significantly better than the noncredible group on all trials, but particularly on word-reading (Stroop A) and color-naming (Stroop B); cut-scores for Stroop A and Stroop B trials were associated with moderate sensitivity (49-53%) as compared to the low sensitivity found for the color interference trial (29%). Some types of diagnoses (including learning disability, severe traumatic brain injury, psychosis, and depression), very advanced age (⩾80), and lowered IQ were associated with increased rates of false positive identifications, suggesting the need for some adjustments to cut-offs in these subgroups. Despite some previous reports of an inverted Stroop effect (i.e., color-naming worse than color interference) in noncredible subjects, individual Stroop word reading and color naming trials were much more effective in identifying response bias.

Microbicide safety/efficacy studies in animals: macaques and small animal models.

PubMed

Veazey, Ronald S

2008-09-01

A number of microbicide candidates have failed to prevent HIV transmission in human clinical trials, and there is uncertainty as to how many additional trials can be supported by the field. Regardless, there are far too many microbicide candidates in development, and a logical and consistent method for screening and selecting candidates for human clinical trials is desperately needed. The unique host and cell specificity of HIV, however, provides challenges for microbicide safety and efficacy screening, that can only be addressed by rigorous testing in relevant laboratory animal models. A number of laboratory animal model systems ranging from rodents to nonhuman primates, and single versus multiple dose challenges have recently been developed to test microbicide candidates. These models have shed light on both the safety and efficacy of candidate microbicides as well as the early mechanisms involved in transmission. This article summarizes the major advantages and disadvantages of the relevant animal models for microbicide safety and efficacy testing. Currently, nonhuman primates are the only relevant and effective laboratory model for screening microbicide candidates. Given the consistent failures of prior strategies, it is now clear that rigorous safety and efficacy testing in nonhuman primates should be a prerequisite for advancing additional microbicide candidates to human clinical trials.

Microbicide Safety/Efficacy studies in animals -macaques and small animal models

PubMed Central

Veazey, Ronald S.

2009-01-01

Purpose of review A number of microbicide candidates have failed to prevent HIV transmission in human clinical trials, and there is uncertainty as to how many additional trials can be supported by the field. Regardless, there are far too many microbicide candidates in development, and a logical and consistent method for screening and selecting candidates for human clinical trials is desperately needed. However, the unique host and cell specificity of HIV provides challenges for microbicide safety and efficacy screening, that can only be addressed by rigorous testing in relevant laboratory animal models. Recent findings A number of laboratory animal model systems ranging from rodents to nonhuman primates, and single versus multiple dose challenges have recently been developed to test microbicide candidates. These models have shed light on both the safety and efficacy of candidate microbicides as well as the early mechanisms involved in transmission. This article summarizes the major advantages and disadvantages of the relevant animal models for microbicide safety and efficacy testing. Summary Currently, nonhuman primates are the only relevant and effective laboratory model for screening microbicide candidates. Given the consistent failures of prior strategies, it is now clear that rigorous safety and efficacy testing in nonhuman primates should be a pre-requisite for advancing additional microbicide candidates to human clinical trials. PMID:19373023

The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model.

PubMed

Bateman, Randall J; Benzinger, Tammie L; Berry, Scott; Clifford, David B; Duggan, Cynthia; Fagan, Anne M; Fanning, Kathleen; Farlow, Martin R; Hassenstab, Jason; McDade, Eric M; Mills, Susan; Paumier, Katrina; Quintana, Melanie; Salloway, Stephen P; Santacruz, Anna; Schneider, Lon S; Wang, Guoqiao; Xiong, Chengjie

2017-01-01

The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD. Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

A randomised controlled trial of multiple periods of outdoor free-play to increase moderate-to-vigorous physical activity among 3 to 6 year old children attending childcare: study protocol.

PubMed

Wolfenden, Luke; Wiggers, John; Morgan, Philip; Razak, Lubna Abdul; Jones, Jannah; Finch, Meghan; Sutherland, Rachel; Lecathelinais, Christophe; Gillham, Karen; Yoong, Sze Lin

2016-09-02

The implementation of physical activity interventions in centre-based childcare services has been recommended to improve child health. This study aims to evaluate the efficacy of scheduling multiple periods of outdoor free play in increasing the time children spend in moderate-to-vigorous physical activity (MVPA) during childcare. The study will employ a between group cluster randomised controlled trial design. Fourteen childcare services in the Hunter New England region of New South Wales, Australia, who currently implement a single session of free outdoor play between their core operational hours of 9 am to 3 pm will be recruited into the trial. Childcare services will be randomised to an intervention or a no intervention control group. Childcare services in the intervention group will be supported by an early childhood education specialist to provide three periods of outdoor free play for children between the hours of 9 am to 3 pm. Each period of outdoor free play will be at least 15 min in duration but must equate to their total usual duration of outdoor play. Services in the control group will continue to implement a single period of outdoor play. The primary trial outcome is minutes of time children spend in MVPA whilst in care assessed objectively via accelerometer over 5 days. Outcome assessment will occur at baseline and 3 months post baseline. Generalised Linear Mixed Models (GLMM) under an intention to treat framework will be used to compare differences between groups in the primary trial outcome at follow-up. Sensitivity analysis will be conducted to test assumptions of missing data. Per protocol analysis will be performed using services that implemented the intervention as intended and subgroup analysis undertaken by gender and baseline physical activity levels of children. The study tests a simple ecological intervention that has the potential to increase child physical activity in care. Australian New Zealand Clinical Trials Registry 12616000347460 . Prospectively registered 17th March 2016.

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

Conflict adaptation in prefrontal cortex: now you see it, now you don't.

PubMed

Kim, Chobok; Johnson, Nathan F; Gold, Brian T

2014-01-01

Daily life requires people to monitor and resolve conflict arising from distracting information irrelevant to current goals. The highly influential conflict monitoring theory (CMT) holds that the anterior cingulate cortex (ACC) detects conflict and subsequently triggers the dorsolateral prefrontal cortex (DLPFC) to regulate that conflict. Multiple lines of evidence have provided support for CMT. For example, performance is faster on incongruent trials that follow other incongruent trials (iI), and is accompanied by reduced ACC and increased DLPFC activation (the conflict adaptation effect). In this fMRI study, we explored whether ACC-DLPFC conflict signaling can result in behavioral adjustments beyond on-line contexts. Participants completed a modified version of the Stroop conflict adaptation paradigm which tested for conflict adaptation effects on the current (N) trial associated with not only the immediately preceding (N - 1) trial, but also 2-back (N - 2) trials. Results demonstrated evidence for direct relationships between ACC activity on N - 2 trials and both N trial DLPFC activity and behavioral adjustment when intervening trials were congruent (i.e., icI). In contrast, when N - 1 trials were incongruent (i.e., iiI), ACC-DLPFC signaling failed and conflict adaptation was absent. These results provide new evidence demonstrating that the conflict monitor-controller maintains previously experienced conflict in the service of subsequent behavioral adjustment. However, the processing of multiple, temporally proximal conflict signals takes a toll on the working memory (WM) system, which appears to require resetting in order to adapt our behavior to frequently changing environmental demands. Copyright © 2013 Elsevier Ltd. All rights reserved.

A new method to address verification bias in studies of clinical screening tests: cervical cancer screening assays as an example.

PubMed

Xue, Xiaonan; Kim, Mimi Y; Castle, Philip E; Strickler, Howard D

2014-03-01

Studies to evaluate clinical screening tests often face the problem that the "gold standard" diagnostic approach is costly and/or invasive. It is therefore common to verify only a subset of negative screening tests using the gold standard method. However, undersampling the screen negatives can lead to substantial overestimation of the sensitivity and underestimation of the specificity of the diagnostic test. Our objective was to develop a simple and accurate statistical method to address this "verification bias." We developed a weighted generalized estimating equation approach to estimate, in a single model, the accuracy (eg, sensitivity/specificity) of multiple assays and simultaneously compare results between assays while addressing verification bias. This approach can be implemented using standard statistical software. Simulations were conducted to assess the proposed method. An example is provided using a cervical cancer screening trial that compared the accuracy of human papillomavirus and Pap tests, with histologic data as the gold standard. The proposed approach performed well in estimating and comparing the accuracy of multiple assays in the presence of verification bias. The proposed approach is an easy to apply and accurate method for addressing verification bias in studies of multiple screening methods. Copyright © 2014 Elsevier Inc. All rights reserved.

Some design issues of strata-matched non-randomized studies with survival outcomes.

PubMed

Mazumdar, Madhu; Tu, Donsheng; Zhou, Xi Kathy

2006-12-15

Non-randomized studies for the evaluation of a medical intervention are useful for quantitative hypothesis generation before the initiation of a randomized trial and also when randomized clinical trials are difficult to conduct. A strata-matched non-randomized design is often utilized where subjects treated by a test intervention are matched to a fixed number of subjects treated by a standard intervention within covariate based strata. In this paper, we consider the issue of sample size calculation for this design. Based on the asymptotic formula for the power of a stratified log-rank test, we derive a formula to calculate the minimum number of subjects in the test intervention group that is required to detect a given relative risk between the test and standard interventions. When this minimum number of subjects in the test intervention group is available, an equation is also derived to find the multiple that determines the number of subjects in the standard intervention group within each stratum. The methodology developed is applied to two illustrative examples in gastric cancer and sarcoma.

Reliability and measurement error of active knee extension range of motion in a modified slump test position: a pilot study.

PubMed

Tucker, Neil; Reid, Duncan; McNair, Peter

2007-01-01

The slump test is a tool to assess the mechanosensitivity of the neuromeningeal structures within the vertebral canal. While some studies have investigated the reliability of aspects of this test within the same day, few have assessed the reliability across days. Therefore, the purpose of this pilot study was to investigate reliability when measuring active knee extension range of motion (AROM) in a modified slump test position within trials on a single day and across days. Ten male and ten female asymptomatic subjects, ages 20-49 (mean age 30.1, SD 6.4) participated in the study. Knee extension AROM in a modified slump position with the cervical spine in a flexed position and then in an extended position was measured via three trials on two separate days. Across three trials, knee extension AROM increased significantly with a mean magnitude of 2 degrees within days for both cervical spine positions (P>0.05). The findings showed that there was no statistically significant difference in knee extension AROM measurements across days (P>0.05). The intraclass correlation coefficients for the mean of the three trials across days were 0.96 (lower limit 95% CI: 0.90) with the cervical spine flexed and 0.93 (lower limit 95% CI: 0.83) with cervical extension. Measurement error was calculated by way of the typical error and 95% limits of agreement, and visually represented in Bland and Altman plots. The typical error for the cervical flexed and extended positions averaged across trials was 2.6 degrees and 3.3 degrees , respectively. The limits of agreement were narrow, and the Bland and Altman plots also showed minimal bias in the joint angles across days with a random distribution of errors across the range of measured angles. This study demonstrated that knee extension AROM could be reliably measured across days in subjects without pathology and that the measurement error was acceptable. Implications of variability over multiple trials are discussed. The modified set-up for the test using the Kincom dynamometer and elevated thigh position may be useful to clinical researchers in determining the mechanosensitivity of the nervous system.

Reliability and Measurement Error of Active Knee Extension Range of Motion in a Modified Slump Test Position: A Pilot Study

PubMed Central

Tucker, Neil; Reid, Duncan; McNair, Peter

2007-01-01

The slump test is a tool to assess the mechanosensitivity of the neuromeningeal structures within the vertebral canal. While some studies have investigated the reliability of aspects of this test within the same day, few have assessed the reliability across days. Therefore, the purpose of this pilot study was to investigate reliability when measuring active knee extension range of motion (AROM) in a modified slump test position within trials on a single day and across days. Ten male and ten female asymptomatic subjects, ages 20–49 (mean age 30.1, SD 6.4) participated in the study. Knee extension AROM in a modified slump position with the cervical spine in a flexed position and then in an extended position was measured via three trials on two separate days. Across three trials, knee extension AROM increased significantly with a mean magnitude of 2° within days for both cervical spine positions (P>0.05). The findings showed that there was no statistically significant difference in knee extension AROM measurements across days (P>0.05). The intraclass correlation coefficients for the mean of the three trials across days were 0.96 (lower limit 95% CI: 0.90) with the cervical spine flexed and 0.93 (lower limit 95% CI: 0.83) with cervical extension. Measurement error was calculated by way of the typical error and 95% limits of agreement, and visually represented in Bland and Altman plots. The typical error for the cervical flexed and extended positions averaged across trials was 2.6° and 3.3°, respectively. The limits of agreement were narrow, and the Bland and Altman plots also showed minimal bias in the joint angles across days with a random distribution of errors across the range of measured angles. This study demonstrated that knee extension AROM could be reliably measured across days in subjects without pathology and that the measurement error was acceptable. Implications of variability over multiple trials are discussed. The modified set-up for the test using the Kincom dynamometer and elevated thigh position may be useful to clinical researchers in determining the mechanosensitivity of the nervous system. PMID:19066666

Effect of respiratory muscle training on exercise performance in healthy individuals: a systematic review and meta-analysis.

PubMed

Illi, Sabine K; Held, Ulrike; Frank, Irène; Spengler, Christina M

2012-08-01

Two distinct types of specific respiratory muscle training (RMT), i.e. respiratory muscle strength (resistive/threshold) and endurance (hyperpnoea) training, have been established to improve the endurance performance of healthy individuals. We performed a systematic review and meta-analysis in order to determine the factors that affect the change in endurance performance after RMT in healthy subjects. A computerized search was performed without language restriction in MEDLINE, EMBASE and CINAHL and references of original studies and reviews were searched for further relevant studies. RMT studies with healthy individuals assessing changes in endurance exercise performance by maximal tests (constant load, time trial, intermittent incremental, conventional [non-intermittent] incremental) were screened and abstracted by two independent investigators. A multiple linear regression model was used to identify effects of subjects' fitness, type of RMT (inspiratory or combined inspiratory/expiratory muscle strength training, respiratory muscle endurance training), type of exercise test, test duration and type of sport (rowing, running, swimming, cycling) on changes in performance after RMT. In addition, a meta-analysis was performed to determine the effect of RMT on endurance performance in those studies providing the necessary data. The multiple linear regression analysis including 46 original studies revealed that less fit subjects benefit more from RMT than highly trained athletes (6.0% per 10 mL · kg⁻¹ · min⁻¹ decrease in maximal oxygen uptake, 95% confidence interval [CI] 1.8, 10.2%; p = 0.005) and that improvements do not differ significantly between inspiratory muscle strength and respiratory muscle endurance training (p = 0.208), while combined inspiratory and expiratory muscle strength training seems to be superior in improving performance, although based on only 6 studies (+12.8% compared with inspiratory muscle strength training, 95% CI 3.6, 22.0%; p = 0.006). Furthermore, constant load tests (+16%, 95% CI 10.2, 22.9%) and intermittent incremental tests (+18.5%, 95% CI 10.8, 26.3%) detect changes in endurance performance better than conventional incremental tests (both p < 0.001) with no difference between time trials and conventional incremental tests (p = 0.286). With increasing test duration, improvements in performance are greater (+0.4% per minute test duration, 95% CI 0.1, 0.6%; p = 0.011) and the type of sport does not influence the magnitude of improvements (all p > 0.05). The meta-analysis, performed on eight controlled trials revealed a significant improvement in performance after RMT, which was detected by constant load tests, time trials and intermittent incremental tests, but not by conventional incremental tests. RMT improves endurance exercise performance in healthy individuals with greater improvements in less fit individuals and in sports of longer durations. The two most common types of RMT (inspiratory muscle strength and respiratory muscle endurance training) do not differ significantly in their effect, while combined inspiratory/expiratory strength training might be superior. Improvements are similar between different types of sports. Changes in performance can be detected by constant load tests, time trials and intermittent incremental tests only. Thus, all types of RMT can be used to improve exercise performance in healthy subjects but care must be taken regarding the test used to investigate the improvements.

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.

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.

General Information about Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

The reliability and validity of fatigue measures during multiple-sprint work: an issue revisited.

PubMed

Glaister, Mark; Howatson, Glyn; Pattison, John R; McInnes, Gill

2008-09-01

The ability to repeatedly produce a high-power output or sprint speed is a key fitness component of most field and court sports. The aim of this study was to evaluate the validity and reliability of eight different approaches to quantify this parameter in tests of multiple-sprint performance. Ten physically active men completed two trials of each of two multiple-sprint running protocols with contrasting recovery periods. Protocol 1 consisted of 12 x 30-m sprints repeated every 35 seconds; protocol 2 consisted of 12 x 30-m sprints repeated every 65 seconds. All testing was performed in an indoor sports facility, and sprint times were recorded using twin-beam photocells. All but one of the formulae showed good construct validity, as evidenced by similar within-protocol fatigue scores. However, the assumptions on which many of the formulae were based, combined with poor or inconsistent test-retest reliability (coefficient of variation range: 0.8-145.7%; intraclass correlation coefficient range: 0.09-0.75), suggested many problems regarding logical validity. In line with previous research, the results support the percentage decrement calculation as the most valid and reliable method of quantifying fatigue in tests of multiple-sprint performance.

Unit: Making Life Easier, Inspection Pack, National Trial Print.

ERIC Educational Resources Information Center

Australian Science Education Project, Toorak, Victoria.

As a part of the unit materials in the series produced by the Australian Science Education Project, this teacher edition is primarily composed of three sections: a core relating to a bicycle, tests, and options. The core is concerned with basic properties of a machine such as force multiplication, speed multiplication, energy dissipation, and…

Recruitment of participants to a multiple sclerosis trial: The CombiRx experience

PubMed Central

Bhanushali, Minal J; Gustafson, Tarah; Powell, Steve; Conwit, Robin A; Wolinsky, Jerry S; Cutter, Gary R; Lublin, Fred; Cofield, Stacey S

2014-01-01

Background and Purpose: Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials. CombiRx was a multi-center, phase III, double-blind, randomized clinical trial comparing the combined use of interferon beta-1a and glatiramer acetate to either agent alone in patients with relapsing-remitting multiple sclerosis (RRMS). This trial was launched in January 2005 in 69 centers in the U.S. and Canada under a co-operative agreement with the National Institute of Neurological Disorders and Stroke (NINDS). The goal was to recruit 1000 patients over 1.5 years after a 6 month startup period. Instead, the investigators required 4.25 years to enroll 1008 patients. Methods: During this trial, we assessed the effectiveness of various recruitment strategies, utility of rescreening prior screen failures, and potential factors and strategies used in study conduct, research and infrastructure, all of which affected recruitment of participants and ultimately time to completion of CombiRx. We particularly were interested in the variability in time to site initiation between academic centers and private practice sites. Results: Physicians who were directly involved in the medical care of patients with RRMS were the primary source of patients recruited to CombiRx. A flexible study design that allowed for re-screening of the initial screen failures after a period of time was useful due to the relapsing/remitting course of the disease. Academic centers took longer to implement the trial than the private practice centers, but once sites were approved for enrollment, there was no important difference in the number of participants enrolled. Limitations: The CombiRx trial was conducted during a period when multiple new medications were being tested, thus affecting the pace of recruitment and limiting ability to generalize our experiences. However, the lessons we learned about process are relevant. Conclusion: Participants can be enrolled successfully in a clinical trial for RRMS, but factors affecting the time to achieve the requirements needed to start screening can be unpredictable and problematic. Prospective planning by the sponsors and investigators, use of central IRBs, master trial agreements and secure remote desktop access to the trial database may expedite trial implementation and participant recruitment. A good scientific research question with flexible study design and active involvement of the clinicians are important factors driving recruitment. Clinical trials can be implemented successfully both in private practices and at academic centers, a consideration when selecting sites. PMID:24686106

Multiple imputation methods for nonparametric inference on cumulative incidence with missing cause of failure

PubMed Central

Lee, Minjung; Dignam, James J.; Han, Junhee

2014-01-01

We propose a nonparametric approach for cumulative incidence estimation when causes of failure are unknown or missing for some subjects. Under the missing at random assumption, we estimate the cumulative incidence function using multiple imputation methods. We develop asymptotic theory for the cumulative incidence estimators obtained from multiple imputation methods. We also discuss how to construct confidence intervals for the cumulative incidence function and perform a test for comparing the cumulative incidence functions in two samples with missing cause of failure. Through simulation studies, we show that the proposed methods perform well. The methods are illustrated with data from a randomized clinical trial in early stage breast cancer. PMID:25043107

The influence of tyre characteristics on measures of rolling performance during cross-country mountain biking.

PubMed

Macdermid, Paul William; Fink, Philip W; Stannard, Stephen R

2015-01-01

This investigation sets out to assess the effect of five different models of mountain bike tyre on rolling performance over hard-pack mud. Independent characteristics included total weight, volume, tread surface area and tread depth. One male cyclist performed multiple (30) trials of a deceleration field test to assess reliability. Further tests performed on a separate occasion included multiple (15) trials of the deceleration test and six fixed power output hill climb tests for each tyre. The deceleration test proved to be reliable as a means of assessing rolling performance via differences in initial and final speed (coefficient of variation (CV) = 4.52%). Overall differences between tyre performance for both deceleration test (P = 0.014) and hill climb (P = 0.032) were found, enabling significant (P < 0.0001 and P = 0.049) models to be generated, allowing tyre performance prediction based on tyre characteristics. The ideal tyre for rolling and climbing performance on hard-pack surfaces would be to decrease tyre weight by way of reductions in tread surface area and tread depth while keeping volume high.

Dispersion of response times reveals cognitive dynamics.

PubMed

Holden, John G; Van Orden, Guy C; Turvey, Michael T

2009-04-01

Trial-to-trial variation in word-pronunciation times exhibits 1/f scaling. One explanation is that human performances are consequent on multiplicative interactions among interdependent processes-interaction dominant dynamics. This article describes simulated distributions of pronunciation times in a further test for multiplicative interactions and interdependence. Individual participant distributions of approximately 1,100 word-pronunciation times were successfully mimicked for each participant in combinations of lognormal and power-law behavior. Successful hazard function simulations generalized these results to establish interaction dominant dynamics, in contrast with component dominant dynamics, as a likely mechanism for cognitive activity. (c) 2009 APA, all rights reserved

Dispersion of Response Times Reveals Cognitive Dynamics

PubMed Central

Holden, John G.; Van Orden, Guy C.; Turvey, Michael T.

2013-01-01

Trial to trial variation in word pronunciation times exhibits 1/f scaling. One explanation is that human performances are consequent on multiplicative interactions among interdependent processes – interaction dominant dynamics. This article describes simulated distributions of pronunciation times in a further test for multiplicative interactions and interdependence. Individual participant distributions of ≈1100 word pronunciation times are successfully mimicked for each participant in combinations of lognormal and power law behavior. Successful hazard function simulations generalize these results to establish interaction dominant dynamics, in contrast with component dominant dynamics, as a likely mechanism for cognitive activity. PMID:19348544

Learning and cognitive fatigue trajectories in multiple sclerosis defined using a burst measurement design.

PubMed

Holtzer, Roee; Foley, Frederick; D'Orio, Vanessa; Spat, Jessica; Shuman, Melissa; Wang, Cuiling

2013-10-01

Compromised learning and cognitive fatigue are critical clinical features in multiple sclerosis. This study was designed to determine the effect of repeated exposures within and across study visits on performance measures of learning and cognitive fatigue in relapsing-remitting multiple sclerosis (RRMS). Thirty patients with RRMS and 30 controls were recruited. Using a burst measurement design (i.e. repeated assessments within and across study visits) the oral version of the Symbol Digit Modalities Test (SDMT) was administered three times during the baseline and two consecutive monthly follow-up visits for a total of nine test administrations. Learning was assessed within and across study visits whereas cognitive fatigue was assessed during the course of each test administration that was divided into three 30-second intervals. Linear mixed-effect models revealed compromised learning within (95% CI: 2.6355 to 3.9867) and across (95% CI: 1.3250 to 3.1861) visits and worse cognitive fatigue (95% CI: -2.1761 to -0.1720) in patients with RRMS compared with controls. Among patients with RRMS, worse self-rated cognitive dysfunction predicted poor learning within (95% CI: -0.1112 to -0.0020) and across (95% CI: -0.0724 to -0.0106) visits. Burst design is optimal to study learning and cognitive fatigue. This methodology, using the SDMT or other time-efficient tests as outcome measures, can be successfully implemented in longitudinal studies and clinical trials.

A commercially available immunoglobulin E-based test for food allergy gives inconsistent results in healthy ponies.

PubMed

Dupont, S; De Spiegeleer, A; Liu, D J X; Lefère, L; van Doorn, D A; Hesta, M

2016-01-01

Commercial immunoglobulin E (IgE)-based tests are available for diagnosis of food allergies and are commonly used in equine practice. However, these tests have been proven unreliable as a screening method in man and other species, but not critically evaluated in equids. Therefore, a commercially available IgE-based test for horses was evaluated. To evaluate the consistency of the results obtained with a commercially available IgE-based test for food allergy diagnosis in ponies (Phase I) and to subject ponies to a provocation trial with the presumed allergens (Phase II). Allergen screening followed by experimental food provocation trials in healthy ponies. Blood samples of 17 healthy Shetland ponies were taken at 2 different time points, sent blinded to a commercial laboratory for screening of common food allergens and the results were evaluated for consistency (Phase I). Ponies that were positive for food allergens were consecutively challenged orally with each allergen separately for 14 days (Phase II). A washout period of one week was applied in ponies with multiple positive results. Clinical parameters and serum amyloid A were monitored during the provocation trial. Only 7/17 ponies were negative on the IgE-based test at the 2 time points, 3 had positive results twice but only one tested positive twice for the same food allergen. No abnormalities were noted during the provocation trials. This study demonstrated that this IgE-based test is not a reliable screening tool for food allergy in healthy equids. © 2015 EVJ Ltd.

Virtual test: A student-centered software to measure student's critical thinking on human disease

NASA Astrophysics Data System (ADS)

Rusyati, Lilit; Firman, Harry

2016-02-01

The study "Virtual Test: A Student-Centered Software to Measure Student's Critical Thinking on Human Disease" is descriptive research. The background is importance of computer-based test that use element and sub element of critical thinking. Aim of this study is development of multiple choices to measure critical thinking that made by student-centered software. Instruments to collect data are (1) construct validity sheet by expert judge (lecturer and medical doctor) and professional judge (science teacher); and (2) test legibility sheet by science teacher and junior high school student. Participants consisted of science teacher, lecturer, and medical doctor as validator; and the students as respondent. Result of this study are describe about characteristic of virtual test that use to measure student's critical thinking on human disease, analyze result of legibility test by students and science teachers, analyze result of expert judgment by science teachers and medical doctor, and analyze result of trial test of virtual test at junior high school. Generally, result analysis shown characteristic of multiple choices to measure critical thinking was made by eight elements and 26 sub elements that developed by Inch et al.; complete by relevant information; and have validity and reliability more than "enough". Furthermore, specific characteristic of multiple choices to measure critical thinking are information in form science comic, table, figure, article, and video; correct structure of language; add source of citation; and question can guide student to critical thinking logically.

Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma

PubMed Central

2014-01-01

Background Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion We present a simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients. PMID:24885819

Resistance of Collard Green Genotypes to Bemisia tabaci Biotype B: Characterization of Antixenosis.

PubMed

Domingos, G M; Baldin, E L L; Canassa, V F; Silva, I F; Lourenção, A L

2018-08-01

Bemisia tabaci (Genn.) biotype B (Hemiptera: Aleyrodidae) is an important pest of vegetable crops, including collard greens Brassica oleracea var. acephala (Brassicaceae). The use of resistant genotypes is an interesting option to reduce insect populations and can be used as an important tool for integrated pest management (IPM). This study evaluated 32 genotypes of collard greens against the attack of silver leaf whitefly, with the aim to characterize antixenosis. Initially, a multiple-choice trial was conducted using all genotypes, in which the adult attractiveness was assessed on two leaves per genotype at 24 and 48 h after infestation. After 48 h, one leaf of each genotype was randomly selected for the determination of the number of eggs per square centimeter. From the results of the multiple-choice trial, 13 genotypes were selected for a no-choice oviposition test, following the same method of the previous test. Colorimetric analyses were also performed to establish possible correlations between leaf color and insect colonization. Genotypes HS-20, OE, and VA were less attractive, demonstrating antixenosis. Genotypes LG, VE, J, MG, MOP, HS-20, VA, and MT had less oviposition in the multiple-choice test, which indicated expression of antixenosis. In the no-choice test, genotypes VE, P1C, CCB, RI-919, H, and J had less oviposition, which also characterized antixenosis. Therefore, genotypes VE and J showed the highest resistance stability because both had less oviposition in both test modalities. Thus, the resistance to B. tabaci biotype B indicates the genotypes HS-20, OE, VA, VE, and J are promising for use in breeding programs to develop resistance to whitefly.

Participant verification: prevention of co-enrolment in clinical trials in South Africa.

PubMed

Harichund, C; Haripersad, K; Ramjee, R

2013-05-15

As KwaZulu-Natal Province is the epicentre of the HIV epidemic in both South Africa (SA) and globally, it is an ideal location to conduct HIV prevention and therapeutic trials. Numerous prevention trials are currently being conducted here; the potential for participant co-enrolment may compromise the validity of these studies and is therefore of great concern. To report the development and feasibility of a digital, fingerprint-based participant identification method to prevent co-enrolment at multiple clinical trial sites. The Medical Research Council (MRC) HIV Prevention Research Unit (HPRU) developed the Biometric Co-enrolment Prevention System (BCEPS), which uses fingerprint-based biometric technology to identify participants. A trial website was used to determine the robustness and usability of the system. After successful testing, the BCEPS was piloted in July 2010 across 7 HPRU clinical research sites. The BCEPS was pre-loaded with study names and clinical trial sites, with new participant information loaded at first visit to a trial site. We successfully implemented the BCEPS at the 7 HPRU sites. Using the BCEPS, we performed real-time 'flagging' of women who were already enrolled in another study as they entered a trial at an HPRU site and, where necessary, excluded them from participation on site. This system has promise in reducing co-enrolment in clinical trials and represents a valuable tool for future implementation by all groups conducting trials. The MRC is currently co-ordinating this effort with clinical trial sites nationally.

The effects of pranayama, hatha and raja yoga on physical pain and the quality of life of women with multiple sclerosis.

PubMed

Doulatabad, Shahla Najafi; Nooreyan, Khirollah; Doulatabad, Ardavan Najafi; Noubandegani, Zinat Mohebbi

2012-01-01

In a clinical trial carried out on 60 women with multiple sclerosis, the researchers obtained data using survey questionnaires. In addition to demographic data, the Multiple Sclerosis Quality of Life-54 (MSQoL-54) instrument was used to determine how multiple sclerosis influences the quality of life of the studied women. Within the frame of this randomized controlled trial, the participants were divided into two equally sized groups (the case and the control group) in which the level of pain and the quality of life were evaluated. The case group exercised pain-managing Yoga methods for three months, keeping the pace of eight 90-minute sessions per month. The control participants were subjected to no intervention. One month after the Yoga therapy, the level of pain and the quality of life were evaluated in both groups and compared to the baseline data. Data were analyzed using SPSS software and paired t-tests. After the Yoga therapy, the case group showed a significant improvement in physical pain management (P=0.007) and the quality of life (P=0.001) as compared to the control group. The results showed that Yoga techniques can alleviate physical pain and improve the quality of life of multiple sclerosis patients.

Comparison of design strategies for a three-arm clinical trial with time-to-event endpoint: Power, time-to-analysis, and operational aspects.

PubMed

Asikanius, Elina; Rufibach, Kaspar; Bahlo, Jasmin; Bieska, Gabriele; Burger, Hans Ulrich

2016-11-01

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three-arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time-to-event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three-arm clinical trial with a time-to-event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions.

PubMed

Cohen, Michael V; Downey, James M

2017-09-26

Scientists and clinicians have been concerned by the lack of a clinically suitable strategy for cardioprotection in patients with acute myocardial infarction despite decades of intensive pre-clinical investigations and a surprising number of clinical trials based on those observations which have uniformly been disappointing. However, it would be a mistake to abandon this search. Rather it would be useful to examine these past efforts and determine reasons for the multiple failures. It appears that earlier clinical trials were often based on results from a single experimental laboratory, thus minimizing the importance of establishing reproducibility in multiple laboratories by multiple scientists and in multiple models. Clinical trials should be discouraged unless robust protection is demonstrated in pre-clinical testing. After approximately 2005 a loading dose of a platelet P2Y 12 receptor antagonist became increasingly widespread in patients with acute myocardial infarction prior to revascularization and quickly became standard-of-care. These agents are now thought to be a cause of failure of recent clinical trials since these pleiotropic drugs also happen to be potent postconditioning mimetics. Thus, introduction of an additional cardioprotective strategy such as ischemic postconditioning which uses the same signaling pathway as these P2Y 12 antagonists would be redundant and doomed to failure. Additive cardioprotection could be achieved only if the second intervention had a different mechanism of cardioprotection. This concept has been demonstrated in experimental animals. So lack of reproducibility of earlier studies and failure to examine interventions in experimental animals also treated with anti-platelet agents could well explain past failures. These realizations should clear the way for development of interventions which can be translated into successful clinical treatments.

Immunotherapy trials for type 1 diabetes: the contribution of George Eisenbarth.

PubMed

Skyler, Jay S; Pugliese, Alberto

2013-06-01

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β-cells, and as such it should respond to immunotherapy. George Eisenbarth gave many significant contributions to this field. He has been involved at some level in most immunotherapy trials during the past three decades. He was among the pioneers who attempted immunotherapy approaches in patients with recent-onset T1D. In the early 1980s he began studying relatives of those with the disease, leading to the concept that T1D was a chronic autoimmune disease, in which islet autoimmune responses would silently destroy β-cells and cause progressive impairment of insulin secretion, years to months before a diagnosis was made. Consequently, he was one of the first to attempt immune intervention in people at high risk of T1D. Throughout his career he developed autoantibody assays and predictive models (which included metabolic testing and later genetics) to identify individuals at risk of T1D. He provided seminal intellectual contributions and critical tools for prevention trials. His focus on insulin as a critical autoantigen led to multiple prevention trials, including the Diabetes Prevention Trial-Type 1 (DPT-1), which studied both parenteral and oral insulin. In the DPT-1 Oral Insulin Trial, a cohort with higher levels of insulin autoantibodies was identified that appeared to have delayed disease progression. Type 1 Diabetes TrialNet is conducting a new trial to verify or refute this observation. Moreover, George identified and tested in the mouse small molecules that block or modulate presentation of a key insulin peptide and in turn prevent the activation of insulin-specific T-lymphocytes. Thus, we believe his greatest contribution is yet to come, as in the near future we should see this most recent work translate into clinical trials.

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.

Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

PubMed

Planchon, Sarah M; Lingas, Karen T; Reese Koç, Jane; Hooper, Brittney M; Maitra, Basabi; Fox, Robert M; Imrey, Peter B; Drake, Kylie M; Aldred, Micheala A; Lazarus, Hillard M; Cohen, Jeffrey A

2018-01-01

Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 10 6 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

The role of exercise in modifying outcomes for people with multiple sclerosis: a randomized trial

PubMed Central

2013-01-01

Background Despite the commonly known benefits of exercise and physical activity evidence shows that persons Multiple Sclerosis (MS) are relatively inactive yet physical activity may be even more important in a population facing functional deterioration. No exercise is effective if it is not done and people with MS face unique barriers to exercise engagement which need to be overcome. We have developed and pilot tested a Multiple Sclerosis Tailored Exercise Program (MSTEP) and it is ready to be tested against general guidelines for superiority and ultimately for its impact on MS relevant outcomes. The primary research question is to what extent does an MS Tailored Exercise Program (MSTEP) result in greater improvements in exercise capacity and related outcomes over a one year period in comparison to a program based on general guidelines for exercise among people with MS who are sedentary and wish to engage in exercise as part of MS self-management. Methods/Design The proposed study is an assessor-blind, parallel-group, randomized controlled trial (RCT). The duration of the intervention will be one year with follow-up to year two. The targeted outcomes are exercise capacity, functional ambulation, strength, and components of quality of life including frequency and intensity of fatigue symptoms, mood, global physical function, health perception, and objective measures of activity level. Logistic regression will be used to test the main hypothesis related to the superiority of the MSTEP program based on a greater proportion of people making a clinically relevant gain in exercise capacity at 1 year and at 2 years, using an intention-to-treat approach. Sample size will be 240 (120 per group). Discussion The MS community is clearly looking for interventions to help alleviate the disabling sequelae of MS and promote health. Exercise is a well-known intervention which has known benefits to all, yet few exercise regularly. For people with MS, the role of exercise in MS management needs to be rigorously assessed to inform people as to how best to use exercise to reduce disability and promote health. Trial registration Clinical Trials.gov: NCT01611987 PMID:23809312

Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: A randomized clinical trial.

PubMed

Khalili, Mohammad; Soltani, Madjid; Moghadam, Shirin Amiri; Dehghan, Parvin; Azimi, Amirreza; Abbaszadeh, Omid

2017-07-01

Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system. Oxidative stress plays a major role in the onset and progression of MS. Asymmetric dimethylarginine (ADMA) formation is dependent on oxidative stress status. We examined whether alpha-lipoic acid (ALA) as a potent antioxidant could improve the Expanded Disability Status Scale (EDSS) and decrease plasma level of ADMA in multiple sclerosis patients. In a randomized, double-blinded clinical trial conducted at Sina Hospital in Tehran, Iran, from September 2009 to July 2011, 24 patients with relapsing-remitting MS were divided into a treatment group receiving ALA (1200mg/day) for 12 weeks and a control group receiving placebo. Then patients' EDSS and Plasma levels of ADMA were measured at baseline and 12 weeks later. Statistical analysis was done by SPSS software version 16 using the K-S test, Chi square, Mann-Whitney U-test and Wilcoxon test. The plasma levels of ADMA in the intervention group were decreased significantly (p=0.04). Also, no patient had increased EDSS score in the supplement group, where 2 out of 12 patients in the placebo group experienced so. Comparing the serum level of ADMA between the two groups failed to show any significant change in the supplement group compared with the control group. Considering that ADMA is produced by oxidative stress in MS patients and leads to increase of inflammation, ALA may have the potential of beneficial effects in them, in part, by decreasing the plasma level of ADMA and stopping progression. The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: No. IRCT138812222602N2. The authors received no financial support for the research, authorship, and/or publication of this article.

TEAMS (Tele-Exercise and Multiple Sclerosis), a Tailored Telerehabilitation mHealth App: Participant-Centered Development and Usability Study

PubMed Central

Rimmer, James H; Johnson, George; Wilroy, Jereme; Young, Hui-Ju; Mehta, Tapan; Lai, Byron

2018-01-01

Background People with multiple sclerosis face varying levels of disability and symptoms, thus requiring highly trained therapists and/or exercise trainers to design personalized exercise programs. However, for people living in geographically isolated communities, access to such trained professionals can be challenging due to a number of barriers associated with cost, access to transportation, and travel distance. Generic mobile health exercise apps often fall short of what people with multiple sclerosis need to become physically active (ie, exercise content that has been adapted to accommodate a wide range of functional limitations). Objective This usability study describes the development process of the TEAMS (Tele-Exercise and Multiple Sclerosis) app, which is being used by people with multiple sclerosis in a large randomized controlled trial to engage in home-based telerehabilitation. Methods Twenty-one participants with disabilities (10 people with multiple sclerosis) were involved in the double iterative design, which included the simultaneous development of the app features and exercise content (exercise videos and articles). Framed within a user-centered design approach, the development process included 2 stages: ground-level creation (focus group followed by early stage evaluations and developments), and proof of concept through 2 usability tests. Usability (effectiveness, usefulness, and satisfaction) was evaluated using a mixed-methods approach. Results During testing of the app’s effectiveness, the second usability test resulted in an average of 1 problem per participant, a decrease of 53% compared to the initial usability test. Five themes were constructed from the qualitative data that related to app usefulness and satisfaction, namely: high perceived confidence for app usability, positive perceptions of exercise videos, viable exercise option at home, orientation and familiarity required for successful participation, and app issues. Participants acknowledged that the final app was ready to be delivered to the public after minor revisions. After including these revisions, the project team released the final app that is being used in the randomized controlled trial. Conclusions A multi-level user-centered development process resulted in the development of an inclusive exercise program for people with multiple sclerosis operated through an easy-to-use app. The promotion of exercise through self-regulated mHealth programs requires a stakeholder-driven approach to app development. This ensures that app and content match the preferences and functional abilities of the end user (ie, people with varying levels of multiple sclerosis). PMID:29798832

TEAMS (Tele-Exercise and Multiple Sclerosis), a Tailored Telerehabilitation mHealth App: Participant-Centered Development and Usability Study.

PubMed

Thirumalai, Mohanraj; Rimmer, James H; Johnson, George; Wilroy, Jereme; Young, Hui-Ju; Mehta, Tapan; Lai, Byron

2018-05-24

People with multiple sclerosis face varying levels of disability and symptoms, thus requiring highly trained therapists and/or exercise trainers to design personalized exercise programs. However, for people living in geographically isolated communities, access to such trained professionals can be challenging due to a number of barriers associated with cost, access to transportation, and travel distance. Generic mobile health exercise apps often fall short of what people with multiple sclerosis need to become physically active (ie, exercise content that has been adapted to accommodate a wide range of functional limitations). This usability study describes the development process of the TEAMS (Tele-Exercise and Multiple Sclerosis) app, which is being used by people with multiple sclerosis in a large randomized controlled trial to engage in home-based telerehabilitation. Twenty-one participants with disabilities (10 people with multiple sclerosis) were involved in the double iterative design, which included the simultaneous development of the app features and exercise content (exercise videos and articles). Framed within a user-centered design approach, the development process included 2 stages: ground-level creation (focus group followed by early stage evaluations and developments), and proof of concept through 2 usability tests. Usability (effectiveness, usefulness, and satisfaction) was evaluated using a mixed-methods approach. During testing of the app's effectiveness, the second usability test resulted in an average of 1 problem per participant, a decrease of 53% compared to the initial usability test. Five themes were constructed from the qualitative data that related to app usefulness and satisfaction, namely: high perceived confidence for app usability, positive perceptions of exercise videos, viable exercise option at home, orientation and familiarity required for successful participation, and app issues. Participants acknowledged that the final app was ready to be delivered to the public after minor revisions. After including these revisions, the project team released the final app that is being used in the randomized controlled trial. A multi-level user-centered development process resulted in the development of an inclusive exercise program for people with multiple sclerosis operated through an easy-to-use app. The promotion of exercise through self-regulated mHealth programs requires a stakeholder-driven approach to app development. This ensures that app and content match the preferences and functional abilities of the end user (ie, people with varying levels of multiple sclerosis). ©Mohanraj Thirumalai, James H Rimmer, George Johnson, Jereme Wilroy, Hui-Ju Young, Tapan Mehta, Byron Lai. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 24.05.2018.

Evaluation of Learning Associated with Multiple Exposures to Computerized Dynamic Posturography

NASA Technical Reports Server (NTRS)

Dean, S. Lance; Paloski, William H.; Taylor, Laura C.; Vanya, Robert D.; Feiveson, Alan H.; Wood, Scott J.

2009-01-01

Computerized dynamic posturography has been used to quantitatively assess the time course of functional sensorimotor recovery after exposure to spaceflight or to groundbased analogs such as head-down bed rest. An assessment of balance recovery may be confounded as subjects develop new strategies through repeated exposures to test paradigms. The purpose of this control study was to characterize the learning effects of sensory organization and motor control tests across multiple sessions. METHODS: Twenty-eight healthy subjects were tested over four sessions. To examine the effects of between-session interval, subjects were assigned to one of four groups in which the interval between the 1 st and 2nd sessions was 7 (+/- 1) days, 14 (+/-1) days, 28 (+/-2) days, or 56 (+/-3) days. The interval between remaining sessions was 28 (+/-4) days. Peak-to-peak anterior-posterior sway was measured during standard Sensory Organization Tests (SOTs) using either fixed or unstable sway-referenced support with eyes open, eyes closed, or sway-referenced vision. Sway was also measured during modified SOTs using eyes-closed conditions with either static or dynamic head tilts. Postural recovery to unexpected support surface perturbations (translations or rotations) was measured during Motor Control Tests. The test order was block randomized across subjects. RESULTS: The learning effects varied with test condition. There were no measurable differences with a stable support surface. The more challenging conditions (unstable support surface with and without head tilts) led to greater differences and took more trials to stabilize. The effect of time interval between the first two sessions was negligible across conditions. Evidence suggested that learning carried across similar conditions (such as unstable support SOTs). DISCUSSION: Familiarization session and/or trials are recommended to minimize learning effects when characterizing functional recovery after exposure to altered sensory environments. The number of practice trials required depends on task difficulty and similarity across conditions. Learning statement: This presentation will review the learning effects of computerized d

Mississippi Communities for Healthy Living: Results of a 6-Month Nutrition Education Comparative Effectiveness Trial

ERIC Educational Resources Information Center

Landry, Alicia S.; Thomson, Jessica L.; Huye, Holly F.; Yadrick, Kathy; Connell, Carol L.

2017-01-01

Background: Improving the diet of communities experiencing health inequities can be challenging given that multiple dietary components are low in quality. Mississippi Communities for Healthy Living was designed to test the comparative effectiveness of nutrition education using a single- versus multiple-message approach to improve the diet of adult…

Behavioral techniques for attenuating the expression of fear associations in an animal model of anxiety.

PubMed

Laborda, Mario A; Polack, Cody W; Miguez, Gonzalo; Miller, Ralph R

2014-09-01

Recent data indicate that extinguished fear often returns when the testing conditions differ from those of treatment. Several manipulations including extensive extinction training, extinction in multiple contexts, and spacing the extinction trials and sessions reduce the return of fear. Moreover, extensive extinction and extinction in multiple contexts summate in reducing return of fear, and the spacing of the extinction trials and the spacing of extinction sessions summate in reducing return of fear. Here we evaluated whether these techniques also attenuate the context specificity of latent inhibition, and whether they summate to further decrease fear responding at test. In two experiments, with rats as subjects in a lick suppression preparation, we assessed the effects of massive CS preexposure, CS preexposure in multiple contexts, and of spacing the CS-preexposure trials and sessions, in reducing the context specificity of latent inhibition. Fear responding was attenuated by all four manipulations. Moreover, extensive CS preexposure in multiple contexts, and conjoint spacing of the CS-preexposure trials and sessions, were more effective in reducing the context specificity of latent inhibition than each manipulation alone. Our experimental designs evaluated degrees of context specificity of latent inhibition but omitted groups in which latent inhibition was assessed without a context shift away from the context of latent inhibition treatment. This precluded us from drawing conclusions concerning absolute (as opposed to relative) levels of recovery from latent inhibition. Techniques effective in decreasing the return of conditioned fear following extinction are also effective in decreasing the context specificity of latent inhibition in an animal model of anxiety. Fear and anxiety disorders might be prevented in anxious human participants with the same techniques used here, but that is still an empirical question. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Randomized Controlled Trial of Team-Based Learning Versus Lectures with Break-Out Groups on Knowledge Retention.

PubMed

Thrall, Grace C; Coverdale, John H; Benjamin, Sophiya; Wiggins, Anna; Lane, Christianne Joy; Pato, Michele T

2016-10-01

This goal of this study was to evaluate the efficacy of team-based learning (TBL) on knowledge retention compared to traditional lectures with small break-out group discussion (teaching as usual (TAU)) using a randomized controlled trial. This randomized controlled trial was conducted during a daylong conference for psychiatric educators on attention-deficit hyperactivity disorder and the research literacy topic of efficacy versus effectiveness trials. Learners (n = 115) were randomized with concealed allocation to either TBL or TAU. Knowledge was measured prior to the intervention, immediately afterward, and 2 months later via multiple-choice tests. Participants were necessarily unblinded. Data enterers, data analysts, and investigators were blinded to group assignment in data analysis. Per-protocol analyses of test scores were performed using change in knowledge from baseline. The primary endpoint was test scores at 2 months. At baseline, there were no statistically significant differences between groups in pre-test knowledge. At immediate post-test, both TBL and TAU groups showed improved knowledge scores compared with their baseline scores. The TBL group performed better statistically on the immediate post-test than the TAU group (Cohen's d = 0.73; p < 0.001), although the differences in knowledge scores were not educationally meaningful, averaging just one additional test question correct (out of 15). On the 2-month remote post-test, there were no group differences in knowledge retention among the 42 % of participants who returned the 2-month test. Both TBL and TAU learners acquired new knowledge at the end of the intervention and retained knowledge over 2 months. At the end of the intervention day and after 2 months, knowledge test scores were not meaningfully different between TBL and TAU completers. In conclusion, this study failed to demonstrate the superiority of TBL over TAU on the primary outcome of knowledge retention at 2 months post-intervention.

Vision function testing for a suprachoroidal retinal prosthesis: effects of image filtering

NASA Astrophysics Data System (ADS)

Barnes, Nick; Scott, Adele F.; Lieby, Paulette; Petoe, Matthew A.; McCarthy, Chris; Stacey, Ashley; Ayton, Lauren N.; Sinclair, Nicholas C.; Shivdasani, Mohit N.; Lovell, Nigel H.; McDermott, Hugh J.; Walker, Janine G.; BVA Consortium,the

2016-06-01

Objective. One strategy to improve the effectiveness of prosthetic vision devices is to process incoming images to ensure that key information can be perceived by the user. This paper presents the first comprehensive results of vision function testing for a suprachoroidal retinal prosthetic device utilizing of 20 stimulating electrodes. Further, we investigate whether using image filtering can improve results on a light localization task for implanted participants compared to minimal vision processing. No controlled implanted participant studies have yet investigated whether vision processing methods that are not task-specific can lead to improved results. Approach. Three participants with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal retinal prosthesis. All three completed multiple trials of a light localization test, and one participant completed multiple trials of acuity tests. The visual representations used were: Lanczos2 (a high quality Nyquist bandlimited downsampling filter); minimal vision processing (MVP); wide view regional averaging filtering (WV); scrambled; and, system off. Main results. Using Lanczos2, all three participants successfully completed a light localization task and obtained a significantly higher percentage of correct responses than using MVP (p≤slant 0.025) or with system off (p\\lt 0.0001). Further, in a preliminary result using Lanczos2, one participant successfully completed grating acuity and Landolt C tasks, and showed significantly better performance (p=0.004) compared to WV, scrambled and system off on the grating acuity task. Significance. Participants successfully completed vision tasks using a 20 electrode suprachoroidal retinal prosthesis. Vision processing with a Nyquist bandlimited image filter has shown an advantage for a light localization task. This result suggests that this and targeted, more advanced vision processing schemes may become important components of retinal prostheses to enhance performance. ClinicalTrials.gov Identifier: NCT01603576.

Change descriptors for determining nodule malignancy in national lung screening trial CT screening images

NASA Astrophysics Data System (ADS)

Geiger, Benjamin; Hawkins, Samuel; Hall, Lawrence O.; Goldgof, Dmitry B.; Balagurunathan, Yoganand; Gatenby, Robert A.; Gillies, Robert J.

2016-03-01

Pulmonary nodules are effectively diagnosed in CT scans, but determining their malignancy has been a challenge. The rate of change of the volume of a pulmonary nodule is known to be a prognostic factor for cancer development. In this study, we propose that other changes in imaging characteristics are similarly informative. We examined the combination of image features across multiple CT scans, taken from the National Lung Screening Trial, with individual scans of the same patient separated by approximately one year. By subtracting the values of existing features in multiple scans for the same patient, we were able to improve the ability of existing classification algorithms to determine whether a nodule will become malignant. We trained each classifier on 83 nodules determined to be malignant by biopsy and 172 nodules determined to be benign by their clinical stability through two years of no change; classifiers were tested on 77 malignant and 144 benign nodules, using a set of features that in a test-retest experiment were shown to be stable. An accuracy of 83.71% and AUC of 0.814 were achieved with the Random Forests classifier on a subset of features determined to be stable via test-retest reproducibility analysis, further reduced with the Correlation-based Feature Selection algorithm.

Classifying four-category visual objects using multiple ERP components in single-trial ERP.

PubMed

Qin, Yu; Zhan, Yu; Wang, Changming; Zhang, Jiacai; Yao, Li; Guo, Xiaojuan; Wu, Xia; Hu, Bin

2016-08-01

Object categorization using single-trial electroencephalography (EEG) data measured while participants view images has been studied intensively. In previous studies, multiple event-related potential (ERP) components (e.g., P1, N1, P2, and P3) were used to improve the performance of object categorization of visual stimuli. In this study, we introduce a novel method that uses multiple-kernel support vector machine to fuse multiple ERP component features. We investigate whether fusing the potential complementary information of different ERP components (e.g., P1, N1, P2a, and P2b) can improve the performance of four-category visual object classification in single-trial EEGs. We also compare the classification accuracy of different ERP component fusion methods. Our experimental results indicate that the classification accuracy increases through multiple ERP fusion. Additional comparative analyses indicate that the multiple-kernel fusion method can achieve a mean classification accuracy higher than 72 %, which is substantially better than that achieved with any single ERP component feature (55.07 % for the best single ERP component, N1). We compare the classification results with those of other fusion methods and determine that the accuracy of the multiple-kernel fusion method is 5.47, 4.06, and 16.90 % higher than those of feature concatenation, feature extraction, and decision fusion, respectively. Our study shows that our multiple-kernel fusion method outperforms other fusion methods and thus provides a means to improve the classification performance of single-trial ERPs in brain-computer interface research.

The use of errorless learning strategies for patients with Alzheimer's disease: a literature review.

PubMed

Li, Ruijie; Liu, Karen P Y

2012-12-01

The aim of this article was to review the evidence of errorless learning on learning outcomes in patients with early-stage Alzheimer's disease. A computer-aided literature search from 1999 to 2011 was carried out using MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and PsycArticles. Keywords included 'errorless learning or practice' and 'Alzheimer's disease'. Four studies that fulfilled the inclusion criteria were selected and reviewed. Two of the studies were clinical controlled trials: one was a single-group pretest-post-test trial and the other was a multiple single-participant study. Demographic variables, design, treatment and outcome measures were summarized. Recall trials were used as the primary outcome measure. Results indicate that the use of errorless learning promotes better retention of specific types of information. Errorless learning is effective in memory rehabilitation of older adults with Alzheimer's disease. However, it would require more studies with unified outcome measures to allow for the formulation of standardized clinical protocol and recommendations.

Resampling-based Methods in Single and Multiple Testing for Equality of Covariance/Correlation Matrices

PubMed Central

Yang, Yang; DeGruttola, Victor

2016-01-01

Traditional resampling-based tests for homogeneity in covariance matrices across multiple groups resample residuals, that is, data centered by group means. These residuals do not share the same second moments when the null hypothesis is false, which makes them difficult to use in the setting of multiple testing. An alternative approach is to resample standardized residuals, data centered by group sample means and standardized by group sample covariance matrices. This approach, however, has been observed to inflate type I error when sample size is small or data are generated from heavy-tailed distributions. We propose to improve this approach by using robust estimation for the first and second moments. We discuss two statistics: the Bartlett statistic and a statistic based on eigen-decomposition of sample covariance matrices. Both statistics can be expressed in terms of standardized errors under the null hypothesis. These methods are extended to test homogeneity in correlation matrices. Using simulation studies, we demonstrate that the robust resampling approach provides comparable or superior performance, relative to traditional approaches, for single testing and reasonable performance for multiple testing. The proposed methods are applied to data collected in an HIV vaccine trial to investigate possible determinants, including vaccine status, vaccine-induced immune response level and viral genotype, of unusual correlation pattern between HIV viral load and CD4 count in newly infected patients. PMID:22740584

Resampling-based methods in single and multiple testing for equality of covariance/correlation matrices.

PubMed

Yang, Yang; DeGruttola, Victor

2012-06-22

Traditional resampling-based tests for homogeneity in covariance matrices across multiple groups resample residuals, that is, data centered by group means. These residuals do not share the same second moments when the null hypothesis is false, which makes them difficult to use in the setting of multiple testing. An alternative approach is to resample standardized residuals, data centered by group sample means and standardized by group sample covariance matrices. This approach, however, has been observed to inflate type I error when sample size is small or data are generated from heavy-tailed distributions. We propose to improve this approach by using robust estimation for the first and second moments. We discuss two statistics: the Bartlett statistic and a statistic based on eigen-decomposition of sample covariance matrices. Both statistics can be expressed in terms of standardized errors under the null hypothesis. These methods are extended to test homogeneity in correlation matrices. Using simulation studies, we demonstrate that the robust resampling approach provides comparable or superior performance, relative to traditional approaches, for single testing and reasonable performance for multiple testing. The proposed methods are applied to data collected in an HIV vaccine trial to investigate possible determinants, including vaccine status, vaccine-induced immune response level and viral genotype, of unusual correlation pattern between HIV viral load and CD4 count in newly infected patients.

The Children’s Attention-deficit Hyperactivity Disorder (ADHD) Telemental Health Treatment Study: Methodology for Conducting a Trial of Telemental Health in Multiple Underserved Communities

PubMed Central

Stoep, Ann Vander; Myers, Kathleen

2013-01-01

Background Children who live in non-metropolitan communities are underserved by evidence-based mental health care and underrepresented in clinical trials of mental health services. Telemental Health (TMH), the use of videoteleconferencing (VTC) to provide care that is usually delivered in person, shows promise for helping to rectify these service disparities. Purpose The Children’s ADHD Telemental Health Treatment Study (CATTS) is a randomized controlled trial designed to test the effectiveness of TMH in providing treatment to children diagnosed with attention-deficit hyperactivity disorder (ADHD) who are living in underserved communities. In this paper we describe the methodologies we developed for the trial and lessons learned. Methods Children ages 5.5-12 years of age with ADHD were referred to CATTS by their primary care physicians (PCP’s). The test intervention group (Group A) received six telepsychiatry sessions followed by in-person caregiver behavioral training delivered by a local therapist who was trained and supervised remotely. A secure website was used to support decision-making by the telepsychiatrists, to facilitate real-time collaboration between the telepsychiatrists and community therapists, and communication with the PCP’s. The control group (Group B) received a single telepsychiatry consultation followed by treatment with their PCP’s who implemented the telepsychiatrists’ recommendations at their discretion. Caregivers completed five sets of questionnaires about children’s symptoms and functioning and their own levels of distress. Older children (aged 10-12 years) completed questionnaires about their symptoms and functioning. Teachers completed ADHD rating scales. Questionnaires were completed online through a secure portal from personal computers. Results Eighty-eight PCP’s in seven communities referred the 223 children who participated in the trial. Attrition was low (3%). Children in Group A completed an average of 5.3 of 6 scheduled sessions; 96% of children in Group B completed their telepsychiatry consultation. Parents in both groups completed an average of 4.8 of 5 assessments. Telepsychiatrists and therapists showed high adherence to treatment protocols. Lessons Learned TMH proved to be a viable means of providing evidence-based pharmacological services to children and of training local therapists in evidence-based caregiver behavioral management. Recruitment was enhanced by offering the control group a telepsychiatry consultation. To meet recruitment targets across multiple dispersed sites, we developed community-specific strategies. A dedicated scheduler was a critical staff role to coordinate the multiple sites, sessions, and clinicians. Trial implementation was easier with sites that shared an electronic medical record system with our research hub. Conclusions The CATTS study used methods and procedures to optimize inclusion of children living in multiple dispersed and underserved areas. These experiences should advance the development of technologies needed to recruit underserved populations into research projects with the goal of reducing disparities in access to quality mental health care. PMID:23897950

Web-based training and interrater reliability testing for scoring the Hamilton Depression Rating Scale.

PubMed

Rosen, Jules; Mulsant, Benoit H; Marino, Patricia; Groening, Christopher; Young, Robert C; Fox, Debra

2008-10-30

Despite the importance of establishing shared scoring conventions and assessing interrater reliability in clinical trials in psychiatry, these elements are often overlooked. Obstacles to rater training and reliability testing include logistic difficulties in providing live training sessions, or mailing videotapes of patients to multiple sites and collecting the data for analysis. To address some of these obstacles, a web-based interactive video system was developed. It uses actors of diverse ages, gender and race to train raters how to score the Hamilton Depression Rating Scale and to assess interrater reliability. This system was tested with a group of experienced and novice raters within a single site. It was subsequently used to train raters of a federally funded multi-center clinical trial on scoring conventions and to test their interrater reliability. The advantages and limitations of using interactive video technology to improve the quality of clinical trials are discussed.

Donepezil improved memory in multiple sclerosis in a randomized clinical trial.

PubMed

Krupp, L B; Christodoulou, C; Melville, P; Scherl, W F; MacAllister, W S; Elkins, L E

2004-11-09

To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS). This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change. Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010). Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia.

PubMed

Montgomery, John H; Byerly, Matthew; Carmody, Thomas; Li, Baitao; Miller, Daniel R; Varghese, Femina; Holland, Rhiannon

2004-12-01

The effect of funding source on the outcome of randomized controlled trials has been investigated in several medical disciplines; however, psychiatry has been largely excluded from such analyses. In this article, randomized controlled trials of second generation antipsychotics in schizophrenia are reviewed and analyzed with respect to funding source (industry vs. non-industry funding). A literature search was conducted for randomized, double-blind trials in which at least one of the tested treatments was a second generation antipsychotic. In each study, design quality and study outcome were assessed quantitatively according to rating scales. Mean quality and outcome scores were compared in the industry-funded studies and non-industry-funded studies. An analysis of the primary author's affiliation with industry was similarly performed. Results of industry-funded studies significantly favored second generation over first generation antipsychotics when compared to non-industry-funded studies. Non-industry-funded studies showed a trend toward higher quality than industry-funded studies; however, the difference between the two was not significant. Also, within the industry-funded studies, outcomes of trials involving first authors employed by industry sponsors demonstrated a trend toward second generation over first generation antipsychotics to a greater degree than did trials involving first authors employed outside the industry (p=0.05). While the retrospective design of the study limits the strength of the findings, the data suggest that industry bias may occur in randomized controlled trials in schizophrenia. There appears to be several sources by which bias may enter clinical research, including trial design, control of data analysis and multiplicity/redundancy of trials.

Using mental visual imagery to improve autobiographical memory and episodic future thinking in relapsing-remitting multiple sclerosis patients: A randomised-controlled trial study.

PubMed

Ernst, Alexandra; Blanc, Frédéric; De Seze, Jérôme; Manning, Liliann

2015-01-01

The co-occurrence of autobiographical memory (AM) and episodic future thinking (EFT) impairment has been documented in relapsing-remitting multiple sclerosis (RR-MS) patients. On these bases, we aimed at probing the efficacy of a mental visual imagery (MVI)-based facilitation programme on AM and EFT functioning in the context of a randomised-controlled trial study in RR-MS patients. Using the Autobiographical Interview (AI), 40 patients presenting with an AM/EFT impairment were randomly assigned in three groups: (i) the experimental (n = 17), who followed the MVI programme, (ii) the verbal control (n = 10), who followed a sham verbal programme, and (iii) the stability groups (n = 13), who underwent the AM/EFT test twice, with no intervention in between. AI's second assessment scores showed a significant improvement of AM and EFT performance only for the experimental group, with a long-term robustness of treatment benefits. The control and stability groups' results ruled out nursing and test learning effects as explanations of AM/EFT improvement. These benefits were corroborated by the patients' comments, which indicated an effective MVI strategy transfer to daily life. Our results suggest that the MVI programme tackles a common cognitive process of scene construction present in AM and EFT.

Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials.

PubMed

Hung, H M James; Wang, Sue-Jane; Yang, Peiling; Jin, Kun; Lawrence, John; Kordzakhia, George; Massie, Tristan

2016-01-01

There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

A Meshless Method Using Radial Basis Functions for Beam Bending Problems

NASA Technical Reports Server (NTRS)

Raju, I. S.; Phillips, D. R.; Krishnamurthy, T.

2004-01-01

A meshless local Petrov-Galerkin (MLPG) method that uses radial basis functions (RBFs) as trial functions in the study of Euler-Bernoulli beam problems is presented. RBFs, rather than generalized moving least squares (GMLS) interpolations, are used to develop the trial functions. This choice yields a computationally simpler method as fewer matrix inversions and multiplications are required than when GMLS interpolations are used. Test functions are chosen as simple weight functions as they are in the conventional MLPG method. Compactly and noncompactly supported RBFs are considered. Noncompactly supported cubic RBFs are found to be preferable. Patch tests, mixed boundary value problems, and problems with complex loading conditions are considered. Results obtained from the radial basis MLPG method are either of comparable or better accuracy than those obtained when using the conventional MLPG method.

Analysis of the psychometric properties of the Multiple Sclerosis Impact Scale-29 (MSIS-29) in relapsing–remitting multiple sclerosis using classical and modern test theory

PubMed Central

Wyrwich, KW; Phillips, GA; Vollmer, T; Guo, S

2016-01-01

Background Investigations using classical test theory support the psychometric properties of the original version of the Multiple Sclerosis Impact Scale (MSIS-29v1), a disease-specific measure of multiple sclerosis (MS) impact (physical and psychological subscales). Later, assessments of the MSIS-29v1 in an MS community-based sample using Rasch analysis led to revisions of the instrument’s response options (MSIS-29v2). Objective The objective of this paper is to evaluate the psychometric properties of the MSIS-29v1 in a clinical trial cohort of relapsing–remitting MS patients (RRMS). Methods Data from 600 patients with RRMS enrolled in the SELECT clinical trial were used. Assessments were performed at baseline and at Weeks 12, 24, and 52. In addition to traditional psychometric analyses, Item Response Theory (IRT) and Rasch analysis were used to evaluate the measurement properties of the MSIS-29v1. Results Both MSIS-29v1 subscales demonstrated strong reliability, construct validity, and responsiveness. The IRT and Rasch analysis showed overall support for response category threshold ordering, person-item fit, and item fit for both subscales. Conclusions Both MSIS-29v1 subscales demonstrated robust measurement properties using classical, IRT, and Rasch techniques. Unlike previous research using a community-based sample, the MSIS-29v1 was found to be psychometrically sound to assess physical and psychological impairments in a clinical trial sample of patients with RRMS. PMID:28607741

Analysis of the psychometric properties of the Multiple Sclerosis Impact Scale-29 (MSIS-29) in relapsing-remitting multiple sclerosis using classical and modern test theory.

PubMed

Bacci, E D; Wyrwich, K W; Phillips, G A; Vollmer, T; Guo, S

2016-01-01

Investigations using classical test theory support the psychometric properties of the original version of the Multiple Sclerosis Impact Scale (MSIS-29v1), a disease-specific measure of multiple sclerosis (MS) impact (physical and psychological subscales). Later, assessments of the MSIS-29v1 in an MS community-based sample using Rasch analysis led to revisions of the instrument's response options (MSIS-29v2). The objective of this paper is to evaluate the psychometric properties of the MSIS-29v1 in a clinical trial cohort of relapsing-remitting MS patients (RRMS). Data from 600 patients with RRMS enrolled in the SELECT clinical trial were used. Assessments were performed at baseline and at Weeks 12, 24, and 52. In addition to traditional psychometric analyses, Item Response Theory (IRT) and Rasch analysis were used to evaluate the measurement properties of the MSIS-29v1. Both MSIS-29v1 subscales demonstrated strong reliability, construct validity, and responsiveness. The IRT and Rasch analysis showed overall support for response category threshold ordering, person-item fit, and item fit for both subscales. Both MSIS-29v1 subscales demonstrated robust measurement properties using classical, IRT, and Rasch techniques. Unlike previous research using a community-based sample, the MSIS-29v1 was found to be psychometrically sound to assess physical and psychological impairments in a clinical trial sample of patients with RRMS.

Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

PubMed Central

Kaduszkiewicz, Hanna; Zimmermann, Thomas; Beck-Bornholdt, Hans-Peter; van den Bussche, Hendrik

2005-01-01

Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents. Data sources The terms “donepezil”, “rivastigmine”, and “galantamine”, limited by “randomized-controlled-trials” were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language. Study selection All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality. Results 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale—cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws—for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation. Conclusion Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable. PMID:16081444

Patient Recruitment into a Multicenter Randomized Clinical Trial 
for Kidney Disease: Report of the Focal Segmental Glomerulosclerosis Clinical Trial (FSGS CT)

PubMed Central

Ferris, Maria; Norwood, Victoria; Radeva, Milena; Gassman, Jennifer J.; Al‐Uzri, Amira; Askenazi, David; Matoo, Tej; Pinsk, Maury; Sharma, Amita; Smoyer, William; Stults, Jenna; Vyas, Shefali; Weiss, Robert; Gipson, Debbie; Kaskel, Frederick; Friedman, Aaron; Moxey‐Mims, Marva

2012-01-01

Abstract We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open‐label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web‐based anonymous survey of site investigators revealed site‐related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start‐up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. Clin Trans Sci 2013; Volume 6: 13–20 PMID:23399084

Patient recruitment into a multicenter randomized clinical trial for kidney disease: report of the focal segmental glomerulosclerosis clinical trial (FSGS CT).

PubMed

Ferris, Maria; Norwood, Victoria; Radeva, Milena; Gassman, Jennifer J; Al-Uzri, Amira; Askenazi, David; Matoo, Tej; Pinsk, Maury; Sharma, Amita; Smoyer, William; Stults, Jenna; Vyas, Shefali; Weiss, Robert; Gipson, Debbie; Kaskel, Frederick; Friedman, Aaron; Moxey-Mims, Marva; Trachtman, Howard

2013-02-01

We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open-label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web-based anonymous survey of site investigators revealed site-related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start-up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. © 2013 Wiley Periodicals, Inc.

Effect of Fee on Cervical Cancer Screening Attendance—ScreenFee, a Swedish Population-Based Randomised Trial

PubMed Central

Alfonzo, Emilia; Andersson Ellström, Agneta; Nemes, Szilard; Strander, Björn

2016-01-01

Background Attendance in the cervical cancer screening programme is one of the most important factors to lower the risk of contracting the disease. Attendance rates are often low in areas with low socioeconomic status. Charging a fee for screening might possibly decrease attendance in this population. Screening programme coverage is low in low socio-economic status areas in Gothenburg, Sweden, but has increased slightly after multiple interventions in recent years. For many years, women in the region have paid a fee for screening. We studied the effect of abolishing this fee in a trial emanating from the regular cervical cancer screening programme. Method Individually randomised controlled trial. All 3 124 women in three low-resource areas in Gothenburg, due for screening during the study period, were randomised to receive an offer of a free test or the standard invitation stating the regular fee of 100 SEK (≈11 €). The study was conducted during the first six months of 2013. Attendance was defined as a registered Pap smear within 90 days from the date the invitation was sent out. Results Attendance did not differ significantly between women who were charged and those offered free screening (RR 0.93; CI 0.85–1.02). No differences were found within the districts or as an effect of age, attendance after the most recent previous invitation or previous experience of smear taking. Conclusion Abolishment of a modest screening fee in socially disadvantaged urban districts with low coverage, after previous multiple systematic interventions, does not increase attendance in the short term. Other interventions might be more important for increasing attendance in low socio-economic status areas. Trial Registration ClinicalTrials.gov NCT02378324 PMID:26986848

Barriers to Clinical Trial Enrollment in Racial and Ethnic Minority Patients With Cancer

PubMed Central

Hamel, Lauren M.; Penner, Louis A.; Albrecht, Terrance L.; Heath, Elisabeth; Gwede, Clement K.; Eggly, Susan

2016-01-01

Background Clinical trials that study cancer are essential for testing the safety and effectiveness of promising treatments, but most people with cancer never enroll in a clinical trial — a challenge exemplified in racial and ethnic minorities. Underenrollment of racial and ethnic minorities reduces the generalizability of research findings and represents a disparity in access to high-quality health care. Methods Using a multilevel model as a framework, potential barriers to trial enrollment of racial and ethnic minorities were identified at system, individual, and interpersonal levels. Exactly how each level directly or indirectly contributes to doctor–patient communication was also reviewed. Selected examples of implemented interventions are included to help address these barriers. We then propose our own evidence-based intervention addressing barriers at the individual and interpersonal levels. Results Barriers to enrolling a diverse population of patients in clinical trials are complex and multilevel. Interventions focused at each level have been relatively successful, but multilevel interventions have the greatest potential for success. Conclusion To increase the enrollment of racial and ethnic minorities in clinical trials, future interventions should address barriers at multiple levels. PMID:27842322

Accounting for multiple births in randomised trials: a systematic review.

PubMed

Yelland, Lisa Nicole; Sullivan, Thomas Richard; Makrides, Maria

2015-03-01

Multiple births are an important subgroup to consider in trials aimed at reducing preterm birth or its consequences. Including multiples results in a unique mixture of independent and clustered data, which has implications for the design, analysis and reporting of the trial. We aimed to determine how multiple births were taken into account in the design and analysis of recent trials involving preterm infants, and whether key information relevant to multiple births was reported. We conducted a systematic review of multicentre randomised trials involving preterm infants published between 2008 and 2013. Information relevant to multiple births was extracted. Of the 56 trials included in the review, 6 (11%) excluded multiples and 24 (43%) failed to indicate whether multiples were included. Among the 26 trials that reported multiples were included, only one (4%) accounted for clustering in the sample size calculations and eight (31%) took the clustering into account in the analysis of the primary outcome. Of the 20 trials that randomised infants, 12 (60%) failed to report how infants from the same birth were randomised. Information on multiple births is often poorly reported in trials involving preterm infants, and clustering due to multiple births is rarely taken into account. Since ignoring clustering could result in inappropriate recommendations for clinical practice, clustering should be taken into account in the design and analysis of future neonatal and perinatal trials including infants from a multiple birth. 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.

Project EX: A Program of Empirical Research on Adolescent Tobacco Use Cessation

PubMed Central

Sussman, Steve; McCuller, William J; Zheng, Hong; Pfingston, Yvonne M; Miyano, James; Dent, Clyde W

2004-01-01

This paper presents the Project EX research program. The historical background for Project EX is presented, including a brief summary of reasons youth fail to quit tobacco use, the disappointing status of previous cessation research, and the teen cessation trial that provided the template for the current project (Project TNT). Next, program development studies for Project EX are described. Through use of focus groups, a theme study (concept evaluation of written activity descriptions), a component study, and pilot studies, an eight-session program was developed. This program involves novel activities (e.g., "talk show enactments," games, and alternative medicine-type activities such as yoga and meditation) in combination with motivation enhancement and cognitive-behavioral strategies to motivate and instruct in cessation initiation and maintenance efforts. The outcomes of the first experimental trial of Project EX, a school-based clinic program, are described, followed by a posthoc analysis of its effects mediation. A second EX study, a multiple baseline single group pilot study design in Wuhan, China, is described next. Description of a second experimental trial follows, which tested EX with nicotine gum versus a natural herb. A third experimental trial that tests a classroom prevention/cessation version of EX is then introduced. Finally, the implications of this work are discussed. The intent-to-treat quit rate for Project EX is approximately 15% across studies, double that of a standard care comparison. Effects last up to a six-month post-program at regular and alternative high schools. Through a systematic protocol of empirical program development and field trials, an effective and replicable model teen tobacco use cessation program is established. Future cessation work might expand on this work.

Project EX: A Program of Empirical Research on Adolescent Tobacco Use Cessation

PubMed Central

Sussman, Steve; McCuller, William J; Zheng, Hong; Pfingston, Yvonne M; Miyano, James; Dent, Clyde W

2004-01-01

This paper presents the Project EX research program. The historical background for Project EX is presented, including a brief summary of reasons youth fail to quit tobacco use, the disappointing status of previous cessation research, and the teen cessation trial that provided the template for the current project (Project TNT). Next, program development studies for Project EX are described. Through use of focus groups, a theme study (concept evaluation of written activity descriptions), a component study, and pilot studies, an eight-session program was developed. This program involves novel activities (e.g., "talk show enactments," games, and alternative medicine-type activities such as yoga and meditation) in combination with motivation enhancement and cognitive-behavioral strategies to motivate and instruct in cessation initiation and maintenance efforts. The outcomes of the first experimental trial of Project EX, a school-based clinic program, are described, followed by a posthoc analysis of its effects mediation. A second EX study, a multiple baseline single group pilot study design in Wuhan, China, is described next. Description of a second experimental trial follows, which tested EX with nicotine gum versus a natural herb. A third experimental trial that tests a classroom prevention/cessation version of EX is then introduced. Finally, the implications of this work are discussed. The intent-to-treat quit rate for Project EX is approximately 15% across studies, double that of a standard care comparison. Effects last up to a six-month post-program at regular and alternative high schools. Through a systematic protocol of empirical program development and field trials, an effective and replicable model teen tobacco use cessation program is established. Future cessation work might expand on this work. PMID:19570278

Is the hibiscus harlequin bug aposematic? The importance of testing multiple predators

PubMed Central

Fabricant, Scott A; Smith, Carolynn L

2014-01-01

Aposematism involves predators learning conspicuous signals of defended prey. However, prey species utilize a wide range of chemical (or physical) defenses, which are not likely to be equally aversive to all predators. Aposematism may therefore only be effective against a physiologically sensitive subset of potential predators, and this can only be identified through behavioral testing. We studied the emerging model organism Tectocoris diophthalmus (Heteroptera: Scutelleridae), an aposematically colored but weakly defended shieldback stinkbug, to test the efficacy of its defenses against a suite of predator types. We predicted the bugs' defenses would be ineffectual against both experienced and naïve birds but aversive to predaceous insects. Surprisingly, the opposite pattern was found. Both habituated wild passerines and naïve chickens avoided the bugs, the chickens after only one or two encounters. To avian predators, T. diophthalmus is aposematic. However, praying mantids showed no repellency, aversion, or toxicity associated with adult or juvenile bugs after multiple trials. Comparison with prior studies on mantids using bugs with chemically similar but more concentrated defenses underscores the importance of dose in addition to chemical identity in the efficacy of chemical defenses. Our results also emphasize the importance of behavioral testing with multiple ecologically relevant predators to understand selective pressures shaping aposematic signals and chemical defenses. PMID:24558567

Design innovations and baseline findings in a long-term Parkinson’s trial: NET-PD LS-1

PubMed Central

2012-01-01

Background Based on the pre-clinical and the results of a phase 2 futility study, creatine was selected for an efficacy trial in Parkinson’s disease (PD). We present the design rationale and a description of the study cohort at baseline. Methods A randomized, multicenter, double-blind, parallel group, placebo controlled Phase 3 study of creatine (10 gm daily) in participants with early, treated PD, the Long-term Study – 1 (LS-1) is being conducted by the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network. The study utilizes a global statistical test (GST) encompassing multiple clinical rating scales to provide a multidimensional assessment of disease progression. Results A total of 1,741 PD participants from 45 sites in the U.S. and Canada were randomized 1:1 to either 10-gm creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS-1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. Conclusions LS-1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit against the background of dopaminergic therapy and best PD care. PMID:23079770

A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients with Major Depressive Disorder.

PubMed

Baune, Bernhard T; Brignone, Mélanie; Larsen, Klaus Groes

2018-02-01

Major depressive disorder is a common condition that often includes cognitive dysfunction. A systematic literature review of studies and a network meta-analysis were carried out to assess the relative effect of antidepressants on cognitive dysfunction in major depressive disorder. MEDLINE, Embase, Cochrane, CDSR, and PsychINFO databases; clinical trial registries; and relevant conference abstracts were searched for randomized controlled trials assessing the effects of antidepressants/placebo on cognition. A network meta-analysis comparing antidepressants was conducted using a random effects model. The database search retrieved 11337 citations, of which 72 randomized controlled trials from 103 publications met the inclusion criteria. The review identified 86 cognitive tests assessing the effect of antidepressants on cognitive functioning. However, the Digit Symbol Substitution Test, which targets multiple domains of cognition and is recognized as being sensitive to change, was the only test that was used across 12 of the included randomized controlled trials and that allowed the construction of a stable network suitable for the network meta-analysis. The interventions assessed included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other non-selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors. The network meta-analysis using the Digit Symbol Substitution Test showed that vortioxetine was the only antidepressant that improved cognitive dysfunction on the Digit Symbol Substitution Test vs placebo {standardized mean difference: 0.325 (95% CI = 0.120; 0.529, P=.009}. Compared with other antidepressants, vortioxetine was statistically more efficacious on the Digit Symbol Substitution Test vs escitalopram, nortriptyline, and the selective serotonin reuptake inhibitor and tricyclic antidepressant classes. This study highlighted the large variability in measures used to assess cognitive functioning. The findings on the Digit Symbol Substitution Test indicate differential effects of various antidepressants on improving cognitive function in patients with major depressive disorder. © The Author 2017. Published by Oxford University Press on behalf of CINP.

An entropy-based nonparametric test for the validation of surrogate endpoints.

PubMed

Miao, Xiaopeng; Wang, Yong-Cheng; Gangopadhyay, Ashis

2012-06-30

We present a nonparametric test to validate surrogate endpoints based on measure of divergence and random permutation. This test is a proposal to directly verify the Prentice statistical definition of surrogacy. The test does not impose distributional assumptions on the endpoints, and it is robust to model misspecification. Our simulation study shows that the proposed nonparametric test outperforms the practical test of the Prentice criterion in terms of both robustness of size and power. We also evaluate the performance of three leading methods that attempt to quantify the effect of surrogate endpoints. The proposed method is applied to validate magnetic resonance imaging lesions as the surrogate endpoint for clinical relapses in a multiple sclerosis trial. Copyright © 2012 John Wiley & Sons, Ltd.

An electronic regulatory document management system for a clinical trial network.

PubMed

Zhao, Wenle; Durkalski, Valerie; Pauls, Keith; Dillon, Catherine; Kim, Jaemyung; Kolk, Deneil; Silbergleit, Robert; Stevenson, Valerie; Palesch, Yuko

2010-01-01

A computerized regulatory document management system has been developed as a module in a comprehensive Clinical Trial Management System (CTMS) designed for an NIH-funded clinical trial network in order to more efficiently manage and track regulatory compliance. Within the network, several institutions and investigators are involved in multiple trials, and each trial has regulatory document requirements. Some of these documents are trial specific while others apply across multiple trials. The latter causes a possible redundancy in document collection and management. To address these and other related challenges, a central regulatory document management system was designed. This manuscript shares the design of the system as well as examples of it use in current studies. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD—‘Assessing QbTest Utility in ADHD’ (AQUA): a randomised controlled trial

PubMed Central

Hall, Charlotte L; Walker, Gemma M; Valentine, Althea Z; Guo, Boliang; Kaylor-Hughes, Catherine; James, Marilyn; Daley, David; Sayal, Kapil; Hollis, Chris

2014-01-01

Introduction The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current ‘gold standard’ ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. Methods and analysis This multisite randomised controlled trial will recruit young people (aged 6–17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. Ethics and dissemination The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. Trial registration number NCT02209116. PMID:25448628

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/.

Omega-3 polyunsaturated fatty acids for the prevention of cardiovascular disease: do formulation, dosage & comparator matter?

PubMed

DiNicolantonio, James J; Meier, Pascal; O'Keefe, James H

2013-01-01

Multiple trials over the past two decades testing omega-3 polyunsaturated fatty acids (PUFAs), containing eicosapentaenoic acid (EPA) and or docosahexaenoic acid (DHA), have shown substantial benefits for reducing major coronary heart disease (CHD) events, all-cause mortality, cardiovascular (CV) death, sudden cardiac death (SCD), and stroke. However, recent trials testing omega-3s have generally failed to confirm these benefits. While increased fish and fish oil intake among the general population, increased use of optimal medical therapy (including statins, aspirin, and modern antihypertensive medications) probably make it more challenging for fish oil supplementation to show additional benefits, there might be further explanations in the formulation, dosage, and comparator used in these recent omega-3 trials.

Addressing small sample size bias in multiple-biomarker trials: Inclusion of biomarker-negative patients and Firth correction.

PubMed

Habermehl, Christina; Benner, Axel; Kopp-Schneider, Annette

2018-03-01

In recent years, numerous approaches for biomarker-based clinical trials have been developed. One of these developments are multiple-biomarker trials, which aim to investigate multiple biomarkers simultaneously in independent subtrials. For low-prevalence biomarkers, small sample sizes within the subtrials have to be expected, as well as many biomarker-negative patients at the screening stage. The small sample sizes may make it unfeasible to analyze the subtrials individually. This imposes the need to develop new approaches for the analysis of such trials. With an expected large group of biomarker-negative patients, it seems reasonable to explore options to benefit from including them in such trials. We consider advantages and disadvantages of the inclusion of biomarker-negative patients in a multiple-biomarker trial with a survival endpoint. We discuss design options that include biomarker-negative patients in the study and address the issue of small sample size bias in such trials. We carry out a simulation study for a design where biomarker-negative patients are kept in the study and are treated with standard of care. We compare three different analysis approaches based on the Cox model to examine if the inclusion of biomarker-negative patients can provide a benefit with respect to bias and variance of the treatment effect estimates. We apply the Firth correction to reduce the small sample size bias. The results of the simulation study suggest that for small sample situations, the Firth correction should be applied to adjust for the small sample size bias. Additional to the Firth penalty, the inclusion of biomarker-negative patients in the analysis can lead to further but small improvements in bias and standard deviation of the estimates. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cervical stitch (cerclage) for preventing preterm birth in multiple pregnancy.

PubMed

Rafael, Timothy J; Berghella, Vincenzo; Alfirevic, Zarko

2014-09-10

Cervical cerclage is a surgical intervention involving placing a stitch around the uterine cervix. The suture material aims to prevent cervical shortening and opening, thereby reducing the risk of preterm birth. The effectiveness and safety of this procedure in multiple gestations remains controversial. To assess whether the use of a cervical cerclage in multiple gestations, either at high risk of pregnancy loss based on just the multiple gestation (history-indicated cerclage), the ultrasound findings of 'short cervix' (ultrasound-indicated cerclage), or the physical exam changes in the cervix (physical exam-indicated cerclage), improves obstetrical and perinatal outcomes. The primary outcomes assessed were perinatal deaths, serious neonatal morbidity, and perinatal deaths and serious neonatal morbidity. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2014) and reference lists of retrieved studies. All randomised controlled trials (RCTs) of cervical cerclage in multiple pregnancies. Quasi-RCTs and RCTs using a cluster-randomised design were eligible for inclusion (but none were identified). Studies using a cross-over design and those presented only as abstracts were not eligible for inclusion.We included studies comparing cervical cerclage with no cervical cerclage in multiple pregnancies.Studies comparing cervical stitch versus any other preventative therapy (e.g. progesterone) in multiple pregnancies, and studies involving comparisons between different cerclage protocols (history-indicated versus ultrasound-indicated versus physical exam-indicated cerclage) were also eligible for inclusion but none were identified. Two review authors independently assessed trials for inclusion and risk of bias. Two review authors extracted data. Data were checked for accuracy. We included five trials, which in total randomised 1577 women, encompassing both singleton and multiple gestations. After excluding singletons, the final analysis included 128 women, of which 122 women had twin gestations, and six women had triplet gestations. Two trials (n = 73 women) assessed history-indicated cerclage, while three trials (n = 55 women) assessed ultrasound-indicated cerclage. The five trials were judged to be of average to above average quality, with three of the trials at unclear risk regarding selection and detection biases.Concerning the primary outcomes, when outcomes for cerclage were pooled together for all indications and compared with no cerclage, there was no statistically significant differences in perinatal deaths (19.2% versus 9.5%; risk ratio (RR) 1.74, 95% confidence intervals (CI) 0.92 to 3.28, five trials, n = 262), serious neonatal morbidity (15.8% versus 13.6%; average RR 0.96, 95% CI 0.13 to 7.10, three trials, n = 116), or composite perinatal death and neonatal morbidity (40.4% versus 20.3%; average RR 1.54, 95% CI 0.58 to 4.11, three trials, n = 116).Among the secondary outcomes, there were no significant differences between the cerclage and the no cerclage groups. To name a few, there were no significant differences among the following: preterm birth less than 34 weeks (average RR 1.16, 95% CI 0.44 to 3.06, four trials, n = 83), preterm birth less than 35 weeks (average RR 1.11, 95% CI 0.58 to 2.14, four trials, n = 83), low birthweight less than 2500 g (average RR 1.10, 95% CI 0.82 to 1.48, four trials, n = 172), very low birthweight less than 1500 g (average RR 1.42, 95% CI 0.52 to 3.85, four trials, n = 172), and respiratory distress syndrome (average RR 1.70, 95% CI 0.15 to 18.77, three trials, n = 116). There were also no significant differences between the cerclage and no cerclage groups when examining caesarean section (elective and emergency) (RR 1.24, 95% CI 0.65 to 2.35, three trials, n = 77) and maternal side-effects (RR 3.92, 95% CI 0.17 to 88.67, one trial, n = 28).Examining the differences between prespecified subgroups, ultrasound-indicated cerclage was associated with an increased risk of low birthweight (average RR 1.39, 95% CI 1.06 to 1.83, Tau² = 0.01, I² = 15%, three trials, n = 98), very low birthweight (average RR 3.31, 95% CI 1.58 to 6.91, Tau² = 0, I² = 0%, three trials, n = 98), and respiratory distress syndrome (average RR 5.07, 95% CI 1.75 to 14.70, Tau² = 0, I² = 0%, three trials, n = 98). However, given the low number of trials, as well as substantial heterogeneity and subgroup differences, these data must be interpreted cautiously.No trials reported on long-term infant neurodevelopmental outcomes. There were no physical exam-indicated cerclages available for comparison among the studies included. This review is based on limited data from five small studies of average to above average quality. For multiple gestations, there is no evidence that cerclage is an effective intervention for preventing preterm births and reducing perinatal deaths or neonatal morbidity.

Failure to replicate the 'work ethic" effect in pigeons.

PubMed

Vasconcelos, Marco; Urcuioli, Peter J; Lionello-DeNolf, Karen M

2007-05-01

We report six unsuccessful attempts to replicate the "work ethic" phenomenon reported by Clement, Feltus, Kaiser, and Zentall (2000). In Experiments 1-5, pigeons learned two simultaneous discriminations in which the S+ and S- stimuli were obtained by pecking an initial stimulus once or multiple (20 or 40) times. Subsequent preference tests between the S+ stimuli and between the S- stimuli mostly revealed indifference, on average, between the S+ from the multiple-peck (high-effort) trials and the S+ from the one-peck (low-effort) trials, and likewise between the two respective Sstimuli. Using a slightly different procedure that permitted assessment of the relative aversiveness of low versus high effort, Experiment 6 again revealed a pattern of indifference despite showing that pigeons took considerably longer to begin pecking on high- than on low-effort trials. Our findings call into question the reliability of the original findings and the sufficiency of the hypothesized within-trial contrast mechanism to produce them.

Structured didactic teaching sessions improve medical student neurology clerkship test scores: a pilot study.

PubMed

Menkes, Daniel L; Reed, Mary

2008-01-01

To determine the effectiveness of didactic case-based instruction methodology to improve medical student comprehension of common neurological illnesses and neurological emergencies. Neurology department, academic university. 415 third and fourth year medical students performing a required four week neurology clerkship. Raw test scores on a 1 hour, 50-item clinical vignette based examination and open-ended questions in a post-clerkship feedback session. There was a statistically significant improvement in overall test scores (p<0.001). Didactic teaching sessions have a significant positive impact on neurology student clerkship test score performance and perception of their educational experience. Confirmation of these results across multiple specialties in a multi-center trial is warranted.

Imaging systems level consolidation of novel associate memories: A longitudinal neuroimaging study

PubMed Central

Smith, Jason F; Alexander, Gene E; Chen, Kewei; Husain, Fatima T; Kim, Jieun; Pajor, Nathan; Horwitz, Barry

2010-01-01

Previously, a standard theory of systems level memory consolidation was developed to describe how memory recall becomes independent of the medial temporal memory system. More recently, an extended consolidation theory was proposed that predicts seven changes in regional neural activity and inter-regional functional connectivity. Using longitudinal event related functional magnetic resonance imaging of an associate memory task, we simultaneously tested all predictions and additionally tested for consolidation related changes in recall of associate memories at a sub-trial temporal resolution, analyzing cue, delay and target periods of each trial separately. Results consistent with the theoretical predictions were observed though two inconsistent results were also obtained. In particular, while recall-related delay period activity decreased with consolidation as predicted, visual cue activity increased for consolidated memories. Though the extended theory of memory consolidation is largely supported by our study, these results suggest the extended theory needs further refinement and the medial temporal memory system has multiple, temporally distinct roles in associate memory recall. Neuroimaging analysis at a sub-trial temporal resolution, as used here, may further clarify the role of the hippocampal complex in memory consolidation. PMID:19948227

AccrualNet: Addressing Low Accrual Via a Knowledge-Based, Community of Practice Platform

PubMed Central

Massett, Holly A.; Parreco, Linda K.; Padberg, Rose Mary; Richmond, Ellen S.; Rienzo, Marie E.; Leonard, Colleen E. Ryan; Quesenbery, Whitney; Killiam, H. William; Johnson, Lenora E.; Dilts, David M.

2011-01-01

Purpose: Present the design and initial evaluation of a unique, Web-enabled platform for the development of a community of practice around issues of oncology clinical trial accrual. Methods: The National Cancer Institute (NCI) conducted research with oncology professionals to identify unmet clinical trial accrual needs in the field. In response, a comprehensive platform for accrual resources, AccrualNet, was created by using an agile development process, storyboarding, and user testing. Literature and resource searches identified relevant content to populate the site. Descriptive statistics were tracked for resource and site usage. Use cases were defined to support implementation. Results: AccrualNet has five levels: (1) clinical trial macrostages (prestudy, active study, and poststudy); (2) substages (developing a protocol, selecting a trial, preparing to open, enrolling patients, managing the trial, retaining participants, and lessons learned); (3) strategies for each substage; (4) multiple activities for each strategy; and (5) multiple resources for each activity. Since its launch, AccrualNet has had more than 45,000 page views, with the Tools & Resources, Conversations, and Training sections being the most viewed. Total resources have increased 69%, to 496 items. Analysis of articles in the site reveals that 22% are from two journals and 46% of the journals supplied a single article. To date, there are 29 conversations with 43 posts. Four use cases are discussed. Conclusion: AccrualNet represents a unique, centralized comprehensive-solution platform to systematically capture accrual knowledge for all stages of a clinical trial. It is designed to foster a community of practice by encouraging users to share additional strategies, resources, and ideas. PMID:22379429

AccrualNet: Addressing Low Accrual Via a Knowledge-Based, Community of Practice Platform.

PubMed

Massett, Holly A; Parreco, Linda K; Padberg, Rose Mary; Richmond, Ellen S; Rienzo, Marie E; Leonard, Colleen E Ryan; Quesenbery, Whitney; Killiam, H William; Johnson, Lenora E; Dilts, David M

2011-11-01

Present the design and initial evaluation of a unique, Web-enabled platform for the development of a community of practice around issues of oncology clinical trial accrual. The National Cancer Institute (NCI) conducted research with oncology professionals to identify unmet clinical trial accrual needs in the field. In response, a comprehensive platform for accrual resources, AccrualNet, was created by using an agile development process, storyboarding, and user testing. Literature and resource searches identified relevant content to populate the site. Descriptive statistics were tracked for resource and site usage. Use cases were defined to support implementation. ACCRUALNET HAS FIVE LEVELS: (1) clinical trial macrostages (prestudy, active study, and poststudy); (2) substages (developing a protocol, selecting a trial, preparing to open, enrolling patients, managing the trial, retaining participants, and lessons learned); (3) strategies for each substage; (4) multiple activities for each strategy; and (5) multiple resources for each activity. Since its launch, AccrualNet has had more than 45,000 page views, with the Tools & Resources, Conversations, and Training sections being the most viewed. Total resources have increased 69%, to 496 items. Analysis of articles in the site reveals that 22% are from two journals and 46% of the journals supplied a single article. To date, there are 29 conversations with 43 posts. Four use cases are discussed. AccrualNet represents a unique, centralized comprehensive-solution platform to systematically capture accrual knowledge for all stages of a clinical trial. It is designed to foster a community of practice by encouraging users to share additional strategies, resources, and ideas.

Spatial and temporal variation in efficiency of the Moore egg collector

USGS Publications Warehouse

Worthington, Thomas A.; Brewer, Shannon K.; Farless, Nicole

2013-01-01

The Moore egg collector (MEC) was developed for quantitative and nondestructive capture of semibuoyant fish eggs. Previous studies have indicated that capture efficiency of the MEC was low and the use of one device did not adequately represent the spatial distribution within the water column of egg surrogates (gellan beads) of pelagic broadcast-spawning cyprinids. The objective of this study was to assess whether use of multiple MECs showed differences in spatial and temporal distribution of bead catches. Capture efficiency of three MECs was tested at four 500-m sites on the South Canadian River, a Great Plains river in Oklahoma. For each trial, approximately 100,000 beads were released and mean capture efficiency was 0.47–2.16%. Kolmogorov–Smirnov tests indicated the spatial distributions of bead catches were different among multiple MECs at three of four sites. Temporal variability in timing of peak catches of gellan beads was also evident between MECs. We concluded that the use of multiple MECs is necessary to properly sample eggs of pelagic broadcast-spawning cyprinids.

Development and validation of a patient self-assessed questionnaire on satisfaction with communication of the multiple sclerosis diagnosis.

PubMed

Solari, A; Mattarozzi, K; Vignatelli, L; Giordano, A; Russo, P M; Uccelli, M Messmer; D'Alessandro, R

2010-10-01

We describe the development and clinical validation of a patient self-administered tool assessing the quality of multiple sclerosis diagnosis disclosure. A multiple sclerosis expert panel generated questionnaire items from the Doctor's Interpersonal Skills Questionnaire, literature review, and interviews with neurology inpatients. The resulting 19-item Comunicazione medico-paziente nella Sclerosi Multipla (COSM) was pilot tested/debriefed on seven patients with multiple sclerosis and administered to 80 patients newly diagnosed with multiple sclerosis. The resulting revised 20-item version (COSM-R) was debriefed on five patients with multiple sclerosis, field tested/debriefed on multiple sclerosis patients, and field tested on 105 patients newly diagnosed with multiple sclerosis participating in a clinical trial on an information aid. The hypothesized monofactorial structure of COSM-R section 2 was tested on the latter two groups. The questionnaire was well accepted. Scaling assumptions were satisfactory in terms of score distributions, item-total correlations and internal consistency. Factor analysis confirmed section 2's monofactorial structure, which was also test-retest reliable (intraclass correlation coefficient [ICC] 0.73; 95% CI 0.54-0.85). Section 1 had only fair test-retest reliability (ICC 0.45; 95% CI 0.12-0.69), and three items had 8-21% missed responses. COSM-R is a brief, easy-to-interpret MS-specific questionnaire for use as a health care indicator.

The computer-based Symbol Digit Modalities Test: establishing age-expected performance in healthy controls and evaluation of pediatric MS patients.

PubMed

Bigi, Sandra; Marrie, R A; Till, C; Yeh, E A; Akbar, N; Feinstein, A; Banwell, B L

2017-04-01

Decreased information processing speed (IPS) is frequently reported in pediatric multiple sclerosis (MS) patients. The computerized version of the Symbol Digit Modalities Test (c-SDMT) measures IPS over eight consecutive trials per session and additionally captures changes in performance within the session. Here, we establish normative c-SDMT performance and test-retest reliability in healthy children (HC) and explore differences in the overall c-SDMT-performance between HC and MS patients. This cross-sectional study included 478 HC (237 female, 49.5%) divided into five age groups (2 years each), and 27 MS patients (22 female, 81.5%) aged 8-18 years. The average time to complete the c-SDMT increased with age (|r| 0.70, 95% CI -0.74, -0.64). Test-retest reliability was high (ICC = 0.91) in HC. The total time to complete the c-SDMT did not differ between children with MS and sex- and age- matched HC (p = 0.23). However, MS patients were less likely to show faster performance across all the successive eight trials compared to HC (p = 0.0001). Healthy children demonstrate faster IPS with increasing age, as well as during successive trials of the c-SDMT. The inability of pediatric MS patients to maintain the increase in processing speed over successive trials suggests a reduced capacity for procedural learning, possibly resulting from cognitive fatigue.

Home-based exercise program and fall-risk reduction in older adults with multiple sclerosis: phase 1 randomized controlled trial.

PubMed

Sosnoff, Jacob J; Finlayson, Marcia; McAuley, Edward; Morrison, Steve; Motl, Robert W

2014-03-01

To determine the feasibility, safety, and efficacy of a home-based exercise intervention targeting fall risk in older adults with multiple sclerosis. A randomized controlled pilot trial. A home-based exercise program. Participants were randomly allocated to either a home-based exercise intervention group (n = 13) or a waiting list control group (n = 14). The exercise group completed exercises targeting lower muscle strength and balance three times a week for 12 weeks. The control group continued normal activity. Fall risk (Physiological Profile Assessment scores), balance (Berg Balance Scale), and walking testing prior to and immediately following the 12-week intervention. Each outcome measure was placed in an analysis of covariance with group as the between-subject factor and baseline values as the covariate. Effect sizes were calculated. Twelve participants from the control group and ten from the exercise group completed the study. There were no related adverse events. Fall risk was found to decrease in the exercise group following the intervention (1.1 SD 1.0 vs. 0.6 SD 0.6) while there was an increase in fall risk in the control group (1.9 SD 1.5 vs. 2.2 SD 1.9). Effect sizes for most outcomes were large (η(2) > 0.15). Home-based exercise was found to be feasible, safe, and effective for reducing physiological fall risk in older adults with multiple sclerosis. Our findings support the implementation of a larger trial to reduce fall risk in persons with multiple sclerosis.

Sample size determination for equivalence assessment with multiple endpoints.

PubMed

Sun, Anna; Dong, Xiaoyu; Tsong, Yi

2014-01-01

Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints.

Robust inference for responder analysis: Innovative clinical trial design using a minimum p-value approach.

PubMed

Lin, Yunzhi

2016-08-15

Responder analysis is in common use in clinical trials, and has been described and endorsed in regulatory guidance documents, especially in trials where "soft" clinical endpoints such as rating scales are used. The procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. However, two major issues arise: 1) such dichotomized outcomes are inefficient in terms of using the information available and can seriously reduce the power of the study; and 2) the results of clinical trials depend considerably on the response cutoff chosen, yet in many disease areas there is no consensus as to what is the most appropriate cutoff. This article addresses these two issues, offering a novel approach for responder analysis that could both improve the power of responder analysis and explore different responder cutoffs if an agreed-upon common cutoff is not present. Specifically, we propose a statistically rigorous clinical trial design that pre-specifies multiple tests of responder rates between treatment groups based on a range of pre-specified responder cutoffs, and uses the minimum of the p-values for formal inference. The critical value for hypothesis testing comes from permutation distributions. Simulation studies are carried out to examine the finite sample performance of the proposed method. We demonstrate that the new method substantially improves the power of responder analysis, and in certain cases, yields power that is approaching the analysis using the original continuous (or ordinal) measure.

A Formative Evaluation of Customized Pamphlets to Promote Physical Activity and Symptom Self-Management in Women with Multiple Sclerosis

ERIC Educational Resources Information Center

Plow, Matthew; Bethoux, Francois; Mai, Kimloan; Marcus, Bess

2014-01-01

Inactivity is a prevalent problem in the population affected with multiple sclerosis (MS). Thus, there is a need to develop and test physical activity (PA) interventions that can be widely disseminated. We conducted a formative evaluation as part of a randomized controlled trial of a pamphlet-based PA intervention among 30 women with MS. Pamphlets…

Demonstration and field trial of a resilient hybrid NG-PON test-bed

NASA Astrophysics Data System (ADS)

Prat, Josep; Polo, Victor; Schrenk, Bernhard; Lazaro, Jose A.; Bonada, Francesc; Lopez, Eduardo T.; Omella, Mireia; Saliou, Fabienne; Le, Quang T.; Chanclou, Philippe; Leino, Dmitri; Soila, Risto; Spirou, Spiros; Costa, Liliana; Teixeira, Antonio; Tosi-Beleffi, Giorgio M.; Klonidis, Dimitrios; Tomkos, Ioannis

2014-10-01

A multi-layer next generation PON prototype has been built and tested, to show the feasibility of extended hybrid DWDM/TDM-XGPON FTTH networks with resilient optically-integrated ring-trees architecture, supporting broadband multimedia services. It constitutes a transparent common platform for the coexistence of multiple operators sharing the optical infrastructure of the central metro ring, passively combining the access and the metropolitan network sections. It features 32 wavelength connections at 10 Gbps, up to 1000 users distributed in 16 independent resilient sub-PONs over 100 km. This paper summarizes the network operation, demonstration and field trial results.

A pilot study to evaluate multi-dimensional effects of dance for people with Parkinson's disease.

PubMed

Ventura, Maria I; Barnes, Deborah E; Ross, Jessica M; Lanni, Kimberly E; Sigvardt, Karen A; Disbrow, Elizabeth A

2016-11-01

Parkinson's disease (PD) is a progressive neurodegenerative disease associated with deficits in motor, cognitive, and emotion/quality of life (QOL) domains, yet most pharmacologic and behavioral interventions focus only on motor function. Our goal was to perform a pilot study of Dance for Parkinson's-a community-based program that is growing in popularity-in order to compare effect sizes across multiple outcomes and to inform selection of primary and secondary outcomes for a larger trial. Study participants were people with PD who self-enrolled in either Dance for Parkinson's classes (intervention group, N=8) or PD support groups (control group, N=7). Assessments of motor function (Timed-Up-and-Go, Gait Speed, Standing Balance Test), cognitive function (Test of Everyday Attention, Verbal Fluency, Alternate Uses, Digit Span Forward and Backward), and emotion/QOL (Geriatric Depression Scale, Falls Efficacy Scale-International, Parkinson's Disease Questionnaire-39 (total score and Activities of Daily Living subscale)) were performed in both groups at baseline and follow-up. Standardized effect sizes were calculated within each group and between groups for all 12 measures. Effect sizes were positive (suggesting improvement) for all 12 measures within the intervention group and 7 of 12 measures within the control group. The largest between-group differences were observed for the Test of Everyday Attention (a measure of cognitive switching), gait speed and falls efficacy. Our findings suggest that dance has potential to improve multiple outcomes in people with PD. Future trials should consider co-primary outcomes given potential benefits in motor, cognitive and emotion/QOL domains. Copyright © 2016 Elsevier Inc. All rights reserved.

A pilot study to evaluate multi-dimensional effects of dance for people with Parkinson’s disease

PubMed Central

Ventura, Maria I.; Barnes, Deborah E.; Ross, Jessica M.; Lanni, Kimberly E.; Sigvardt, Karen A.; Disbrow, Elizabeth A.

2016-01-01

Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with deficits in motor, cognitive, and emotion/quality of life (QOL) domains, yet most pharmacologic and behavioral interventions focus only on motor function. Our goal was to perform a pilot study of Dance for Parkinson’s—a community-based program that is growing in popularity—in order to compare effect sizes across multiple outcomes and to inform selection of primary and secondary outcomes for a larger trial. Study participants were people with PD who self-enrolled in either Dance for Parkinson’s classes (intervention group, N=8) or PD support groups (control group, N=7). Assessments of motor function (Timed-Up-and-Go, Gait Speed, Standing Balance Test), cognitive function (Test of Everyday Attention, Verbal Fluency, Alternate Uses, Digit Span Forward and Backward), and emotion/QOL (Geriatric Depression Scale, Falls Efficacy Scale-International, Parkinson’s Disease Questionnaire-39 (total score and Activities of Daily Living subscale)) were performed in both groups at baseline and follow-up. Standardized effect sizes were calculated within each group and between groups for all 12 measures. Effect sizes were positive (suggesting improvement) for all 12 measures within the intervention group and 7 of 12 measures within the control group. The largest between-group differences were observed for the Test of Everyday Attention (a measure of cognitive switching), gait speed and falls efficacy. Our findings suggest that dance has potential to improve multiple outcomes in people with PD. Future trials should consider co-primary outcomes given potential benefits in motor, cognitive and emotion/QOL domains. PMID:27765693

Alcohol Use Problems and Sexual Risk among Young Adult African American Mothers

PubMed Central

Swartzendruber, Andrea; Sales, Jessica M.; Rose, Eve S.; DiClemente, Ralph J.

2015-01-01

Studies have documented high levels of alcohol use and sexual risk among young mothers. We examined parenting satisfaction and self-efficacy in relation to alcohol use problems and sexual risk among 346 young African American women enrolled in an HIV prevention trial, 41% (n=141) of whom were mothers. Among mothers, greater parenting satisfaction was associated with a reduced likelihood of problematic alcohol use, having multiple sex partners, and testing positive for Trichomonas vaginalis. Relative to non-parenting women, mothers reported lower condom use. Compared to non-parenting women, mothers with the highest parenting satisfaction reported fewer alcohol use problems; mothers with the lowest parenting satisfaction reported lower condom use and were more likely to have multiple partners and test positive for T. vaginalis. Parenting self-efficacy was not associated with the outcomes examined. Future research investigating relationships between parenting satisfaction, alcohol use and sexual risk may be useful for improving multiple maternal health outcomes. PMID:26499334

Breastfeeding education and support for women with twins or higher order multiples.

PubMed

Whitford, Heather M; Wallis, Selina K; Dowswell, Therese; West, Helen M; Renfrew, Mary J

2017-02-28

There are rising rates of multiple births worldwide with associated higher rates of complications and more hospital care, often due to prematurity. While there is strong evidence about the risks of not breastfeeding, rates of breastfeeding in women who have given birth to more than one infant are lower than with singleton births. Breastfeeding more than one infant can be more challenging because of difficulties associated with the birth or prematurity. The extra demands on the mother of frequent suckling, coordinating the needs of more than one infant or admission to the neonatal intensive care unit can lead to delayed initiation or early cessation. Additional options such as breast milk expression, the use of donor milk or different methods of supplementary feeding may be considered. Support and education about breastfeeding has been found to improve the duration of any breastfeeding for healthy term infants and their mothers, however evidence is lacking about interventions that are effective to support women with twins or higher order multiples. To assess effectiveness of breastfeeding education and support for women with twins or higher order multiples. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2016), ClinicalTrials.gov (30 June 2016), the WHO International Clinical Trials Registry Platform (ICTRP) (1 July 2016), the excluded studies list from the equivalent Cochrane review of singletons, and reference lists of retrieved studies. Randomised or quasi-randomised trials comparing extra education or support for women with twins or higher order multiples were included. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We planned to assess the quality of evidence using the GRADE approach, but were unable to analyse any data. We found 10 trials (23 reports) of education and support for breastfeeding that included women with twins or higher order multiples. The quality of evidence was mixed, and the risk of bias was mostly high or unclear. It is difficult to blind women or staff to group allocation for this intervention, so in all studies there was high risk of performance and high or unclear risk of detection bias. Trials recruited 5787 women (this included 512 women interviewed as part of a cluster randomised trial); of these, data were available from two studies for 42 women with twins or higher order multiples. None of the interventions were specifically designed for women with more than one infant, and the outcomes for multiples were not reported separately for each infant. Due to the scarcity of evidence and the format in which data were reported, a narrative description of the data is presented, no analyses are presented in this review, and we were unable to GRADE the evidence.The two trials with data for women with multiple births compared home nurse visits versus usual care (15 women), and telephone peer counselling versus usual care (27 women). The number of women who initiated breastfeeding was reported (all 15 women in one study, 25 out of 27 women in one study). Stopping any breastfeeding before four to six weeks postpartum, stopping exclusive breastfeeding before four to six weeks postpartum, stopping any breastfeeding before six months postpartum andstopping exclusive breastfeeding before six months postpartum were not explicitly reported, and there were insufficient data to draw any meaningful conclusions from survival data. Stopping breast milk expression before four to six weeks postpartum, andstopping breast milk expression before six months postpartum were not reported. Measures ofmaternal satisfaction were reported in one study of 15 women, but there were insufficient data to draw any conclusions; no other secondary outcomes were reported for women with multiple births in either study. No adverse events were reported. We found no evidence from randomised controlled trials about the effectiveness of breastfeeding education and support for women with twins or higher order multiples, or the most effective way to provide education and support . There was no evidence about the best way to deliver the intervention, the timing of care, or the best person to deliver the care. There is a need for well-designed, adequately powered studies of interventions designed for women with twins or higher order multiples to find out what types of education and support are effective in helping these mothers to breastfeed their babies.

The role of physician characteristics in clinical trial acceptance: testing pathways of influence.

PubMed

Curbow, Barbara; Fogarty, Linda A; McDonnell, Karen A; Chill, Julia; Scott, Lisa Benz

2006-03-01

Eight videotaped vignettes were developed that assessed the effects of three physician-related experimental variables (in a 2 x 2 x 2 factorial design) on clinical trial (CT) knowledge, video knowledge, information processing, CT beliefs, affective evaluations (attitudes), and CT acceptance. It was hypothesized that the physician variables (community versus academic-based affiliation, enthusiastic versus neutral presentation of the trial, and new versus previous relationship with the patient) would serve as communication cues that would interrupt message processing, leading to lower knowledge gain but more positive beliefs, attitudes, and CT acceptance. A total of 262 women (161 survivors and 101 controls) participated in the study. The manipulated variables primarily influenced the intermediary variables of post-test CT beliefs and satisfaction with information rather than knowledge or information processing. Multiple regression results indicated that CT acceptance was associated with positive post-CT beliefs, a lower level of information processing, satisfaction with information, and control status. Based on these results, CT acceptance does not appear to be based on a rational decision-making model; this has implications for both the ethics of informed consent and research conceptual models.

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

PubMed

Ball, Susan; Vickery, Jane; Hobart, Jeremy; Wright, Dave; Green, Colin; Shearer, James; Nunn, Andrew; Cano, Mayam Gomez; MacManus, David; Miller, David; Mallik, Shahrukh; Zajicek, John

2015-02-01

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. Twenty-seven UK sites. Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. Three and 6 months, and then 6-monthly up to 36 or 42 months. Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. Current Controlled Trials ISRCTN62942668. The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

Increasing the response rate of text messaging data collection: a delayed randomized controlled trial

PubMed Central

Li, Ye; Wang, Wei; Wu, Qiong; van Velthoven, Michelle Helena; Chen, Li; Du, Xiaozhen; Zhang, Yanfeng; Rudan, Igor; Car, Josip

2015-01-01

Objective To test the effectiveness of multiple interventions on increasing the response rate of text messaging for longitudinal data collection. Methods Our cohort included 283 caregivers of children aged 6–12 months who were participating in an anemia program in rural China. Using text messages to collect data on anemia medication adherence, we conducted a delayed randomized controlled trial to test multiple interventions (an additional four reminders; a ¥5.0 (US$0.79) credit reward for replying; and a feedback text message). After a 6-week pilot study with week 7 as the baseline measurement, we randomly allocated all participants into two groups: group 1 (n = 142) and group 2 (n = 141). During weeks 8–11, we introduced the interventions to group 1, and in weeks 12–15 the intervention was introduced to both groups. We compared the response rates between groups and explored factors affecting the response rate. Results During weeks 8–11, the response rates in group 1 increased and were significantly higher than in group 2 (p<0.05). During weeks 12–15, the response rate increased significantly in group 2 (p>0.05) and slightly decreased in group 1. Younger participants or participants who had children with lower hemoglobin concentration were more likely to reply (p = 0.02). Sending four reminders on the second day contributed to only 286 (11.7%) extra text messages. Discussion Our study showed that multiple interventions were effective in increasing response rate of text messaging data collection in rural China. Conclusions Larger multi-site studies are needed to find the most effective way of using these interventions to allow usage of text messaging data collection for health research. PMID:25332355

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

PubMed

Phillips, Dawn; Leiro, Beth

2018-05-01

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution. Gross and fine motor skills, communication, cognition, and independence in activities of daily living vary by age, and it may be difficult to distinguish between treatment effect and change due to developmental maturation. Asfotase alfa was granted breakthrough therapy designation and subsequently approved for the treatment of hypophosphatasia (HPP; a genetic metabolic musculoskeletal disorder) and is used in this discussion to illustrate COA selection in a pediatric rare disease. Multiple COAs with normative data in HPP clinical trials for asfotase alfa are presented. The assessment instruments included the Bayley Scales of Infant and Toddler Development-Third Edition, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, the Childhood Health Assessment Questionnaire, the Pediatric Outcomes Data Collection Instrument, handheld dynamometry, the 6-minute walk test, and the Modified Performance-Oriented Mobility Assessment-Gait scale. Multiple end points were required to adequately capture the impact of asfotase alfa treatment on the multiple systems affected in HPP. These data illustrate the importance of using multiple COAs that provide normative data and to use COAs early in the drug development process for rare pediatric disease. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Evaluating Merger and Intersection of Equivalence Classes with One Member in Common

ERIC Educational Resources Information Center

MacKay, Harry A.; Wilkinson, Krista M.; Farrell, Colleen; Serna, Richard W.

2011-01-01

Sidman (1994) noted that the existence of a member that is common to more than one class may produce either class merger (union) or class intersection. A multiple-selection, matching-to-sample test was developed to examine the conditions under which these outcomes occur. Test trials each required three conditional discriminations involving…

Development of dapivirine vaginal ring for HIV prevention.

PubMed

Devlin, Bríd; Nuttall, Jeremy; Wilder, Susan; Woodsong, Cynthia; Rosenberg, Zeda

2013-12-01

In the continuing effort to develop effective HIV prevention methods for women, a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine is currently being tested in two safety and efficacy trials. This paper reviews dapivirine ring's pipeline development process, including efforts to determine safe and effective dosing levels as well as identify delivery platforms with the greatest likelihood of success for correct and consistent use. Dapivirine gel and other formulations were developed and tested in preclinical and clinical studies. Multiple vaginal ring prototypes were also tested, resulting in the current ring design as well as additional designs under consideration for future testing. Efficacy results from clinical trials are expected in 2015. Through ongoing consultations with national regulatory authorities, licensure requirements for dapivirine vaginal ring approval have been defined. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research. Copyright © 2013 Elsevier B.V. All rights reserved.

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

Sequential effects in pigeon delayed matching-to-sample performance.

PubMed

Roitblat, H L; Scopatz, R A

1983-04-01

Pigeons were tested in a three-alternative delayed matching-to-sample task in which second-choices were permitted following first-choice errors. Sequences of responses both within and between trials were examined in three experiments. The first experiment demonstrates that the sample information contained in first-choice errors is not sufficient to account for the observed pattern of second choices. This result implies that second-choices following first-choice errors are based on a second examination of the contents of working memory. Proactive interference was found in the second experiment in the form of a dependency, beyond that expected on the basis of trial independent response bias, of first-choices from one trial on the first-choice emitted on the previous trial. Samples from the previous trial were not found to exert a significant influence on later trials. The magnitude of the intertrial association (Experiment 3) did not depend on the duration of the intertrial interval. In contrast, longer intertrial intervals and longer sample durations did facilitate choice accuracy, by strengthening the association between current samples and choices. These results are incompatible with a trace-decay and competition model; they suggest strongly that multiple influences act simultaneously and independently to control delayed matching-to-sample responding. These multiple influences include memory for the choice occurring on the previous trial, memory for the sample, and general effects of trial spacing.

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

Prioritization in comparative effectiveness research: the CANCERGEN Experience.

PubMed

Thariani, Rahber; Wong, William; Carlson, Josh J; Garrison, Louis; Ramsey, Scott; Deverka, Patricia A; Esmail, Laura; Rangarao, Sneha; Hoban, Carolyn J; Baker, Laurence H; Veenstra, David L

2012-05-01

Systematic approaches to stakeholder-informed research prioritization are a central focus of comparative effectiveness research. Genomic testing in cancer is an ideal area to refine such approaches given rapid innovation and potentially significant impacts on patient outcomes. To develop and pilot test a stakeholder-informed approach to prioritizing genomic tests for future study in collaboration with the cancer clinical trials consortium SWOG. We conducted a landscape analysis to identify genomic tests in oncology using a systematic search of published and unpublished studies, and expert consultation. Clinically valid tests suitable for evaluation in a comparative study were presented to an external stakeholder group. Domains to guide the prioritization process were identified with stakeholder input, and stakeholders ranked tests using multiple voting rounds. A stakeholder group was created including representatives from patient-advocacy groups, payers, test developers, regulators, policy makers, and community-based oncologists. We identified 9 domains for research prioritization with stakeholder feedback: population impact; current standard of care, strength of association; potential clinical benefits, potential clinical harms, economic impacts, evidence of need, trial feasibility, and market factors. The landscape analysis identified 635 studies; of 9 tests deemed to have sufficient clinical validity, 6 were presented to stakeholders. Two tests in lung cancer (ERCC1 and EGFR) and 1 test in breast cancer (CEA/CA15-3/CA27.29) were identified as top research priorities. Use of a diverse stakeholder group to inform research prioritization is feasible in a pragmatic and timely manner. Additional research is needed to optimize search strategies, stakeholder group composition, and integration with existing prioritization mechanisms.

Prioritization in Comparative Effectiveness Research: The CANCERGEN Experience in Cancer Genomics

PubMed Central

Thariani, Rahber; Wong, William; Carlson, Josh J; Garrison, Louis; Ramsey, Scott; Deverka, Patricia A; Esmail, Laura; Rangarao, Sneha; Hoban, Carolyn J; Baker, Laurence H; Veenstra, David L

2012-01-01

Background Systematic approaches to stakeholder-informed research prioritization are a central focus of comparative effectiveness research. Genomic testing in cancer is an ideal area to refine such approaches given rapid innovation and potentially significant impacts on patient outcomes. Objective To develop and pilot-test a stakeholder-informed approach to prioritizing genomic tests for future study in collaboration with the cancer clinical trials consortium SWOG. Methods We conducted a landscape-analysis to identify genomic tests in oncology using a systematic search of published and unpublished studies, and expert consultation. Clinically valid tests suitable for evaluation in a comparative study were presented to an external stakeholder group. Domains to guide the prioritization process were identified with stakeholder input, and stakeholders ranked tests using multiple voting rounds. Results A stakeholder group was created including representatives from patient-advocacy groups, payers, test developers, regulators, policy-makers, and community-based oncologists. We identified nine domains for research prioritization with stakeholder feedback: population impact; current standard of care, strength of association; potential clinical benefits, potential clinical harms, economic impacts, evidence of need, trial feasibility, and market factors. The landscape-analysis identified 635 studies; of 9 tests deemed to have sufficient clinical validity, 6 were presented to stakeholders. Two tests in lung cancer (ERCC1 and EGFR) and one test in breast cancer (CEA/CA15-3/CA27.29) were identified as top research priorities. Conclusions Use of a diverse stakeholder group to inform research prioritization is feasible in a pragmatic and timely manner. Additional research is needed to optimize search strategies, stakeholder group composition and integration with existing prioritization mechanisms. PMID:22274803

Nutritional supplements for people being treated for active tuberculosis.

PubMed

Abba, Katharine; Sudarsanam, Thambu D; Grobler, Liesl; Volmink, Jimmy

2008-10-08

Tuberculosis is a serious infection affecting mainly the lungs. It may contribute to nutritional deficiencies which in turn may delay recovery by depressing immune functions. Nutritional supplements might therefore promote recovery in people being treated for tuberculosis. To assess the provision of oral nutritional supplements to promote the recovery of people being treated with antituberculous drug therapy for active tuberculosis. We searched the Cochrane Infectious Disease Group Specialized Register (June 2008), CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE (June 2008), EMBASE (June 2008), LILACS (June 2008), mRCT (June 2008), the Indian Journal of Tuberculosis (1983 to June 2008), and checked the reference lists of all included studies. Randomized controlled trials comparing any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. Two authors independently selected trials, extracted data, and assessed risk of bias. We calculated risk ratios (RR) for dichotomous variables and mean differences (MD) for continuous variables, with 95% confidence intervals (CI). We pooled data from trials with similar interventions and outcomes. Twelve trials (3393 participants) were included. Five trials had adequate allocation concealment. Interventions included a high energy supplement, high cholesterol diet, vitamin D, vitamin A, zinc, arginine, multiple micronutrient supplements, combined multiple micronutrient supplements and zinc, combined vitamin A and zinc, and combined vitamin A and selenium. The following supplements were associated with increased body weight at follow up: high energy supplements (MD 1.73 kg, 95% CI 0.81 to 2.65; 34 participants, 1 trial); multiple micronutrients plus additional zinc (MD 2.37 kg, 95% CI 2.21 to 2.53; 192 participants, 1 trial); and vitamin A plus zinc (MD 3.10 kg, 95% CI 0.74 to 5.46; 80 participants, 1 trial). There was no evidence that any supplement affected the number of deaths or number of participants with sputum test positive results at the end of treatment. There is limited evidence that high energy supplements and some combinations of zinc with other micronutrients may help people with tuberculosis to gain weight. There is not enough evidence to assess the effect of other combinations of nutrients. A number of relevant trials are in progress, and, where appropriate, the results will be incorporated into future updates of this review.

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

Animal models for microbicide safety and efficacy testing.

PubMed

Veazey, Ronald S

2013-07-01

Early studies have cast doubt on the utility of animal models for predicting success or failure of HIV-prevention strategies, but results of multiple human phase 3 microbicide trials, and interrogations into the discrepancies between human and animal model trials, indicate that animal models were, and are, predictive of safety and efficacy of microbicide candidates. Recent studies have shown that topically applied vaginal gels, and oral prophylaxis using single or combination antiretrovirals are indeed effective in preventing sexual HIV transmission in humans, and all of these successes were predicted in animal models. Further, prior discrepancies between animal and human results are finally being deciphered as inadequacies in study design in the model, or quite often, noncompliance in human trials, the latter being increasingly recognized as a major problem in human microbicide trials. Successful microbicide studies in humans have validated results in animal models, and several ongoing studies are further investigating questions of tissue distribution, duration of efficacy, and continued safety with repeated application of these, and other promising microbicide candidates in both murine and nonhuman primate models. Now that we finally have positive correlations with prevention strategies and protection from HIV transmission, we can retrospectively validate animal models for their ability to predict these results, and more importantly, prospectively use these models to select and advance even safer, more effective, and importantly, more durable microbicide candidates into human trials.

Screening for Obstructive Sleep Apnea in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.

PubMed

Jonas, Daniel E; Amick, Halle R; Feltner, Cynthia; Weber, Rachel Palmieri; Arvanitis, Marina; Stine, Alexander; Lux, Linda; Harris, Russell P

2017-01-24

Many adverse health outcomes are associated with obstructive sleep apnea (OSA). To review primary care-relevant evidence on screening adults for OSA, test accuracy, and treatment of OSA, to inform the US Preventive Services Task Force. MEDLINE, Cochrane Library, EMBASE, and trial registries through October 2015, references, and experts, with surveillance of the literature through October 5, 2016. English-language randomized clinical trials (RCTs); studies evaluating accuracy of screening questionnaires or prediction tools, diagnostic accuracy of portable monitors, or association between apnea-hypopnea index (AHI) and health outcomes among community-based participants. Two investigators independently reviewed abstracts and full-text articles. When multiple similar studies were available, random-effects meta-analyses were conducted. Sensitivity, specificity, area under the curve (AUC), AHI, Epworth Sleepiness Scale (ESS) scores, blood pressure, mortality, cardiovascular events, motor vehicle crashes, quality of life, and harms. A total of 110 studies were included (N = 46 188). No RCTs compared screening with no screening. In 2 studies (n = 702), the screening accuracy of the multivariable apnea prediction score followed by home portable monitor testing for detecting severe OSA syndrome (AHI ≥30 and ESS score >10) was AUC 0.80 (95% CI, 0.78 to 0.82) and 0.83 (95% CI, 0.77 to 0.90), respectively, but the studies oversampled high-risk participants and those with OSA and OSA syndrome. No studies prospectively evaluated screening tools to report calibration or clinical utility for improving health outcomes. Meta-analysis found that continuous positive airway pressure (CPAP) compared with sham was significantly associated with reduction of AHI (weighted mean difference [WMD], -33.8 [95% CI, -42.0 to -25.6]; 13 trials, 543 participants), excessive sleepiness assessed by ESS score (WMD, -2.0 [95% CI, -2.6 to -1.4]; 22 trials, 2721 participants), diurnal systolic blood pressure (WMD, -2.4 points [95% CI, -3.9 to -0.9]; 15 trials, 1190 participants), and diurnal diastolic blood pressure (WMD, -1.3 points [95% CI, -2.2 to -0.4]; 15 trials, 1190 participants). CPAP was associated with modest improvement in sleep-related quality of life (Cohen d, 0.28 [95% CI, 0.14 to 0.42]; 13 trials, 2325 participants). Mandibular advancement devices (MADs) and weight loss programs were also associated with reduced AHI and excessive sleepiness. Common adverse effects of CPAP and MADs included oral or nasal dryness, irritation, and pain, among others. In cohort studies, there was a consistent association between AHI and all-cause mortality. There is uncertainty about the accuracy or clinical utility of all potential screening tools. Multiple treatments for OSA reduce AHI, ESS scores, and blood pressure. Trials of CPAP and other treatments have not established whether treatment reduces mortality or improves most other health outcomes, except for modest improvement in sleep-related quality of life.

The Evidence for Dietary Interventions and Nutritional Supplements as Treatment Options in Multiple Sclerosis: a Review.

PubMed

Mische, Leah J; Mowry, Ellen M

2018-03-17

This review aims to critically evaluate published studies examining diets and nutritional supplements (excepting vitamin D) for the impact on prevention and prognosis of multiple sclerosis (MS). There is a negative relationship between the Mediterranean diet and vascular disease, and vascular co-morbidities are associated with a worse MS prognosis. Low-fat, fish-based diets, sodium-restricted diets, calorie restriction, the paleo diet, and gluten-free diets have been examined, mostly in observational studies; results are inconclusive. With regard to nutritional supplements, pilot data show a possible benefit of biotin with respect to disability worsening in people with progressive MS (PMS). The best designed randomized controlled trials (RCTs) for PUFA supplementation have not shown significant impact, but several weaker RCTs have. Many other nutritional supplements have been tested, including several anti-oxidants. While some early studies show positive results, no result has been definitive. Unfortunately, there is no strong evidence for a direct benefit of any given dietary intervention on MS risk or prognosis. However, due to its relationship with vascular co-morbidities, the Mediterranean diet has the strongest rationale for employment in PwMS. Higher-quality clinical trials are needed to ascertain the possible benefits of nutritional supplements.

Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis.

PubMed

Feys, Peter; Moumdjian, Lousin; Van Halewyck, Florian; Wens, Inez; Eijnde, Bert O; Van Wijmeersch, Bart; Popescu, Veronica; Van Asch, Paul

2017-11-01

Exercise therapy studies in persons with multiple sclerosis (pwMS) primarily focused on motor outcomes in mid disease stage, while cognitive function and neural correlates were only limitedly addressed. This pragmatic randomized controlled study investigated the effects of a remotely supervised community-located "start-to-run" program on physical and cognitive function, fatigue, quality of life, brain volume, and connectivity. In all, 42 pwMS were randomized to either experimental (EXP) or waiting list control (WLC) group. The EXP group received individualized training instructions during 12 weeks (3×/week), to be performed in their community aiming to participate in a running event. Measures were physical (VO 2max , sit-to-stand test, Six-Minute Walk Test (6MWT), Multiple Sclerosis Walking Scale-12 (MSWS-12)) and cognitive function (Rao's Brief Repeatable Battery (BRB), Paced Auditory Serial Attention Test (PASAT)), fatigue (Fatigue Scale for Motor and Cognitive Function (FSMC)), quality of life (Multiple Sclerosis Impact Scale-29 (MSIS-29)), and imaging. Brain volumes and diffusion tensor imaging (DTI) were quantified using FSL-SIENA/FIRST and FSL-TBSS. In all, 35 pwMS completed the trial. Interaction effects in favor of the EXP group were found for VO 2max , sit-to-stand test, MSWS-12, Spatial Recall Test, FSMC, MSIS-29, and pallidum volume. VO 2max improved by 1.5 mL/kg/min, MSWS-12 by 4, FSMC by 11, and MSIS-29 by 14 points. The Spatial Recall Test improved by more than 10%. Community-located run training improved aerobic capacity, functional mobility, visuospatial memory, fatigue, and quality of life and pallidum volume in pwMS.

Predictors of the physical impact of Multiple Sclerosis following community-based, exercise trial.

PubMed

Kehoe, M; Saunders, J; Jakeman, P; Coote, S

2015-04-01

Studies evaluating exercise interventions in people with multiple sclerosis (PwMS) demonstrate small to medium positive effects and large variability on a number of outcome measures. No study to date has tried to explain this variability. This paper presents a novel exploration of data examining the predictors of outcome for PwMS with minimal gait impairment following a randomised, controlled trial evaluating community-based exercise interventions (N = 242). The primary variable was the physical component of the Multiple Sclerosis Impact Scale-29, version 2 (MSIS-29, v2) after a 10-week, controlled intervention period. Predictors were identified a priori and were measured at baseline. Multiple linear regression was conducted. Four models are presented lower MSIS-29, v2 scores after the intervention period were best predicted by a lower baseline MSIS-29,v2, a lower baseline Modified Fatigue Impact Score (physical subscale), randomisation to an exercise intervention, a longer baseline walking distance measured by the Six Minute Walk Test and female gender. This model explained 57.4% of the variance (F (5, 211) = 59.24, p < 0.01). These results suggest that fatigue and walking distance at baseline contribute significantly to predicting MSIS-29, v29 (physical component) after intervention, and thus should be the focus of intervention and assessment. Exercise is an important contributor to minimising the physical impact of MS, and gender-specific interventions may be warranted. © The Author(s), 2014.

Update of treatment algorithms for Clostridium difficile infection.

PubMed

Ooijevaar, R E; van Beurden, Y H; Terveer, E M; Goorhuis, A; Bauer, M P; Keller, J J; Mulder, C J J; Kuijper, E J

2018-05-01

Clostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI. To review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies. A literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017. We analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2). Metronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

A pragmatic cluster randomised controlled trial to evaluate the safety, clinical effectiveness, cost effectiveness and satisfaction with point of care testing in a general practice setting - rationale, design and baseline characteristics.

PubMed

Laurence, Caroline; Gialamas, Angela; Yelland, Lisa; Bubner, Tanya; Ryan, Philip; Willson, Kristyn; Glastonbury, Briony; Gill, Janice; Shephard, Mark; Beilby, Justin

2008-08-06

Point of care testing (PoCT) may be a useful adjunct in the management of chronic conditions in general practice (GP). The provision of pathology test results at the time of the consultation could lead to enhanced clinical management, better health outcomes, greater convenience and satisfaction for patients and general practitioners (GPs), and savings in costs and time. It could also result in inappropriate testing, increased consultations and poor health outcomes resulting from inaccurate results. Currently there are very few randomised controlled trials (RCTs) in GP that have investigated these aspects of PoCT. The Point of Care Testing in General Practice Trial (PoCT Trial) was an Australian Government funded multi-centre, cluster randomised controlled trial to determine the safety, clinical effectiveness, cost effectiveness and satisfaction of PoCT in a GP setting.The PoCT Trial covered an 18 month period with the intervention consisting of the use of PoCT for seven tests used in the management of patients with diabetes, hyperlipidaemia and patients on anticoagulant therapy. The primary outcome measure was the proportion of patients within target range, a measure of therapeutic control. In addition, the PoCT Trial investigated the safety of PoCT, impact of PoCT on patient compliance to medication, stakeholder satisfaction, cost effectiveness of PoCT versus laboratory testing, and influence of geographic location. The paper provides an overview of the Trial Design, the rationale for the research methodology chosen and how the Trial was implemented in a GP environment. The evaluation protocol and data collection processes took into account the large number of patients, the broad range of practice types distributed over a large geographic area, and the inclusion of pathology test results from multiple pathology laboratories.The evaluation protocol developed reflects the complexity of the Trial setting, the Trial Design and the approach taken within the funding provided. The PoCT Trial is regarded as a pragmatic RCT, evaluating the effectiveness of implementing PoCT in GP and every effort was made to ensure that, in these circumstances, internal and external validity was maintained. 12612605000272695.

The Cultural Adaptability of Intermediate Measures of Functional Outcome in Schizophrenia*

PubMed Central

Rubin, Maureen; Fredrick, Megan M.; Mintz, Jim; Nuechterlein, Keith H.; Schooler, Nina R.; Jaeger, Judith; Peters, Nancy M.; Buller, Raimund; Marder, Stephen R.; Dube, Sanjay

2012-01-01

The Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative was designed to encourage the development of cognitive enhancing agents for schizophrenia. For a medication to receive this indication, regulatory agencies require evidence of improvement in both cognition and functional outcome. Because medication trials are conducted across multiple countries, we examined ratings of the cross-cultural adaptability of 4 intermediate measures of functional outcome (Independent Living Scales, UCSD Performance-based Skills Assessment, Test of Adaptive Behavior in Schizophrenia, Cognitive Assessment Interview [CAI]) made by experienced clinical researchers at 31 sites in 8 countries. English-speaking research staff familiar with conducting medication trials rated the extent to which each subscale of each intermediate measure could be applied to their culture and to subgroups within their culture based on gender, geographic region, ethnicity, and socioeconomic status on the Cultural Adaptation Rating Scale. Ratings suggested that the CAI would be easiest to adapt across cultures. However, in a recent study, the CAI was found to have weaker psychometric properties than some of the other measures. Problems were identified for specific subscales on all the performance-based assessments across multiple countries. India, China, and Mexico presented the greatest challenges in adaptation. For international clinical trials, it would be important to use the measures that are most adaptable, to adapt subscales that are problematic for specific countries or regions, or to develop a battery composed of the subscales from different instruments that may be most acceptable across multiple cultures with minimal adaptation. PMID:21134973

The DIAMIND study: postpartum SMS reminders to women who have had gestational diabetes mellitus to test for type 2 diabetes: a randomised controlled trial - study protocol.

PubMed

Heatley, Emer; Middleton, Philippa; Hague, William; Crowther, Caroline

2013-04-12

Postpartum follow up of women who have been found to have gestational diabetes during pregnancy is essential because of the strong association of gestational diabetes with subsequent type 2 diabetes. Postal reminders have been shown to increase significantly attendance for oral glucose tolerance testing postpartum. It is possible that a short message service (text) reminder system may also be effective. This trial aims to assess whether a text message reminder system for women who have experienced gestational diabetes in their index pregnancy will increase attendance for oral glucose tolerance testing within six months after birth. Single centre (Women's and Children's Hospital, South Australia), parallel group randomised controlled trial. Women diagnosed with gestational diabetes in their index pregnancy (oral glucose tolerance test with fasting glucose ≥ 5.5 mmol/L and/or two hour glucose ≥ 7.8 mmol/L), with access to a mobile phone, whose capillary blood glucose profile measurements prior to postnatal discharge are all normal (fasting glucose < 6.0 mmol/L, postprandial glucoses < 8.0 mmol/L). Pregestational diabetes mellitus, triplet/higher order multiple birth or stillbirth in the index pregnancy, requirement for interpreter.Trial entry and randomisation: Allocation to intervention will be undertaken using a telephone randomisation service (computer-generated random number sequence generation, with balanced variable blocks, and stratification by insulin requirement).Study groups: Women in the intervention group will receive a text reminder to attend for an oral glucose tolerance test at 6 weeks postpartum, with further reminders at 3 months and 6 months if they do not respond to indicate test completion. Women in the control group will receive a single text message reminder at 6 months postpartum.Blinding: Baseline data collection will be undertaken blinded. Blinding of participants and blinded collection of primary outcome data will not be possible for this study.Primary study outcome: Attendance for the oral glucose tolerance test within 6 months postpartum. 276 subjects will be required to show an 18% absolute increase in the rate of attendance (α=0.05 two tailed, β=80%, 5% loss to follow up) from 37% to 55% in the intervention group. Given the heightened risk of impaired glucose tolerance and type 2 diabetes in women who have had gestational diabetes, ensuring the highest possible rate of attendance for postpartum glucose tolerance testing, so that early diagnosis and intervention can occur, is important. A text message reminder system may prove to be an effective method for achieving improved attendance for such testing. This randomised controlled trial will assess whether such a system will increase rates of attendance for postpartum oral glucose tolerance testing in women who have experienced gestational diabetes. Australian New Zealand Clinical Trials Registry - ACTRN12612000621819.

Local Fields in Human Subthalamic Nucleus Track the Lead-up to Impulsive Choices.

PubMed

Pearson, John M; Hickey, Patrick T; Lad, Shivanand P; Platt, Michael L; Turner, Dennis A

2017-01-01

The ability to adaptively minimize not only motor but cognitive symptoms of neurological diseases, such as Parkinson's Disease (PD) and obsessive-compulsive disorder (OCD), is a primary goal of next-generation deep brain stimulation (DBS) devices. On the basis of studies demonstrating a link between beta-band synchronization and severity of motor symptoms in PD, the minimization of beta band activity has been proposed as a potential training target for closed-loop DBS. At present, no comparable signal is known for the impulsive side effects of PD, though multiple studies have implicated theta band activity within the subthalamic nucleus (STN), the site of DBS treatment, in processes of conflict monitoring and countermanding. Here, we address this challenge by recording from multiple independent channels within the STN in a self-paced decision task to test whether these signals carry information sufficient to predict stopping behavior on a trial-by-trial basis. As in previous studies, we found that local field potentials (LFPs) exhibited modulations preceding self-initiated movements, with power ramping across multiple frequencies during the deliberation period. In addition, signals showed phasic changes in power around the time of decision. However, a prospective model that attempted to use these signals to predict decision times showed effects of risk level did not improve with the addition of LFPs as regressors. These findings suggest information tracking the lead-up to impulsive choices is distributed across multiple frequency scales in STN, though current techniques may not possess sufficient signal-to-noise ratios to predict-and thus curb-impulsive behavior on a moment-to-moment basis.

A Systematic Review and Meta-Analysis of Strength Training in Individuals With Multiple Sclerosis Or Parkinson Disease

PubMed Central

Cruickshank, Travis M.; Reyes, Alvaro R.; Ziman, Melanie R.

2015-01-01

Abstract Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson disease or multiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%–83.2%) and multiple sclerosis (4.5%–36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electromyography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis. PMID:25634170

A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease.

PubMed

Cruickshank, Travis M; Reyes, Alvaro R; Ziman, Melanie R

2015-01-01

Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson disease or multiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%-83.2%) and multiple sclerosis (4.5%-36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electromyography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis.

The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial.

PubMed

Sharafaddinzadeh, Naser; Moghtaderi, Ali; Kashipazha, Davood; Majdinasab, Nastaran; Shalbafan, Bita

2010-08-01

Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire. A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups. Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study. The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

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.

Auditory memory in monkeys: costs and benefits of proactive interference.

PubMed

Bigelow, James; Poremba, Amy

2013-05-01

Proactive interference (PI) has traditionally been understood as an adverse consequence of stimulus repetition during memory tasks. Herein, we present data that emphasize costs as well as benefits of PI for monkeys performing an auditory delayed matching-to-sample (DMTS) task. The animals made same/different judgments for a variety of simple and complex sounds separated by a 5-s memory delay. Each session used a stimulus set that included eight sounds; thus, each sound was repeated multiple times per session for match trials and for nonmatch trials as the sample (Cue 1) or test (Cue 2) stimulus. For nonmatch trials, performance was substantially diminished when the test stimulus had been previously presented on a recent trial. However, when the sample stimulus had been recently presented, performance was significantly improved. We also observed a marginal performance benefit when stimuli for match trials had been recently presented. The costs of PI for nonmatch test stimuli were greater than the combined benefits of PI for nonmatch sample stimuli and match trials, indicating that the net influence of PI is detrimental. For all three manifestations of PI, the effects are shown to extend beyond the immediately subsequent trial. Our data suggest that PI in auditory DMTS is best understood as an enduring influence that can be both detrimental and beneficial to memory-task performance. © 2012 Wiley Periodicals, Inc.

Determinants of response and resistance to cytotoxics.

PubMed

Rosell, Rafael; Monzó, Mariano; Alberola, Vicente; Taron, Miquel; Barnadas, Agustin; Sánchez, Jose Miguel; Manzano, Jose Luis; Sanchez, José Javier

2002-02-01

There is an underlying feeling in the oncology community that chemotherapy has reached a therapeutic "glass ceiling" in non-small cell lung cancer, and that we will never attain the acceptable survival rates that are just beyond our reach. Multiple clinical trials have tested doublets, triplets, and sequential chemotherapy in what is often regarded as a futile attempt to break through this ceiling. Recent large randomized trials have not shown that any of these combinations is superior to any of the others. Nevertheless, the analysis of DNA and RNA from patients' serum can permit us to assess genes that may be specific targets of certain cytotoxic agents and others that may be markers of multidrug resistance. With this information, we will hopefully be able to create guidelines for individualized chemotherapy. With this in mind, the Spanish Lung Cancer Group has designed a trial to test the involvement of various genes in resistance to gemcitabine and cisplatin. With the gene corral that will emerge from this trial, we will create an up-front diagnostic test for selecting the most appropriate gemcitabine plus cisplatin regimen for the treatment of non-small cell lung cancer.

Transfusion Indication Threshold Reduction (TITRe2) randomized controlled trial in cardiac surgery: statistical analysis plan.

PubMed

Pike, Katie; Nash, Rachel L; Murphy, Gavin J; Reeves, Barnaby C; Rogers, Chris A

2015-02-22

The Transfusion Indication Threshold Reduction (TITRe2) trial is the largest randomized controlled trial to date to compare red blood cell transfusion strategies following cardiac surgery. This update presents the statistical analysis plan, detailing how the study will be analyzed and presented. The statistical analysis plan has been written following recommendations from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, prior to database lock and the final analysis of trial data. Outlined analyses are in line with the Consolidated Standards of Reporting Trials (CONSORT). The study aims to randomize 2000 patients from 17 UK centres. Patients are randomized to either a restrictive (transfuse if haemoglobin concentration <7.5 g/dl) or liberal (transfuse if haemoglobin concentration <9 g/dl) transfusion strategy. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first 3 months following randomization. The statistical analysis plan details how non-adherence with the intervention, withdrawals from the study, and the study population will be derived and dealt with in the analysis. The planned analyses of the trial primary and secondary outcome measures are described in detail, including approaches taken to deal with multiple testing, model assumptions not being met and missing data. Details of planned subgroup and sensitivity analyses and pre-specified ancillary analyses are given, along with potential issues that have been identified with such analyses and possible approaches to overcome such issues. ISRCTN70923932 .

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

Correlates of Adherence to a Telephone-Based Multiple Health Behavior Change Cancer Preventive Intervention for Teens: The Healthy for Life Program (HELP)

ERIC Educational Resources Information Center

Mays, Darren; Peshkin, Beth N.; Sharff, McKane E.; Walker, Leslie R.; Abraham, Anisha A.; Hawkins, Kirsten B.; Tercyak, Kenneth P.

2012-01-01

This study examined factors associated with teens' adherence to a multiple health behavior cancer preventive intervention. Analyses identified predictors of trial enrollment, run-in completion, and adherence (intervention initiation, number of sessions completed). Of 104 teens screened, 73% (n = 76) were trial eligible. White teens were more…

Meta-Analysis of the Effect of Chest Shielding on Preventing Patent Ductus Arteriosus in Premature Infants.

PubMed

Mannan, Javed; Amin, Sanjiv B

2017-03-01

Objective  This study aims to perform a meta-analysis of randomized studies to evaluate if chest shielding during phototherapy is associated with decreased incidence of patent ductus arteriosus (PDA) in premature infants. Design/Methods  We used published guidelines for the meta-analysis of clinical trials. The search strategy included electronic searches of CINAHL, CENTRAL Cochrane Library, MEDLINE, PubMed, and abstracts presented at the Pediatric Academic Societies. Inclusion criteria were randomized controlled trials (RCTs), quasi-RCTs or cluster RCTs published in English and involving chest shielding during phototherapy in premature infants with PDA as an outcome. Exclusion criteria involved case reports, case series, and multiple publications from the same author. Heterogeneity testing using Q statistics was performed to evaluate the variance between studies. Results  Two RCTs met study criteria. There was heterogeneity (I 2 : 55.4%) between the two trials. Meta-analysis of RCTs using the random effect model demonstrated that chest shielding during phototherapy was associated with decreased incidence of PDA (odds ratio: 0.47, 95% confidence interval: 0.23-0.96). There was no publication bias on Eggers test. Heterogeneity was seen in gestational age, gender, prophylactic use of postnatal indomethacin, duration of phototherapy, and assessment of PDA. Conclusion  Chest shielding during phototherapy may be associated with decreased incidence of PDA among premature infants. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Stroop performance in multiple sclerosis: information processing, selective attention, or executive functioning?

PubMed

Macniven, J A B; Davis, C; Ho, M-Y; Bradshaw, C M; Szabadi, E; Constantinescu, C S

2008-09-01

Cognitive impairments in information processing speed, attention and executive functioning are widely reported in patients with multiple sclerosis (MS). Several studies have identified impaired performance on the Stroop test in people with MS, yet uncertainty remains over the cause of this phenomenon. In this study, 25 patients with MS were assessed with a neuropsychological test battery including a computerized Stroop test and a computerized test of information processing speed, the Graded Conditional Discrimination Tasks (GCDT). The patient group was compared with an individually age, sex and estimated premorbid IQ-matched healthy control group. The patients' reaction times (RTs) were significantly longer than those of the controls on all Stroop test trials and there was a significantly enhanced absolute (RT(incongruent)-RT(neutral)) and relative (100 x [RT(incongruent)-RT(neutral)]/RT(neutral)) Stroop interference effect for the MS group. The linear function relating RT to stimulus complexity in the GCDT was significantly steeper in the patient group, indicating slowed information processing. The results are discussed with reference to the difference engine model, a theory of diversity in speeded cognition. It is concluded that, in the assessment of people with MS, great caution must be used in the interpretation of performance on neuropsychological tests which rely on RT as the primary measure.

Are multiple visual short-term memory storages necessary to explain the retro-cue effect?

PubMed

Makovski, Tal

2012-06-01

Recent research has shown that change detection performance is enhanced when, during the retention interval, attention is cued to the location of the upcoming test item. This retro-cue advantage has led some researchers to suggest that visual short-term memory (VSTM) is divided into a durable, limited-capacity storage and a more fragile, high-capacity storage. Consequently, performance is poor on the no-cue trials because fragile VSTM is overwritten by the test display and only durable VSTM is accessible under these conditions. In contrast, performance is improved in the retro-cue condition because attention keeps fragile VSTM accessible. The aim of the present study was to test the assumptions underlying this two-storage account. Participants were asked to encode an array of colors for a change detection task involving no-cue and retro-cue trials. A retro-cue advantage was found even when the cue was presented after a visual (Experiment 1) or a central (Experiment 2) interference. Furthermore, the magnitude of the interference was comparable between the no-cue and retro-cue trials. These data undermine the main empirical support for the two-storage account and suggest that the presence of a retro-cue benefit cannot be used to differentiate between different VSTM storages.

Effect of Fee on Cervical Cancer Screening Attendance--ScreenFee, a Swedish Population-Based Randomised Trial.

PubMed

Alfonzo, Emilia; Andersson Ellström, Agneta; Nemes, Szilard; Strander, Björn

2016-01-01

Attendance in the cervical cancer screening programme is one of the most important factors to lower the risk of contracting the disease. Attendance rates are often low in areas with low socioeconomic status. Charging a fee for screening might possibly decrease attendance in this population. Screening programme coverage is low in low socio-economic status areas in Gothenburg, Sweden, but has increased slightly after multiple interventions in recent years. For many years, women in the region have paid a fee for screening. We studied the effect of abolishing this fee in a trial emanating from the regular cervical cancer screening programme. Individually randomised controlled trial. All 3 124 women in three low-resource areas in Gothenburg, due for screening during the study period, were randomised to receive an offer of a free test or the standard invitation stating the regular fee of 100 SEK (≈11 €). The study was conducted during the first six months of 2013. Attendance was defined as a registered Pap smear within 90 days from the date the invitation was sent out. Attendance did not differ significantly between women who were charged and those offered free screening (RR 0.93; CI 0.85-1.02). No differences were found within the districts or as an effect of age, attendance after the most recent previous invitation or previous experience of smear taking. Abolishment of a modest screening fee in socially disadvantaged urban districts with low coverage, after previous multiple systematic interventions, does not increase attendance in the short term. Other interventions might be more important for increasing attendance in low socio-economic status areas. ClinicalTrials.gov NCT02378324.

Pharmacological treatment for memory disorder in multiple sclerosis.

PubMed

He, Dian; Zhang, Yun; Dong, Shuai; Wang, Dongfeng; Gao, Xiangdong; Zhou, Hongyu

2013-12-17

This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation. We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups. We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

Quantifying the impact of fixed effects modeling of clusters in multiple imputation for cluster randomized trials

PubMed Central

Andridge, Rebecca. R.

2011-01-01

In cluster randomized trials (CRTs), identifiable clusters rather than individuals are randomized to study groups. Resulting data often consist of a small number of clusters with correlated observations within a treatment group. Missing data often present a problem in the analysis of such trials, and multiple imputation (MI) has been used to create complete data sets, enabling subsequent analysis with well-established analysis methods for CRTs. We discuss strategies for accounting for clustering when multiply imputing a missing continuous outcome, focusing on estimation of the variance of group means as used in an adjusted t-test or ANOVA. These analysis procedures are congenial to (can be derived from) a mixed effects imputation model; however, this imputation procedure is not yet available in commercial statistical software. An alternative approach that is readily available and has been used in recent studies is to include fixed effects for cluster, but the impact of using this convenient method has not been studied. We show that under this imputation model the MI variance estimator is positively biased and that smaller ICCs lead to larger overestimation of the MI variance. Analytical expressions for the bias of the variance estimator are derived in the case of data missing completely at random (MCAR), and cases in which data are missing at random (MAR) are illustrated through simulation. Finally, various imputation methods are applied to data from the Detroit Middle School Asthma Project, a recent school-based CRT, and differences in inference are compared. PMID:21259309

Effects of Tai Chi on Cognition and Fall Risk in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial.

PubMed

Sungkarat, Somporn; Boripuntakul, Sirinun; Chattipakorn, Nipon; Watcharasaksilp, Kanokwan; Lord, Stephen R

2017-04-01

To examine whether combined center- and home-based Tai Chi training can improve cognitive ability and reduce physiological fall risk in older adults with amnestic mild cognitive impairment (a-MCI). Randomized controlled trial. Chiang Mai, Thailand. Adults aged 60 and older who met Petersen's criteria for multiple-domain a-MCI (N = 66). Three weeks center-based and 12 weeks home-based Tai Chi (50 minutes per session, 3 times per week). Cognitive tests, including Logical Memory (LM) delayed recall, Block Design, Digit Span forward and backward, and Trail-Making Test Part B-A (TMT B-A), and fall risk index using the Physiological Profile Assessment (PPA). At the end of the trial, performance on LM, Block Design, and TMT B-A were significantly better for the Tai Chi group than the control group after adjusting for baseline test performance. The Tai Chi group also had significantly better composite PPA score and PPA parameter scores: knee extension strength, reaction time, postural sway, and lower limb proprioception. Combined center- and home-based Tai Chi training three times per week for 15 weeks significantly improved cognitive function and moderately reduced physiological fall risk in older adults with multiple-domain a-MCI. Tai Chi may be particularly beneficial to older adults with this condition. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Evidence for proactive interference in the focus of attention of working memory.

PubMed

Carroll, Lauren M; Jalbert, Annie; Penney, Alexander M; Neath, Ian; Surprenant, Aimée M; Tehan, Gerald

2010-09-01

Proactive interference (PI) occurs when an earlier item interferes with memory for a newer item. Whereas some researchers (e.g., Surprenant & Neath, 2009a) argue that PI can be observed in all memory systems, some multiple systems theorists (e.g., Cowan, 1999) propose that items in the focus of attention of working memory are immune to PI. Two experiments tested whether PI occurs when the to-be-remembered items are assumed, by multiple-systems theorists, to be held in the focus of attention. In each experiment, subjects saw four trials in a row with the same type of to-be-remembered items, followed by four trials in a row with a different type of material. On each trial, only 3 stimuli were shown, which is below the capacity limit of the focus of attention, and subjects were asked if a probe item was one of those 3 items seen. In both experiments, response time increased from Trial 1 to Trial 4, suggesting that items from the earlier trials interfered with memory on the later trials. In addition, release from PI was shown in that response times decreased with a change of materials. The results replicate those first reported by Hanley and Scheirer (1975), and pose a problem for theorists who argue that parts of short-term memory are immune to PI. Copyright 2010 APA, all rights reserved.

Effectiveness of a multi-level implementation strategy for ASD interventions: study protocol for two linked cluster randomized trials.

PubMed

Brookman-Frazee, Lauren; Stahmer, Aubyn C

2018-05-09

The Centers for Disease Control (2018) estimates that 1 in 59 children has autism spectrum disorder, and the annual cost of ASD in the U.S. is estimated to be $236 billion. Evidence-based interventions have been developed and demonstrate effectiveness in improving child outcomes. However, research on generalizable methods to scale up these practices in the multiple service systems caring for these children has been limited and is critical to meet this growing public health need. This project includes two, coordinated studies testing the effectiveness of the Translating Evidence-based Interventions (EBI) for ASD: Multi-Level Implementation Strategy (TEAMS) model. TEAMS focuses on improving implementation leadership, organizational climate, and provider attitudes and motivation in order to improve two key implementation outcomes-provider training completion and intervention fidelity and subsequent child outcomes. The TEAMS Leadership Institute applies implementation leadership strategies and TEAMS Individualized Provider Strategies for training applies motivational interviewing strategies to facilitate provider and organizational behavior change. A cluster randomized implementation/effectiveness Hybrid, type 3, trial with a dismantling design will be used to understand the effectiveness of TEAMS and the mechanisms of change across settings and participants. Study #1 will test the TEAMS model with AIM HI (An Individualized Mental Health Intervention for ASD) in publicly funded mental health services. Study #2 will test TEAMS with CPRT (Classroom Pivotal Response Teaching) in education settings. Thirty-seven mental health programs and 37 school districts will be randomized, stratified by county and study, to one of four groups (Standard Provider Training Only, Standard Provider Training + Leader Training, Enhanced Provider Training, Enhanced Provider Training + Leader Training) to test the effectiveness of combining standard, EBI-specific training with the two TEAMS modules individually and together on multiple implementation outcomes. Implementation outcomes including provider training completion, fidelity (coded by observers blind to group assignment) and child behavior change will be examined for 295 mental health providers, 295 teachers, and 590 children. This implementation intervention has the potential to increase quality of care for ASD in publicly funded settings by improving effectiveness of intervention implementation. The process and modules will be generalizable to multiple service systems, providers, and interventions, providing broad impact in community services. This study is registered with Clinicaltrials.gov ( NCT03380078 ). Registered 20 December 2017, retrospectively registered.

Malaria Diagnostics in Clinical Trials

PubMed Central

Murphy, Sean C.; Shott, Joseph P.; Parikh, Sunil; Etter, Paige; Prescott, William R.; Stewart, V. Ann

2013-01-01

Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests. PMID:24062484

Eating the elephant whole or in slices: views of participants in a smoking cessation intervention trial on multiple behaviour changes as sequential or concurrent tasks

PubMed Central

2012-01-01

Background This paper explores smoking cessation participants’ perceptions of attempting weight management alongside smoking cessation within the context of a health improvement intervention implemented in Glasgow, Scotland. Methods One hundred and thirty-eight participants were recruited from smoking cessation classes in areas of multiple deprivation in Glasgow and randomised to intervention, receiving dietary advice, or to control groups. The primary outcome of the study was to determine the % change in body weight. Semi-structured interviews were conducted with a purposive sample of 15 intervention and 15 control participants at weeks 6 (during the intervention) and 24 (at the end of the intervention). The current paper, though predominantly qualitative, links perceptions of behaviour modification to % weight change and cessation rates at week 24 thereby enabling a better understanding of the mediators influencing multiple behaviour change. Results Our findings suggest that participants who perceive separate behaviour changes as part of a broader approach to a healthier lifestyle, and hence attempt behaviour changes concurrently, may be at comparative advantage in positively achieving dual outcomes. Conclusions These findings highlight the need to assess participants’ preference for attempting multiple behaviour changes sequentially or simultaneously in addition to assessing their readiness to change. Further testing of this hypothesis is warranted. Trial Registration ISRCTN94961361 PMID:22759785

Type-II generalized family-wise error rate formulas with application to sample size determination.

PubMed

Delorme, Phillipe; de Micheaux, Pierre Lafaye; Liquet, Benoit; Riou, Jérémie

2016-07-20

Multiple endpoints are increasingly used in clinical trials. The significance of some of these clinical trials is established if at least r null hypotheses are rejected among m that are simultaneously tested. The usual approach in multiple hypothesis testing is to control the family-wise error rate, which is defined as the probability that at least one type-I error is made. More recently, the q-generalized family-wise error rate has been introduced to control the probability of making at least q false rejections. For procedures controlling this global type-I error rate, we define a type-II r-generalized family-wise error rate, which is directly related to the r-power defined as the probability of rejecting at least r false null hypotheses. We obtain very general power formulas that can be used to compute the sample size for single-step and step-wise procedures. These are implemented in our R package rPowerSampleSize available on the CRAN, making them directly available to end users. Complexities of the formulas are presented to gain insight into computation time issues. Comparison with Monte Carlo strategy is also presented. We compute sample sizes for two clinical trials involving multiple endpoints: one designed to investigate the effectiveness of a drug against acute heart failure and the other for the immunogenicity of a vaccine strategy against pneumococcus. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of dual-task balance training on postural performance in patients with Multiple Sclerosis: a double-blind, randomized controlled pilot trial.

PubMed

Monjezi, Saeideh; Negahban, Hossein; Tajali, Shirin; Yadollahpour, Nava; Majdinasab, Nastaran

2017-02-01

To investigate the effects of dual-task balance training on postural performance in patients with multiple sclerosis as compared with single-task balance training. Double-blind, pretest-posttest, randomized controlled pilot trial. Local Multiple Sclerosis Society. A total of 47 patients were randomly assigned to two equal groups labeled as single-task training and dual-task training groups. All patients received supervised balance training sessions, 3 times per week for 4 weeks. The patients in the single-task group performed balance activities, alone. However, patients in dual-task group practiced balance activities while simultaneously performing cognitive tasks. The 10-Meter Walk Test and Timed Up-and-Go under single-task and dual-task conditions, in addition to Activities-specific Balance Confidence, Berg Balance Scale, and Functional Gait Assessment were assessed pre-, and post intervention and also 6-weeks after the end of intervention. Only 38 patients completed the treatment plan. There was no difference in the amount of improvement seen between the two study groups. In both groups there was a significant effect of time for dual-10 Meter Walk Test (F 1, 36 =11.33, p=0.002) and dual-Timed Up-and-Go (F 1, 36 =14.27, p=0.001) but not for their single-tasks. Moreover, there was a significant effect of time for Activities-specific Balance Confidence, Berg Balance Scale, and Functional Gait Assessment ( P<0.01). This pilot study did not show more benefits from undertaking dual-task training than single-task training. A power analysis showed 71 patients per group would be needed to determine whether there was a clinically relevant difference for dual-task gait speed between the groups.

USSR Report Earth Sciences Tables of Contents JPRS-UES-86-001, 10 January 1986-JPRS-UES-86-008, 4 December 1986.

DTIC Science & Technology

1987-03-27

Research Ship ’Shuleykin’ in Studies of Arctic Seas (B. Moiseyev; VODNYY TRANSPORT, 7 Sep 85) l6 Scanning Submersible Craft Tested From Research...Data Bank can Process Satellite Signals (NTR: PROBLEMY I RESHENIYA, No 9, 17 Sep-7 Oct 1985) 13 Trials of Manned Submersible Craft ’Osmotr’ (I...Specifics of Electromagnetic Field of Multiple- Spaced Arrays of Frequency Sounding and Resistivity Detectors Over Horst (A.N. Kuznetsov; IZVESTIYA

The current status of clinical trials focusing on nasopharyngeal carcinoma: A comprehensive analysis of ClinicalTrials.gov database.

PubMed

Peng, Hao; Chen, Lei; Chen, Yu-Pei; Li, Wen-Fei; Tang, Ling-Long; Lin, Ai-Hua; Sun, Ying; Ma, Jun

2018-01-01

Clinical Trials have emerged as the main force in driving the development of medicine. However, little is known about the current status of clinical trials regarding nasopharyngeal carcinoma (NPC). This study aimed at providing a comprehensive landscape of NPC-related trials on the basis of ClinicalTrials.gov database. We used the keyword "nasopharyngeal carcinoma" to search the ClinicalTrials.gov database and assessed the characteristics of these trials. Up to December 30, 2016, 462 eligible trials in total were identified, of which 222 (48.0%) recruited only NPC (NPC trials) and the other 240 (52.0%) recruited both NPC and other cancers (multiple cancer trials). Moreover, 47 (10.2%) were Epstein-Barr virus (EBV)-related trials and 267 (57.8%) focused on metastatic/recurrent disease. Compared with NPC trials, the multiple cancer trials had a higher percentage of phase 1 (26.7% vs. 6.7%, P < 0.001) studies and more patients with metastatic/recurrent disease (72.5% vs. 41.9%, P < 0.001). Notably, non-EBV trials had more phase 2 or 3 (78.4% vs. 48.8%, P < 0.001) and interventional studies (89.5% vs. 70.7%, P = 0.002) than EBV trials. Obviously, more phase 2/3 or 3 trials were conducted in patients with non-metastatic/recurrent disease (29.4% vs. 4.9%, P < 0.001); however, metastatic/recurrent trials were more likely to be anticancer (94.6% vs. 63.6%, P < 0.001). The role of plasma EBV DNA in clinical trials is underestimated, and high-level randomized clinical trials should be performed for patients with metastatic/recurrent disease.

Validity of the Instrumented Push and Release Test to Quantify Postural Responses in Persons With Multiple Sclerosis.

PubMed

El-Gohary, Mahmoud; Peterson, Daniel; Gera, Geetanjali; Horak, Fay B; Huisinga, Jessie M

2017-07-01

To test the validity of wearable inertial sensors to provide objective measures of postural stepping responses to the push and release clinical test in people with multiple sclerosis. Cross-sectional study. University medical center balance disorder laboratory. Total sample N=73; persons with multiple sclerosis (PwMS) n=52; healthy controls n=21. Stepping latency, time and number of steps required to reach stability, and initial step length were calculated using 3 inertial measurement units placed on participants' lumbar spine and feet. Correlations between inertial sensor measures and measures obtained from the laboratory-based systems were moderate to strong and statistically significant for all variables: time to release (r=.992), latency (r=.655), time to stability (r=.847), time of first heel strike (r=.665), number of steps (r=.825), and first step length (r=.592). Compared with healthy controls, PwMS demonstrated a longer time to stability and required a larger number of steps to reach stability. The instrumented push and release test is a valid measure of postural responses in PwMS and could be used as a clinical outcome measures for patient care decisions or for clinical trials aimed at improving postural control in PwMS. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Factorial versus multi-arm multi-stage designs for clinical trials with multiple treatments.

PubMed

Jaki, Thomas; Vasileiou, Despina

2017-02-20

When several treatments are available for evaluation in a clinical trial, different design options are available. We compare multi-arm multi-stage with factorial designs, and in particular, we will consider a 2 × 2 factorial design, where groups of patients will either take treatments A, B, both or neither. We investigate the performance and characteristics of both types of designs under different scenarios and compare them using both theory and simulations. For the factorial designs, we construct appropriate test statistics to test the hypothesis of no treatment effect against the control group with overall control of the type I error. We study the effect of the choice of the allocation ratios on the critical value and sample size requirements for a target power. We also study how the possibility of an interaction between the two treatments A and B affects type I and type II errors when testing for significance of each of the treatment effects. We present both simulation results and a case study on an osteoarthritis clinical trial. We discover that in an optimal factorial design in terms of minimising the associated critical value, the corresponding allocation ratios differ substantially to those of a balanced design. We also find evidence of potentially big losses in power in factorial designs for moderate deviations from the study design assumptions and little gain compared with multi-arm multi-stage designs when the assumptions hold. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Evaluations of indoor noise criteria systems based on human response

NASA Astrophysics Data System (ADS)

Bowden, Erica E.; Wang, Lily M.

2005-09-01

The goal of this research is to examine human response to background noise, and relate results to indoor noise criteria. In previous work by the authors, subjects completed perception surveys, typing tasks, and proofreading tasks under typical heating, ventilating, and air-conditioning (HVAC) noise conditions. Results were correlated with commonly used indoor noise criteria systems including noise criteria (NC), room criteria (RC) and others. The findings suggested that the types of tasks used and the length of exposure can impact the results. To examine these two issues, the authors conducted a new study in which each test subject completed 38 total hours of testing over multiple days. Subjects were exposed to several background noise exposures over 20, 40, 80, and 240 minute trials. During the trials, subjects completed a variety of performance tasks and answered questions about their perception of the noise, the thermal environment, and various other factors. Findings from this study were used to determine optimum testing conditions for on-going research examining the effects of tonal or fluctuating background noise on performance, annoyance, and spectral perception. Results are being used to evaluate the effectiveness of commonly used indoor noise criteria systems. [Work supported by INCE and ASHRAE.

Sugarcane Genotype Performance in Three Environments (Based on Crop Cycle) at Mardan, Pakistan

USDA-ARS?s Scientific Manuscript database

Sugarcane breeders often face significant genotype x environment interactions in their trials grown under multiple environments. Hence, genotypes need to be tested for their stability across different environments keeping in view the significant interactions. An experiment comprising 28 sugarcane ge...

Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial.

PubMed

Keohane, Denis; Schwartz, Jeffrey; Gundapaneni, Balarama; Stewart, Michelle; Amass, Leslie

2017-03-01

Tafamidis, a non-NSAID highly specific transthyretin stabilizer, delayed neurologic disease progression as measured by Neuropathy Impairment Score-Lower Limbs (NIS-LL) in an 18-month, double-blind, placebo-controlled randomized trial in 128 patients with early-stage transthyretin V30M familial amyloid polyneuropathy (ATTRV30M-FAP). The current post hoc analyses aimed to further evaluate the effects of tafamidis in delaying ATTRV30M-FAP progression in this trial. Pre-specified, repeated-measures analysis of change from baseline in NIS-LL in this trial (ClinicalTrials.gov NCT00409175) was repeated with addition of baseline as covariate and multiple imputation analysis for missing data by treatment group. Change in NIS-LL plus three small-fiber nerve tests (NIS-LL + Σ3) and NIS-LL plus seven nerve tests (NIS-LL + Σ7) were assessed without baseline as covariate. Treatment outcomes over the NIS-LL, Σ3, Σ7, modified body mass index and Norfolk Quality of Life-Diabetic Neuropathy Total Quality of Life Score were also examined using multivariate analysis techniques. Neuropathy progression based on NIS-LL change from baseline to Month 18 remained significantly reduced for tafamidis versus placebo in the baseline-adjusted and multiple imputation analyses. NIS-LL + Σ3 and NIS-LL + Σ7 captured significant treatment group differences. Multivariate analyses provided strong statistical evidence for a superior tafamidis treatment effect. These supportive analyses confirm that tafamidis delays neurologic progression in early-stage ATTRV30M-FAP. NCT00409175.

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.

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.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

PubMed

Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.

Assessments of the quality of randomized controlled trials published in International Journal of Urology from 1994 to 2011.

PubMed

Cho, Hee Ju; Chung, Jae Hoon; Jo, Jung Ki; Kang, Dong Hyuk; Cho, Jeong Man; Yoo, Tag Keun; Lee, Seung Wook

2013-12-01

Randomized controlled trials are one of the most reliable resources for assessing the effectiveness and safety of medical treatments. Low quality randomized controlled trials carry a large bias that can ultimately impair the reliability of their conclusions. The present study aimed to evaluate the quality of randomized controlled trials published in International Journal of Urology by using multiple quality assessment tools. Randomized controlled trials articles published in International Journal of Urology were found using the PubMed MEDLINE database, and qualitative analysis was carried out with three distinct assessment tools: the Jadad scale, the van Tulder scale and the Cochrane Collaboration Risk of Bias Tool. The quality of randomized controlled trials was analyzed by publication year, type of subjects, intervention, presence of funding and whether an institutional review board reviewed the study. A total of 68 randomized controlled trial articles were published among a total of 1399 original articles in International Journal of Urology. Among these randomized controlled trials, 10 (2.70%) were from 1994 to 1999, 23 (4.10%) were from 2000 to 2005 and 35 (4.00%) were from 2006 to 2011 (P = 0.494). On the assessment with the Jadad and van Tulder scale, the numbers and percentage of high quality randomized controlled trials increased over time. The studies that had institutional review board reviews, funding resources or that were carried out in multiple institutions had an increased percentage of high quality articles. The numbers and percentage of high-quality randomized controlled trials published in International Journal of Urology have increased over time. Furthermore, randomized controlled trials with funding resources, institutional review board reviews or carried out in multiple institutions have been found to be of higher quality compared with others not presenting these features. © 2013 The Japanese Urological Association.

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.

Maternal side-effects after multiple courses of antenatal corticosteroids (MACS): the three-month follow-up of women in the randomized controlled trial of MACS for preterm birth study.

PubMed

Murphy, Kellie E; Hannah, Mary E; Willan, Andrew R; Ohlsson, Arne; Kelly, Edmond N; Matthews, Stephen G; Saigal, Saroj; Asztalos, Elizabeth; Ross, Sue; Delisle, Marie-France; Tomat, Laura; Amankwah, Kofi; Guselle, Patricia; Gafni, Amiram; Lee, Shoo K; Armson, B Anthony

2011-09-01

A single course of antenatal corticosteroids (ACS) is associated with a reduction in respiratory distress syndrome and neonatal death. Multiple Courses of Antenatal Corticosteroids Study (MACS), a study involving 1858 women, was a multicentre randomized placebo-controlled trial of multiple courses of ACS, given every 14 days until 33+6 weeks or birth, whichever came first. The primary outcome of the study, a composite of neonatal mortality and morbidity, was similar for the multiple ACS and placebo groups (12.9% vs. 12.5%), but infants exposed to multiple courses of ACS weighed less, were shorter, and had smaller head circumferences. Thus for women who remain at increased risk of preterm birth, multiple courses of ACS (every 14 days) are not recommended. Chronic use of corticosteroids is associated with numerous side effects including weight gain and depression. The aim of this postpartum assessment was to ascertain if multiple courses of ACS were associated with maternal side effects. Three months postpartum, women who participated in MACS were asked to complete a structured questionnaire that asked about maternal side effects of corticosteroid use during MACS and included the Edinburgh Postnatal Depression Scale. Women were also asked to evaluate their study participation. Of the 1858 women randomized, 1712 (92.1%) completed the postpartum questionnaire. There were no significant differences in the risk of maternal side effects between the two groups. Large numbers of women met the criteria for postpartum depression (14.1% in the ACS vs. 16.0% in the placebo group). Most women (94.1%) responded that they would participate in the trial again. In pregnancy, corticosteroids are given to women for fetal lung maturation and for the treatment of various maternal diseases. In this international multicentre randomized controlled trial, multiple courses of ACS (every 14 days) were not associated with maternal side effects, and the majority of women responded that they would participate in such a study again.

Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

PubMed Central

Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

2015-01-01

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899

Comparing cluster-level dynamic treatment regimens using sequential, multiple assignment, randomized trials: Regression estimation and sample size considerations.

PubMed

NeCamp, Timothy; Kilbourne, Amy; Almirall, Daniel

2017-08-01

Cluster-level dynamic treatment regimens can be used to guide sequential treatment decision-making at the cluster level in order to improve outcomes at the individual or patient-level. In a cluster-level dynamic treatment regimen, the treatment is potentially adapted and re-adapted over time based on changes in the cluster that could be impacted by prior intervention, including aggregate measures of the individuals or patients that compose it. Cluster-randomized sequential multiple assignment randomized trials can be used to answer multiple open questions preventing scientists from developing high-quality cluster-level dynamic treatment regimens. In a cluster-randomized sequential multiple assignment randomized trial, sequential randomizations occur at the cluster level and outcomes are observed at the individual level. This manuscript makes two contributions to the design and analysis of cluster-randomized sequential multiple assignment randomized trials. First, a weighted least squares regression approach is proposed for comparing the mean of a patient-level outcome between the cluster-level dynamic treatment regimens embedded in a sequential multiple assignment randomized trial. The regression approach facilitates the use of baseline covariates which is often critical in the analysis of cluster-level trials. Second, sample size calculators are derived for two common cluster-randomized sequential multiple assignment randomized trial designs for use when the primary aim is a between-dynamic treatment regimen comparison of the mean of a continuous patient-level outcome. The methods are motivated by the Adaptive Implementation of Effective Programs Trial which is, to our knowledge, the first-ever cluster-randomized sequential multiple assignment randomized trial in psychiatry.

Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1.

PubMed

van der Vaart, Thijs; Rietman, André B; Plasschaert, Ellen; Legius, Eric; Elgersma, Ype; Moll, Henriëtte A

2016-01-12

To evaluate the appropriateness of cognitive and behavioral outcome measures in clinical trials in neurofibromatosis type 1 (NF1) by analyzing the degree of deficits compared to reference groups, test-retest reliability, and how scores correlate between outcome measures. Data were analyzed from the Simvastatin for cognitive deficits and behavioral problems in patients with neurofibromatosis type 1 (NF1-SIMCODA) trial, a randomized placebo-controlled trial of simvastatin for cognitive deficits and behavioral problems in children with NF1. Outcome measures were compared with age-specific reference groups to identify domains of dysfunction. Pearson r was computed for before and after measurements within the placebo group to assess test-retest reliability. Principal component analysis was used to identify the internal structure in the outcome data. Strongest mean score deviations from the reference groups were observed for full-scale intelligence (-1.1 SD), Rey Complex Figure Test delayed recall (-2.0 SD), attention problems (-1.2 SD), and social problems (-1.1 SD). Long-term test-retest reliability were excellent for Wechsler scales (r > 0.88), but poor to moderate for other neuropsychological tests (r range 0.52-0.81) and Child Behavioral Checklist subscales (r range 0.40-0.79). The correlation structure revealed 2 strong components in the outcome measures behavior and cognition, with no correlation between these components. Scores on psychosocial quality of life correlate strongly with behavioral problems and less with cognitive deficits. Children with NF1 show distinct deficits in multiple domains. Many outcome measures showed weak test-retest correlations over the 1-year trial period. Cognitive and behavioral outcomes are complementary. This analysis demonstrates the need to include reliable outcome measures on a variety of cognitive and behavioral domains in clinical trials for NF1. © 2015 American Academy of Neurology.

Management of optic neuritis

PubMed Central

Menon, Vimla; Saxena, Rohit; Misra, Ruby; Phuljhele, Swati

2011-01-01

Optic neuritis is an inflammatory condition of the optic nerve characterized by a sudden onset of unilateral visual loss, usually affecting young females. Demyelination associated with multiple sclerosis (MS) is the most common cause in regions where MS is prevalent; while in other places, there are a substantial proportion of cases where infective or autoimmune causes are seen. Optic Neuritis Treatment Trial (ONTT) was the first major study that provided information on the natural history, role of steroids in treatment and risk of development of MS. Subsequently, numerous clinical trials have evaluated different modalities of management of optic neuritis and MS. The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS); the Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) Trial; and, most recently, the Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) Study have provided large amount of information on the natural history of optic neuritis and management options available. However, due to the low prevalence of MS reported in Asian studies, high cost of therapy and indefinite time period of treatment, it may not be cost effective to start interferon therapy in most cases. PMID:21350281

Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants.

PubMed

López de Romaña, Guillermo; Cusirramos, Sandra; López de Romaña, Daniel; Gross, Rainer

2005-03-01

Anemia, micronutrient deficiencies, and growth faltering are still common in Peru. The study objective was to determine the efficacy of different micronutrient supplements in preventing growth failure, anemia, and micronutrient deficiencies in Peruvian infants. Three hundred and thirteen infants aged 6 to 12 mo participated in a double-blind, masked, controlled trial in which they were randomly assigned to receive either a daily dose of iron (DI), a daily dose of multiple micronutrients (DMM), a weekly dose of multiple micronutrients, or a placebo (P) for 6 mo. None of the supplements tested prevented growth faltering or the morbidities common during infancy. Anemia and plasma homocysteine concentrations fell significantly in all groups during the study, but the mean change of plasma homocysteine during the trial period was significantly smaller in the DI group than in other groups, and the increase in hemoglobin concentrations was smaller in the P group than the micronutrient treatment groups. Plasma ferritin concentrations decreased least in the groups taking daily micronutrient supplements containing iron (DI and DMM). There were no significant differences among groups in mean final values or changes in plasma zinc, retinol, tocopherol, or riboflavin. Although the DMM intervention was the most efficacious for preventing anemia, iron, and zinc deficiencies, 15%, 20%, and 50% of this group still remained anemic, zinc deficient, and iron deficient, respectively, at the end of the study. Further research thus should investigate whether higher doses of iron and zinc, together with infection control measures, are more efficacious.

Evaluation of pulsing magnetic field effects on paresthesia in multiple sclerosis patients, a randomized, double-blind, parallel-group clinical trial.

PubMed

Afshari, Daryoush; Moradian, Nasrin; Khalili, Majid; Razazian, Nazanin; Bostani, Arash; Hoseini, Jamal; Moradian, Mohamad; Ghiasian, Masoud

2016-10-01

Evidence is mounting that magnet therapy could alleviate the symptoms of multiple sclerosis (MS). This study was performed to test the effects of the pulsing magnetic fields on the paresthesia in MS patients. This study has been conducted as a randomized, double-blind, parallel-group clinical trial during the April 2012 to October 2013. The subjects were selected among patients referred to MS clinic of Imam Reza Hospital; affiliated to Kermanshah University of Medical Sciences, Iran. Sixty three patients with MS were included in the study and randomly were divided into two groups, 35 patients were exposed to a magnetic pulsing field of 4mT intensity and 15-Hz frequency sinusoidal wave for 20min per session 2 times per week over a period of 2 months involving 16 sessions and 28 patients was exposed to a magnetically inactive field (placebo) for 20min per session 2 times per week over a period of 2 months involving 16 sessions. The severity of paresthesia was measured by the numerical rating scale (NRS) at 30, 60days. The study primary end point was NRS change between baseline and 60days. The secondary outcome was NRS change between baseline and 30days. Patients exposing to magnetic field showed significant paresthesia improvement compared with the group of patients exposing to placebo. According to our results pulsed magnetic therapy could alleviate paresthesia in MS patients .But trials with more patients and longer duration are mandatory to describe long-term effects. Copyright © 2016 Elsevier B.V. All rights reserved.

Asian Americans and Cancer Clinical Trials: A Mixed-Methods Approach to Understanding Awareness and Experience

PubMed Central

Paterniti, Debora A.; Chen, Moon S.; Chiechi, Christine; Beckett, Laurel A.; Horan, Nora; Turrell, Corinne; Smith, Ligaya; Morain, Claudia; Montell, Lisa; Gonzalez, Jose Luis; Davis, Sharon; Lara, Primo N.

2006-01-01

Cancer clinical trials have been based on low accrual rates. Barriers to recruitment of minority populations affect the generalizability and impact of trial findings for those populations. The authors undertook a mixed-methods approach to understanding levels of awareness and experiences with cancer clinical trials. A survey was administered to new cancer patients and their caretakers (family, close friends, or other social support) at outpatient oncology clinics. Field observations of the trial accrual process also were conducted by employing the grounded theory approach in qualitative methods. Comparison of survey results for Asian-American respondents and non-Asian respondents indicated that Asians were less likely to have heard the term “clinical trial” and were more likely to define a clinical trial as “an experiment” or “a test procedure in a clinic” than non-Asians. Asians were more likely to have employer-based insurance and to report understanding issues related to cost reimbursement. Asians were less likely to have been involved in or to know someone in a trial and reported less willingness than white respondents to consider trial participation. Qualitative observations suggested that Asians who presented for a potential trial were interested in the availability of a novel cancer therapy but were not eligible for available trials. Multiple strategies will be necessary to enhance awareness of and experience with accrual to cancer clinical trials for Asians, including richer understanding and increased involvement of Asians in cancer clinical trials and greater attention to the location and diversity of the Asian population in structuring study centers and evaluating trial results. PMID:16247795

Predicting Performance in Higher Education Using Proximal Predictors.

PubMed

Niessen, A Susan M; Meijer, Rob R; Tendeiro, Jorge N

2016-01-01

We studied the validity of two methods for predicting academic performance and student-program fit that were proximal to important study criteria. Applicants to an undergraduate psychology program participated in a selection procedure containing a trial-studying test based on a work sample approach, and specific skills tests in English and math. Test scores were used to predict academic achievement and progress after the first year, achievement in specific course types, enrollment, and dropout after the first year. All tests showed positive significant correlations with the criteria. The trial-studying test was consistently the best predictor in the admission procedure. We found no significant differences between the predictive validity of the trial-studying test and prior educational performance, and substantial shared explained variance between the two predictors. Only applicants with lower trial-studying scores were significantly less likely to enroll in the program. In conclusion, the trial-studying test yielded predictive validities similar to that of prior educational performance and possibly enabled self-selection. In admissions aimed at student-program fit, or in admissions in which past educational performance is difficult to use, a trial-studying test is a good instrument to predict academic performance.

When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts.

PubMed

Jakobsen, Janus Christian; Gluud, Christian; Wetterslev, Jørn; Winkel, Per

2017-12-06

Missing data may seriously compromise inferences from randomised clinical trials, especially if missing data are not handled appropriately. The potential bias due to missing data depends on the mechanism causing the data to be missing, and the analytical methods applied to amend the missingness. Therefore, the analysis of trial data with missing values requires careful planning and attention. The authors had several meetings and discussions considering optimal ways of handling missing data to minimise the bias potential. We also searched PubMed (key words: missing data; randomi*; statistical analysis) and reference lists of known studies for papers (theoretical papers; empirical studies; simulation studies; etc.) on how to deal with missing data when analysing randomised clinical trials. Handling missing data is an important, yet difficult and complex task when analysing results of randomised clinical trials. We consider how to optimise the handling of missing data during the planning stage of a randomised clinical trial and recommend analytical approaches which may prevent bias caused by unavoidable missing data. We consider the strengths and limitations of using of best-worst and worst-best sensitivity analyses, multiple imputation, and full information maximum likelihood. We also present practical flowcharts on how to deal with missing data and an overview of the steps that always need to be considered during the analysis stage of a trial. We present a practical guide and flowcharts describing when and how multiple imputation should be used to handle missing data in randomised clinical.

A Combined Intervention of Zinc, Multiple Micronutrients, and Albendazole Does Not Ameliorate Environmental Enteric Dysfunction or Stunting in Rural Malawian Children in a Double-Blind Randomized Controlled Trial.

PubMed

Wang, Alfred Z; Shulman, Robert J; Crocker, Audrey H; Thakwalakwa, Chrissie; Maleta, Kenneth M; Devaraj, Sridevi; Manary, Mark J; Trehan, Indi

2017-01-01

Environmental enteric dysfunction (EED) and linear growth stunting affect many rural agrarian children in the developing world and contribute to the persistently high rates of stunting that are observed worldwide. Effective interventions to consistently ameliorate EED are lacking. We tested whether a bundle of safe and affordable interventions would decrease EED and stunting over 12-24 wk in a cohort of rural Malawian children 12-35 mo old. This was a randomized, double-blind, placebo-controlled clinical trial in which the intervention group received a single dose of albendazole and 14 d of zinc at enrollment and after 20 wk. The intervention group also received a daily multiple micronutrient powder throughout the 24 wk of study. The primary outcomes were improvements in EED, as measured by the urinary lactulose-to-mannitol ratio (L:M ratio) from dual-sugar absorption testing, and linear growth. Urinary L:M ratios and anthropometric measurements were evaluated after 12 and 24 wk of intervention and compared with a placebo group that did not receive any of these interventions. A total of 254 children were enrolled at a mean age of 24 mo; 55% were female. Their mean weight-for-age z score was -1.5, and their mean length-for-age z score was -0.9. After 12 and 24 wk of study, increases in the L:M ratio did not differ between the intervention group (0.071 and 0.088 units, respectively) and the placebo group (0.073 and 0.080 units, respectively) (P = 0.87 and 0.19, respectively). Relative changes in length and weight also did not differ significantly between groups at any time point. The combined usage of albendazole, zinc, and a daily multiple micronutrient powder did not decrease EED or stunting in this population of agrarian children 12-35 mo old in rural Malawi. Alternative interventions to improve these diseases should be investigated. This trial was registered at clinicaltrials.gov as NCT02253095. © 2017 American Society for Nutrition.

Prepare, a randomized trial to promote and evaluate weight loss among overweight and obese women planning pregnancy: Study design and rationale

PubMed Central

Vesco, Kimberly K.; Funk, Kristine L.; Karanja, Njeri; Smith, Ning; Stevens, Victor J.

2017-01-01

Background Women who are overweight or have obesity at pregnancy onset, and those who gain excessive weight during pregnancy, are at increased risk of pregnancy-related complications and large for gestational age infants. Objective This report describes methodology for the Prepare study, a randomized, controlled clinical trial testing a preconception and pregnancy weight management program for women who are overweight or have obesity (BMI ≥ 27 kg/m2). Outcomes This trial examines multiple pregnancy and neonatal outcomes, with the primary outcome being gestational weight gain (GWG). Secondary outcomes include change in weight before conception, offspring birth weight adjusted for gestational age, offspring weight for length, and pregnancy diet quality and physical activity level. Methods Nonpregnant women who anticipate becoming pregnant in the next 2 years are randomly assigned to an intervention program or a usual care control condition. Intervention participants receive weight management counseling by telephone before and during pregnancy, with weekly contacts during the first 6 months and monthly contacts for the next 18 months. Intervention participants also have unlimited access to a study website that provides self-management tools. All participants who become pregnant are contacted at 20 weeks' gestation to assess physical activity levels and dietary habits. All other outcome data are obtained from medical records. Intervention satisfaction is assessed via questionnaire. Summary This clinical trial tests the efficacy of an intervention program designed to help overweight and obese women achieve healthy lifestyle changes that will result in a healthy weight prior to pregnancy and appropriate weight gain during pregnancy. PMID:27394386

The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies.

PubMed

Sosenko, Jay M; Yu, Liping; Skyler, Jay S; Krischer, Jeffrey P; Gottlieb, Peter A; Boulware, David; Miao, Dongmei; Palmer, Jerry P; Steck, Andrea K

2017-03-01

Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL + ) were compared with those ECL negative (ECL - ) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. The progression to multiple autoantibodies was significantly higher for those GADA/ECL + (n = 107) than those GADA/ECL - (n = 78) (P = 0.001) and for those mIAA/ECL + (n = 24) than those mIAA/ECL - (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58-7.39; P < 0.01) for GADA and 8.15 (3.02-22.00; P < 0.001) for mIAA. GADA/ECL + and mIAA/ECL + participants had significantly higher PS6M values than their ECL - counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL + , 14% progressed to T1D; of those mIAA/ECL + , 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL - progressed to T1D (median follow-up: 5 years). ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL + are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL - are at very low risk.

Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial.

PubMed

Lappin, Martha S; Lawrie, Fraser Wilson; Richards, Todd L; Kramer, Eric D

2003-01-01

There is a growing literature on the biological and clinical effects of pulsed electromagnetic fields. Some studies suggest that electromagnetic therapies may be useful in the treatment of chronic illnesses. This study is a follow-up to a placebo controlled pilot study in which multiple sclerosis (MS) patients exposed to weak, extremely low frequency pulsed electromagnetic fields showed significant improvements on a composite symptom measure. To evaluate the effects of a pulsed electromagnetic therapy on MS related fatigue, spasticity, bladder control, and overall quality of life. A multi-site, double-blind, placebo controlled, crossover trial. Each subject received 4 weeks of the active and placebo treatments separated by a 2-week washout period. The University of Washington Medical Center in Seattle Wash, the Neurology Center of Fairfax in Fairfax, Va, and the headquarters of the Multiple Sclerosis Association of America in Cherry Hill, NJ. 117 patients with clinically definite MS. Daily exposure to a small, portable pulsing electromagnetic field generator. The MS Quality of Life Inventory (MSQLI) was used to assess changes in fatigue, bladder control, spasticity, and a quality of life composite. Paired t-tests were used to assess treatment differences in the 117 subjects (81% of the initial sample) who completed both treatment sessions. Improvements in fatigue and overall quality of life were significantly greater on the active device. There were no treatment effects for bladder control and a disability composite, and mixed results for spasticity. Evidence from this randomized, double-bind, placebo controlled trial is consistent with results from smaller studies suggesting that exposure to pulsing, weak electromagnetic fields can alleviate symptoms of MS. The clinical effects were small, however, and need to be replicated. Additional research is also needed to examine the possibility that ambulatory patients and patients taking interferons for their MS may be most responsive to this kind of treatment.

Mild deficits in mice lacking pituitary adenylate cyclase-activating polypeptide receptor type 1 (PAC1) performing on memory tasks.

PubMed

Sauvage, M; Brabet, P; Holsboer, F; Bockaert, J; Steckler, T

2000-12-08

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor subtype 1 (PAC1) have been suggested to play a role in the modulation of learning and memory. However, behavioral evidence for altered mnemonic function due to altered PAC1 activity is missing. Therefore, the role of PAC1 in learning and memory was studied in mouse mutants lacking this receptor (PAC1 knock-out mice), tested in water maze two-choice spatial discrimination, one-trial contextual and cued fear conditioning, and multiple-session contextual discrimination. Water maze spatial discrimination was unaffected in PAC1 mutants, while a mild deficit was observed in multiple session contextual discrimination in PAC1 knock-out mice. Furthermore, PAC1 knock-out mice were able to learn the association between context and shock in one-trial contextual conditioning, but showed faster return to baseline than wild-type mice. Thus, the effects of PAC1 knock-out on modulating performance in these tasks were subtle and suggest that PAC1 only plays a limited role in learning and memory.

A perspective on B-cell-targeting therapy for SLE.

PubMed

Looney, R John; Anolik, Jennifer; Sanz, Inaki

2010-02-01

In recent years, large controlled trials have tested several new agents for systemic lupus erythematosus (SLE). Unfortunately, none of these trials has met its primary outcome. This does not mean progress has not been made. In fact, a great deal has been learned about doing clinical trials in lupus and about the biological and clinical effects of the drugs being tested. Many of these drugs were designed to target B cells directly, e.g., rituximab, belimumab, epratuzumab, and transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig). The enthusiasm for targeting B cells derives from substantial evidence showing the critical role of B cells in murine models of SLE, as well promising results from multiple open trials with rituximab, a chimeric anti-CD20 monoclonal antibody that specifically depletes B cells (Martin and Chan in Immunity 20(5):517-527, 2004; Sobel et al. in J Exp Med 173:1441-1449, 1991; Silverman and Weisman in Arthritis Rheum 48:1484-1492, 2003; Silverman in Arthritis Rheum 52(4):1342, 2005; Shlomchik et al. in Nat Rev Immunol 1:147-153, 2001; Looney et al. in Arthritis Rheum 50:2580-2589, 2004; Lu et al. in Arthritis Rheum 61(4):482-487, 2009; Saito et al. in Lupus 12(10):798-800, 2003; van Vollenhoven et al. in Scand J Rheumatol 33(6):423-427, 2004; Sfikakis et al. Arthritis Rheum 52(2):501-513, 2005). Why have the controlled trials of B-cell-targeting therapies failed to demonstrate efficacy? Were there flaws in design or execution of these trials? Or, were promising animal studies and open trials misleading, as so often happens? This perspective discusses the current state of B-cell-targeting therapies for human lupus and the future development of these therapies.

A multi-centre randomised controlled trial of rehabilitation aimed at improving outdoor mobility for people after stroke: Study protocol for a randomised controlled trial

PubMed Central

2012-01-01

Background Up to 42% of all stroke patients do not get out of the house as much as they would like. This can impede a person’s quality of life. This study is testing the clinical effectiveness and cost effectiveness of a new outdoor mobility rehabilitation intervention by comparing it to usual care. Methods/design This is a multi-centre parallel group individually randomised, controlled trial. At least 506 participants will be recruited through 15 primary and secondary care settings and will be eligible if they are over 18 years of age, have had a stroke and wish to get out of the house more often. Participants are being randomly allocated to either the intervention group or the control group. Intervention group participants receive up to 12 rehabilitation outdoor mobility sessions over up to four months. The main component of the intervention is repeated practice of outdoor mobility with a therapist. Control group participants are receiving the usual intervention for outdoor mobility limitations: verbal advice and provision of leaflets provided over one session. Outcome measures are being collected using postal questionnaires, travel calendars and by independent assessors. The primary outcome measure is the Social Function domain of the SF36v2 quality of life assessment six months after recruitment. The secondary outcome measures include: functional ability, mobility, the number of journeys (monthly travel diaries), satisfaction with outdoor mobility, mood, health-related quality of life, resource use of health and social care. Carer mood information is also being collected. The mean Social Function score of the SF-36v2 will be compared between treatment arms using a multiple membership form of mixed effects multiple regression analysis adjusting for centre (as a fixed effect), age and baseline Social Function score as covariates and therapist as a multiple membership random effect. Regression coefficients and 95% confidence intervals will be presented. Discussion This study protocol describes a pragmatic randomised controlled trial that will hopefully provide robust evidence of the benefit of outdoor mobility interventions after stroke for clinicians working in the community. The results will be available towards the end of 2012. Trial registration ISRCTN58683841 PMID:22721452

Positional priming of visual pop-out search is supported by multiple spatial reference frames

PubMed Central

Gokce, Ahu; Müller, Hermann J.; Geyer, Thomas

2015-01-01

The present study investigates the representations(s) underlying positional priming of visual ‘pop-out’ search (Maljkovic and Nakayama, 1996). Three search items (one target and two distractors) were presented at different locations, in invariant (Experiment 1) or random (Experiment 2) cross-trial sequences. By these manipulations it was possible to disentangle retinotopic, spatiotopic, and object-centered priming representations. Two forms of priming were tested: target location facilitation (i.e., faster reaction times – RTs– when the trial n target is presented at a trial n-1 target relative to n-1 blank location) and distractor location inhibition (i.e., slower RTs for n targets presented at n-1 distractor compared to n-1 blank locations). It was found that target locations were coded in positional short-term memory with reference to both spatiotopic and object-centered representations (Experiment 1 vs. 2). In contrast, distractor locations were maintained in an object-centered reference frame (Experiments 1 and 2). We put forward the idea that the uncertainty induced by the experiment manipulation (predictable versus random cross-trial item displacements) modulates the transition from object- to space-based representations in cross-trial memory for target positions. PMID:26136718

The challenge of comorbidity in clinical trials for multiple sclerosis.

PubMed

Marrie, Ruth Ann; Miller, Aaron; Sormani, Maria Pia; Thompson, Alan; Waubant, Emmanuelle; Trojano, Maria; O'Connor, Paul; Reingold, Stephen; Cohen, Jeffrey A

2016-04-12

We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS). We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS. We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies. Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to "real world" settings where the MS population commonly has comorbid conditions. © 2016 American Academy of Neurology.

The challenge of comorbidity in clinical trials for multiple sclerosis

PubMed Central

Miller, Aaron; Sormani, Maria Pia; Thompson, Alan; Waubant, Emmanuelle; Trojano, Maria; O'Connor, Paul; Reingold, Stephen; Cohen, Jeffrey A.

2016-01-01

Objective: We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS). Methods: We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS. Results: We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies. Conclusion: Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to “real world” settings where the MS population commonly has comorbid conditions. PMID:26888986

Preferential Cyclooxygenase 2 Inhibitors as a Nonhormonal Method of Emergency Contraception: A Look at the Evidence.

PubMed

Weiss, Erich A; Gandhi, Mona

2016-04-01

To review the literature surrounding the use of preferential cyclooxygenase 2 (COX-2) inhibitors as an alternative form of emergency contraception. MEDLINE (1950 to February 2014) was searched using the key words cyclooxygenase or COX-2 combined with contraception, emergency contraception, or ovulation. Results were limited to randomized control trials, controlled clinical trials, and clinical trials. Human trials that measured the effects of COX inhibition on female reproductive potential were included for review. The effects of the COX-2 inhibitors rofecoxib, celecoxib, and meloxicam were evaluated in 6 trials. Each of which was small in scope, enrolled women of variable fertility status, used different dosing regimens, included multiple end points, and had variable results. Insufficient evidence exists to fully support the use of preferential COX-2 inhibitors as a form of emergency contraception. Although all trials resulted in a decrease in ovulatory cycles, outcomes varied between dosing strategies and agents used. A lack of homogeneity in these studies makes comparisons difficult. However, success of meloxicam in multiple trials warrants further study. Larger human trials are necessary before the clinical utility of this method of emergency contraception can be fully appreciated. © The Author(s) 2014.

Comparing strategies to assess multiple behavior change in behavioral intervention studies.

PubMed

Drake, Bettina F; Quintiliani, Lisa M; Sapp, Amy L; Li, Yi; Harley, Amy E; Emmons, Karen M; Sorensen, Glorian

2013-03-01

Alternatives to individual behavior change methods have been proposed, however, little has been done to investigate how these methods compare. To explore four methods that quantify change in multiple risk behaviors targeting four common behaviors. We utilized data from two cluster-randomized, multiple behavior change trials conducted in two settings: small businesses and health centers. Methods used were: (1) summative; (2) z-score; (3) optimal linear combination; and (4) impact score. In the Small Business study, methods 2 and 3 revealed similar outcomes. However, physical activity did not contribute to method 3. In the Health Centers study, similar results were found with each of the methods. Multivitamin intake contributed significantly more to each of the summary measures than other behaviors. Selection of methods to assess multiple behavior change in intervention trials must consider study design, and the targeted population when determining the appropriate method/s to use.

Evaluations and Comparisons of Treatment Effects Based on Best Combinations of Biomarkers with Applications to Biomedical Studies

PubMed Central

Chen, Xiwei; Yu, Jihnhee

2014-01-01

Abstract Many clinical and biomedical studies evaluate treatment effects based on multiple biomarkers that commonly consist of pre- and post-treatment measurements. Some biomarkers can show significant positive treatment effects, while other biomarkers can reflect no effects or even negative effects of the treatments, giving rise to a necessity to develop methodologies that may correctly and efficiently evaluate the treatment effects based on multiple biomarkers as a whole. In the setting of pre- and post-treatment measurements of multiple biomarkers, we propose to apply a receiver operating characteristic (ROC) curve methodology based on the best combination of biomarkers maximizing the area under the receiver operating characteristic curve (AUC)-type criterion among all possible linear combinations. In the particular case with independent pre- and post-treatment measurements, we show that the proposed method represents the well-known Su and Liu's (1993) result. Further, proceeding from derived best combinations of biomarkers' measurements, we propose an efficient technique via likelihood ratio tests to compare treatment effects. We show an extensive Monte Carlo study that confirms the superiority of the proposed test in comparison with treatment effects based on multiple biomarkers in a paired data setting. For practical applications, the proposed method is illustrated with a randomized trial of chlorhexidine gluconate on oral bacterial pathogens in mechanically ventilated patients as well as a treatment study for children with attention deficit-hyperactivity disorder and severe mood dysregulation. PMID:25019920

Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor.

PubMed

Bayguinov, Peter O; Ma, Yihe; Gao, Yu; Zhao, Xinyu; Jackson, Meyer B

2017-09-20

Genetically encoded voltage indicators create an opportunity to monitor electrical activity in defined sets of neurons as they participate in the complex patterns of coordinated electrical activity that underlie nervous system function. Taking full advantage of genetically encoded voltage indicators requires a generalized strategy for targeting the probe to genetically defined populations of cells. To this end, we have generated a mouse line with an optimized hybrid voltage sensor (hVOS) probe within a locus designed for efficient Cre recombinase-dependent expression. Crossing this mouse with Cre drivers generated double transgenics expressing hVOS probe in GABAergic, parvalbumin, and calretinin interneurons, as well as hilar mossy cells, new adult-born neurons, and recently active neurons. In each case, imaging in brain slices from male or female animals revealed electrically evoked optical signals from multiple individual neurons in single trials. These imaging experiments revealed action potentials, dynamic aspects of dendritic integration, and trial-to-trial fluctuations in response latency. The rapid time response of hVOS imaging revealed action potentials with high temporal fidelity, and enabled accurate measurements of spike half-widths characteristic of each cell type. Simultaneous recording of rapid voltage changes in multiple neurons with a common genetic signature offers a powerful approach to the study of neural circuit function and the investigation of how neural networks encode, process, and store information. SIGNIFICANCE STATEMENT Genetically encoded voltage indicators hold great promise in the study of neural circuitry, but realizing their full potential depends on targeting the sensor to distinct cell types. Here we present a new mouse line that expresses a hybrid optical voltage sensor under the control of Cre recombinase. Crossing this line with Cre drivers generated double-transgenic mice, which express this sensor in targeted cell types. In brain slices from these animals, single-trial hybrid optical voltage sensor recordings revealed voltage changes with submillisecond resolution in multiple neurons simultaneously. This imaging tool will allow for the study of the emergent properties of neural circuits and permit experimental tests of the roles of specific types of neurons in complex circuit activity. Copyright © 2017 the authors 0270-6474/17/379305-15$15.00/0.

Estimating scaled treatment effects with multiple outcomes.

PubMed

Kennedy, Edward H; Kangovi, Shreya; Mitra, Nandita

2017-01-01

In classical study designs, the aim is often to learn about the effects of a treatment or intervention on a single outcome; in many modern studies, however, data on multiple outcomes are collected and it is of interest to explore effects on multiple outcomes simultaneously. Such designs can be particularly useful in patient-centered research, where different outcomes might be more or less important to different patients. In this paper, we propose scaled effect measures (via potential outcomes) that translate effects on multiple outcomes to a common scale, using mean-variance and median-interquartile range based standardizations. We present efficient, nonparametric, doubly robust methods for estimating these scaled effects (and weighted average summary measures), and for testing the null hypothesis that treatment affects all outcomes equally. We also discuss methods for exploring how treatment effects depend on covariates (i.e., effect modification). In addition to describing efficiency theory for our estimands and the asymptotic behavior of our estimators, we illustrate the methods in a simulation study and a data analysis. Importantly, and in contrast to much of the literature concerning effects on multiple outcomes, our methods are nonparametric and can be used not only in randomized trials to yield increased efficiency, but also in observational studies with high-dimensional covariates to reduce confounding bias.

Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.

PubMed

Briken, S; Gold, S M; Patra, S; Vettorazzi, E; Harbs, D; Tallner, A; Ketels, G; Schulz, K H; Heesen, C

2014-03-01

Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. ISRCTN (trial number 76467492) http://isrctn.org.

Hepatocellular carcinoma: early-stage management challenges

PubMed Central

Erstad, Derek J; Tanabe, Kenneth K

2017-01-01

Hepatocellular carcinoma (HCC) is a major cause of cancer death and is increasing in incidence. This review focuses on HCC surveillance and treatment of early-stage disease, which are essential to improving outcomes. Multiple societies have published HCC surveillance guidelines, but screening efforts have been limited by noncompliance and overall lack of testing for patients with undiagnosed chronic liver disease. Treatment of early-stage HCC has become increasingly complex due to expanding therapeutic options and better outcomes with established treatments. Surgical indications for HCC have broadened with improved preoperative liver testing, neoadjuvant therapy, portal vein embolization, and perioperative care. Advances in post-procedural monitoring have improved efficacies of transarterial chemoembolization and radiofrequency ablation, and novel therapies involving delivery of radiochemicals are being studied in small trials. Finally, advances in liver transplantation have allowed for expanded indications beyond Milan criteria with non-inferior outcomes. More clinical trials evaluating new therapies and multimodal regimens are necessary to help clinicians design better treatment algorithms and improve outcomes. PMID:28721349

Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases.

PubMed

Kaplan, Frederick S; Andolina, Jeffrey R; Adamson, Peter C; Teachey, David T; Finklestein, Jerry Z; Ebb, David H; Whitehead, Benjamin; Jacobs, Benjamin; Siegel, David M; Keen, Richard; Hsiao, Edward; Pignolo, Robert J

2018-04-01

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases. Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Patient-reported questionnaires in MS rehabilitation: responsiveness and minimal important difference of the multiple sclerosis questionnaire for physiotherapists (MSQPT).

PubMed

van der Maas, Nico Arie

2017-03-16

The Multiple Sclerosis Questionnaire for Physical Therapists (MSQPT) is a patient-rated outcome questionnaire for evaluating the rehabilitation of persons with multiple sclerosis (MS). Responsiveness was evaluated, and minimal important difference (MID) estimates were calculated to provide thresholds for clinical change for four items, three sections and the total score of the MSQPT. This multicentre study used a combined distribution- and anchor-based approach with multiple anchors and multiple rating of change questions. Responsiveness was evaluated using effect size, standardized response mean (SRM), modified SRM and relative efficiency. For distribution-based MID estimates, 0.2 and 0.33 standard deviations (SD), standard error of measurement (SEM) and minimal detectable change were used . Triangulation of anchor- and distribution-based MID estimates provided a range of MID values for each of the four items, the three sections and the total score of the MSQPT. The MID values were tested for their sensitivity and specificity for amelioration and deterioration for each of the four items, the three sections and the total score of the MSQPT. The MID values of each item and section and of the total score with the best sensitivity and specificity were selected as thresholds for clinical change. The outcome measures were the MSQPT, Hamburg Quality of Life Questionnaire for Multiple Sclerosis (HAQUAMS), rating of change questionnaires, Expanded Disability Status Scale, 6-metre timed walking test, Berg Balance Scale and 6-minute walking test. The effect size ranged from 0.46 to 1.49. The SRM data showed comparable results. The modified SRM ranged from 0.00 to 0.60. Anchor-based MID estimates were very low and were comparable with SD- and SEM-based estimates. The MSQPT was more responsive than the HAQUAMS in detecting improvement but less responsive in finding deterioration. The best MID estimates of the items, sections and total score, expressed in percentage of their maximum score, were between 5.4% (activity) and 22% (item 10) change for improvement and between 5.7% (total score) and 22% (item 10) change for deterioration. The MSQPT is a responsive questionnaire with an adequate MID that may be used as threshold for change during rehabilitation of MS patients. This trial was retrospectively (01/24/2015) registered in ClinicalTrials.gov as NCT02346279.

Hypofractionated radiation therapy for prostate cancer: biologic and technical considerations

PubMed Central

Sanfilippo, Nicholas J; Cooper, Benjamin T

2014-01-01

The optimal radiation schedule for the curative treatment of prostate cancer is not known. The dose-response of tumors and normal tissues to fractionated irradiation can be described according to a parameter called the alpha-beta ratio (α/β). In the past several years numerous reports have been published that suggest that the alpha-beta ratio for prostate cancer may be quite low; between 1 and 3. If this hypothesis is true, then a radiation therapy schedule that employs less frequent and larger fractions, termed hypofractionation, may be more efficacious. Multiple randomized trials have been conducted comparing moderate (less than 5 Gy/day) hypofractionated radiation therapy and standard radiation therapy in men with prostate cancer. In the majority of these studies the moderate hypofractionated arm had equivalent efficacy with a similar or improved side effect profile. One area to use caution may be in patients with compromised (IPSS > 12) urinary function at baseline due to an increase in urinary toxicity observed in patients treated with hypofractionated radiation in one study. Extreme hypofractionation (greater than or equal to 5 Gy/day), is currently being compared in a randomized trial. Early prospectively collected data from multiple institutions demonstrates efficacy and toxicity that compares favorably with historical controls. The cost savings from hypofractionation could be profound on a national level and only increases the necessity of testing hypofractionated treatment schedules. Long term data and future trials will help radiation oncologists determine the ideal fractionation scheme based on cost, efficacy, and toxicity. PMID:25606574

Combination of robot-assisted and conventional body-weight-supported treadmill training improves gait in persons with multiple sclerosis: a pilot study.

PubMed

Ruiz, Jennifer; Labas, Michele P; Triche, Elizabeth W; Lo, Albert C

2013-12-01

The majority of persons with multiple sclerosis (MS) experience problems with gait, which they characterize as highly disabling impairments that adversely impact their quality of life. Thus, it is crucial to develop effective therapies to improve mobility for these individuals. The purpose of this study was to determine whether combination gait training, using robot-assisted treadmill training followed by conventional body-weight-supported treadmill training within the same session, improved gait and balance in individuals with MS. This study tested combination gait training in 7 persons with MS. The participants were randomized into the immediate therapy group (IT group) or the delayed therapy group (DT group). In phase I of the trial, the IT group received treatment while the DT group served as a concurrent comparison group. In phase II of the trial, the DT group received treatment identical to the treatment received by the IT group in phase I. Outcome measures included the 6-Minute Walk Test (6MWT), the Timed 25-Foot Walk Test, velocity, cadence, and the Functional Reach Test (FRT). Nonparametric statistical techniques were used for analysis. Combination gait training resulted in significantly greater improvements in the 6MWT for the IT group (median change = +59 m) compared with Phase I DT group (median change = -8 m) (P = 0.08) and FRT (median change = +3.3 cm in IT vs -0.8 cm in the DT group phase I; P = 0.03). Significant overall pre-post improvements following combination gait training were found in 6MWT (+32 m; P = 0.02) and FRT (+3.3 cm; P = 0.06) for IT and Phase II DT groups combined. Combination of robot with body-weight-supported treadmill training gait training is feasible and improved 6MWT and FRT distances in persons with MS.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A62) for more insights from the authors.

Evaluation of Performance and Perceptions of Electronic vs. Paper Multiple-Choice Exams

ERIC Educational Resources Information Center

Washburn, Shannon; Herman, James; Stewart, Randolph

2017-01-01

In the veterinary professional curriculum, methods of examination in many courses are transitioning from the traditional paper-based exams to electronic-based exams. Therefore, a controlled trial to evaluate the impact of testing methodology on examination performance in a veterinary physiology course was designed and implemented. Formalized…

Improving the quality of depression and pain care in multiple sclerosis using collaborative care: The MS-care trial protocol.

PubMed

Ehde, Dawn M; Alschuler, Kevin N; Sullivan, Mark D; Molton, Ivan P; Ciol, Marcia A; Bombardier, Charles H; Curran, Mary C; Gertz, Kevin J; Wundes, Annette; Fann, Jesse R

2018-01-01

Evidence-based pharmacological and behavioral interventions are often underutilized or inaccessible to persons with multiple sclerosis (MS) who have chronic pain and/or depression. Collaborative care is an evidence-based patient-centered, integrated, system-level approach to improving the quality and outcomes of depression care. We describe the development of and randomized controlled trial testing a novel intervention, MS Care, which uses a collaborative care model to improve the care of depression and chronic pain in a MS specialty care setting. We describe a 16-week randomized controlled trial comparing the MS Care collaborative care intervention to usual care in an outpatient MS specialty center. Eligible participants with chronic pain of at least moderate intensity (≥3/10) and/or major depressive disorder are randomly assigned to MS Care or usual care. MS Care utilizes a care manager to implement and coordinate guideline-based medical and behavioral treatments with the patient, clinic providers, and pain/depression treatment experts. We will compare outcomes at post-treatment and 6-month follow up. We hypothesize that participants randomly assigned to MS Care will demonstrate significantly greater control of both pain and depression at post-treatment (primary endpoint) relative to those assigned to usual care. Secondary analyses will examine quality of care, patient satisfaction, adherence to MS care, and quality of life. Study findings will aid patients, clinicians, healthcare system leaders, and policy makers in making decisions about effective care for pain and depression in MS healthcare systems. (PCORI- IH-1304-6379; clinicaltrials.gov: NCT02137044). This trial is registered at ClinicalTrials.gov, protocol NCT02137044. Copyright © 2017 Elsevier Inc. All rights reserved.

Familiarisation and Reliability of Sprint Test Indices During Laboratory and Field Assessment

PubMed Central

Hopker, James G.; Coleman, Damian A.; Wiles, Jonathan D.; Galbraith, Andrew

2009-01-01

The aim of the study was to assess the reliability of sprint performance in both field and laboratory conditions. Twenty-one male (mean ± s: 19 ± 1 years, 1.79 ± 0.07 m, 77.6 ± 7.1 kg) and seventeen female team sport players (mean ± s: 21 ± 4 years, 1.68 ± 0. 07 m, 62.7 ± 4.7 kg) performed a maximal 20-metre sprint running test on eight separate occasions. Four trials were conducted on a non-motorised treadmill in the laboratory; the other four were conducted outdoors on a hard-court training surface with time recorded by single-beam photocells. Trials were conducted in random order with no familiarisation prior to testing. There was a significant difference between times recorded during outdoor field trials (OFT) and indoor laboratory trials (ILT) using a non-motorised treadmill (3.47 ± 0.53 vs. 6.06 ±1.17s; p < 0.001). The coefficient of variation (CV) for time was 2.55-4.22% for OFT and 5.1-7.2% for ILT. During ILT peak force (420.9 ± 87.7N), mean force (147.2 ± 24.7N), peak power (1376.8 ± 451.9W) and mean power (514.8 ± 164.4W), and were measured. The CV for all ILT variables was highest during trial 1-2 comparison. The CV (95% confidence interval) for the trial 3-4 comparison yielded: 9.4% (7.7-12. 1%), 7.9% (6.4-10.2%), 10.1% (8.2-13.1%) and 6.2% (5.1-8.0%) for PF, MF, PP and MP and respectively. The results indicate that reliable data can be derived for single maximal sprint measures, using fixed distance protocols. However, significant differences in time/speed over 20-m exist between field and laboratory conditions. This is primarily due to the frictional resistance in the non- motorised treadmill. Measures of force and power during ILT require at least 3 familiarisations to reduce variability in test scores. Key points Reliable data can be derived from single maximal sprint measures in both indoor and outdoor environments using fixed distance protocols. There may be significant time differences to complete fixed distance trials between the two environments. Measures of mean force, peak force and peak power during indoor trials may require multiple trials to reduce variability in test scores. PMID:24149593

The Long Term Impact of Micronutrient Supplementation during Infancy on Cognition and Executive Function Performance in Pre-School Children

PubMed Central

Warthon-Medina, Marisol; Qualter, Pamela; Zavaleta, Nelly; Dillon, Stephanie; Lazarte, Fabiola; Lowe, Nicola M.

2015-01-01

Brain growth and development are critically dependent on several micronutrients. During early development cellular activity may be sensitive to micronutrient deficiencies, however the evidence from human studies is equivocal. The objective of this study was to examine the long-term cognitive and social-emotional effects of multiple micronutrient supplementation compared with iron supplementation alone, administered during infancy. This study was a follow-up to an initial randomized, double-blind controlled trial (RCT) in 2010 in which 902 infants, aged 6–17 months, from Lima, Peru, were given daily supplements of either iron (Fe) or multiple micronutrients (MMN) including zinc (451 in each group). The supplementation period for both groups was six months. In 2012, a subsample of 184 children from the original cohort (now aged 36–48 months) was randomly selected to participate in a follow-up trial and was assessed for intelligence, working memory, inhibition, and executive function. The tests showed no significant differences between the supplementation groups though there were some gender differences, with girls displaying higher scores than boys across both groups on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) Verbal IQ sentences subtest, the Day-Night cognitive test and on the Brief Infant-Toddler Social Emotional Assessment (BITSEA) social competency, and boys scoring higher than girls in problem behaviour. The results indicate that MMN supplementation had no long term additional effects on cognitive function compared with iron supplementation alone. The timing of supplement administration for maximum impact on a child’s cognitive development requires further investigation. PMID:26262642

Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD-'Assessing QbTest Utility in ADHD' (AQUA): a randomised controlled trial.

PubMed

Hall, Charlotte L; Walker, Gemma M; Valentine, Althea Z; Guo, Boliang; Kaylor-Hughes, Catherine; James, Marilyn; Daley, David; Sayal, Kapil; Hollis, Chris

2014-12-01

The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current 'gold standard' ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. This multisite randomised controlled trial will recruit young people (aged 6-17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. NCT02209116. 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.

‘Alzheimer’s Progression Score’: Development of a Biomarker Summary Outcome for AD Prevention Trials

PubMed Central

Leoutsakos, J.-M.; Gross, A.L.; Jones, R.N.; Albert, M.S.; Breitner, J.C.S.

2017-01-01

BACKGROUND Alzheimer’s disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers. OBJECTIVES Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression. DESIGN Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn. SETTING BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011–2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years. PARTICIPANTS 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples. MEASUREMENTS Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio. RESULTS Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample. CONCLUSIONS An IRT-based APS can summarize multimodal information to provide a longitudinal measure of pre-clinical AD progression, and holds promise as an outcome for AD prevention trials. PMID:29034223

'Alzheimer's Progression Score': Development of a Biomarker Summary Outcome for AD Prevention Trials.

PubMed

Leoutsakos, J-M; Gross, A L; Jones, R N; Albert, M S; Breitner, J C S

2016-01-01

Alzheimer's disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers. Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression. Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn. BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011-2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years. 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples. Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio. Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample. An IRT-based APS can summarize multimodal information to provide a longitudinal measure of pre-clinical AD progression, and holds promise as an outcome for AD prevention trials.

Consistency of peak and mean concentric and eccentric force using a novel squat testing device.

PubMed

Stock, Matt S; Luera, Micheal J

2014-04-01

The ability to examine force curves from multiple-joint assessments combines many of the benefits of dynamic constant external resistance exercise and isokinetic dynamometry. The purpose of this investigation was to examine test-retest reliability statistics for peak and mean force using the Exerbotics eSQ during maximal concentric and eccentric squats. Seventeen resistance-trained men (mean±SD age=21±2 years) visited the laboratory on two occasions. For each trial, the subjects performed two maximal concentric and eccentric squats, and the muscle actions with the highest force values were analyzed. There were no mean differences between the trials (P>.05), and the effect sizes were <0.12. When the entire force curve was examined, the intraclass correlation coefficients (model 2,1) and standard errors of measurement, respectively, were concentric peak force=0.743 (8.8%); concentric mean force=0.804 (6.0%); eccentric peak force=0.696 (10.6%); eccentric mean force=0.736 (9.6%). These findings indicated moderate-to-high reliability for the peak and mean force values obtained from the Exerbotics eSQ during maximal squat testing. The analysis of force curves from multiple-joint testing provides researchers and practitioners with a reliable means of assessing performance, especially during concentric muscle actions.

Innovations in Clinical Trial Design in the Era of Molecular Profiling.

PubMed

Wulfkuhle, Julia D; Spira, Alexander; Edmiston, Kirsten H; Petricoin, Emanuel F

2017-01-01

Historically, cancer has been studied, and therapeutic agents have been evaluated based on organ site, clinical staging, and histology. The science of molecular profiling has expanded our knowledge of cancer at the cellular and molecular level such that numerous subtypes are being described based on biomarker expression and genetic mutations rather than traditional classifications of the disease. Drug development has experienced a concomitant revolution in response to this knowledge with many new targeted therapeutic agents becoming available, and this has necessitated an evolution in clinical trial design. The traditional, large phase II and phase III adjuvant trial models need to be replaced with smaller, shorter, and more focused trials. These trials need to be more efficient and adaptive in order to quickly assess the efficacy of new agents and develop new companion diagnostics. We are now seeing a substantial shift from the traditional multiphase trial model to an increase in phase II adjuvant and neoadjuvant trials in earlier-stage disease incorporating surrogate endpoints for long-term survival to assess efficacy of therapeutic agents in shorter time frames. New trial designs have emerged with capabilities to assess more efficiently multiple disease types, multiple molecular subtypes, and multiple agents simultaneously, and regulatory agencies have responded by outlining new pathways for accelerated drug approval that can help bring effective targeted therapeutic agents to the clinic more quickly for patients in need.

The Recruitment Experience of a Randomized Clinical Trial to Aid Young Adult Smokers to Stop Smoking without Weight Gain with Interactive Technology.

PubMed

Coday, Mace; Richey, Phyllis; Thomas, Fridtjof; Tran, Quynh T; Terrell, Sarah B; Tylavsky, Fran; Miro, Danielle; Caufield, Margaret; Johnson, Karen C

2016-04-15

Multiple recruitment strategies are often needed to recruit an adequate number of participants, especially hard to reach groups. Technology-based recruitment methods hold promise as a more robust form of reaching and enrolling historically hard to reach young adults. The TARGIT study is a randomized two-arm clinical trial in young adults using interactive technology testing an efficacious proactive telephone Quitline versus the Quitline plus a behavioral weight management intervention focusing on smoking cessation and weight change. All randomized participants in the TARGIT study were required to be a young adult smoker (18-35 years), who reported smoking at least 10 cigarettes per day, had a BMI < 40 kg/m 2, and were willing to stop smoking and not gain weight. Traditional recruitment methods were compared to technology-based strategies using standard descriptive statistics based on counts and proportions to describe the recruitment process from initial pre-screening (PS) to randomization into TARGIT. Participants at PS were majority Black (59.80%), female (52.66%), normal or over weight (combined 62.42%), 29.5 years old, and smoked 18.4 cigarettes per day. There were differences in men and women with respect to reasons for ineligibility during PS (p < 0.001; ignoring gender specific pregnancy-related ineligibility). TARGIT experienced a disproportionate loss of minorities during recruitment as well as a prolonged recruitment period due to either study ineligibility or not completing screening activities. Recruitment into longer term behavioral change intervention trials can be challenging and multiple methods are often required to recruit hard to reach groups.

Factors predicting publication of spinal cord injury trials registered on www.ClinicalTrials. gov.

PubMed

DePasse, J Mason; Park, Sara; Eltorai, Adam E M; Daniels, Alan H

2018-02-06

Treatment options for spinal cord injuries are currently limited, but multiple clinical trials are underway for a variety of interventions, drugs, and devices. The Food and Drug Administration website www.ClinicalTrials.gov catalogues these trials and includes information on the status of the trial, date of initiation and completion, source of funding, and region. This investigation assesses the factors associated with publication and the publication rate of spinal cord injury trials. Retrospective analysis of publically available data on www.ClinicalTrials.gov. The www.ClinicalTrials.gov was queried for all trials on patients with spinal cord injury, and these trials were assessed for status, type of intervention, source of funding, and region. Multiple literature searches were performed on all completed trials to determine publication status. There were 626 studies identified concerning the treatment of patients with spinal cord injury, of which 250 (39.9%) were completed. Of these, only 119 (47.6%) were published. There was no significant difference in the rate of publication between regions (p> 0.16) or by study type (p> 0.29). However, trials that were funded by the NIH were more likely to be published than trials funded by industry (p= 0.01). The current publication rate of spinal cord injury trials is only 47.6%, though this rate is similar to the publication rate for trials in other fields. NIH-funded trials are significantly more likely to become published than industry-funded trials, which could indicate that some trials remain unpublished due to undesirable results. However, it is also likely that many trials on spinal cord injury yield negative results, as treatments are often ineffective.

Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study.

PubMed

Maahs, David M; Caramori, Luiza; Cherney, David Z I; Galecki, Andrzej T; Gao, Chuanyun; Jalal, Diana; Perkins, Bruce A; Pop-Busui, Rodica; Rossing, Peter; Mauer, Michael; Doria, Alessandro

2013-08-01

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

Pilot study of a point-of-use decision support tool for cancer clinical trials eligibility.

PubMed

Breitfeld, P P; Weisburd, M; Overhage, J M; Sledge, G; Tierney, W M

1999-01-01

Many adults with cancer are not enrolled in clinical trials because caregivers do not have the time to match the patient's clinical findings with varying eligibility criteria associated with multiple trials for which the patient might be eligible. The authors developed a point-of-use portable decision support tool (DS-TRIEL) to automate this matching process. The support tool consists of a hand-held computer with a programmable relational database. A two-level hierarchic decision framework was used for the identification of eligible subjects for two open breast cancer clinical trials. The hand-held computer also provides protocol consent forms and schemas to further help the busy oncologist. This decision support tool and the decision framework on which it is based could be used for multiple trials and different cancer sites.

Pilot Study of a Point-of-use Decision Support Tool for Cancer Clinical Trials Eligibility

PubMed Central

Breitfeld, Philip P.; Weisburd, Marina; Overhage, J. Marc; Sledge, George; Tierney, William M.

1999-01-01

Many adults with cancer are not enrolled in clinical trials because caregivers do not have the time to match the patient's clinical findings with varying eligibility criteria associated with multiple trials for which the patient might be eligible. The authors developed a point-of-use portable decision support tool (DS-TRIEL) to automate this matching process. The support tool consists of a hand-held computer with a programmable relational database. A two-level hierarchic decision framework was used for the identification of eligible subjects for two open breast cancer clinical trials. The hand-held computer also provides protocol consent forms and schemas to further help the busy oncologist. This decision support tool and the decision framework on which it is based could be used for multiple trials and different cancer sites. PMID:10579605

Video modelling and reducing anxiety related to dental injections - a randomised clinical trial.

PubMed

Al-Namankany, A; Petrie, A; Ashley, P

2014-06-01

This study was part of a successfully completed PhD and was presented at the IADR/AADR General Session (2013) in Seattle, Washington, USA. The report of this clinical trial conforms to the CONSORT statement. A randomised controlled trial to investigate if video modelling can influence a child's anxiety before the administration of local anaesthesia (LA). A sample of 180 (6- to 12-year-old) children due to have dental treatments under LA were randomly allocated to the modelling video or the control video (oral hygiene instruction). The level of anxiety was recorded before and after watching the video on the Abeer Children Dental Anxiety Scale (ACDAS) and the child's ability to cope with the subsequent procedure was assessed on the visual analogue scale (VAS). A two group chi-square test was used as the basis for the sample size calculation; a significance level of 0.025 was chosen rather than the conventional 0.05 to avoid spurious results arising from multiple testing. Children in the test group had significantly less anxiety after watching the video than children in the control group throughout the subsequent dental procedure; in particular at the time of the LA administration (p <0.001). Video modelling appeared to be effective at reducing dental anxiety and has a significant impact on needle phobia in children.

Osteo-cise: Strong Bones for Life: Protocol for a community-based randomised controlled trial of a multi-modal exercise and osteoporosis education program for older adults at risk of falls and fractures

PubMed Central

2012-01-01

Background Osteoporosis affects over 220 million people worldwide, and currently there is no ‘cure’ for the disease. Thus, there is a need to develop evidence-based, safe and acceptable prevention strategies at the population level that target multiple risk factors for fragility fractures to reduce the health and economic burden of the condition. Methods/design The Osteo-cise: Strong Bones for Life study will investigate the effectiveness and feasibility of a multi-component targeted exercise, osteoporosis education/awareness and behavioural change program for improving bone health and muscle function and reducing falls risk in community-dwelling older adults at an increased risk of fracture. Men and women aged ≥60 years will participate in an 18-month randomised controlled trial comprising a 12-month structured and supervised community-based program and a 6-month ‘research to practise’ translational phase. Participants will be randomly assigned to either the Osteo-cise intervention or a self-management control group. The intervention will comprise a multi-modal exercise program incorporating high velocity progressive resistance training, moderate impact weight-bearing exercise and high challenging balance exercises performed three times weekly at local community-based fitness centres. A behavioural change program will be used to enhance exercise adoption and adherence to the program. Community-based osteoporosis education seminars will be conducted to improve participant knowledge and understanding of the risk factors and preventative measures for osteoporosis, falls and fractures. The primary outcomes measures, to be collected at baseline, 6, 12, and 18 months, will include DXA-derived hip and spine bone mineral density measurements and functional muscle power (timed stair-climb test). Secondary outcomes measures include: MRI-assessed distal femur and proximal tibia trabecular bone micro-architecture, lower limb and back maximal muscle strength, balance and function (four square step test, functional reach test, timed up-and-go test and 30-second sit-to-stand), falls incidence and health-related quality of life. Cost-effectiveness will also be assessed. Discussion The findings from the Osteo-cise: Strong Bones for Life study will provide new information on the efficacy of a targeted multi-modal community-based exercise program incorporating high velocity resistance training, together with an osteoporosis education and behavioural change program for improving multiple risk factors for falls and fracture in older adults at risk of fragility fracture. Trial registration Australian New Zealand Clinical Trials Registry reference ACTRN12609000100291 PMID:22640372

A multi-stage drop-the-losers design for multi-arm clinical trials.

PubMed

Wason, James; Stallard, Nigel; Bowden, Jack; Jennison, Christopher

2017-02-01

Multi-arm multi-stage trials can improve the efficiency of the drug development process when multiple new treatments are available for testing. A group-sequential approach can be used in order to design multi-arm multi-stage trials, using an extension to Dunnett's multiple-testing procedure. The actual sample size used in such a trial is a random variable that has high variability. This can cause problems when applying for funding as the cost will also be generally highly variable. This motivates a type of design that provides the efficiency advantages of a group-sequential multi-arm multi-stage design, but has a fixed sample size. One such design is the two-stage drop-the-losers design, in which a number of experimental treatments, and a control treatment, are assessed at a prescheduled interim analysis. The best-performing experimental treatment and the control treatment then continue to a second stage. In this paper, we discuss extending this design to have more than two stages, which is shown to considerably reduce the sample size required. We also compare the resulting sample size requirements to the sample size distribution of analogous group-sequential multi-arm multi-stage designs. The sample size required for a multi-stage drop-the-losers design is usually higher than, but close to, the median sample size of a group-sequential multi-arm multi-stage trial. In many practical scenarios, the disadvantage of a slight loss in average efficiency would be overcome by the huge advantage of a fixed sample size. We assess the impact of delay between recruitment and assessment as well as unknown variance on the drop-the-losers designs.

The effects of acupuncture on rates of clinical pregnancy among women undergoing in vitro fertilization: a systematic review and meta-analysis

PubMed Central

Manheimer, Eric; van der Windt, Daniëlle; Cheng, Ke; Stafford, Kristen; Liu, Jianping; Tierney, Jayne; Lao, Lixing; Berman, Brian M.; Langenberg, Patricia; Bouter, Lex M.

2013-01-01

BACKGROUND Recent systematic reviews of adjuvant acupuncture for IVF have pooled heterogeneous trials, without examining variables that might explain the heterogeneity. The aims of our meta-analysis were to quantify the overall pooled effects of adjuvant acupuncture on IVF clinical pregnancy success rates, and evaluate whether study design-, treatment- and population-related factors influence effect estimates. METHODS We included randomized controlled trials that compared needle acupuncture administered within 1 day of embryo transfer, versus sham acupuncture or no adjuvant treatment. Our primary outcome was clinical pregnancy rates. We obtained from all investigators additional methodological details and outcome data not included in their original publications. We analysed sham-controlled and no adjuvant treatment-controlled trials separately, but since there were no large or significant differences between these two subsets, we pooled all trials for subgroup analyses. We prespecified 11 subgroup variables (5 clinical and 6 methodological) to investigate sources of heterogeneity, using single covariate meta-regressions. RESULTS Sixteen trials (4021 participants) were included in the meta-analyses. There was no statistically significant difference between acupuncture and controls when combining all trials [risk ratio (RR) 1.12, 95% confidence interval (CI), 0.96–1.31; I2 = 68%; 16 trials; 4021 participants], or when restricting to sham-controlled (RR 1.02, 0.83–1.26; I2 = 66%; 7 trials; 2044 participants) or no adjuvant treatment-controlled trials (RR 1.22, 0.97–1.52; I2 = 67%; 9 trials; 1977 participants). The type of control used did not significantly explain the statistical heterogeneity (interaction P = 0.27). Baseline pregnancy rate, measured as the observed rate of clinical pregnancy in the control group of each trial, was a statistically significant effect modifier (interaction P < 0.001), and this covariate explained most of the heterogeneity of the effects of adjuvant acupuncture across all trials (adjusted R2 = 93%; I2 residual = 9%). Trials with lower control group rates of clinical pregnancy showed larger effects of adjuvant acupuncture (RR 1.53, 1.28–1.84; 7 trials; 1732 participants) than trials with higher control group rates of clinical pregnancy (RR 0.90, 0.80–1.01; 9 trials; 2289 participants). The asymmetric funnel plot showed a tendency for the intervention effects to be more beneficial in smaller trials. CONCLUSIONS We found no pooled benefit of adjuvant acupuncture for IVF. The subgroup finding of a benefit in trials with lower, but not higher, baseline pregnancy rates (the only statistically significant subgroup finding in our earlier review) has been confirmed in this update, and was not explained by any confounding variables evaluated. However, this baseline pregnancy rate subgroup finding among published trials requires further confirmation and exploration in additional studies because of the multiple subgroup tests conducted, the risk of unidentified confounders, the multiple different factors that determine baseline rates, and the possibility of publication bias. PMID:23814102

Association of Cortical β-Amyloid with Erythrocyte Membrane Monounsaturated and Saturated Fatty Acids in Older Adults at Risk of Dementia.

PubMed

Hooper, C; De Souto Barreto, P; Payoux, P; Salabert, A S; Guyonnet, S; Andrieu, S; Sourdet, S; Delrieu, J; Vellas, B

2017-01-01

We examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical β-amyloid (Aβ) load in older adults reporting subjective memory complaints. This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. Participants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aβ load. Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aβ load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing. We found no significant associations between fatty acids and cortical Aβ load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aβ (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis. Future research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aβ.

Estimating the optimal dynamic antipsychotic treatment regime: Evidence from the sequential multiple assignment randomized CATIE Schizophrenia Study

PubMed Central

Shortreed, Susan M.; Moodie, Erica E. M.

2012-01-01

Summary Treatment of schizophrenia is notoriously difficult and typically requires personalized adaption of treatment due to lack of efficacy of treatment, poor adherence, or intolerable side effects. The Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) Schizophrenia Study is a sequential multiple assignment randomized trial comparing the typical antipsychotic medication, perphenazine, to several newer atypical antipsychotics. This paper describes the marginal structural modeling method for estimating optimal dynamic treatment regimes and applies the approach to the CATIE Schizophrenia Study. Missing data and valid estimation of confidence intervals are also addressed. PMID:23087488

Collaborative Care for Patients With Severe Personality Disorders: Preliminary Results and Active Ingredients From a Pilot Study (Part I).

PubMed

Stringer, Barbara; van Meijel, Berno; Karman, Pieter; Koekkoek, Bauke; Hoogendoorn, Adriaan W; Kerkhof, Ad J F M; Beekman, Aartjan T F

2015-07-01

To test if a collaborative care program (CCP) with nurses in a coordinating position is beneficial for patients with severe personality disorders. A pilot study with a comparative multiple case study design using mixed methods investigating active ingredients and preliminary results. Most patients, their informal caregivers, and nurses value (parts of) the CCP positively; preliminary results show a significant decrease in severity of borderline symptoms. With the CCP, we may expand the supply of available treatments for patients with (severe) personality disorders, but a larger randomized controlled trial is warranted to confirm our preliminary results. © 2014 Wiley Periodicals, Inc.

Neuromuscular taping versus sham therapy on muscular strength and motor performance in multiple sclerosis patients.

PubMed

Costantino, Cosimo; Pedrini, Martina Francesca; Licari, Oriana

2016-01-01

Purpose of this study is to evaluate differences in leg muscles strength and motor performance between neuromuscular taping (NT) and sham tape groups. Relapsing-remitting (RR) multiple sclerosis (MS) patients were recruited and randomly assigned to NT or sham tape groups. All patients underwent the treatment 5 times at 5-d intervals. They were submitted to a 6-minute walk test and isokinetic test (peak torque) at the beginning (T0), at the end (T1) and 2 months after the end of the treatment (T2). Forty MS patients (38 F; 2 M; mean age 45.5 ± 6.5 years) were assigned to NT group (n = 20) and to sham tape group (n = 20). Delta Peak Torque T1-T0 and T2-T0 between two groups were statistically significant in quadriceps (p = 0.007; 0.000) and hamstrings (p = 0.011; 0.007). The difference between the two groups according to 6-minute walk test was not statistically significant but in NT group it was noticed an increasing trend about the distance run. In this single-blind randomized controlled trial, NT seemed to increase strength in leg muscles, compared to a sham device, in RR MS patients. Further studies are needed to consider this therapy as a complement to classic physical therapy. Neuromuscular taping (NT) in multiple sclerosis: NT is well tolerated by multiple sclerosis patients and should be a complement to classic physical therapy. This technique normalizes muscular function, strengthens weakened muscles and assists the postural alignment.

Physical barriers formed from gelling liquids: 1. numerical design of laboratory and field experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Finsterle, S.; Moridis, G.J.; Pruess, K.

1994-01-01

The emplacement of liquids under controlled viscosity conditions is investigated by means of numerical simulations. Design calculations are performed for a laboratory experiment on a decimeter scale, and a field experiment on a meter scale. The purpose of the laboratory experiment is to study the behavior of multiple gout plumes when injected in a porous medium. The calculations for the field trial aim at designing a grout injection test from a vertical well in order to create a grout plume of a significant extent in the subsurface.

An exploratory trial exploring the use of a multiple intelligences teaching approach (MITA) for teaching clinical skills to first year undergraduate nursing students.

PubMed

Sheahan, Linda; While, Alison; Bloomfield, Jacqueline

2015-12-01

The teaching and learning of clinical skills is a key component of nurse education programmes. The clinical competency of pre-registration nursing students has raised questions about the proficiency of teaching strategies for clinical skill acquisition within pre-registration education. This study aimed to test the effectiveness of teaching clinical skills using a multiple intelligences teaching approach (MITA) compared with the conventional teaching approach. A randomised controlled trial was conducted. Participants were randomly allocated to an experimental group (MITA intervention) (n=46) and a control group (conventional teaching) (n=44) to learn clinical skills. Setting was in one Irish third-level educational institution. Participants were all first year nursing students (n=90) in one institution. The experimental group was taught using MITA delivered by the researcher while the control group was taught by a team of six experienced lecturers. Participant preference for learning was measured by the Index of Learning Styles (ILS). Participants' multiple intelligence (MI) preferences were measured with a multiple intelligences development assessment scale (MIDAS). All participants were assessed using the same objective structured clinical examination (OSCE) at the end of semester one and semester two. MI assessment preferences were measured by a multiple intelligences assessment preferences questionnaire. The MITA intervention was evaluated using a questionnaire. The strongest preference on ILS for both groups was the sensing style. The highest MI was interpersonal intelligence. Participants in the experimental group had higher scores in all three OSCEs (p<0.05) at Time 1, suggesting that MITA had a positive effect on clinical skill acquisition. Most participants favoured practical examinations, followed by multiple choice questions as methods of assessment. MITA was evaluated positively. The study findings support the use of MITA for clinical skills teaching and advance the understanding of how MI teaching approaches may be used in nursing education. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effectiveness of Robot-Assisted Gait Training versus conventional therapy on mobility in severely disabled progressIve MultiplE sclerosis patients (RAGTIME): study protocol for a randomized controlled trial.

PubMed

Straudi, Sofia; Manfredini, Fabio; Lamberti, Nicola; Zamboni, Paolo; Bernardi, Francesco; Marchetti, Giovanna; Pinton, Paolo; Bonora, Massimo; Secchiero, Paola; Tisato, Veronica; Volpato, Stefano; Basaglia, Nino

2017-02-27

Gait and mobility impairments affect the quality of life (QoL) of patients with progressive multiple sclerosis (MS). Robot-assisted gait training (RAGT) is an effective rehabilitative treatment but evidence of its superiority compared to other options is lacking. Furthermore, the response to rehabilitation is multidimensional, person-specific and possibly involves functional reorganization processes. The aims of this study are: (1) to test the effectiveness on gait speed, mobility, balance, fatigue and QoL of RAGT compared to conventional therapy (CT) in progressive MS and (2) to explore changes of clinical and circulating biomarkers of neural plasticity. This will be a parallel-group, randomized controlled trial design with the assessor blinded to the group allocation of participants. Ninety-eight (49 per arm) progressive MS patients (EDSS scale 6-7) will be randomly assigned to receive twelve 2-h training sessions over a 4-week period (three sessions/week) of either: (1) RAGT intervention on a robotic-driven gait orthosis (Lokomat, Hocoma, Switzerland). The training parameters (torque of the knee and hip drives, treadmill speed, body weight support) are set during the first session and progressively adjusted during training progression or (2) individual conventional physiotherapy focusing on over-ground walking training performed with the habitual walking device. The same assessors will perform outcome measurements at four time points: baseline (before the first intervention session); intermediate (after six training sessions); end of treatment (after the completion of 12 sessions); and follow-up (after 3 months from the end of the training program). The primary outcome is gait speed, assessed by the Timed 25-Foot Walk Test. We will also assess walking endurance, balance, depression, fatigue and QoL as well as instrumental laboratory markers (muscle metabolism, cerebral venous hemodynamics, cortical activation) and circulating laboratory markers (rare circulating cell populations pro and anti-inflammatory cytokines/chemokines, growth factors, neurotrophic factors, coagulation factors, other plasma proteins suggested by transcriptomic analysis and metabolic parameters). The RAGT training is expected to improve mobility compared to the active control intervention in progressive MS. Unique to this study is the analysis of various potential markers of plasticity in relation with clinical outcomes. ClinicalTrials.gov, identifier: NCT02421731 . Registered on 19 January 2015 (retrospectively registered).

Predicting Low Accrual in the National Cancer Institute’s Cooperative Group Clinical Trials

PubMed Central

Bennette, Caroline S.; Ramsey, Scott D.; McDermott, Cara L.; Carlson, Josh J.; Basu, Anirban; Veenstra, David L.

2016-01-01

Background: The extent to which trial-level factors differentially influence accrual to trials has not been comprehensively studied. Our objective was to evaluate the empirical relationship and predictive properties of putative risk factors for low accrual in the National Cancer Institute’s (NCI’s) Cooperative Group Program, now the National Clinical Trials Network (NCTN). Methods: Data from 787 phase II/III adult NCTN-sponsored trials launched between 2000 and 2011 were used to develop a logistic regression model to predict low accrual, defined as trials that closed with or were accruing at less than 50% of target; 46 trials opened between 2012 and 2013 were used for prospective validation. Candidate predictors were identified from a literature review and expert interviews; final predictors were selected using stepwise regression. Model performance was evaluated by calibration and discrimination via the area under the curve (AUC). All statistical tests were two-sided. Results: Eighteen percent (n = 145) of NCTN-sponsored trials closed with low accrual or were accruing at less than 50% of target three years or more after initiation. A multivariable model of twelve trial-level risk factors had good calibration and discrimination for predicting trials with low accrual (AUC in trials launched 2000–2011 = 0.739, 95% confidence interval [CI] = 0.696 to 0.783]; 2012–2013: AUC = 0.732, 95% CI = 0.547 to 0.917). Results were robust to different definitions of low accrual and predictor selection strategies. Conclusions: We identified multiple characteristics of NCTN-sponsored trials associated with low accrual, several of which have not been previously empirically described, and developed a prediction model that can provide a useful estimate of accrual risk based on these factors. Future work should assess the role of such prediction tools in trial design and prioritization decisions. PMID:26714555

The Social Attribution Task-Multiple Choice (SAT-MC): A Psychometric and Equivalence Study of an Alternate Form.

PubMed

Johannesen, Jason K; Lurie, Jessica B; Fiszdon, Joanna M; Bell, Morris D

2013-01-01

The Social Attribution Task-Multiple Choice (SAT-MC) uses a 64-second video of geometric shapes set in motion to portray themes of social relatedness and intentions. Considered a test of "Theory of Mind," the SAT-MC assesses implicit social attribution formation while reducing verbal and basic cognitive demands required of other common measures. We present a comparability analysis of the SAT-MC and the new SAT-MC-II, an alternate form created for repeat testing, in a university sample (n = 92). Score distributions and patterns of association with external validation measures were nearly identical between the two forms, with convergent and discriminant validity supported by association with affect recognition ability and lack of association with basic visual reasoning. Internal consistency of the SAT-MC-II was superior (alpha = .81) to the SAT-MC (alpha = .56). Results support the use of SAT-MC and new SAT-MC-II as equivalent test forms. Demonstrating relatively higher association to social cognitive than basic cognitive abilities, the SAT-MC may provide enhanced sensitivity as an outcome measure of social cognitive intervention trials.

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

Fall risk and incidence reduction in high risk individuals with multiple sclerosis: a pilot randomized control trial.

PubMed

Sosnoff, Jacob J; Moon, Yaejin; Wajda, Douglas A; Finlayson, Marcia L; McAuley, Edward; Peterson, Elizabeth W; Morrison, Steve; Motl, Robert W

2015-10-01

To determine the feasibility of three fall prevention programs delivered over 12 weeks among individuals with multiple sclerosis: (A) a home-based exercise program targeting physiological risk factors; (B) an educational program targeting behavioral risk factors; and (C) a combined exercise-and-education program targeting both factors. Randomized controlled trial. Home-based training with assessments at research laboratory. A total of 103 individuals inquired about the investigation. After screening, 37 individuals with multiple sclerosis who had fallen in the last year and ranged in age from 45-75 years volunteered for the investigation. A total of 34 participants completed postassessment following the 12-week intervention. Participants were randomly assigned into one of four conditions: (1) wait-list control (n = 9); (2) home-based exercise (n = 11); (3) education (n = 9); or (4) a combined exercise and education (n = 8) group. Before and after the 12-week interventions, participants underwent a fall risk assessment as determined by the physiological profile assessment and provided information on their fall prevention behaviors as indexed by the Falls Prevention Strategy Survey. Participants completed falls diaries during the three-months postintervention. A total of 34 participants completed postintervention testing. Procedures and processes were found to be feasible. Overall, fall risk scores were lower in the exercise groups (1.15 SD 1.31) compared with the non-exercise groups (2.04 SD 1.04) following the intervention (p < 0.01). There was no group difference in fall prevention behaviors (p > 0.05). Further examination of home-based exercise/education programs for reducing falls in individuals with multiple sclerosis is warranted. A total of 108 participants would be needed in a larger randomized controlled trial.ClinicalTrials.org #NCT01956227. © The Author(s) 2014.

Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson’s Disease

DTIC Science & Technology

2008-10-30

these have advanced molecules to clinical studies.2,3 Thus, the NIH clinical trial registry lists over a dozen actively recruiting or completed trials ...into clinical trials ,4 and multiple other preclinical programs are apparently progressing (including publicly announced programs at Neurocrine5 and...unpublished results). Adenosine A2AR antagonists are currently in clinical trials for PD because of their symptom- improving abilities. The

Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD. Methods/Design The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n = 102), test the findings in the second half, and then extend the analyses to the total sample. Trial registration International Study to Predict Optimized Treatment - in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849. PMID:23866851

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.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

PubMed

Polman, C H; Reingold, S C; Barkhof, F; Calabresi, P A; Clanet, M; Cohen, J A; Cutter, G R; Freedman, M S; Kappos, L; Lublin, F D; McFarland, H F; Metz, L M; Miller, A E; Montalban, X; O'Connor, P W; Panitch, H; Richert, J R; Petkau, J; Schwid, S R; Sormani, M P; Thompson, A J; Weinshenker, B G; Wolinsky, J S

2008-03-25

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Accuracy and precision of smartphone applications and commercially available motion sensors in multiple sclerosis

PubMed Central

Balto, Julia M; Kinnett-Hopkins, Dominique L

2016-01-01

Background There is increased interest in the application of smartphone applications and wearable motion sensors among multiple sclerosis (MS) patients. Objective This study examined the accuracy and precision of common smartphone applications and motion sensors for measuring steps taken by MS patients while walking on a treadmill. Methods Forty-five MS patients (Expanded Disability Status Scale (EDSS) = 1.0–5.0) underwent two 500-step walking trials at comfortable walking speed on a treadmill. Participants wore five motion sensors: the Digi-Walker SW-200 pedometer (Yamax), the UP2 and UP Move (Jawbone), and the Flex and One (Fitbit). The smartphone applications were Health (Apple), Health Mate (Withings), and Moves (ProtoGeo Oy). Results The Fitbit One had the best absolute (mean = 490.6 steps, 95% confidence interval (CI) = 485.6–495.5 steps) and relative accuracy (1.9% error), and absolute (SD = 16.4) and relative precision (coefficient of variation (CV) = 0.0), for the first 500-step walking trial; this was repeated with the second trial. Relative accuracy was correlated with slower walking speed for the first (rs = −.53) and second (rs = −.53) trials. Conclusion The results suggest that the waist-worn Fitbit One is the most precise and accurate sensor for measuring steps when walking on a treadmill, but future research is needed (testing the device across a broader range of disability, at different speeds, and in real-life walking conditions) before inclusion in clinical research and practice with MS patients. PMID:28607720

Accuracy and precision of smartphone applications and commercially available motion sensors in multiple sclerosis.

PubMed

Balto, Julia M; Kinnett-Hopkins, Dominique L; Motl, Robert W

2016-01-01

There is increased interest in the application of smartphone applications and wearable motion sensors among multiple sclerosis (MS) patients. This study examined the accuracy and precision of common smartphone applications and motion sensors for measuring steps taken by MS patients while walking on a treadmill. Forty-five MS patients (Expanded Disability Status Scale (EDSS) = 1.0-5.0) underwent two 500-step walking trials at comfortable walking speed on a treadmill. Participants wore five motion sensors: the Digi-Walker SW-200 pedometer (Yamax), the UP2 and UP Move (Jawbone), and the Flex and One (Fitbit). The smartphone applications were Health (Apple), Health Mate (Withings), and Moves (ProtoGeo Oy). The Fitbit One had the best absolute (mean = 490.6 steps, 95% confidence interval (CI) = 485.6-495.5 steps) and relative accuracy (1.9% error), and absolute (SD = 16.4) and relative precision (coefficient of variation (CV) = 0.0), for the first 500-step walking trial; this was repeated with the second trial. Relative accuracy was correlated with slower walking speed for the first ( r s  =  -.53) and second ( r s  =  -.53) trials. The results suggest that the waist-worn Fitbit One is the most precise and accurate sensor for measuring steps when walking on a treadmill, but future research is needed (testing the device across a broader range of disability, at different speeds, and in real-life walking conditions) before inclusion in clinical research and practice with MS patients.

Reliable volumetry of the cervical spinal cord in MS patient follow-up data with cord image analyzer (Cordial).

PubMed

Amann, Michael; Pezold, Simon; Naegelin, Yvonne; Fundana, Ketut; Andělová, Michaela; Weier, Katrin; Stippich, Christoph; Kappos, Ludwig; Radue, Ernst-Wilhelm; Cattin, Philippe; Sprenger, Till

2016-07-01

Spinal cord (SC) atrophy is an important contributor to the development of disability in many neurological disorders including multiple sclerosis (MS). To assess the spinal cord atrophy in clinical trials and clinical practice, largely automated methods are needed due to the sheer amount of data. Moreover, using these methods in longitudinal trials requires them to deliver highly reliable measurements, enabling comparisons of multiple data sets of the same subject over time. We present a method for SC volumetry using 3D MRI data providing volume measurements for SC sections of fixed length and location. The segmentation combines a continuous max flow approach with SC surface reconstruction that locates the SC boundary based on image voxel intensities. Two cutting planes perpendicular to the SC centerline are determined based on predefined distances to an anatomical landmark, and the cervical SC volume (CSCV) is then calculated in-between these boundaries. The development of the method focused on its application in MRI follow-up studies; the method provides a high scan-rescan reliability, which was tested on healthy subject data. Scan-rescan reliability coefficients of variation (COV) were below 1 %, intra- and interrater COV were even lower (0.1-0.2 %). To show the applicability in longitudinal trials, 3-year follow-up data of 48 patients with a progressive course of MS were assessed. In this cohort, CSCV loss was the only significant predictor of disability progression (p = 0.02). We are, therefore, confident that our method provides a reliable tool for SC volumetry in longitudinal clinical trials.

Does the radiologically isolated syndrome exist? A dual-task cost pilot study.

PubMed

Dattola, Vincenzo; Logiudice, Anna Lisa; Bonanno, Lilla; Famà, Fausto; Milardi, Demetrio; Chillemi, Gaetana; D'Aleo, Giangaetano; Marino, Silvia; Calabrò, Rocco Salvatore; Russo, Margherita

2017-11-01

Simultaneous performance of motor and cognitive tasks may compete for common brain network resources in aging or patients with some neurological diseases, suggesting the occurrence of a cognitive-motor interference. While this phenomenon has been well described for multiple sclerosis (MS) patients, it never has been tested on asymptomatic subject with magnetic resonance imaging (MRI) findings suggestive of demyelinating disease (i.e., radiologically isolated syndrome: RIS). In this pilot study, 10 RIS subjects and 10 sex/age-matched healthy controls were tested by means of static posturography under eyes opened (single-task trial) and while performing two different cognitive tasks (semantic modified word list generation for first dual-task trial and phonemic semantic modified word list generation for second dual-task trial), to estimate the dual-task cost (DTC) of standing balance. In our sample, under cognitive interference (without any substantial differences between semantic and phonemic modified word list generation), the RIS group showed significance differences in CoP (center of pressure) total sway area, ellipse eccentricity, CoP sway path length, CoP median sway velocity along the AP (anteroposterior) axis and along the ML (mediolateral) axis, reflecting a higher negative DTC respect to healthy subjects (which have simply shown a statistical trend, failing to reach a significance, in some trials). The phenomenon of cognitive-motor interference might be unmasked by a dual-task posturography in RIS subjects, too. We hypothesize that this approach could be useful to early reveal the presence of a demyelinating disease and to reach a MS diagnosis in subjects otherwise classified as RIS.

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

[Challenges in the organization of investigator initiated trials: in transplantation medicine].

PubMed

Schnitzbauer, A A; Lamby, P E; Mutzbauer, I; von Hassel, J; Geissler, E K; Schlitt, H J

2011-03-01

Transplantation medicine offers multiple translational questions which should preferably be transferred to clinical evidence. The current gold standard for testing such questions and hypotheses is by prospective randomized controlled trials (RCT). The trials should be performed independently from the medical industry to avoid conflicts of interests and to guarantee a strict scientific approach. A good model is an investigator initiated trial (IIT) in which academic institutions function as the sponsor and in which normally a scientific idea stands before marketing interests of a certain medical product. We present a model for an IIT which is sponsored and coordinated by Regensburg University Hospital at 45 sites in 13 nations (SiLVER study), highlight special pitfalls of this study and offer alternatives to this approach. Finances: financial support in clinical trials can be obtained from the medical industry. Alternatively in Germany the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) offers annual grants. The expansion of financial support through foundations is desirable. Infrastructure: sponsorship within the pharmaceutics act (Arzneimittelgesetz) demands excellent infrastructural conditions and a professional team to accomplish clinical, logistic, regulatory, legal and ethical challenges in a RCT. If a large trial has sufficient financial support certain tasks can be outsourced and delegated to contract research organizations, coordinating centers for clinical trials or partners in the medical industry. Clinical scientific advances to improve evidence are an enormous challenge when performed as an IIT. However, academic sponsors can perform (international) IITs when certain rules are followed and should be defined as the gold standard when scientific findings have to be established clinically.

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

ERIC Educational Resources Information Center

Chang, Sau Hou

2013-01-01

The purpose of the present study was to investigate the effects of test trial and processing level on immediate and delayed retention. Seventy-six college students were randomly assigned first to the single test and the repeated test trials, and then to the shallow processing level and the deep processing level to study forty stimulus words.…

A randomized trial to investigate the effects of pre-natal and infant nutritional supplementation on infant immune development in rural Gambia: the ENID trial: Early Nutrition and Immune Development.

PubMed

Moore, Sophie E; Fulford, Anthony Jc; Darboe, Momodou K; Jobarteh, Modou Lamin; Jarjou, Landing M; Prentice, Andrew M

2012-10-11

Recent observational research indicates that immune development may be programmed by nutritional exposures early in life. Such findings require replication from trials specifically designed to assess the impact of nutritional intervention during pregnancy on infant immune development. The current trial seeks to establish: (a) which combination of protein-energy (PE) and multiple-micronutrient (MMN) supplements would be most effective; and (b) the most critical periods for intervention in pregnancy and infancy, for optimal immune development in infancy. The ENID Trial is a 2 x 2 x 2 factorial randomized, partially blind trial to assess whether nutritional supplementation to pregnant women (from < 20 weeks gestation to term) and their infants (from 6 to 12 months of age) can enhance infant immune development. Eligible pregnant women from the West Kiang region of The Gambia (pregnancy dated by ultrasound examination) are randomized on entry to 4 intervention groups (Iron-folate (FeFol = standard care), multiple micronutrients (MMN), protein-energy (PE), PE + MMN). Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination, including ultrasound. At delivery, cord blood and placental samples are collected, with detailed infant anthropometry collected within 72 hours. Infants are visited weekly thereafter for a morbidity questionnaire. From 6 to 12 months of age, infants are further randomized to a lipid-based nutritional supplement, with or without additional MMN. The primary outcome measures of this study are thymic development during infancy, and antibody response to vaccination. Measures of cellular markers of immunity will be made in a selected sub-cohort. Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age. The proposed trial is designed to test whether nutritional repletion can enhance early immune development and, if so, to help determine the most efficacious form of nutritional support. Where there is evidence of benefit from a specific intervention/combination of interventions, future research should focus on refining the supplements to achieve the optimal, most cost-effective balance of interventions for improved health outcomes.

Analysis of risk factors for mild cognitive impairment based on word list memory test results and questionnaire responses in healthy Japanese individuals registered in an online database.

PubMed

Ogawa, Masayo; Sone, Daichi; Maruo, Kazushi; Shimada, Hiroyuki; Suzuki, Keisuke; Watanabe, Hiroshi; Matsuda, Hiroshi; Mizusawa, Hidehiro

2018-01-01

Although the development of effective therapeutic drugs and radical treatment options for dementia and Alzheimer's disease (AD) remains urgent, progress in recent clinical trials of AD drugs has been less than adequate. In order to advance the progress of clinical trials, it is necessary to establish more efficient methods of recruitment. In Japan, there are registration systems stratified by mild cognitive impairment and preclinical and clinical stages of early and advanced stage dementia, but there is no registration system for healthy individuals yet. Therefore, in the present study, we developed a large-scale, internet-based health registry to investigate factors associated with cognitive function among registered participants. A total of 1038 participants completed the initial questionnaire and word list memory test. Among these participants, 353 individuals completed a second questionnaire and memory test. Stepwise multiple regression analysis was performed using IBM SPSS version 23.0 for Windows at a statistical significance level of p<0.05. We found that mood, motivation, and a decreased ability to perform activities of daily living were significantly associated with cognitive function. The results of the present study suggest that maintaining social involvement is important to prevent decreases in physical activity, daily function, mood, and motivation.

Case Study: An Ethics Case Study of HIV Prevention Research on Facebook: The Just/Us Study

PubMed Central

Breslin, Lindsey T.; Wright, Erin E.; Black, Sandra R.; Levine, Deborah; Santelli, John S.

2011-01-01

Objective To consider issues related to research with youth on social networking sites online. Methods Description of the data collection process from 1,588 participants in a randomized controlled trial testing the efficacy of HIV prevention education delivered on Facebook. Using respondent-driven sampling, staff-recruited participants are encouraged to recruit up to three friends to enroll in the study. Results Researchers should (a) consider whether an online social networking site is an appropriate place to implement a research study; (b) offer opportunities to review informed consent documents at multiple times and in multiple locations throughout the study; and (c) collect data outside the social networking site and store it behind secure firewalls to ensure it will not be accessible to any person on the social networking site. Conclusions Online social networks are growing in popularity. Conducting research on social media sites requires deliberate attention to consent, confidentiality, and security. PMID:21292724

Genome Wide Association Study for Drought, Aflatoxin Resistance, and Important Agronomic Traits of Maize Hybrids in the Sub-Tropics

PubMed Central

Farfan, Ivan D. Barrero; De La Fuente, Gerald N.; Murray, Seth C.; Isakeit, Thomas; Huang, Pei-Cheng; Warburton, Marilyn; Williams, Paul; Windham, Gary L.; Kolomiets, Mike

2015-01-01

The primary maize (Zea mays L.) production areas are in temperate regions throughout the world and this is where most maize breeding is focused. Important but lower yielding maize growing regions such as the sub-tropics experience unique challenges, the greatest of which are drought stress and aflatoxin contamination. Here we used a diversity panel consisting of 346 maize inbred lines originating in temperate, sub-tropical and tropical areas testcrossed to stiff-stalk line Tx714 to investigate these traits. Testcross hybrids were evaluated under irrigated and non-irrigated trials for yield, plant height, ear height, days to anthesis, days to silking and other agronomic traits. Irrigated trials were also inoculated with Aspergillus flavus and evaluated for aflatoxin content. Diverse maize testcrosses out-yielded commercial checks in most trials, which indicated the potential for genetic diversity to improve sub-tropical breeding programs. To identify genomic regions associated with yield, aflatoxin resistance and other important agronomic traits, a genome wide association analysis was performed. Using 60,000 SNPs, this study found 10 quantitative trait variants for grain yield, plant and ear height, and flowering time after stringent multiple test corrections, and after fitting different models. Three of these variants explained 5–10% of the variation in grain yield under both water conditions. Multiple identified SNPs co-localized with previously reported QTL, which narrows the possible location of causal polymorphisms. Novel significant SNPs were also identified. This study demonstrated the potential to use genome wide association studies to identify major variants of quantitative and complex traits such as yield under drought that are still segregating between elite inbred lines. PMID:25714370

Multiple micronutrient supplementation transiently ameliorates environmental enteropathy in Malawian children aged 12-35 months in a randomized controlled clinical trial

USDA-ARS?s Scientific Manuscript database

Environmental enteropathy (EE) is subclinical, diffuse villous atrophy characterized by T cell infiltration of the small intestinal mucosa associated with nutrient malabsorption and stunting. EE is assessed by the lactulose:mannitol (L:M) test, whereby nonmetabolized sugars are ingested and quantifi...

Motivational Aspects of Learning Genetics with Interactive Multimedia

ERIC Educational Resources Information Center

Tsui, Chi-Yan; Treagust, David F.

2004-01-01

A BioLogica trial in six U.S. schools using interpretive approach is conducted by the Concord Consortium that examined the student motivation of learning genetics. Multiple data sources like online tests, computer data log files and classroom observation are used that found the result in terms of interviewees' perception, class-wide online…

Maternal multiple micronutrient supplementation and other biomedical and socioenvironmental influences on children's cognition at age 9-12 years in Indonesia: follow-up of the SUMMIT randomised trial.

PubMed

Prado, Elizabeth L; Sebayang, Susy K; Apriatni, Mandri; Adawiyah, Siti R; Hidayati, Nina; Islamiyah, Ayuniarti; Siddiq, Sudirman; Harefa, Benyamin; Lum, Jarrad; Alcock, Katherine J; Ullman, Michael T; Muadz, Husni; Shankar, Anuraj H

2017-02-01

Brain and cognitive development during the first 1000 days from conception are affected by multiple biomedical and socioenvironmental determinants including nutrition, health, nurturing, and stimulation. An improved understanding of the long-term influence of these factors is needed to prioritise public health investments to optimise human development. We did a follow-up study of the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind, cluster-randomised trial of maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA) in Indonesia. Of 27 356 live infants from birth to 3 months of age in 2001-04, we re-enrolled 19 274 (70%) children at age 9-12 years, and randomly selected 2879 from the 18 230 who were attending school at a known location. Of these, 574 children were oversampled from mothers who were anaemic or malnourished at SUMMIT enrolment. We assessed the effects of MMN and associations of biomedical (ie, maternal and child anthropometry and haemoglobin and preterm birth) and socioenvironmental determinants (ie, parental education, socioeconomic status, home environment, and maternal depression) on general intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fine motor dexterity, and socioemotional health. The SUMMIT trial was registered, number ISRCTN34151616. Children of mothers given MMN had a mean score of 0·11 SD (95% CI 0·01-0·20, p=0·0319) higher in procedural memory than those given IFA, equivalent to the increase in scores with half a year of schooling. Children of anaemic mothers in the MMN group scored 0·18 SD (0·06-0·31, p=0·0047) higher in general intellectual ability, similar to the increase with 1 year of schooling. Overall, 18 of 21 tests showed a positive coefficient of MMN versus IFA (p=0·0431) with effect sizes from 0·00-0·18 SD. In multiple regression models, socioenvironmental determinants had coefficients of 0·00-0·43 SD and 22 of 35 tests were significant at the 95% CI level, whereas biomedical coefficients were 0·00-0·10 SD and eight of 56 tests were significant, indicating larger and more consistent impact of socioenvironmental factors (p<0·0001). Maternal MMN had long-term benefits for child cognitive development at 9-12 years of age, thereby supporting its role in early childhood development, and policy change toward MMN. The stronger association of socioenvironmental determinants with improved cognition suggests present reproductive, maternal, neonatal, and child health programmes focused on biomedical determinants might not sufficiently enhance child cognition, and that programmes addressing socioenvironmental determinants are essential to achieve thriving populations. Grand Challenges Canada Saving Brains Program. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.

Closing the Loop on Deep Brain Stimulation for Treatment-Resistant Depression.

PubMed

Widge, Alik S; Malone, Donald A; Dougherty, Darin D

2018-01-01

Major depressive episodes are the largest cause of psychiatric disability, and can often resist treatment with medication and psychotherapy. Advances in the understanding of the neural circuit basis of depression, combined with the success of deep brain stimulation (DBS) in movement disorders, spurred several groups to test DBS for treatment-resistant depression. Multiple brain sites have now been stimulated in open-label and blinded studies. Initial open-label results were dramatic, but follow-on controlled/blinded clinical trials produced inconsistent results, with both successes and failures to meet endpoints. Data from follow-on studies suggest that this is because DBS in these trials was not targeted to achieve physiologic responses. We review these results within a technology-lifecycle framework, in which these early trial "failures" are a natural consequence of over-enthusiasm for an immature technology. That framework predicts that from this "valley of disillusionment," DBS may be nearing a "slope of enlightenment." Specifically, by combining recent mechanistic insights and the maturing technology of brain-computer interfaces (BCI), the next generation of trials will be better able to target pathophysiology. Key to that will be the development of closed-loop systems that semi-autonomously alter stimulation strategies based on a patient's individual phenotype. Such next-generation DBS approaches hold great promise for improving psychiatric care.

Development and Psychometric Evaluation of the HPV Clinical Trial Survey for Parents (CTSP-HPV) Using Traditional Survey Development Methods and Community Engagement Principles.

PubMed

Cunningham, Jennifer; Wallston, Kenneth A; Wilkins, Consuelo H; Hull, Pamela C; Miller, Stephania T

2015-12-01

This study describes the development and psychometric evaluation of HPV Clinical Trial Survey for Parents with Children Aged 9 to 15 (CTSP-HPV) using traditional instrument development methods and community engagement principles. An expert panel and parental input informed survey content and parents recommended study design changes (e.g., flyer wording). A convenience sample of 256 parents completed the final survey measuring parental willingness to consent to HPV clinical trial (CT) participation and other factors hypothesized to influence willingness (e.g., HPV vaccine benefits). Cronbach's a, Spearman correlations, and multiple linear regression were used to estimate internal consistency, convergent and discriminant validity, and predictively validity, respectively. Internal reliability was confirmed for all scales (a ≥ 0.70.). Parental willingness was positively associated (p < 0.05) with trust in medical researchers, adolescent CT knowledge, HPV vaccine benefits, advantages of adolescent CTs (r range 0.33-0.42), supporting convergent validity. Moderate discriminant construct validity was also demonstrated. Regression results indicate reasonable predictive validity with the six scales accounting for 31% of the variance in parents' willingness. This instrument can inform interventions based on factors that influence parental willingness, which may lead to the eventual increase in trial participation. Further psychometric testing is warranted. © 2015 Wiley Periodicals, Inc.

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

Improving the Reporting of Clinical Trials of Infertility Treatments (IMPRINT): modifying the CONSORT statement.

PubMed

2014-10-01

Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor on the harms, including maternal risks during pregnancy and fetal anomalies. This is complicated by the multiple participants in infertility trials which may include a woman (mother), a man (father), and a third individual if successful, their offspring (child), who is also the desired outcome of treatment. The primary outcome of interest and many adverse events occur after cessation of infertility treatment and during pregnancy and the puerperium, which creates a unique burden of follow-up for clinical trial investigators and participants. In 2013, because of the inconsistencies in trial reporting and the unique aspects of infertility trials not adequately addressed by existing Consolidated Standards of Reporting Trials (CONSORT) statements, we convened a consensus conference in Harbin, China, with the aim of planning modifications to the CONSORT checklist to improve the quality of reporting of clinical trials testing infertility treatment. The consensus group recommended that the preferred primary outcome of all infertility trials is live birth (defined as any delivery of a live infant after ≥20 weeks' gestation) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles). In addition, harms to all participants should be systematically collected and reported, including during the intervention, any resulting pregnancy, and the neonatal period. Routine information should be collected and reported on both male and female participants in the trial. We propose to track the change in quality that these guidelines may produce in published trials testing infertility treatments. Our ultimate goal is to increase the transparency of benefits and risks of infertility treatments to provide better medical care to affected individuals and couples. Copyright © 2014 The Author. Published by Elsevier Inc. All rights reserved.

Does robot-assisted gait training ameliorate gait abnormalities in multiple sclerosis? A pilot randomized-control trial.

PubMed

Straudi, S; Benedetti, M G; Venturini, E; Manca, M; Foti, C; Basaglia, N

2013-01-01

Gait disorders are common in multiple sclerosis (MS) and lead to a progressive reduction of function and quality of life. Test the effects of robot-assisted gait rehabilitation in MS subjects through a pilot randomized-controlled study. We enrolled MS subjects with Expanded Disability Status Scale scores within 4.5-6.5. The experimental group received 12 robot-assisted gait training sessions over 6 weeks. The control group received the same amount of conventional physiotherapy. Outcomes measures were both biomechanical assessment of gait, including kinematics and spatio-temporal parameters, and clinical test of walking endurance (six-minute walk test) and mobility (Up and Go Test). 16 subjects (n = 8 experimental group, n = 8 control group) were included in the final analysis. At baseline the two groups were similar in all variables, except for step length. Data showed walking endurance, as well as spatio-temporal gait parameters improvements after robot-assisted gait training. Pelvic antiversion and reduced hip extension during terminal stance ameliorated after aforementioned intervention. Robot-assisted gait training seems to be effective in increasing walking competency in MS subjects. Moreover, it could be helpful in restoring the kinematic of the hip and pelvis.

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

Screening for colorectal cancer in adults at average risk: a summary of the evidence for the U.S. Preventive Services Task Force.

PubMed

Pignone, Michael; Rich, Melissa; Teutsch, Steven M; Berg, Alfred O; Lohr, Kathleen N

2002-07-16

To assess the effectiveness of different colorectal cancer screening tests for adults at average risk. Recent systematic reviews; Guide to Clinical Preventive Services, 2nd edition; and focused searches of MEDLINE from 1966 through September 2001. The authors also conducted hand searches, reviewed bibliographies, and consulted context experts to ensure completeness. When available, the most recent high-quality systematic review was used to identify relevant articles. This review was then supplemented with a MEDLINE search for more recent articles. One reviewer abstracted information from the final set of studies into evidence tables, and a second reviewer checked the tables for accuracy. Discrepancies were resolved by consensus. For average-risk adults older than 50 years of age, evidence from multiple well-conducted randomized trials supported the effectiveness of fecal occult blood testing in reducing colorectal cancer incidence and mortality rates compared with no screening. Data from well-conducted case-control studies supported the effectiveness of sigmoidoscopy and possibly colonoscopy in reducing colon cancer incidence and mortality rates. A nonrandomized, controlled trial examining colorectal cancer mortality rates and randomized trials examining diagnostic yield supported the use of fecal occult blood testing plus sigmoidoscopy. The effectiveness of barium enema is unclear. Data are insufficient to support a definitive determination of the most effective screening strategy. Colorectal cancer screening reduces death from colorectal cancer and can decrease the incidence of disease through removal of adenomatous polyps. Several available screening options seem to be effective, but the single best screening approach cannot be determined because data are insufficient.

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

PubMed

Peyro Saint Paul, Laure; Debruyne, Danièle; Bernard, Delphine; Mock, Donald M; Defer, Gilles L

2016-01-01

Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

PubMed Central

Pagano, Giovanni; Aiello Talamanca, Annarita; Castello, Giuseppe; Cordero, Mario D.; d’Ischia, Marco; Gadaleta, Maria Nicola; Pallardó, Federico V.; Petrović, Sandra; Tiano, Luca; Zatterale, Adriana

2014-01-01

An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed. PMID:25380523

Testing a Dutch web-based tailored lifestyle programme among adults: a study protocol.

PubMed

Schulz, Daniela N; Kremers, Stef Pj; van Osch, Liesbeth Adm; Schneider, Francine; van Adrichem, Mathieu Jg; de Vries, Hein

2011-02-16

Smoking, high alcohol consumption, unhealthy eating habits and physical inactivity often lead to (chronic) diseases, such as cardiovascular diseases and cancer. Tailored online interventions have been proven to be effective in changing health behaviours. The aim of this study is to test and compare the effectiveness of two different tailoring strategies for changing lifestyle compared to a control group using a multiple health behaviour web-based approach. In our Internet-based tailored programme, the five lifestyle behaviours of smoking, alcohol intake, fruit consumption, vegetable consumption, and physical activity are addressed. This randomized controlled trial, conducted among Dutch adults, includes two experimental groups (i.e., a sequential behaviour tailoring condition and a simultaneous behaviour tailoring condition) and a control group. People in the sequential behaviour tailoring condition obtain feedback on whether their lifestyle behaviours meet the Dutch recommendations. Using a step-by-step approach, they are stimulated to continue with a computer tailored module to change only one unhealthy behaviour first. In the course of the study, they can proceed to change a second behaviour. People in the simultaneous behaviour tailoring condition receive computer tailored feedback about all their unhealthy behaviours during their first visit as a stimulation to change all unhealthy behaviours. The experimental groups can re-visit the website and can then receive ipsative feedback (i.e., current scores are compared to previous scores in order to give feedback about potential changes). The (difference in) effectiveness of the different versions of the programme will be tested and compared to a control group, in which respondents only receive a short health risk appraisal. Programme evaluations will assess satisfaction with and appreciation and personal relevance of the intervention among the respondents. Finally, potential subgroup differences pertaining to gender, age and socioeconomic status regarding the behaviour effects and programme evaluation will be assessed. Research regarding multiple behaviour change is in its infancy. We study how to offer multiple behaviour change interventions optimally. Using these results could strengthen the effectiveness of web-based computer-tailoring lifestyle programmes. This study will yield new results about the need for differential lifestyle approaches using Internet-based expert systems and potential differences in subgroups concerning the effectiveness and appreciation. Dutch Trial Register NTR2168.

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

Cholinesterase inhibitors for rarer dementias associated with neurological conditions.

PubMed

Li, Ying; Hai, Shan; Zhou, Yan; Dong, Bi Rong

2015-03-03

Rarer dementias include Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), frontotemporal dementia (FTD), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP). Cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, are considered to be the first-line medicines for Alzheimer's disease and some other dementias, such as dementia in Parkinson's disease. Cholinesterase inhibitors are hypothesised to work by inhibiting the enzyme acetylcholinesterase (AChE) which breaks down the neurotransmitter acetylcholine. Cholinesterase inhibitors may also lead to clinical improvement for rarer dementias associated with neurological conditions. To assess the efficacy and safety of cholinesterase inhibitors for cognitive impairment or dementia associated with neurological conditions. We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, several trial registries and grey literature sources in August 2013. We included randomised, double-blind, controlled trials assessing the efficacy of treatment of rarer dementias associated with neurological conditions with currently marketed cholinesterase inhibitors. Two review authors independently assessed eligibility and quality of trials, and extracted data. We used the standard methodological procedures of the Cochrane Collaboration. We included eight RCTs involving 567 participants. Six studies used a simple parallel-group design; the other two consisted of an open-label treatment period followed by a randomised phase. All trials were well concealed for allocation and double-blind, however the sample sizes of most trials were small. All trials used placebo as control. We performed meta-analyses for some outcomes in patients with MS. For all other conditions, results are presented narratively.Two trials included patients with HD; one found that cholinesterase inhibitor use in the short-term had no statistically significant impact on the cognitive portion of the Alzheimer Disease Assessment Scale (ADAS-Cog; 1 study, WMD 1.00, 95% CI -1.66 to 3.66, P = 0.46; low quality evidence), Unified Huntington's Disease Rating Scale (UHDRS) Verbal Fluency Test (1 study, WMD -1.20, 95% CI -7.97 to 5.57, P = 0.73; low quality evidence), UHDRS Symbol Digit Modalities Test (SDMT; 1 study, WMD 2.70, 95% CI -0.95 to 6.35, P = 0.15; low quality evidence) and other psychometric tests. The other study found that cholinesterase inhibitor use in the medium-term improved the results of the verbal fluency test (1 study, WMD 6.43, 95% CI 0.66 to 12.20, P = 0.03; moderate quality evidence) and California Verbal Learning Test - Second Edition (CVLT-II) Recognition Task (1 study, WMD 2.42, 95% CI 0.17 to 4.67, P = 0.04; moderate quality evidence). There was no statistically significant difference between groups on the SDMT (1 study, WMD -0.31, 95% CI -7.77 to 7.15, P = 0.94; moderate quality evidence), CVLT-II trials 1-5 (1 study, WMD -2.09, 95% CI -11.65 to 7.47, P = 0.67; moderate quality evidence), short-delay recall (1 study, WMD 0.35, 95% CI -2.87 to 3.57, P = 0.83; moderate quality evidence), or long-delay recall (1 study, WMD -0.14, 95% CI -3.08 to 2.80, P = 0.93; moderate quality evidence), and other psychometric tests.Four trials included patients with MS; one found no differences between the cholinesterase inhibitors (short-term) and placebo groups on the Wechsler Memory Scales general memory score (1 study, WMD 0.90, 95% CI -0.52 to 2.32, P = 0.22; low quality evidence). The three other trials found that, in the medium-term - cholinesterase inhibitors improved the clinician's impression of cognitive change (2 studies, OR 1.96, 95% CI 1.06 to 3.62, P = 0.03; high quality evidence). However, the treatment effect on other aspects of cognitive change were unclear, measured by the Selective Reminding Test (3 studies, WMD 1.47, 95% CI -0.39 to 3.32, P = 0.12; high quality evidence), patient's self-reported impression of memory change (2 studies, OR 1.67, 95% CI 0.93 to 3.00, P = 0.08; high quality evidence) and cognitive change (1 study, OR 0.95, 95% CI 0.45 to 1.98, P = 0.89; high quality evidence), clinician's impression of memory change (1 study, OR 1.50, 95% CI 0.59 to 3.84, P = 0.39; moderate quality evidence), other psychometric tests, and activities of daily living - patient reported impact of multiple sclerosis activities (1 study, WMD -1.18, 95% CI -3.02 to 0.66, P = 0.21; low quality evidence).One study on patients with CADASIL found a beneficial effect of cholinesterase inhibitors on the Executive interview, and Trail Making Test parts A and B. The impact of cholinesterase inhibitors on the Vascular ADAS-Cog score (1 study, WMD 0.04, 95% CI -1.57 to 1.65, P = 0.96; high quality evidence), the Clinical Dementia Rating Scale Sum of Boxes (1 study, WMD -0.09, 95% CI -0.48 to 0.03, P = 0.65; high quality evidence) Disability Assessment for Dementia scale (1 study, WMD 0.58, 95% CI -2.72 to 3.88, P = 0.73; moderate quality evidence), and other measures was unclearOne study included patients with FTD. This trial consisted of an open-label treatment period followed by a randomised, double-blind, placebo-controlled phase. No data of primary outcomes were reported in this study.In the included studies, the most common side effect was gastrointestinal symptoms. For all conditions, compared to the treatment group, the placebo group experienced significantly less nausea (6 studies, 44/257 vs. 22/246, OR 2.10, 95% CI 1.22 to 3.62, P = 0.007; high quality evidence), diarrhoea (6 studies, 40/257 vs. 13/246, OR 3.26, 95% CI 1.72 to 6.19, P = 0.0003; moderate quality evidence) and vomiting (3 studies, 17/192 vs. 3/182, OR 5.76, 95% CI 1.67 to 19.87, P = 0.006; moderate quality evidence). The sample sizes of most included trials were small, and some of the results were extracted from only one study. There were no poolable data for HD, CADASIL and FTD patients and there were no results for patients with PSP. Current evidence shows that the efficacy on cognitive function and activities of daily living of cholinesterase inhibitors in people with HD, CADASIL, MS, PSP or FTD is unclear, although cholinesterase inhibitors are associated with more gastrointestinal side effects compared with placebo.

Test-Retest Reliability of Measures Commonly Used to Measure Striatal Dysfunction across Multiple Testing Sessions: A Longitudinal Study.

PubMed

Palmer, Clare E; Langbehn, Douglas; Tabrizi, Sarah J; Papoutsi, Marina

2017-01-01

Cognitive impairment is common amongst many neurodegenerative movement disorders such as Huntington's disease (HD) and Parkinson's disease (PD) across multiple domains. There are many tasks available to assess different aspects of this dysfunction, however, it is imperative that these show high test-retest reliability if they are to be used to track disease progression or response to treatment in patient populations. Moreover, in order to ensure effects of practice across testing sessions are not misconstrued as clinical improvement in clinical trials, tasks which are particularly vulnerable to practice effects need to be highlighted. In this study we evaluated test-retest reliability in mean performance across three testing sessions of four tasks that are commonly used to measure cognitive dysfunction associated with striatal impairment: a combined Simon Stop-Signal Task; a modified emotion recognition task; a circle tracing task; and the trail making task. Practice effects were seen between sessions 1 and 2 across all tasks for the majority of dependent variables, particularly reaction time variables; some, but not all, diminished in the third session. Good test-retest reliability across all sessions was seen for the emotion recognition, circle tracing, and trail making test. The Simon interference effect and stop-signal reaction time (SSRT) from the combined-Simon-Stop-Signal task showed moderate test-retest reliability, however, the combined SSRT interference effect showed poor test-retest reliability. Our results emphasize the need to use control groups when tracking clinical progression or use pre-baseline training on tasks susceptible to practice effects.

Manipulation and mobilisation for neck pain contrasted against an inactive control or another active treatment.

PubMed

Gross, Anita; Langevin, Pierre; Burnie, Stephen J; Bédard-Brochu, Marie-Sophie; Empey, Brian; Dugas, Estelle; Faber-Dobrescu, Michael; Andres, Cristy; Graham, Nadine; Goldsmith, Charles H; Brønfort, Gert; Hoving, Jan L; LeBlanc, Francis

2015-09-23

Manipulation and mobilisation are commonly used to treat neck pain. This is an update of a Cochrane review first published in 2003, and previously updated in 2010. To assess the effects of manipulation or mobilisation alone compared wiith those of an inactive control or another active treatment on pain, function, disability, patient satisfaction, quality of life and global perceived effect in adults experiencing neck pain with or without radicular symptoms and cervicogenic headache (CGH) at immediate- to long-term follow-up. When appropriate, to assess the influence of treatment characteristics (i.e. technique, dosage), methodological quality, symptom duration and subtypes of neck disorder on treatment outcomes. Review authors searched the following computerised databases to November 2014 to identify additional studies: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched ClinicalTrials.gov, checked references, searched citations and contacted study authors to find relevant studies. We updated this search in June 2015, but these results have not yet been incorporated. Randomised controlled trials (RCTs) undertaken to assess whether manipulation or mobilisation improves clinical outcomes for adults with acute/subacute/chronic neck pain. Two review authors independently selected studies, abstracted data, assessed risk of bias and applied Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods (very low, low, moderate, high quality). We calculated pooled risk ratios (RRs) and standardised mean differences (SMDs). We included 51 trials (2920 participants, 18 trials of manipulation/mobilisation versus control; 34 trials of manipulation/mobilisation versus another treatment, 1 trial had two comparisons). Cervical manipulation versus inactive control: For subacute and chronic neck pain, a single manipulation (three trials, no meta-analysis, 154 participants, ranged from very low to low quality) relieved pain at immediate- but not short-term follow-up. Cervical manipulation versus another active treatment: For acute and chronic neck pain, multiple sessions of cervical manipulation (two trials, 446 participants, ranged from moderate to high quality) produced similar changes in pain, function, quality of life (QoL), global perceived effect (GPE) and patient satisfaction when compared with multiple sessions of cervical mobilisation at immediate-, short- and intermediate-term follow-up. For acute and subacute neck pain, multiple sessions of cervical manipulation were more effective than certain medications in improving pain and function at immediate- (one trial, 182 participants, moderate quality) and long-term follow-up (one trial, 181 participants, moderate quality). These findings are consistent for function at intermediate-term follow-up (one trial, 182 participants, moderate quality). For chronic CGH, multiple sessions of cervical manipulation (two trials, 125 participants, low quality) may be more effective than massage in improving pain and function at short/intermediate-term follow-up. Multiple sessions of cervical manipulation (one trial, 65 participants, very low quality) may be favoured over transcutaneous electrical nerve stimulation (TENS) for pain reduction at short-term follow-up. For acute neck pain, multiple sessions of cervical manipulation (one trial, 20 participants, very low quality) may be more effective than thoracic manipulation in improving pain and function at short/intermediate-term follow-up. Thoracic manipulation versus inactive control: Three trials (150 participants) using a single session were assessed at immediate-, short- and intermediate-term follow-up. At short-term follow-up, manipulation improved pain in participants with acute and subacute neck pain (five trials, 346 participants, moderate quality, pooled SMD -1.26, 95% confidence interval (CI) -1.86 to -0.66) and improved function (four trials, 258 participants, moderate quality, pooled SMD -1.40, 95% CI -2.24 to -0.55) in participants with acute and chronic neck pain. A funnel plot of these data suggests publication bias. These findings were consistent at intermediate follow-up for pain/function/quality of life (one trial, 111 participants, low quality). Thoracic manipulation versus another active treatment: No studies provided sufficient data for statistical analyses. A single session of thoracic manipulation (one trial, 100 participants, moderate quality) was comparable with thoracic mobilisation for pain relief at immediate-term follow-up for chronic neck pain. Mobilisation versus inactive control: Mobilisation as a stand-alone intervention (two trials, 57 participants, ranged from very low to low quality) may not reduce pain more than an inactive control. Mobilisation versus another active treatment: For acute and subacute neck pain, anterior-posterior mobilisation (one trial, 95 participants, very low quality) may favour pain reduction over rotatory or transverse mobilisations at immediate-term follow-up. For chronic CGH with temporomandibular joint (TMJ) dysfunction, multiple sessions of TMJ manual therapy (one trial, 38 participants, very low quality) may be more effective than cervical mobilisation in improving pain/function at immediate- and intermediate-term follow-up. For subacute and chronic neck pain, cervical mobilisation alone (four trials, 165 participants, ranged from low to very low quality) may not be different from ultrasound, TENS, acupuncture and massage in improving pain, function, QoL and participant satisfaction at immediate- and intermediate-term follow-up. Additionally, combining laser with manipulation may be superior to using manipulation or laser alone (one trial, 56 participants, very low quality). Although support can be found for use of thoracic manipulation versus control for neck pain, function and QoL, results for cervical manipulation and mobilisation versus control are few and diverse. Publication bias cannot be ruled out. Research designed to protect against various biases is needed. Findings suggest that manipulation and mobilisation present similar results for every outcome at immediate/short/intermediate-term follow-up. Multiple cervical manipulation sessions may provide better pain relief and functional improvement than certain medications at immediate/intermediate/long-term follow-up. Since the risk of rare but serious adverse events for manipulation exists, further high-quality research focusing on mobilisation and comparing mobilisation or manipulation versus other treatment options is needed to guide clinicians in their optimal treatment choices.

An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions.

PubMed

Pattee, Gary L; Wymer, James P; Lomen-Hoerth, Catherine; Appel, Stanley H; Formella, Andrea E; Pope, Laura E

2014-11-01

Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient's emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain. To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions. Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. #NCT00056524. A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.

Evaluation of empowerment model on indicators of metabolic control in patients with type 2 diabetes, a randomized clinical trial study.

PubMed

Ebrahimi, Hossein; Sadeghi, Mahdi; Amanpour, Farzaneh; Vahedi, Hamid

2016-04-01

Diabetes education is a major subject in achieving optimal glycemic control. Effective empowerment approach can be beneficial for improving patients' health. The aim of this study was to evaluate the effect of empowerment model on indicators of metabolic control in patients with type 2 diabetes. a randomized controlled trial of 103 patients with type 2 diabetes were randomly assigned to either the intervention (empowerment approach training) or the control group (conventional training) 2014. Empowerment approach training were performed for the experimental group for eight weeks. Data collection tool included demographic information form and indicators of metabolic control checklist. Analysis was performed by one-way analysis of variance, chi-square test, paired t-test, independent t-test and multiple linear regression. Before the intervention, two groups were homogeneous in terms of demographic variables, glycosylated hemoglobin (HbA1C), and other indicators of metabolic control. After the intervention, average HbA1C and other metabolic indicators except for LDL showed significant differences in the experimental group compared to the control group. study results indicated the positive effects of applying the empowerment model on the metabolic control indicators. Therefore, applying this model is recommended to nurses and the relevant authorities in order to improve clinical outcomes in diabetic patients. Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Neuromuscular electrical stimulation and the treatment of lower urinary tract dysfunction in multiple sclerosis--a double blind, placebo controlled, randomised clinical trial.

PubMed

McClurg, D; Ashe, R G; Lowe-Strong, A S

2008-01-01

Lower urinary tract dysfunction affects up to 75% of the multiple sclerosis population. Results from our recent Pilot Study (McClurg et al., 2006) indicated that a combined programme of pelvic floor muscle training, electromyography biofeedback and neuromuscular electrical stimulation modalities may alleviate some of the distressing symptoms within this population. This clinical trial aimed to evaluate further the efficacy of these interventions and to establish the benefit of neuromuscular electrical stimulation above and beyond that of EMG biofeedback and pelvic floor muscle training. 74 multiple sclerosis patients who presented with lower urinary tract dysfunction were randomly allocated to one of two groups - Group 1 received Pelvic Floor Muscle Training, Electromyography Biofeedback and Placebo Neuromuscular Electrical Stimulation (n=37), and Group 2 which received Pelvic Floor Muscle Training, Electromyography Biofeedback, and Active Neuromuscular Electrical Stimulation (n=37). Treatment was for nine weeks with outcome measures recorded at weeks 0, 9, 16 and 24. The Primary Outcome Measure was the number of leakage episodes. Within group analysis was by Paired Samples t-test. Group differences were analysed using Repeated Measures Analysis of Variance and Post-hoc tests were used to determine the significance of differences between Groups at each time point. The mean number of incontinence episodes were reduced in Group 2 by 85% (p=0.001) whereas in Group 1 a lesser reduction of 47% (p=0.001) was observed. However, there was a statistically superior benefit in Group 2 when compared to Group 1 (p=0.0028). This superior benefit was evident in all other outcome measures. The addition of Active Neuromuscular Electrical Stimulation to a programme of Pelvic Floor Muscle Training and Electromyography Biofeedback should be considered as a first-line option in alleviating some of the symptoms of lower urinary tract dysfunction associated with multiple sclerosis. (c) 2007 Wiley-Liss, Inc.

Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries.

PubMed

Smith, Emily R; Shankar, Anuraj H; Wu, Lee S-F; Aboud, Said; Adu-Afarwuah, Seth; Ali, Hasmot; Agustina, Rina; Arifeen, Shams; Ashorn, Per; Bhutta, Zulfiqar A; Christian, Parul; Devakumar, Delanjathan; Dewey, Kathryn G; Friis, Henrik; Gomo, Exnevia; Gupta, Piyush; Kæstel, Pernille; Kolsteren, Patrick; Lanou, Hermann; Maleta, Kenneth; Mamadoultaibou, Aissa; Msamanga, Gernard; Osrin, David; Persson, Lars-Åke; Ramakrishnan, Usha; Rivera, Juan A; Rizvi, Arjumand; Sachdev, H P S; Urassa, Willy; West, Keith P; Zagre, Noel; Zeng, Lingxia; Zhu, Zhonghai; Fawzi, Wafaie W; Sudfeld, Christopher R

2017-11-01

Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ 2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m 2 ; RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups. Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex. None. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Chinese Obstetrics & Gynecology journal club: a randomised controlled trial

PubMed Central

Tsui, Ilene K; Dodson, William C; Kunselman, Allen R; Kuang, Hongying; Han, Feng-Juan; Legro, Richard S; Wu, Xiao-Ke

2016-01-01

Objectives To assess whether a journal club model could improve comprehension and written and spoken medical English in a population of Chinese medical professionals. Setting and participants The study population consisted of 52 medical professionals who were residents or postgraduate master or PhD students in the Department of Obstetrics and Gynecology, Heilongjiang University of Chinese Medicine, China. Intervention After a three-part baseline examination to assess medical English comprehension, participants were randomised to either (1) an intensive journal club treatment arm or (2) a self-study group. At the conclusion of the 8-week intervention participants (n=52) were re-tested with new questions. Outcome measures The primary outcome was the change in score on a multiple choice examination. Secondary outcomes included change in scores on written and oral examinations which were modelled on the Test of English as a Foreign Language (TOEFL). Results Both groups had improved scores on the multiple choice examination without a statistically significant difference between them (90% power). However, there was a statistically significant difference between the groups in mean improvement in scores for both written (95% CI 1.1 to 5.0; p=0.003) and spoken English (95% CI 0.06 to 3.7; p=0.04) favouring the journal club intervention. Conclusions Interacting with colleagues and an English-speaking facilitator in a journal club improved both written and spoken medical English in Chinese medical professionals. Journal clubs may be suitable for use as a self-sustainable teaching model to improve fluency in medical English in foreign medical professionals. Trial registration number NCT01844609. PMID:26823180

Entomopathogenic Nematodes Are Not an Alternative to Fenamiphos for Management of Plant-Parasitic Nematodes on Golf Courses in Florida

PubMed Central

Crow, WT; Porazinska, DL; Giblin-Davis, RM; Grewal, PS

2006-01-01

With the cancellation of fenamiphos in the near future, alternative nematode management tactics for plant-parasitic nematodes (PPN) on golf courses need to be identified. The use of entomopathogenic nematodes (EPN) has been suggested as one possible alternative. This paper presents the results of 10 experiments evaluating the efficacy of EPN at managing PPN on turfgrasses and improving turf performance. These experiments were conducted at various locations throughout Florida over the course of a decade. In different experiments, different EPN species were tested against different species of PPN. Separate experiments evaluated multiple rates and applications of EPN, compared different EPN species, and compared single EPN species against multiple species of PPN. In a few trials, EPN were associated with reductions in certain plant-parasite species, but in other trials were associated with increases. In most trials, EPN had no effect on plant parasites. Because EPN were so inconsistent in their results, we conclude that EPN are not acceptable alternatives to fenamiphos by most turf managers in Florida at this time. PMID:19259430

Genome-wide association study of coronary and aortic calcification in lung cancer screening CT

NASA Astrophysics Data System (ADS)

de Vos, Bob D.; van Setten, Jessica; de Jong, Pim A.; Mali, Willem P.; Oudkerk, Matthijs; Viergever, Max A.; Išgum, Ivana

2016-03-01

Arterial calcification has been related to cardiovascular disease (CVD) and osteoporosis. However, little is known about the role of genetics and exact pathways leading to arterial calcification and its relation to bone density changes indicating osteoporosis. In this study, we conducted a genome-wide association study of arterial calcification burden, followed by a look-up of known single nucleotide polymorphisms (SNPs) for coronary artery disease (CAD) and myocardial infarction (MI), and bone mineral density (BMD) to test for a shared genetic basis between the traits. The study included a subcohort of the Dutch-Belgian lung cancer screening trial comprised of 2,561 participants. Participants underwent baseline CT screening in one of two hospitals participating in the trial. Low-dose chest CT images were acquired without contrast enhancement and without ECG-synchronization. In these images coronary and aortic calcifications were identified automatically. Subsequently, the detected calcifications were quantified using coronary artery calcium Agatston and volume scores. Genotype data was available for these participants. A genome-wide association study was conducted on 10,220,814 SNPs using a linear regression model. To reduce multiple testing burden, known CAD/MI and BMD SNPs were specifically tested (45 SNPs from the CARDIoGRAMplusC4D consortium and 60 SNPS from the GEFOS consortium). No novel significant SNPs were found. Significant enrichment for CAD/MI SNPs was observed in testing Agatston and coronary artery calcium volume scores. Moreover, a significant enrichment of BMD SNPs was shown in aortic calcium volume scores. This may indicate genetic relation of BMD SNPs and arterial calcification burden.

Carnitine for fatigue in multiple sclerosis.

PubMed

Tejani, Aaron M; Wasdell, Michael; Spiwak, Rae; Rowell, Greg; Nathwani, Shabita

2012-05-16

Fatigue is reported to occur in up to 92% of patients with multiple sclerosis (MS) and has been described as the most debilitating of all MS symptoms by 28% to 40% of MS patients. To assess whether carnitine (enteral or intravenous) supplementation can improve the quality of life and reduce the symptoms of fatigue in patients with MS-related fatigue and to identify any adverse effects of carnitine when used for this purpose. A literature search was performed using Cochrane MS Group Trials Register (09 September 2011), Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library 2011, issue 3", MEDLINE (PubMed) (1966-09 September 2011), EMBASE (1974-09 September 2011), and www.clinicaltrials.gov for ongoing trials retrieval. Reference lists of review articles and primary studies were also screened. A hand search of the abstract book of recent relevant conference symposia was also conducted. Personal contact with MS experts and a manufacturer (Source Naturals, United States) of carnitine formulation was contacted to determine if they knew of other clinical trials. No language restrictions were applied. Full reports of published and unpublished randomized controlled trials and quasi-randomized trials of any carnitine intervention in adults affected by multiple sclerosis with a clinical diagnosis of fatigue associated with multiple sclerosis were included. Data from the eligible trials was extracted and coded using a standardized data extraction form and entered into RevMan 5. Discrepancies were to be resolved by discussion with a third reviewer, however this was not necessary.The quality items to be assessed were method of randomization, allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention-to-treat analysis and completeness of follow up. The search identified one ongoing randomized, placebo-controlled, cross-over trial (expected completion 2013) and one completed randomized, active-comparator, cross-over trial. In the completed study, adult patients with relapsing-remitting and secondary progressive MS were exposed to both acetyl L-carnitine 2 grams daily and amantadine 200 mg daily The effects of carnitine on fatigue are unclear. There was no difference between carnitine and amantadine for the number of patients withdrawing from the study due to an adverse event (relative risk ratio 0.20; 95% confidence interval 0.03 to 1.55) and no patients experienced a serious adverse event in either treatment group. Mortality and quality of life were not reported. There is insufficient evidence that carnitine for the treatment of MS-related fatigue offers a therapeutic advantage over placebo or active comparators. Results of the ongoing trial are eagerly anticipated in order to provide clarity.

Randomized trials are frequently fragmented in multiple secondary publications.

PubMed

Ebrahim, Shanil; Montoya, Luis; Kamal El Din, Mostafa; Sohani, Zahra N; Agarwal, Arnav; Bance, Sheena; Saquib, Juliann; Saquib, Nazmus; Ioannidis, John P A

2016-11-01

To assess the frequency and features of secondary publications of randomized controlled trials (RCTs). For 191 RCTs published in high-impact journals in 2009, we searched for secondary publications coauthored by at least one same author of the primary trial publication. We evaluated the probability of having secondary publications, characteristics of the primary trial publication that predict having secondary publications, types of secondary analyses conducted, and statistical significance of those analyses. Of 191 primary trials, 88 (46%) had a total of 475 secondary publications by 2/2014. Eight trials had >10 (up to 51) secondary publications each. In multivariable modeling, the risk of having subsequent secondary publications increased 1.32-fold (95% CI 1.05-1.68) per 10-fold increase in sample size, and 1.71-fold (95% CI 1.19-2.45) in the presence of a design article. In a sample of 197 secondary publications examined in depth, 193 tested different hypotheses than the primary publication. Of the 193, 43 tested differences between subgroups, 85 assessed predictive factors associated with an outcome of interest, 118 evaluated different outcomes than the original article, 71 had differences in eligibility criteria, and 21 assessed different durations of follow-up; 176 (91%) presented at least one analysis with statistically significant results. Approximately half of randomized trials in high-impact journals have secondary publications published with a few trials followed by numerous secondary publications. Almost all of these publications report some statistically significant results. Copyright © 2016 Elsevier Inc. All rights reserved.

A wireless body measurement system to study fatigue in multiple sclerosis.

PubMed

Yu, Fei; Bilberg, Arne; Stenager, Egon; Rabotti, Chiara; Zhang, Bin; Mischi, Massimo

2012-12-01

Fatigue is reported as the most common symptom by patients with multiple sclerosis (MS). The physiological and functional parameters related to fatigue in MS patients are currently not well established. A new wearable wireless body measurement system, named Fatigue Monitoring System (FAMOS), was developed to study fatigue in MS. It can continuously measure electrocardiogram, body-skin temperature, electromyogram and motions of feet. The goal of this study is to test the ability of distinguishing fatigued MS patients from healthy subjects by the use of FAMOS. This paper presents the realization of the measurement system including the design of both hardware and dedicated signal processing algorithms. Twenty-six participants including 17 MS patients with fatigue and 9 sex- and age-matched healthy controls were included in the study for continuous 24 h monitoring. The preliminary results show significant differences between fatigued MS patients and healthy controls. In conclusion, the FAMOS enables continuous data acquisition and estimation of multiple physiological and functional parameters. It provides a new, flexible and objective approach to study fatigue in MS, which can distinguish between fatigued MS patients and healthy controls. The usability and reliability of the FAMOS should however be further improved and validated through larger clinical trials.

Compression set in gas-blown condensation-cured polysiloxane elastomers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patel, Mogon; Chinn, Sarah; Maxwell, Robert S.

2010-12-01

Accelerated thermal ageing studies on foamed condensation cured polysiloxane materials have been performed in support of life assessment and material replacement programmes. Two different types of filled hydrogen-blown and condensation cured polysiloxane foams were tested; commercial (RTV S5370), and an in-house formulated polysiloxane elastomer (Silfoam). Compression set properties were investigated using Thermomechanical (TMA) studies and compared against two separate longer term ageing trials carried out in air and in dry inert gas atmospheres using compression jigs. Isotherms measured from these studies were assessed using time-temperature (T/t) superposition. Acceleration factors were determined and fitted to Arrhenius kinetics. For both materials, themore » thermo-mechanical results were found to closely follow the longer term accelerated ageing trials. Comparison of the accelerated ageing data in dry nitrogen atmospheres against field trial results showed the accelerated ageing trends over predict, however the comparison is difficult as the field data suffer from significant component to component variability. Of the long term ageing trials reported here, those carried out in air deviate more significantly from field trials data compared to those carried out in dry nitrogen atmospheres. For field return samples, there is evidence for residual post-curing reactions influencing mechanical performance, which would accelerate compression set. Multiple quantum-NMR studies suggest that compression set is not associated with significant changes in net crosslink density, but that some degree of network rearrangement has occurred due to viscoelastic relaxation as well as bond breaking and forming processes, with possible post-curing reactions at early times.« less

An empirical study using permutation-based resampling in meta-regression

PubMed Central

2012-01-01

Background In meta-regression, as the number of trials in the analyses decreases, the risk of false positives or false negatives increases. This is partly due to the assumption of normality that may not hold in small samples. Creation of a distribution from the observed trials using permutation methods to calculate P values may allow for less spurious findings. Permutation has not been empirically tested in meta-regression. The objective of this study was to perform an empirical investigation to explore the differences in results for meta-analyses on a small number of trials using standard large sample approaches verses permutation-based methods for meta-regression. Methods We isolated a sample of randomized controlled clinical trials (RCTs) for interventions that have a small number of trials (herbal medicine trials). Trials were then grouped by herbal species and condition and assessed for methodological quality using the Jadad scale, and data were extracted for each outcome. Finally, we performed meta-analyses on the primary outcome of each group of trials and meta-regression for methodological quality subgroups within each meta-analysis. We used large sample methods and permutation methods in our meta-regression modeling. We then compared final models and final P values between methods. Results We collected 110 trials across 5 intervention/outcome pairings and 5 to 10 trials per covariate. When applying large sample methods and permutation-based methods in our backwards stepwise regression the covariates in the final models were identical in all cases. The P values for the covariates in the final model were larger in 78% (7/9) of the cases for permutation and identical for 22% (2/9) of the cases. Conclusions We present empirical evidence that permutation-based resampling may not change final models when using backwards stepwise regression, but may increase P values in meta-regression of multiple covariates for relatively small amount of trials. PMID:22587815

A studentized permutation test for three-arm trials in the 'gold standard' design.

PubMed

Mütze, Tobias; Konietschke, Frank; Munk, Axel; Friede, Tim

2017-03-15

The 'gold standard' design for three-arm trials refers to trials with an active control and a placebo control in addition to the experimental treatment group. This trial design is recommended when being ethically justifiable and it allows the simultaneous comparison of experimental treatment, active control, and placebo. Parametric testing methods have been studied plentifully over the past years. However, these methods often tend to be liberal or conservative when distributional assumptions are not met particularly with small sample sizes. In this article, we introduce a studentized permutation test for testing non-inferiority and superiority of the experimental treatment compared with the active control in three-arm trials in the 'gold standard' design. The performance of the studentized permutation test for finite sample sizes is assessed in a Monte Carlo simulation study under various parameter constellations. Emphasis is put on whether the studentized permutation test meets the target significance level. For comparison purposes, commonly used Wald-type tests, which do not make any distributional assumptions, are included in the simulation study. The simulation study shows that the presented studentized permutation test for assessing non-inferiority in three-arm trials in the 'gold standard' design outperforms its competitors, for instance the test based on a quasi-Poisson model, for count data. The methods discussed in this paper are implemented in the R package ThreeArmedTrials which is available on the comprehensive R archive network (CRAN). Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Does mediator use contribute to the spacing effect for cued recall? Critical tests of the mediator hypothesis.

PubMed

Morehead, Kayla; Dunlosky, John; Rawson, Katherine A; Bishop, Melissa; Pyc, Mary A

2018-04-01

When study is spaced across sessions (versus massed within a single session), final performance is greater after spacing. This spacing effect may have multiple causes, and according to the mediator hypothesis, part of the effect can be explained by the use of mediator-based strategies. This hypothesis proposes that when study is spaced across sessions, rather than massed within a session, more mediators will be generated that are longer lasting and hence more mediators will be available to support criterion recall. In two experiments, participants were randomly assigned to study paired associates using either a spaced or massed schedule. They reported strategy use for each item during study trials and during the final test. Consistent with the mediator hypothesis, participants who had spaced (as compared to massed) practice reported using more mediators on the final test. This use of effective mediators also statistically accounted for some - but not all of - the spacing effect on final performance.

Methodological and clinical implications of a three-in-one Russian doll design for tracking health trajectories and improving health and function through innovative exercise treatments in adults with disability.

PubMed

Rimmer, James H; Herman, Cassandra; Wingo, Brooks; Fontaine, Kevin; Mehta, Tapan

2018-03-14

Hybrid research designs targeting adults with neurologic disability are critical for improving the efficiency of models that can identify, track and intervene on identified health issues. Our Russian doll framework encompasses three study phases. Phase 1 involves prospectively following a cohort of participants with disability to examine the relationships between rates of health and functional deficits (e.g., pain, fatigue, deconditioning), functional measures (e.g., cardiorespiratory endurance, strength, balance), and environmental and sociocultural factors. In Phase 2, eligible participants with neurologic disability from Phase 1 (in our example, individuals with multiple sclerosis) are screened and randomized to a clinical exercise efficacy trial. In Phase 3, study participants are enrolled in a home-based teleexercise trial to test the feasibility and replicability of delivering the clinical exercise study in the home. This unique three-in-one Russian doll framework serves as a foundation for informing and guiding researchers and clinicians in treating certain health and functional deficits in people with neurologic disability using exercise as a primary treatment modality in both the clinical and home settings. It offers a unique perspective for understanding the critical issues of functioning, health maintenance and quality of life for people with neurologic disability across a longitudinal framework. Study 2 ClinicalTrials.gov identifier NCT02533882 (retroactively registered 03/06/2015). Study 3 ClinicalTrials.gov identifier NCT03108950 (retroactively registered 04/05/2017).

An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions

PubMed Central

Pattee, Gary L.; Wymer, James P.; Lomen-Hoerth, Catherine; Appel, Stanley H.; Formella, Andrea E.; Pope, Laura E.

2014-01-01

Abstract Background: Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient’s emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain. Objective: To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions. Methods: Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. Clinical trial registration: #NCT00056524. Results: A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. Conclusions: DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions. PMID:25062507

Attitude of pregnant women towards HIV testing in Abidjan, Côte d'Ivoire and Bobo-Dioulasso, Burkina Faso. DITRAME Study Group (ANRS 049 Clinical Trial). Diminution de la Transmission Mère Enfant du VIH. Agence Nationale de Recherches sur le SIDA.

PubMed

Cartoux, M; Msellati, P; Meda, N; Welffens-Ekra, C; Mandelbrot, L; Leroy, V; Van de Perre, P; Dabis, F

1998-12-03

To evaluate the attitude of pregnant women towards HIV testing in two cities of West Africa: Abidjan, Côte d'Ivoire and Bobo-Dioulasso, Burkina Faso. In the context of a clinical trial to prevent HIV vertical transmission, HIV counselling and testing was offered systematically to women attending antenatal clinics. Informed consent was obtained and test results were given anonymously. Multiple logistic regression was performed to identify factors associated with refusal for testing and failure to return for test results. A total of 9724 pregnant women were interviewed from January 1995 to September 1996. In Abidjan (n=5766) and Bobo-Dioulasso (n=3958), 78 and 92.4% of the women consented to HIV testing, respectively, and 58.4 and 81.8% of them returned for the test results disclosure, respectively. In the two sites, the counsellors themselves and high educational level of the women appeared to be related to refusal of the test, whereas last trimester gestation was associated with failure to return for test results. In Abidjan, foreigners and employees were more likely to refuse testing, and HIV-infected women were three times less likely to return for results than uninfected women. Future implementation of interventions to reduce vertical transmission of HIV that require antenatal HIV testing and counselling will have to solve issue of acceptability of HIV testing by pregnant women.

Characterizing switching and congruency effects in the Implicit Association Test as reactive and proactive cognitive control.

PubMed

Hilgard, Joseph; Bartholow, Bruce D; Dickter, Cheryl L; Blanton, Hart

2015-03-01

Recent research has identified an important role for task switching, a cognitive control process often associated with executive functioning, in the Implicit Association Test (IAT). However, switching does not fully account for IAT effects, particularly when performance is scored using more recent d-score formulations. The current study sought to characterize multiple control processes involved in IAT performance through the use of event-related brain potentials (ERPs). Participants performed a race-evaluative IAT while ERPs were recorded. Behaviorally, participants experienced superadditive reaction time costs of incongruency and task switching, consistent with previous studies. The ERP showed a marked medial frontal negativity (MFN) 250-450 ms post-stimulus at midline fronto-central locations that were more negative for incongruent than congruent trials but more positive for switch than for no-switch trials, suggesting separable control processes are engaged by these two factors. Greater behavioral IAT bias was associated with both greater switch-related and congruency-related ERP activity. Findings are discussed in terms of the Dual Mechanisms of Control model of reactive and proactive cognitive control. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Differences in dynamic balance scores in one sport versus multiple sport high school athletes.

PubMed

Gorman, Paul P; Butler, Robert J; Rauh, Mitchell J; Kiesel, Kyle; Plisky, Phillip J

2012-04-01

Researchers have previously reported on the importance of dynamic balance in assessing an individual's risk for injury during sport. However, to date there is no research on whether multiple sport participation affects dynamic balance ability. Therefore, the purpose of this study was to determine if there was a difference in dynamic balance scores in high school athletes that competed in one sport only as compared athletes who competed in multiple sports, as tested by the Lower Quarter Y Balance Test (YBT-LQ). Ninety-two high school athletes who participated in one sport were matched, by age, gender and sport played, to athletes who participated in the same sport as well as additional sports. All individuals were assessed using the YBT-LQ to examine differences in composite reach score and reach direction asymmetry between single sport and multiple sport athletes. The greatest reach distance of three trials in each reach direction for right and left lower-extremities was normalized by limb length and used for analysis. A two-way ANOVA (gender x number of sports played) was used to statistically analyze the variables in the study. No significant interactions or main effects related to number of sports played were observed for any YBT-LQ score (p>0.05). Male athletes exhibited significantly greater normalized reach values for the posteromedial, posterolateral, and composite reach while also exhibiting a larger anterior reach difference when compared to the females. Athletes who participated in multiple sports had similar performances on the YBT-LQ when compared to athletes who participated in a single sport. The findings of this study suggest that the number of sports played by a high school athlete does not need to be controlled for when evaluating dynamic balance with the YBT-LQ.

Training in multiple breath washout testing for respiratory physiotherapists.

PubMed

O'Neill, Katherine; Elborn, J Stuart; Tunney, Michael M; O'Neill, Philip; Rowan, Stephen; Martin, Susan; Bradley, Judy M

2018-03-01

The development of multiple breath washout (MBW) testing in respiratory disease highlights the need for increased awareness amongst respiratory physiotherapists and a potential opportunity for professional development in the use of an important outcome measure for clinical trials. To rationalise how MBW may be a useful assessment tool for respiratory physiotherapists and to describe a local MBW training and certification programme for physiotherapists. The respiratory Multidisciplinary Team in the Belfast Health and Social Care Trust (BHSCT) identified a need for MBW testing to be available to facilitate clinical research and assessment. A 2day training programme consisting of prereading preparation, self-directed learning, theory presentations, practical demonstrations and hands-on practice was developed and delivered. All participants underwent a certification process. We have demonstrated the successful training and certification of clinical and research physiotherapists and encourage other respiratory physiotherapists to consider MBW test training. Copyright © 2017 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

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.

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

PubMed

Snowdon, Claire; Elbourne, Diana R; Garcia, Jo; Campbell, Marion K; Entwistle, Vikki A; Francis, David; Grant, Adrian M; Knight, Rosemary C; McDonald, Alison M; Roberts, Ian

2006-12-21

Securing and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS). In-depth semi-structured telephone interviews were conducted in 2003-04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti. The data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA. This study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research.

[Categorization in infancy: differentiation of global object classes].

PubMed

Pauen, S

1996-01-01

Two studies tested whether preverbal children distinguish global categories (animal and furniture) on a conceptual basis. A total of 59 eleven-month-olds solved an object examination task. During habituation, infants freely explored different natural-looking toy models from the same category. In Study 1, the same series of four different examplars was presented twice. In Study 2, ten different exemplares were presented. In both cases, a significant habituation effect could be observed. When a perceptually new object of the same category was presented on the first test trial after habituation, a significant increase in examination time from the last habituation trial to the first test trial could be observed in Study 1. When a new object of the contrasting category was presented on the second test trial, examination times increased significantly from the first to the second test trial in both studies. These results support earlier findings suggesting that preverbal infants are able to distinguish global categories on a conceptual basis.

Cryopreservation-related loss of antigen-specific IFNγ producing CD4+ T-cells can skew immunogenicity data in vaccine trials: Lessons from a malaria vaccine trial substudy.

PubMed

Ford, Tom; Wenden, Claire; Mbekeani, Alison; Dally, Len; Cox, Josephine H; Morin, Merribeth; Winstone, Nicola; Hill, Adrian V S; Gilmour, Jill; Ewer, Katie J

2017-04-04

Ex vivo functional immunoassays such as ELISpot and intracellular cytokine staining (ICS) by flow cytometry are crucial tools in vaccine development both in the identification of novel immunogenic targets and in the immunological assessment of samples from clinical trials. Cryopreservation and subsequent thawing of PBMCs via validated processes has become a mainstay of clinical trials due to processing restrictions inherent in the disparate location and capacity of trial centres, and also in the need to standardize biological assays at central testing facilities. Logistical and financial requirement to batch process samples from multiple study timepoints are also key. We used ELISpot and ICS assays to assess antigen-specific immunogenicity in blood samples taken from subjects enrolled in a phase II malaria heterologous prime-boost vaccine trial and showed that the freeze thaw process can result in a 3-5-fold reduction of malaria antigen-specific IFNγ-producing CD3 + CD4 + effector populations from PBMC samples taken post vaccination. We have also demonstrated that peptide responsive CD8 + T cells are relatively unaffected, as well as CD4 + T cell populations that do not produce IFNγ. These findings contribute to a growing body of data that could be consolidated and synthesised as guidelines for clinical trials with the aim of increasing the efficiency of vaccine development pipelines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy.

PubMed

de Haas, Sanne; Delmar, Paul; Bansal, Aruna T; Moisse, Matthieu; Miles, David W; Leighl, Natasha; Escudier, Bernard; Van Cutsem, Eric; Carmeliet, Peter; Scherer, Stefan J; Pallaud, Celine; Lambrechts, Diether

2014-10-01

Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.

Discrimination performance in aging is vulnerable to interference and dissociable from spatial memory

PubMed Central

Johnson, Sarah A.; Sacks, Patricia K.; Turner, Sean M.; Gaynor, Leslie S.; Ormerod, Brandi K.; Maurer, Andrew P.; Bizon, Jennifer L.

2016-01-01

Hippocampal-dependent episodic memory and stimulus discrimination abilities are both compromised in the elderly. The reduced capacity to discriminate between similar stimuli likely contributes to multiple aspects of age-related cognitive impairment; however, the association of these behaviors within individuals has never been examined in an animal model. In the present study, young and aged F344×BN F1 hybrid rats were cross-characterized on the Morris water maze test of spatial memory and a dentate gyrus-dependent match-to-position test of spatial discrimination ability. Aged rats showed overall impairments relative to young in spatial learning and memory on the water maze task. Although young and aged learned to apply a match-to-position response strategy in performing easy spatial discriminations within a similar number of trials, a majority of aged rats were impaired relative to young in performing difficult spatial discriminations on subsequent tests. Moreover, all aged rats were susceptible to cumulative interference during spatial discrimination tests, such that error rate increased on later trials of test sessions. These data suggest that when faced with difficult discriminations, the aged rats were less able to distinguish current goal locations from those of previous trials. Increasing acetylcholine levels with donepezil did not improve aged rats’ abilities to accurately perform difficult spatial discriminations or reduce their susceptibility to interference. Interestingly, better spatial memory abilities were not significantly associated with higher performance on difficult spatial discriminations. This observation, along with the finding that aged rats made more errors under conditions in which interference was high, suggests that match-to-position spatial discrimination performance may rely on extra-hippocampal structures such as the prefrontal cortex, in addition to the dentate gyrus. PMID:27317194

Contextual cuing contributes to the independent modification of multiple internal models for vocal control

PubMed Central

Keough, Dwayne

2011-01-01

Research on the control of visually guided limb movements indicates that the brain learns and continuously updates an internal model that maps the relationship between motor commands and sensory feedback. A growing body of work suggests that an internal model that relates motor commands to sensory feedback also supports vocal control. There is evidence from arm-reaching studies that shows that when provided with a contextual cue, the motor system can acquire multiple internal models, which allows an animal to adapt to different perturbations in diverse contexts. In this study we show that trained singers can rapidly acquire multiple internal models regarding voice fundamental frequency (F0). These models accommodate different perturbations to ongoing auditory feedback. Participants heard three musical notes and reproduced each one in succession. The musical targets could serve as a contextual cue to indicate which direction (up or down) feedback would be altered on each trial; however, participants were not explicitly instructed to use this strategy. When participants were gradually exposed to altered feedback adaptation was observed immediately following vocal onset. Aftereffects were target specific and did not influence vocal productions on subsequent trials. When target notes were no longer a contextual cue, adaptation occurred during altered feedback trials and evidence for trial-by-trial adaptation was found. These findings indicate that the brain is exceptionally sensitive to the deviations between auditory feedback and the predicted consequence of a motor command during vocalization. Moreover, these results indicate that, with contextual cues, the vocal control system may maintain multiple internal models that are capable of independent modification during different tasks or environments. PMID:21346208

Imputation of a true endpoint from a surrogate: application to a cluster randomized controlled trial with partial information on the true endpoint.

PubMed

Nixon, Richard M; Duffy, Stephen W; Fender, Guy R K

2003-09-24

The Anglia Menorrhagia Education Study (AMES) is a randomized controlled trial testing the effectiveness of an education package applied to general practices. Binary data are available from two sources; general practitioner reported referrals to hospital, and referrals to hospital determined by independent audit of the general practices. The former may be regarded as a surrogate for the latter, which is regarded as the true endpoint. Data are only available for the true end point on a sub set of the practices, but there are surrogate data for almost all of the audited practices and for most of the remaining practices. The aim of this paper was to estimate the treatment effect using data from every practice in the study. Where the true endpoint was not available, it was estimated by three approaches, a regression method, multiple imputation and a full likelihood model. Including the surrogate data in the analysis yielded an estimate of the treatment effect which was more precise than an estimate gained from using the true end point data alone. The full likelihood method provides a new imputation tool at the disposal of trials with surrogate data.

Improving Diabetes care through Examining, Advising, and prescribing (IDEA): protocol for a theory-based cluster randomised controlled trial of a multiple behaviour change intervention aimed at primary healthcare professionals

PubMed Central

2014-01-01

Background New clinical research findings may require clinicians to change their behaviour to provide high-quality care to people with type 2 diabetes, likely requiring them to change multiple different clinical behaviours. The present study builds on findings from a UK-wide study of theory-based behavioural and organisational factors associated with prescribing, advising, and examining consistent with high-quality diabetes care. Aim To develop and evaluate the effectiveness and cost of an intervention to improve multiple behaviours in clinicians involved in delivering high-quality care for type 2 diabetes. Design/methods We will conduct a two-armed cluster randomised controlled trial in 44 general practices in the North East of England to evaluate a theory-based behaviour change intervention. We will target improvement in six underperformed clinical behaviours highlighted in quality standards for type 2 diabetes: prescribing for hypertension; prescribing for glycaemic control; providing physical activity advice; providing nutrition advice; providing on-going education; and ensuring that feet have been examined. The primary outcome will be the proportion of patients appropriately prescribed and examined (using anonymised computer records), and advised (using anonymous patient surveys) at 12 months. We will use behaviour change techniques targeting motivational, volitional, and impulsive factors that we have previously demonstrated to be predictive of multiple health professional behaviours involved in high-quality type 2 diabetes care. We will also investigate whether the intervention was delivered as designed (fidelity) by coding audiotaped workshops and interventionist delivery reports, and operated as hypothesised (process evaluation) by analysing responses to theory-based postal questionnaires. In addition, we will conduct post-trial qualitative interviews with practice teams to further inform the process evaluation, and a post-trial economic analysis to estimate the costs of the intervention and cost of service use. Discussion Consistent with UK Medical Research Council guidance and building on previous development research, this pragmatic cluster randomised trial will evaluate the effectiveness of a theory-based complex intervention focusing on changing multiple clinical behaviours to improve quality of diabetes care. Trial registration ISRCTN66498413. PMID:24886606

The dilemma of aneuploidy screening on low responders.

PubMed

Morin, Scott J; Kaser, Daniel J; Franasiak, Jason M

2018-06-01

Preimplantation genetic testing for aneuploidy (PGT-A) has been demonstrated to improve implantation and pregnancy rates and decrease miscarriage rates over standard morphology-based embryo selection. However, there are limited data on its efficacy in patients with diminished ovarian reserve or a poor response to stimulation who may have fewer embryos to select amongst. Early findings demonstrate that PGT-A reduces the miscarriage rate and decreases the time to delivery in poor responders. These studies highlight the importance of designing trials that compare outcomes over multiple cycles as the benefit of PGT-A in this patient population lies in eliminating the time lost to futile transfers of aneuploid embryos. Furthermore, recent studies have demonstrated that a catch-all category of 'poor responder' may need to be reevaluated as different subpopulations of patients with low response exhibit different clinical characteristics. More information is needed on characterizing the physiology of ovarian aging across multiple phenotypes of diminished ovarian reserve and establishing the predictive value of aneuploid results across multiple PGT-A platforms. However, initial data suggests benefit of PGT-A in poor responders.

Deformable microparticles with multiple functions for drug delivery and device testing

NASA Astrophysics Data System (ADS)

Thula, Taili T.

Since the HIV epidemic of the 1990s, researchers have attempted to develop a red blood cell analog. Even though some of these substitutes are now in Phase III of clinical trials, their use is limited by side effects and short half-life in the human body. As a result, there is still a need for an effective erythrocyte analog with minimum immunogenic and side effects, so that it can be used for multiple applications. Finding new approaches to develop more efficient blood substitutes will not only bring valuable advances in the clinical approach, but also in the area of in vitro testing of medical devices. We examined the feasibility of creating a deformable multi-functional, biodegradable, biocompatible particle for applications in drug delivery and device testing. As a preliminary evaluation, we synthesized different types of microcapsules using natural and synthetic polymers, various cross-linking agents, and diverse manufacturing techniques. After fully characterizing of each system, we determined the most promising red blood cell analog in terms of deformability, stability and toxicity. We also examined the encapsulation and release of bovine serum albumin (BSA) within these deformable particles. After removal of cross-linkers, zinc- and copper-alginate microparticles surrounded by multiple polyelectrolyte layers of chitosan oligosaccharide and alginate were deformable and remained stable under physiological pressures applied by the micropipette technique. In addition, multiple coatings decreased toxicity of heavy-metal crosslinked particles. BSA encapsulation and release from chitosan-alginate microspheres were contingent on the crosslinker and number of polyelectrolyte coatings, respectively. Further rheological studies are needed to determine how closely these particles simulate the behavior of erythrocytes. Also, studies on the encapsulation and release of different proteins, including hemoglobin, are needed to establish the desired controlled release of bioactive agents for the proposed delivery system.

Test-retest reliability and sensitivity of the 20-meter walk test among patients with knee osteoarthritis.

PubMed

Motyl, Jillian M; Driban, Jeffrey B; McAdams, Erica; Price, Lori Lyn; McAlindon, Timothy E

2013-05-10

The 20-meter walk test is a physical function measure commonly used in clinical research studies and rehabilitation clinics to measure gait speed and monitor changes in patients' physical function over time. Unfortunately, the reliability and sensitivity of this walk test are not well defined and, therefore, limit our ability to evaluate real changes in gait speed not attributable to normal variability. The aim of this study was to assess the test-restest reliability and sensitivity of the 20-meter walk test, at a self-selected pace, among patients with mild to moderate knee osteoarthritis (OA) and to suggest a standardized protocol for future test administration. This was a measurement reliability study. Fifteen consecutive people enrolled in a randomized-controlled trial of intra-articular corticosteroid injections for knee OA participated in this study. All participants completed 4 trials on 2 separate days, 7 to 21 days apart (8 trials total). Each day was divided into 2 sessions, which each involved 2 walking trials. We compared walk times between trials with Wilcoxon signed-rank tests. Similar analyses compared average walk times between sessions. To confirm these analyses, we also calculated Spearman correlation coefficients to assess the relationship between sessions. Finally, smallest detectable differences (SDD) were calculated to estimate the sensitivity of the 20-meter walk test. Wilcoxon signed-rank tests between trials within the same session demonstrated that trials in session 1 were significantly different and in the subsequent 3 sessions, the median differences between trials were not significantly different. Therefore, the first session of each day was considered a practice session, and the SDD between the second session of each day were calculated. SDD was -1.59 seconds (walking slower) and 0.15 seconds (walking faster). Practice trials and a standardized protocol should be used in administration of the 20-meter walk test. Changes in walk time between -1.59 seconds (walking slower) and 0.15 seconds (walking faster) should be considered within the range of normal variability of 20-meter walking speed. The primary limitation of our study was a small sample size, which may influence the generalizability of our findings.

Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial.

PubMed

Karim, Quarraisha Abdool; Kharsany, Ayesha B M; Naidoo, Kasavan; Yende, Nonhlanhla; Gengiah, Tanuja; Omar, Zaheen; Arulappan, Natasha; Mlisana, Koleka P; Luthuli, Londiwe R; Karim, Salim S Abdool

2011-05-01

In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments. Copyright © 2011 Elsevier Inc. All rights reserved.

Prior Exercise Does Not Reduce Postprandial Lipemia Following a Mixed Glucose Meal When Compared with a Mixed Fructose Meal.

PubMed

Rowe, James R; Biggerstaff, Kyle D; Ben-Ezra, Vic; Nichols, David L; DiMarco, Nancy

2016-10-01

This study examined the effect of prior exercise on postprandial lipemia (PPL) concentration following a mixed meal (MM) made with either glucose or fructose. Sedentary women completed four trials in random order: 1) Rest-Fructose: RF, 2) Rest-Glucose: RG, 3) Exercise-Fructose: EF, 4) Exercise-Glucose: EG. Exercise expended 500 kcal while walking at 70%VO 2max . Rest was 60 min of sitting. The morning after each trial, a fasting (12 hr) blood sample was collected followed by consumption of the MM. The MM was blended with whole milk and ice cream plus a glucose or fructose powder. Glucose and fructose powder accounted for 30% of the total kcal within the MM. Blood was collected periodically for 6 hr post-MM and analyzed for PPL. Magnitude of PPL over the 6 hr postmeal was quantified using the triglyceride incremental area under the curve (TG AUC I ). Significant differences (p < .05) between trials were determined using repeated-measures ANOVA and Bonferroni post hoc test. There was no significant difference in the TG AUC I between the four trials (p > .05). A significant trial by time interaction for TG concentration was reported (p < .05). Despite lack of change in the AUC I with prior exercise, the lower TG concentration at multiple time points in the EG trial does indicate that prior exercise has some desirable effect on PPL. This study suggests that replacing fructose with glucose sugars and incorporating exercise may minimize PPL following a mixed meal but exercise will need to elicit greater energy expenditure.

Temporal Dependency and the Structure of Early Looking.

PubMed

Messinger, Daniel S; Mattson, Whitney I; Todd, James Torrence; Gangi, Devon N; Myers, Nicholas D; Bahrick, Lorraine E

2017-01-01

Although looking time is used to assess infant perceptual and cognitive processing, little is known about the temporal structure of infant looking. To shed light on this temporal structure, 127 three-month-olds were assessed in an infant-controlled habituation procedure and presented with a pre-recorded display of a woman addressing the infant using infant-directed speech. Previous individual look durations positively predicted subsequent look durations over a six look window, suggesting a temporal dependency between successive infant looks. The previous look duration continued to predict the subsequent look duration after accounting for habituation-linked declines in look duration, and when looks were separated by an inter-trial interval in which no stimulus was displayed. Individual differences in temporal dependency, the strength of associations between consecutive look durations, are distinct from individual differences in mean infant look duration. Nevertheless, infants with stronger temporal dependency had briefer mean look durations, a potential index of stimulus processing. Temporal dependency was evident not only between individual infant looks but between the durations of successive habituation trials (total looking within a trial). Finally, temporal dependency was evident in associations between the last look at the habituation stimulus and the first look at a novel test stimulus. Thus temporal dependency was evident across multiple timescales (individual looks and trials comprised of multiple individual looks) and persisted across conditions including brief periods of no stimulus presentation and changes from a familiar to novel stimulus. Associations between consecutive look durations over multiple timescales and stimuli suggest a temporal structure of infant attention that has been largely ignored in previous work on infant looking.

Temporal Dependency and the Structure of Early Looking

PubMed Central

Messinger, Daniel S.; Mattson, Whitney I.; Todd, James Torrence; Gangi, Devon N.; Myers, Nicholas D.; Bahrick, Lorraine E.

2017-01-01

Although looking time is used to assess infant perceptual and cognitive processing, little is known about the temporal structure of infant looking. To shed light on this temporal structure, 127 three-month-olds were assessed in an infant-controlled habituation procedure and presented with a pre-recorded display of a woman addressing the infant using infant-directed speech. Previous individual look durations positively predicted subsequent look durations over a six look window, suggesting a temporal dependency between successive infant looks. The previous look duration continued to predict the subsequent look duration after accounting for habituation-linked declines in look duration, and when looks were separated by an inter-trial interval in which no stimulus was displayed. Individual differences in temporal dependency, the strength of associations between consecutive look durations, are distinct from individual differences in mean infant look duration. Nevertheless, infants with stronger temporal dependency had briefer mean look durations, a potential index of stimulus processing. Temporal dependency was evident not only between individual infant looks but between the durations of successive habituation trials (total looking within a trial). Finally, temporal dependency was evident in associations between the last look at the habituation stimulus and the first look at a novel test stimulus. Thus temporal dependency was evident across multiple timescales (individual looks and trials comprised of multiple individual looks) and persisted across conditions including brief periods of no stimulus presentation and changes from a familiar to novel stimulus. Associations between consecutive look durations over multiple timescales and stimuli suggest a temporal structure of infant attention that has been largely ignored in previous work on infant looking. PMID:28076362

A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens

PubMed Central

Gilbert, Peter B.; Grove, Douglas; Gabriel, Erin; Huang, Ying; Gray, Glenda; Hammer, Scott M.; Buchbinder, Susan P.; Kublin, James; Corey, Lawrence; Self, Steven G.

2012-01-01

Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection. PMID:23181167

The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies

PubMed Central

Yu, Liping; Skyler, Jay S.; Krischer, Jeffrey P.; Gottlieb, Peter A.; Boulware, David; Miao, Dongmei; Palmer, Jerry P.; Steck, Andrea K.

2017-01-01

Abstract Background: Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. Subjects and Methods: TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL+) were compared with those ECL negative (ECL−) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. Results: The progression to multiple autoantibodies was significantly higher for those GADA/ECL+ (n = 107) than those GADA/ECL− (n = 78) (P = 0.001) and for those mIAA/ECL+ (n = 24) than those mIAA/ECL− (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58–7.39; P < 0.01) for GADA and 8.15 (3.02–22.00; P < 0.001) for mIAA. GADA/ECL+ and mIAA/ECL+ participants had significantly higher PS6M values than their ECL− counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL+, 14% progressed to T1D; of those mIAA/ECL+, 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL− progressed to T1D (median follow-up: 5 years). Conclusion: ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL+ are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL− are at very low risk. PMID:28177779

Language-specific memory for everyday arithmetic facts in Chinese-English bilinguals.

PubMed

Chen, Yalin; Yanke, Jill; Campbell, Jamie I D

2016-04-01

The role of language in memory for arithmetic facts remains controversial. Here, we examined transfer of memory training for evidence that bilinguals may acquire language-specific memory stores for everyday arithmetic facts. Chinese-English bilingual adults (n = 32) were trained on different subsets of simple addition and multiplication problems. Each operation was trained in one language or the other. The subsequent test phase included all problems with addition and multiplication alternating across trials in two blocks, one in each language. Averaging over training language, the response time (RT) gains for trained problems relative to untrained problems were greater in the trained language than in the untrained language. Subsequent analysis showed that English training produced larger RT gains for trained problems relative to untrained problems in English at test relative to the untrained Chinese language. In contrast, there was no evidence with Chinese training that problem-specific RT gains differed between Chinese and the untrained English language. We propose that training in Chinese promoted a translation strategy for English arithmetic (particularly multiplication) that produced strong cross-language generalization of practice, whereas training in English strengthened relatively weak, English-language arithmetic memories and produced little generalization to Chinese (i.e., English training did not induce an English translation strategy for Chinese language trials). The results support the existence of language-specific strengthening of memory for everyday arithmetic facts.

South Yorkshire Cohort: a 'cohort trials facility' study of health and weight - protocol for the recruitment phase.

PubMed

Relton, Clare; Bissell, Paul; Smith, Christine; Blackburn, Joanna; Cooper, Cindy L; Nicholl, Jon; Tod, Angela; Copeland, Rob; Loban, Amanda; Chater, Tim; Thomas, Kate; Young, Tracy; Weir, Carol; Harrison, Gill; Millbourn, Alison; Manners, Rachel

2011-08-11

Growing levels of both obesity and chronic disease in the general population pose a major public health problem. In the UK, an innovative 'health and weight' cohort trials facility, the 'South Yorkshire Cohort', is being built in order to provide robust evidence to inform policy, commissioning and clinical decisions in this field. This protocol reports the design of the facility and outlines the recruitment phase methods. The South Yorkshire Cohort health and weight study uses the cohort multiple randomised controlled trial design. This design recruits a large observational cohort of patients with the condition(s) of interest which then provides a facility for multiple randomised controlled trials (with large representative samples of participants, long term outcomes as standard, increased comparability between each trial conducted within the cohort and increased efficiency particularly for trials of expensive interventions) as well as ongoing information as to the natural history of the condition and treatment as usual.This study aims to recruit 20,000 participants to the population based South Yorkshire Cohort health and weight research trials facility. Participants are recruited by invitation letters from their General Practitioners. Data is collected using postal and/or online patient self completed Health Questionnaires. NHS numbers will be used to facilitate record linkage and access to routine data. Participants are eligible if they are: aged 16 - 85 years, registered with one of 40 practices in South Yorkshire, provide consent for further contact from the researchers and to have their information used to look at the benefit of health treatments. The first wave of data is being collected during 2010/12 and further waves are planned at 2 - 5 year intervals for the planned 20 year duration of the facility. The South Yorkshire Cohort combines the strengths of the standard observational, longitudinal cohort study design with a population based cohort facility for multiple randomised controlled trials in a range of long term health and weight related conditions (including obesity). This infrastructure will allow the rapid and cheap identification and recruitment of patients, and facilitate the provision of robust evidence to inform the management and self-management of health and weight.

South Yorkshire Cohort: a 'cohort trials facility' study of health and weight - Protocol for the recruitment phase

PubMed Central

2011-01-01

Background Growing levels of both obesity and chronic disease in the general population pose a major public health problem. In the UK, an innovative 'health and weight' cohort trials facility, the 'South Yorkshire Cohort', is being built in order to provide robust evidence to inform policy, commissioning and clinical decisions in this field. This protocol reports the design of the facility and outlines the recruitment phase methods. Method/Design The South Yorkshire Cohort health and weight study uses the cohort multiple randomised controlled trial design. This design recruits a large observational cohort of patients with the condition(s) of interest which then provides a facility for multiple randomised controlled trials (with large representative samples of participants, long term outcomes as standard, increased comparability between each trial conducted within the cohort and increased efficiency particularly for trials of expensive interventions) as well as ongoing information as to the natural history of the condition and treatment as usual. This study aims to recruit 20,000 participants to the population based South Yorkshire Cohort health and weight research trials facility. Participants are recruited by invitation letters from their General Practitioners. Data is collected using postal and/or online patient self completed Health Questionnaires. NHS numbers will be used to facilitate record linkage and access to routine data. Participants are eligible if they are: aged 16 - 85 years, registered with one of 40 practices in South Yorkshire, provide consent for further contact from the researchers and to have their information used to look at the benefit of health treatments. The first wave of data is being collected during 2010/12 and further waves are planned at 2 - 5 year intervals for the planned 20 year duration of the facility. Discussion The South Yorkshire Cohort combines the strengths of the standard observational, longitudinal cohort study design with a population based cohort facility for multiple randomised controlled trials in a range of long term health and weight related conditions (including obesity). This infrastructure will allow the rapid and cheap identification and recruitment of patients, and facilitate the provision of robust evidence to inform the management and self-management of health and weight. PMID:21834964

A mixed methods study to assess the feasibility of a randomised controlled trial of invasive urodynamic testing versus clinical assessment and non-invasive tests prior to surgery for stress urinary incontinence in women: the INVESTIGATE-I study.

PubMed

Hilton, Paul; Armstrong, Natalie; Brennand, Catherine; Howel, Denise; Shen, Jing; Bryant, Andrew; Tincello, Douglas G; Lucas, Malcolm G; Buckley, Brian S; Chapple, Christopher R; Homer, Tara; Vale, Luke; McColl, Elaine

2015-09-08

The position of invasive urodynamic testing (IUT) in diagnostic pathways for urinary incontinence is unclear, and systematic reviews have called for further trials evaluating clinical utility. The objective of this study was to inform the decision whether to proceed to a definitive randomised trial of IUT compared to clinical assessment with non-invasive tests, prior to surgery in women with stress urinary incontinence (SUI) or stress-predominant mixed urinary incontinence (MUI). A mixed methods study comprising a pragmatic multicentre randomised pilot trial, a qualitative face-to face interview study with patients eligible for the trial, an exploratory economic evaluation including value of information study, a survey of clinicians' views about IUT, and qualitative telephone interviews with purposively sampled survey respondents. Only the first and second of these elements are reported here. Trial participants were randomised to either clinical assessment with non-invasive tests (control arm) or clinical assessment with non-invasive tests plus IUT (intervention arm). The main outcome measures of these feasibility studies were confirmation that units can identify and recruit eligible women, acceptability of investigation strategies and data collection tools, and acquisition of outcome data to determine the sample size for a definitive trial. The primary outcome proposed for a definitive trial was ICIQ-FLUTS (total score) 6 months after surgery or the start of nonsurgical treatment. Of 284 eligible women, 222 (78%) were recruited, 165/219 (75%) returned questionnaires at baseline, and 125/200 returned them (63%) at follow-up. Most women underwent surgery; management plans were changed in 19 (19%) participants following IUT. Participants interviewed were positive about the trial and the associated documentation. All elements of a definitive trial were rehearsed. Such a trial would require between 232 and 922 participants, depending on the target difference in the primary outcome. We identified possible modifications to our protocol for application in a definitive trial including clarity over inclusion/exclusions, screening processes, reduction in secondary outcomes, and modification to patient questionnaire booklets and bladder diaries. A definitive trial of IUT versus clinical assessment prior to surgery for SUI or stress predominant MUI is feasible and remains relevant. Current Controlled Trials: ISRCTN 71327395, registered 7 June 2010.

Can social dancing prevent falls in older adults? a protocol of the Dance, Aging, Cognition, Economics (DAnCE) fall prevention randomised controlled trial

PubMed Central

2013-01-01

Background Falls are one of the most common health problems among older people and pose a major economic burden on health care systems. Exercise is an accepted stand-alone fall prevention strategy particularly if it is balance training or regular participation in Tai chi. Dance shares the ‘holistic’ approach of practices such as Tai chi. It is a complex sensorimotor rhythmic activity integrating multiple physical, cognitive and social elements. Small-scale randomised controlled trials have indicated that diverse dance styles can improve measures of balance and mobility in older people, but none of these studies has examined the effect of dance on falls or cognition. This study aims to determine whether participation in social dancing: i) reduces the number of falls; and ii) improves cognitive functions associated with fall risk in older people. Methods/design A single-blind, cluster randomised controlled trial of 12 months duration will be conducted. Approximately 450 participants will be recruited from 24 self-care retirement villages that house at least 60 residents each in Sydney, Australia. Village residents without cognitive impairment and obtain medical clearance will be eligible. After comprehensive baseline measurements including physiological and cognitive tests and self-completed questionnaires, villages will be randomised to intervention sites (ballroom or folk dance) or to a wait-listed control using a computer randomisation method that minimises imbalances between villages based on two baseline fall risk measures. Main outcome measures are falls, prospectively measured, and the Trail Making cognitive function test. Cost-effectiveness and cost-utility analyses will be performed. Discussion This study offers a novel approach to balance training for older people. As a community-based approach to fall prevention, dance offers older people an opportunity for greater social engagement, thereby making a major contribution to healthy ageing. Providing diversity in exercise programs targeting seniors recognises the heterogeneity of multicultural populations and may further increase the number of taking part in exercise. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12612000889853 The trial is now in progress with 12 villages already have been randomised. PMID:23675705

Note on simultaneous inferences about non-inferiority and superiority for a primary and a secondary endpoint.

PubMed

Guilbaud, Olivier

2011-11-01

In their review of challenges to multiple testing in clinical trials, Hung and Wang (2010) considered the situation where a treatment is to be compared with an active comparator and the aim is to show non-inferiority and (if possible) superiority with respect to a primary and a secondary endpoint. This note extends their discussion of this particular situation, taking the sequentially rejective procedure they used for illustration as a starting point. Some alternative multiple testing procedures (MTPs) are considered, and corresponding simultaneous confidence regions are discussed that provide additional information "for free". The choice may then be based on the properties of these MTPs and corresponding confidence regions. 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

III. NIH Toolbox Cognition Battery (CB): measuring episodic memory.

PubMed

Bauer, Patricia J; Dikmen, Sureyya S; Heaton, Robert K; Mungas, Dan; Slotkin, Jerry; Beaumont, Jennifer L

2013-08-01

One of the most significant domains of cognition is episodic memory, which allows for rapid acquisition and long-term storage of new information. For purposes of the NIH Toolbox, we devised a new test of episodic memory. The nonverbal NIH Toolbox Picture Sequence Memory Test (TPSMT) requires participants to reproduce the order of an arbitrarily ordered sequence of pictures presented on a computer. To adjust for ability, sequence length varies from 6 to 15 pictures. Multiple trials are administered to increase reliability. Pediatric data from the validation study revealed the TPSMT to be sensitive to age-related changes. The task also has high test-retest reliability and promising construct validity. Steps to further increase the sensitivity of the instrument to individual and age-related variability are described. © 2013 The Society for Research in Child Development, Inc.

The FOAM study: is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial.

PubMed

van Rijswijk, Joukje; van Welie, Nienke; Dreyer, Kim; van Hooff, Machiel H A; de Bruin, Jan Peter; Verhoeve, Harold R; Mol, Femke; Kleiman-Broeze, Kimiko A; Traas, Maaike A F; Muijsers, Guido J J M; Manger, Arentje P; Gianotten, Judith; de Koning, Cornelia H; Koning, Aafke M H; Bayram, Neriman; van der Ham, David P; Vrouenraets, Francisca P J M; Kalafusova, Michaela; van de Laar, Bob I G; Kaijser, Jeroen; van Oostwaard, Miriam F; Meijer, Wouter J; Broekmans, Frank J M; Valkenburg, Olivier; van der Voet, Lucy F; van Disseldorp, Jeroen; Lambers, Marieke J; Peters, Henrike E; Lier, Marit C I; Lambalk, Cornelis B; van Wely, Madelon; Bossuyt, Patrick M M; Stoker, Jaap; van der Veen, Fulco; Mol, Ben W J; Mijatovic, Velja

2018-05-09

Tubal pathology is a causative factor in 20% of subfertile couples. Traditionally, tubal testing during fertility work-up is performed by hysterosalpingography (HSG). Hysterosalpingo-foam sonography (HyFoSy) is a new technique that is thought to have comparable accuracy as HSG, while it is less expensive and more patient friendly. HyFoSy would be an acceptable alternative for HSG, provided it has similar effectiveness in terms of patient outcomes. We aim to compare the effectiveness and costs of management guided by HyFoSy or by HSG. Consenting women will undergo tubal testing by both HyFoSy and HSG in a randomized order during fertility work-up. The study group will consist of 1163 subfertile women between 18 and 41 years old who are scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male subfertility or a known contrast (iodine) allergy will be excluded. We anticipate that 7 % (N = 82) of the participants will have discordant test results for HyFoSy and HSG. These participants will be randomly allocated to either a management strategy based on HyFoSy or a management strategy based on HSG, resulting in either a diagnostic laparoscopy with chromopertubation or a strategy that assumes tubal patency (intrauterine insemination or expectant management). The primary outcome is ongoing pregnancy leading to live birth within 12 months after randomization. Secondary outcomes are patient pain scores, time to pregnancy, clinical pregnancy, miscarriage rate, multiple pregnancy rate, preterm birth rate and number of additional treatments. Costs will be estimated by counting resource use and calculating unit prices. This trial will compare the effectiveness and costs of HyFoSy versus HSG in assessing tubal patency in subfertile women. Dutch Trial Register (NTR 4746, http://www.trialregister.nl ). Date of registration: 19 August 2014.

Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study

PubMed Central

Schnorbus, Boris; Daiber, Andreas; Jurk, Kerstin; Warnke, Silke; König, Jochem; Krahn, Ulrike; Lackner, Karl; Munzel, Thomas; Gori, Tommaso

2014-01-01

Introduction Particularly in the setting of acute coronary syndromes, the interplay between vascular and platelet function has been postulated to have direct clinical implications. The present trial is designed to test the effect of clopidogrel, prasugrel and ticagrelor on multiple parameters of vascular function, platelet aggregation, oxidative and inflammatory stress before and up to 4 weeks after coronary artery stenting. Methods and analysis The study is designed as a three-arm, parallel design, randomised, investigator-blinded study. Patients with unstable angina or non-ST elevation myocardial infarction undergoing coronary intervention with a drug-eluting stent will be randomised to receive 600 mg clopidogrel, 60 mg prasugrel or 180 mg ticagrelor followed by oral therapy with the same drug. The primary endpoint of the trial is the impact of antiplatelet treatments on endothelial function as assessed by flow-mediated dilation at 1 day, 1 week and 1 month in patients who have undergone stenting. Secondary endpoints include the impact of study medications on parameters of macrovascular and microvascular function, platelet reactivity, oxidative and inflammatory stress. The study recruitment is currently ongoing and, after an interim analysis which was performed at 50% of the initially planned population, it is planned to continue until July 2015. Ethics and dissemination The protocol was approved by the local ethics committee. The trial will provide important pathophysiological insight on the relationship between platelet aggregation and endothelial function, two parameters that have been shown to influence patients’ prognosis. Trial registration number ClinicalTrials.gov Identifier: NCT01700322; EudraCT-Nr.: 2011-005305-73. Current V.1.3, from 24 February 2014. PMID:24801283

Kā-HOLO Project: a protocol for a randomized controlled trial of a native cultural dance program for cardiovascular disease prevention in Native Hawaiians.

PubMed

Kaholokula, Joseph Keawe'aimoku; Look, Mele A; Wills, Thomas A; de Silva, Māpuana; Mabellos, Tricia; Seto, Todd B; Ahn, Hyeong Jun; Sinclair, Ka'imi A; Buchwald, Dedra

2017-04-17

As a major risk factor for cardiovascular and cerebrovascular disease (CVD), hypertension affects 33% of U.S. adults. Relative to other US races and ethnicities, Native Hawaiians have a high prevalence of hypertension and are 3 to 4 times more likely to have CVD. Effective, culturally-relevant interventions are needed to address CVD risk in this population. Investigators of the Kā-HOLO Project developed a study design to test the efficacy of an intervention that uses hula, a traditional Hawaiian dance, to increase physical activity and reduce CVD risk. A 2-arm randomized controlled trial with a wait-list control design will be implemented to test a 6-month intervention based on hula to manage blood pressure and reduce CVD risk in 250 adult Native Hawaiians with diagnosed hypertension. Half of the sample will be randomized to each arm, stratified across multiple study sites. Primary outcomes are reduction in systolic blood pressure and improvement in CVD risk as measured by the Framingham Risk Score. Other psychosocial and sociocultural measures will be included to determine mediators of intervention effects on primary outcomes. Assessments will be conducted at baseline, 3 months, and 6 months for all participants, and at 12 months for intervention participants only. This trial will elucidate the efficacy of a novel hypertension management program designed to reduce CVD risk in an indigenous population by using a cultural dance form as its physical activity component. The results of this culturally-based intervention will have implications for other indigenous populations globally and will offer a sustainable, culturally-relevant means of addressing CVD disparities. ClinicalTrials.gov: NCT02620709 , registration date November 23, 2015.

Patterns of detection of Strongyloides stercoralis in stool specimens: implications for diagnosis and clinical trials.

PubMed Central

Dreyer, G; Fernandes-Silva, E; Alves, S; Rocha, A; Albuquerque, R; Addiss, D

1996-01-01

Reported efficacies of drugs used to treat Strongyloides stercoralis infection vary widely. Because diagnostic methods are insensitive, therapeutic trials generally require multiple negative posttreatment stool specimens as evidence of drug efficacy. However, only a single positive stool specimen is usually required for study enrollment. To determine the reproducibility of detection of S. stercoralis larvae in the stool, 108 asymptomatic infected men submitted 25 g of fresh stool once a week for eight consecutive weeks for examination by the Baermann technique. During the 8-week study, 239 (27.7%) of 864 stool specimens were positive for S. stercoralis. Rates of detection of larvae in the stool specimens ranged from eight of eight specimens in 3 (2.8%) men to none of eight specimens in 36 (33.3%) men. Of 43 men for whom S. stercoralis was detected in at least two of the first four stool specimens, only 1 (2.3%) man tested negative on all of the next four specimens. In comparison, of 29 men who had detectable larvae in only one of the first four specimens, 22 (75.9%) tested negative on all of the next four samples. Thus, if these 29 men had been enrolled in a therapeutic trial between the first and second sets of four specimens, the efficacy of a drug with no activity against this parasite would have been estimated to be 76%. These data suggest that patterns of S. stercoralis detection vary widely among infected persons and that intermittent larval shedding can lead to inflated estimates of drug efficacy. Before a patient is entered in a clinical trial of drug efficacy, four consecutive stool specimens should be examined for S. stercoralis; only persons with two or more positive specimens should be enrolled. PMID:8880521

Safety and efficacy of dual-lead thalamic deep brain stimulation for patients with treatment-refractory multiple sclerosis tremor: a single-centre, randomised, single-blind, pilot trial.

PubMed

Oliveria, Seth F; Rodriguez, Ramon L; Bowers, Dawn; Kantor, Daniel; Hilliard, Justin D; Monari, Erin H; Scott, Bonnie M; Okun, Michael S; Foote, Kelly D

2017-09-01

Efficacy in previous studies of surgical treatments of refractory multiple sclerosis tremor using lesioning or deep brain stimulation (DBS) has been variable. The aim of this study was to investigate the safety and efficacy of dual-lead thalamic DBS (one targeting the ventralis intermedius-ventralis oralis posterior nucleus border [the VIM lead] and one targeting the ventralis oralis anterior-ventralis oralis posterior border [the VO lead]) for the treatment of multiple sclerosis tremor. We did a single centre, single-blind, prospective, randomised pilot trial at the University of Florida Center for Movement Disorders and Neurorestoration clinic (Gainesville, FL, USA). We recruited adult patients with a clinical diagnosis of multiple sclerosis tremor refractory to previous medical therapy. Before surgery to implant both leads, we randomly assigned patients (1:1) to receive 3 months of optimised single-lead DBS-either VIM or VO. We did the randomisation with a computer-generated sequence, using three blocks of four patients, and independent members of the Center did the assignment. Patients and all clinicians other than the DBS programming nurse were masked to the choice of lead. Patients underwent surgery 1 month after their baseline visit for implantation of the dual lead DBS system. A pulse generator and two extension cables were implanted in a second surgery 3-4 weeks later. Patients then received an initial 3-month period of continuous stimulation of either the VIM or VO lead followed by blinded safety assessment of their tremor with the Tolosa-Fahn-Marin Tremor Rating Scale (TRS) during optimised VIM or VO lead stimulation at the end of the 3 months. After this visit, both leads were activated in all patients for an additional 3 months, and optimally programmed during serial visits as dictated by a prespecified programming algorithm. At the 6-month follow-up visit, TRS score was measured, and mood and psychological batteries were administered under four stimulation conditions: VIM on, VO on, both on, and both off (the order of testing was chosen by a computer-generated random sequence, assigned by independent members of the centre, and enacted by an unmasked DBS programming nurse). Each of four stimulation settings were tested over 4 consecutive days, with stimulation settings held constant for at least 12 h before testing. The primary outcome was change in mean total TRS score at the 6-month postoperative assessment with both leads activated, compared with the preoperative baseline mean TRS score. Analysis was by intention to treat. Safety was analysed in all patients who received the surgical implantation except in one patient who discontinued before the safety assessment. This trial is registered with ClinicalTrials.gov, number NCT00954421. Between Jan 16, 2007, and Dec 17, 2013, we enrolled 12 patients who were randomly assigned either to 3 initial months of VIM-only or VO-only stimulation. One patient from the VO-only group developed an infection necessitating DBS explantation, and was excluded from the assessment of the primary outcome. Compared with the mean baseline TRS score of 57·0 (SD 10·2), the mean score at 6 months decreased to 40·1 (17·6), -29·6% reduction; t=-0·28, p=0·03. Three of 11 patients did not respond to surgical intervention. One patient died suddenly 2 years after surgery, but this was judged to be unrelated to DBS implantation. Serious adverse events included a superficial wound infection in one patient that resolved with antibiotic therapy, and transient altered mental status and late multiple sclerosis exacerbation in another patient. The most common non-serious adverse events were headache and fatigue. Dual lead thalamic DBS might be a safe and effective option for improving severe, refractory multiple sclerosis tremor. Larger studies are necessary to show whether this technique is widely applicable, safe in the long-term, and effective in treating multiple sclerosis tremor or other severe tremor disorders. US National Institutes of Health, the Cathy Donnellan, Albert E Einstein, and Birdie W Einstein Fund, and the William Merz Professorship. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design and Implementation of a Randomized Controlled Trial of Genomic Counseling for Patients with Chronic Disease

PubMed Central

Sweet, Kevin; Gordon, Erynn S.; Sturm, Amy C.; Schmidlen, Tara J.; Manickam, Kandamurugu; Toland, Amanda Ewart; Keller, Margaret A.; Stack, Catharine B.; García-España, J. Felipe; Bellafante, Mark; Tayal, Neeraj; Embi, Peter; Binkley, Philip; Hershberger, Ray E.; Sadee, Wolfgang; Christman, Michael; Marsh, Clay

2014-01-01

We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices. PMID:24926413

The impact of loss to follow-up on hypothesis tests of the treatment effect for several statistical methods in substance abuse clinical trials.

PubMed

Hedden, Sarra L; Woolson, Robert F; Carter, Rickey E; Palesch, Yuko; Upadhyaya, Himanshu P; Malcolm, Robert J

2009-07-01

"Loss to follow-up" can be substantial in substance abuse clinical trials. When extensive losses to follow-up occur, one must cautiously analyze and interpret the findings of a research study. Aims of this project were to introduce the types of missing data mechanisms and describe several methods for analyzing data with loss to follow-up. Furthermore, a simulation study compared Type I error and power of several methods when missing data amount and mechanism varies. Methods compared were the following: Last observation carried forward (LOCF), multiple imputation (MI), modified stratified summary statistics (SSS), and mixed effects models. Results demonstrated nominal Type I error for all methods; power was high for all methods except LOCF. Mixed effect model, modified SSS, and MI are generally recommended for use; however, many methods require that the data are missing at random or missing completely at random (i.e., "ignorable"). If the missing data are presumed to be nonignorable, a sensitivity analysis is recommended.

Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639].

PubMed

Gasparovic, Hrvoje; Petricevic, Mate; Kopjar, Tomislav; Djuric, Zeljko; Svetina, Lucija; Biocina, Bojan

2012-08-25

Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive. The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology) as well as bleeding events will be recorded. This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management. This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639).

Effects of a soybean nutrition bar on the postprandial blood glucose and lipid levels in patients with diabetes mellitus.

PubMed

Urita, Yoshihisa; Noda, Tsuneyuki; Watanabe, Daisuke; Iwashita, Soh; Hamada, Koichiro; Sugimoto, Motonobu

2012-12-01

We investigated the influence of a soybean nutrition bar made from whole soy powder on the blood glucose, insulin and lipid levels in comparison with a test cookie with the same amount of energy in patients with diabetes mellitus. In the cross-over designed study, meal tolerance tests using the soybean nutrition bar and test cookie were performed. Two kinds of test meals were used: Study 1 80 kcal, Study 2 592 kcal. The blood glucose response was significantly lower in the soybean nutrition bar trial than in the cookie trial (Studies 1 and 2, p < 0.001). The blood insulin response was also significantly lower in the soybean nutrition bar trial than in the cookie trial (Study 2, p < 0.001). The blood triglyceride and non-esterified fatty acid responses were not significantly different between the two trials, nor were the changes in breath H₂ enrichment (Study 2). The soybean nutrition bar did not induce postprandial hyperglycaemia in diabetic patients unlike the isoenergetic test cookies.

Effects of a Carbohydrate-Electrolyte Drink on Specific Soccer Tests and Performance

PubMed Central

Ostojic, Sergej M.; Mazic, Sanja

2002-01-01

The aim of this study was to examine the effects of a carbohydrate-electrolyte drink on specific soccer tests and performance. Twenty-two professional male soccer players volunteered to participate in the study. The players were allocated to two assigned trials ingesting carbohydrate-electrolyte drink (7% carbohydrates, sodium 24 mmol.l-1, chloride 12 mmol.l-1, potassium 3 mmol.l-1) or placebo during a 90 min on-field soccer match. The trials were matched for subjects’ age, weight, height and maximal oxygen uptake. Immediately after the match, players completed four soccer-specific skill tests. Blood glucose concentration [mean (SD)] was higher at the end of the match-play in the carbohydrate-electrolyte trial than in the placebo trial (4.4 (0.3) vs. 4.0 (0.3) mmol.l-1, P < 0.05). Subjects in the carbohydrate-electrolyte trial finished the specific dribble test faster in comparison with subjects in the placebo trial (12.9 (0.4) vs. 13.6 (0.5) s, P < 0.05). Ratings of the precision test were higher in the carbohydrate-electrolyte trial as compared to the placebo trial (17.2 (4.8) vs. 15.1 (5.2), P < 0.05) but there were no differences in coordination test and power test results between trials. The main finding of the present study indicates that supplementation with carbohydrate-electrolyte solution improved soccer-specific skill performance and recovery after an on-field soccer match compared with ingestion of placebo. This suggests that soccer players should consume carbohydrate-electrolyte fluid throughout a game to help prevent deterioration in specific skill performance. PMID:24688270

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.

Observational Word Learning: Beyond Propose-But-Verify and Associative Bean Counting.

PubMed

Roembke, Tanja; McMurray, Bob

2016-04-01

Learning new words is difficult. In any naming situation, there are multiple possible interpretations of a novel word. Recent approaches suggest that learners may solve this problem by tracking co-occurrence statistics between words and referents across multiple naming situations (e.g. Yu & Smith, 2007), overcoming the ambiguity in any one situation. Yet, there remains debate around the underlying mechanisms. We conducted two experiments in which learners acquired eight word-object mappings using cross-situational statistics while eye-movements were tracked. These addressed four unresolved questions regarding the learning mechanism. First, eye-movements during learning showed evidence that listeners maintain multiple hypotheses for a given word and bring them all to bear in the moment of naming. Second, trial-by-trial analyses of accuracy suggested that listeners accumulate continuous statistics about word/object mappings, over and above prior hypotheses they have about a word. Third, consistent, probabilistic context can impede learning, as false associations between words and highly co-occurring referents are formed. Finally, a number of factors not previously considered in prior analysis impact observational word learning: knowledge of the foils, spatial consistency of the target object, and the number of trials between presentations of the same word. This evidence suggests that observational word learning may derive from a combination of gradual statistical or associative learning mechanisms and more rapid real-time processes such as competition, mutual exclusivity and even inference or hypothesis testing.

Sensory integration balance training in patients with multiple sclerosis: A randomized, controlled trial.

PubMed

Gandolfi, Marialuisa; Munari, Daniele; Geroin, Christian; Gajofatto, Alberto; Benedetti, Maria Donata; Midiri, Alessandro; Carla, Fontana; Picelli, Alessandro; Waldner, Andreas; Smania, Nicola

2015-10-01

Impaired sensory integration contributes to balance disorders in patients with multiple sclerosis (MS). The objective of this paper is to compare the effects of sensory integration balance training against conventional rehabilitation on balance disorders, the level of balance confidence perceived, quality of life, fatigue, frequency of falls, and sensory integration processing on a large sample of patients with MS. This single-blind, randomized, controlled trial involved 80 outpatients with MS (EDSS: 1.5-6.0) and subjective symptoms of balance disorders. The experimental group (n = 39) received specific training to improve central integration of afferent sensory inputs; the control group (n = 41) received conventional rehabilitation (15 treatment sessions of 50 minutes each). Before, after treatment, and at one month post-treatment, patients were evaluated by a blinded rater using the Berg Balance Scale (BBS), Activities-specific Balance Confidence Scale (ABC), Multiple Sclerosis Quality of Life-54, Fatigue Severity Scale (FSS), number of falls and the Sensory Organization Balance Test (SOT). The experimental training program produced greater improvements than the control group training on the BBS (p < 0.001), the FSS (p < 0.002), number of falls (p = 0.002) and SOT (p < 0.05). Specific training to improve central integration of afferent sensory inputs may ameliorate balance disorders in patients with MS. Clinical Trial Registration (NCT01040117). © The Author(s), 2015.

Different Patterns of Walking and Postprandial Triglycerides in Older Women

PubMed Central

KASHIWABARA, KYOKO; KIDOKORO, TETSUHIRO; YANAOKA, TAKUMA; BURNS, STEPHEN F.; STENSEL, DAVID J.; MIYASHITA, MASASHI

2018-01-01

ABSTRACT Purpose Although a single bout of continuous exercise (≥30 min) reduces postprandial triglyceride (TG), little evidence is available regarding the effect of multiple short (≤10 min) bouts of exercise on postprandial TG in individuals at increased risk for cardiovascular diseases. This study compared the effects of different patterns of walking on postprandial TG in postmenopausal, older women with hypertriglyceridemia. Methods Twelve inactive women (mean age ± SD, 71 ± 5 yr) with hypertriglyceridemia (fasting TG ≥1.70 mmol·L−1) completed three, 1-d laboratory-based trials in a random order: 1) control, 2) continuous walking, and 3) multiple short bouts of walking. On the control trial, participants sat in a chair for 8 h. For the walking trials, participants walked briskly in either one 30-min bout in the morning (0900–0930 h) or twenty 90-s bouts over 8 h. Except for walking, both exercise trials mimicked the control trial. In each trial, participants consumed a standardized breakfast (0800 h) and lunch (1100 h). Venous blood samples were collected in the fasted state and at 2, 4, 6, and 8 h after breakfast. Results The serum TG incremental area under the curve was 35% and 33% lower on the continuous and multiple short bouts of walking trials than that on the control trial (8.2 ± 3.1 vs 8.5 ± 5.4 vs 12.7 ± 5.8 mmol per 8 h·L−1, respectively; main effect of trial: effect size = 0.459, P = 0.001). Conclusions Accumulating walking in short bouts limits postprandial TG in at-risk, inactive older women with fasting hypertriglyceridemia. PMID:28857839

Testing the implementation and sustainment facilitation (ISF) strategy as an effective adjunct to the Addiction Technology Transfer Center (ATTC) strategy: study protocol for a cluster randomized trial.

PubMed

Garner, Bryan R; Zehner, Mark; Roosa, Mathew R; Martino, Steve; Gotham, Heather J; Ball, Elizabeth L; Stilen, Patricia; Speck, Kathryn; Vandersloot, Denna; Rieckmann, Traci R; Chaple, Michael; Martin, Erika G; Kaiser, David; Ford, James H

2017-11-17

Improving the extent to which evidence-based practices (EBPs)-treatments that have been empirically shown to be efficacious or effective-are integrated within routine practice is a well-documented challenge across numerous areas of health. In 2014, the National Institute on Drug Abuse funded a type 2 effectiveness-implementation hybrid trial titled the substance abuse treatment to HIV Care (SAT2HIV) Project. Aim 1 of the SAT2HIV Project tests the effectiveness of a motivational interviewing-based brief intervention (MIBI) for substance use as an adjunct to usual care within AIDS service organizations (ASOs) as part of its MIBI Experiment. Aim 2 of the SAT2HIV Project tests the effectiveness of implementation and sustainment facilitation (ISF) as an adjunct to the Addiction Technology Transfer Center (ATTC) model for training staff in motivational interviewing as part of its ISF Experiment. The current paper describes the study protocol for the ISF Experiment. Using a cluster randomized design, case management and leadership staff from 39 ASOs across the United States were randomized to receive either the ATTC strategy (control condition) or the ATTC + ISF strategy (experimental condition). The ATTC strategy is staff-focused and includes 10 discrete strategies (e.g., provide centralized technical assistance, conduct educational meetings, provide ongoing consultation). The ISF strategy is organization-focused and includes seven discrete strategies (e.g., use an implementation advisor, organize implementation team meetings, conduct cyclical small tests of change). Building upon the exploration-preparation-implementation-sustainment (EPIS) framework, the effectiveness of the ISF strategy is examined via three staff-level measures: (1) time-to-proficiency (i.e., preparation phase outcome), (2) implementation effectiveness (i.e., implementation phase outcome), and (3) level of sustainment (i.e., sustainment phase outcome). Although not without limitations, the ISF experiment has several strengths: a highly rigorous design (randomized, hypothesis-driven), high-need setting (ASOs), large sample size (39 ASOs), large geographic representation (23 states and the District of Columbia), and testing along multiple phases of the EPIS continuum (preparation, implementation, and sustainment). Thus, study findings will significantly improve generalizable knowledge regarding the best preparation, implementation, and sustainment strategies for advancing EBPs along the EPIS continuum. Moreover, increasing ASO's capacity to address substance use may improve the HIV Care Continuum. Trial registration ClinicalTrials.gov: NCT03120598.

Multidisciplinary approaches to managing osteoarthritis in multiple joint sites: a systematic review.

PubMed

Finney, Andrew; Healey, Emma; Jordan, Joanne L; Ryan, Sarah; Dziedzic, Krysia S

2016-07-08

The National Institute for Health and Care Excellence's Osteoarthritis (OA) guidelines recommended that future research should consider the benefits of combination therapies in people with OA across multiple joint sites. However, the clinical effectiveness of such approaches to OA management is unknown. This systematic review therefore aimed to identify the clinical and cost effectiveness of multidisciplinary approaches targeting multiple joint sites for OA in primary care. A systematic review of randomised controlled trials. Computerised bibliographic databases were searched (MEDLINE, EMBASE, CINAHL, PsychINFO, BNI, HBE, HMIC, AMED, Web of Science and Cochrane). Studies were included if they met the following criteria; a randomised controlled trial (RCT), a primary care population with OA across at least two different peripheral joint sites (multiple joint sites), and interventions undertaken by at least two different health disciplines (multidisciplinary). The Cochrane 'Risk of Bias' tool and PEDro were used for quality assessment of eligible studies. Clinical and cost effectiveness was determined by extracting and examining self-reported outcomes for pain, function, quality of life (QoL) and health care utilisation. The date range for the search was from database inception until August 2015. The search identified 1148 individual titles of which four were included in the review. A narrative review was conducted due to the heterogeneity of the included trials. Each of the four trials used either educational or exercise interventions facilitated by a range of different health disciplines. Moderate clinical benefits on pain, function and QoL were reported across the studies. The beneficial effects of exercise generally decreased over time within all studies. Two studies were able to show a reduction in healthcare utilisation due to a reduction in visits to a physiotherapist or a reduction in x-rays and orthopaedic referrals. The intervention that showed the most promise used educational interventions delivered by GPs with reinforcement by practice nurses. There are currently very few studies that target multidisciplinary approaches suitable for OA across multiple joint sites, in primary care. A more consistent approach to outcome measurement in future studies of this nature should be considered to allow for better comparison.

A generalized concept of power helped to choose optimal endpoints in clinical trials.

PubMed

Borm, George F; van der Wilt, Gert J; Kremer, Jan A M; Zielhuis, Gerhard A

2007-04-01

A clinical trial may have multiple objectives. Sometimes the results for several parameters may need to be significant or meet certain other criteria. In such cases, it is important to evaluate the probability that all these objectives will be met, rather than the probability that each will be met. The purpose of this article is to introduce a definition of power that is tailored to handle this situation and that is helpful for the design of such trials. We introduce a generalized concept of power. It can handle complex situations, for example, in which there is a logical combination of partial objectives. These may be formulated not only in terms of statistical tests and of confidence intervals, but also in nonstatistical terms, such as "selecting the optimal by dose." The power of a trial was calculated for various objectives and combinations of objectives. The generalized concept of power may lead to power calculations that closely match the objectives of the trial and contribute to choosing more efficient endpoints and designs.

Use of surveillance data to identify target populations for Staphylococcus aureus vaccines and prevent surgical site infections: A pilot study

PubMed Central

Gustin, Marie-Paule; Giard, Marine; Bénet, Thomas; Vanhems, Philippe

2015-01-01

The development of anti-staphylococcal vaccines is nowadays a priority to prevent surgical site infections (SSI). The objective of the present study was to identify a potential target population by assessing surveillance data on surgery patients for possible anti-staphylococcal vaccine administration. Individuals at high risk of SSI by Staphylococcus aureus (SA) were targeted by the French SSI Surveillance Network in south-eastern France between 2008 and 2011. Among 238,470 patients, those undergoing primary total hip replacement appeared to be an interesting and healthy enough population for anti-staphylococcal vaccine testing. These male patients, subjected to multiple procedures and with American Society of Anesthesiologists score >2, had a probability of SA SSI about 21 times higher than females with no severe systemic disease and no multiple procedures. Our study indicates that surveillance data on SSI might be an interesting epidemiological source for planning vaccine trials to prevent nosocomial infections. PMID:25668663

Analysis of Classical Time-Trial Performance and Technique-Specific Physiological Determinants in Elite Female Cross-Country Skiers.

PubMed

Sandbakk, Øyvind; Losnegard, Thomas; Skattebo, Øyvind; Hegge, Ann M; Tønnessen, Espen; Kocbach, Jan

2016-01-01

The present study investigated the contribution of performance on uphill, flat, and downhill sections to overall performance in an international 10-km classical time-trial in elite female cross-country skiers, as well as the relationships between performance on snow and laboratory-measured physiological variables in the double poling (DP) and diagonal (DIA) techniques. Ten elite female cross-country skiers were continuously measured by a global positioning system device during an international 10-km cross-country skiing time-trial in the classical technique. One month prior to the race, all skiers performed a 5-min submaximal and 3-min self-paced performance test while roller skiing on a treadmill, both in the DP and DIA techniques. The time spent on uphill (r = 0.98) and flat (r = 0.91) sections of the race correlated most strongly with the overall 10-km performance (both p < 0.05). Approximately 56% of the racing time was spent uphill, and stepwise multiple regression revealed that uphill time explained 95.5% of the variance in overall performance (p < 0.001). Distance covered during the 3-min roller-skiing test and body-mass normalized peak oxygen uptake (VO2peak) in both techniques showed the strongest correlations with overall time-trial performance (r = 0.66-0.78), with DP capacity tending to have greatest impact on the flat and DIA capacity on uphill terrain (all p < 0.05). Our present findings reveal that the time spent uphill most strongly determine classical time-trial performance, and that the major portion of the performance differences among elite female cross-country skiers can be explained by variations in technique-specific aerobic power.

Analysis of Classical Time-Trial Performance and Technique-Specific Physiological Determinants in Elite Female Cross-Country Skiers

PubMed Central

Sandbakk, Øyvind; Losnegard, Thomas; Skattebo, Øyvind; Hegge, Ann M.; Tønnessen, Espen; Kocbach, Jan

2016-01-01

The present study investigated the contribution of performance on uphill, flat, and downhill sections to overall performance in an international 10-km classical time-trial in elite female cross-country skiers, as well as the relationships between performance on snow and laboratory-measured physiological variables in the double poling (DP) and diagonal (DIA) techniques. Ten elite female cross-country skiers were continuously measured by a global positioning system device during an international 10-km cross-country skiing time-trial in the classical technique. One month prior to the race, all skiers performed a 5-min submaximal and 3-min self-paced performance test while roller skiing on a treadmill, both in the DP and DIA techniques. The time spent on uphill (r = 0.98) and flat (r = 0.91) sections of the race correlated most strongly with the overall 10-km performance (both p < 0.05). Approximately 56% of the racing time was spent uphill, and stepwise multiple regression revealed that uphill time explained 95.5% of the variance in overall performance (p < 0.001). Distance covered during the 3-min roller-skiing test and body-mass normalized peak oxygen uptake (VO2peak) in both techniques showed the strongest correlations with overall time-trial performance (r = 0.66–0.78), with DP capacity tending to have greatest impact on the flat and DIA capacity on uphill terrain (all p < 0.05). Our present findings reveal that the time spent uphill most strongly determine classical time-trial performance, and that the major portion of the performance differences among elite female cross-country skiers can be explained by variations in technique-specific aerobic power. PMID:27536245

Testing the 4Rs and 2Ss Multiple Family Group intervention: study protocol for a randomized controlled trial.

PubMed

Acri, Mary; Hamovitch, Emily; Mini, Maria; Garay, Elene; Connolly, Claire; McKay, Mary

2017-12-04

Oppositional defiant disorder (ODD) is a major mental health concern and highly prevalent among children living in poverty-impacted communities. Despite that treatments for ODD are among the most effective, few children living in poverty receive these services due to substantial barriers to access, as well as difficulties in the uptake and sustained adoption of evidence-based practices (EBPs) in community settings. The purpose of this study is to examine implementation processes that impact uptake of an evidence-based practice for childhood ODD, and the impact of a Clinic Implementation Team (CIT)-driven structured adaptation to enhance its fit within the public mental health clinic setting. This study, a Hybrid Type II effectiveness-implementation research trial, blends clinical effectiveness and implementation research methods to examine the impact of the 4Rs and 2Ss Multiple Family Group (MFG) intervention, family level mediators of child outcomes, clinic/provider-level mediators of implementation, and the impact of CITs on uptake and long-term utilization of this model. All New York City public outpatient mental health clinics have been invited to participate. A sampling procedure that included randomization at the agency level and a sub-study to examine the impact of clinic choice upon outcomes yielded a distribution of clinics across three study conditions. Quantitative data measuring child outcomes, organizational factors and implementation fidelity will be collected from caregivers and providers at baseline, 8, and 16 weeks from baseline, and 6 months from treatment completion. The expected participation is 134 clinics, 268 providers, and 2688 caregiver/child dyads. We will use mediation analysis with a multi-level Structural Equation Modeling (SEM) (MSEM including family level variables, provider variables, and clinic variables), as well as mediation tests to examine study hypotheses. The aim of the study is to generate knowledge about effectiveness and mediating factors in the treatment of ODDs in children in the context of family functioning, and to propose an innovative approach to the adaptation and implementation of new treatment interventions within clinic settings. The proposed CIT adaptation and implementation model has the potential to enhance implementation and sustainability, and ultimately increase the extent to which effective interventions are available and can impact children and families in need of services for serious behavior problems. ClinicalTrials.gov, ID: NCT02715414 . Registered on 3 March 2016.

Clinical trials transparency and the Trial and Experimental Studies Transparency (TEST) act.

PubMed

Logvinov, Ilana

2014-03-01

Clinical trial research is the cornerstone for successful advancement of medicine that provides hope for millions of people in the future. Full transparency in clinical trials may allow independent investigators to evaluate study designs, perform additional analysis of data, and potentially eliminate duplicate studies. Current regulatory system and publishers rely on investigators and pharmaceutical industries for complete and accurate reporting of results from completed clinical trials. Legislation seems to be the only way to enforce mandatory disclosure of results. The Trial and Experimental Studies Transparency (TEST) Act of 2012 was introduced to the legislators in the United States to promote greater transparency in research industry. Public safety and advancement of science are the driving forces for the proposed policy change. The TEST Act may benefit the society and researchers; however, there are major concerns with participants' privacy and intellectual property protection. Copyright © 2014 Elsevier Inc. All rights reserved.

A Randomized Controlled Trial Evaluating Efficacy of Promoting a Home-Based HIV Self-Testing with Online Counseling on Increasing HIV Testing Among Men Who Have Sex with Men.

PubMed

Wang, Zixin; Lau, Joseph T F; Ip, Mary; Ho, Shara P Y; Mo, Phoenix K H; Latkin, Carl; Ma, Yee Ling; Kim, Yoona

2018-01-01

We developed an innovative home-based HIV self-testing (HIVST) service that included mailing of a free HIVST kit, and providing online real-time instructions and pre-test/post-test counseling (HIVST-OIC). The present parallel-group and non-blinded randomized controlled trial was conducted to evaluate the efficacy of promoting HIVST-OIC in increasing HIV testing rate among 430 men who have sex with men (MSM), with access to online live-chat applications in Hong Kong. At month 6, as compared to the control group, the intervention group reported significantly higher prevalence of HIV testing of any type (89.8 vs. 50.7%; relative risk (RR): 1.77; p < 0.001). Among those who have taken up any HIV testing in the last six months, significant between-group difference was found in multiple male sex partnerships (34.2 vs. 47.7%, RR: 0.72; p = 0.021). HIVST-OIC has a strong potential in increasing prevalence of HIV testing and reducing sexual risk behaviors. Implementation research is warranted.

P-value interpretation and alpha allocation in clinical trials.

PubMed

Moyé, L A

1998-08-01

Although much value has been placed on type I error event probabilities in clinical trials, interpretive difficulties often arise that are directly related to clinical trial complexity. Deviations of the trial execution from its protocol, the presence of multiple treatment arms, and the inclusion of multiple end points complicate the interpretation of an experiment's reported alpha level. The purpose of this manuscript is to formulate the discussion of P values (and power for studies showing no significant differences) on the basis of the event whose relative frequency they represent. Experimental discordance (discrepancies between the protocol's directives and the experiment's execution) is linked to difficulty in alpha and beta interpretation. Mild experimental discordance leads to an acceptable adjustment for alpha or beta, while severe discordance results in their corruption. Finally, guidelines are provided for allocating type I error among a collection of end points in a prospectively designed, randomized controlled clinical trial. When considering secondary end point inclusion in clinical trials, investigators should increase the sample size to preserve the type I error rates at acceptable levels.

The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants.

PubMed

Meah, Farah A; DiMeglio, Linda A; Greenbaum, Carla J; Blum, Janice S; Sosenko, Jay M; Pugliese, Alberto; Geyer, Susan; Xu, Ping; Evans-Molina, Carmella

2016-06-01

The incidence of type 1 diabetes is increasing at a rate of 3-5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk. To test this in the TrialNet Pathway to Prevention (PTP) cohort, we analysed the influence of BMI, weight status and insulin resistance on progression from single to multiple islet autoantibodies (Aab) and progression from normoglycaemia to diabetes. HOMA1-IR was used to estimate insulin resistance in Aab-positive PTP participants. Cox proportional hazards models were used to evaluate the effects of BMI, BMI percentile (BMI%), weight status and HOMA1-IR on the progression of autoimmunity or the development of diabetes. Data from 1,310 single and 1,897 multiple Aab-positive PTP participants were included. We found no significant relationships between BMI, BMI%, weight status or HOMA1-IR and the progression from one to multiple Aabs. Similarly, among all Aab-positive participants, no significant relationships were found between BMI, weight status or HOMA1-IR and progression to diabetes. Diabetes risk was modestly increased with increasing BMI% among the entire cohort, in obese participants 13-20 years of age and with increasing HOMA1-IR in adult Aab-positive participants. Analysis of the accelerator hypothesis in the TrialNet PTP cohort does not suggest a broad influence of metabolic variables on diabetes risk. Efforts to identify other potentially modifiable environmental factors should continue.

Multiple imputation methods for bivariate outcomes in cluster randomised trials.

PubMed

DiazOrdaz, K; Kenward, M G; Gomes, M; Grieve, R

2016-09-10

Missing observations are common in cluster randomised trials. The problem is exacerbated when modelling bivariate outcomes jointly, as the proportion of complete cases is often considerably smaller than the proportion having either of the outcomes fully observed. Approaches taken to handling such missing data include the following: complete case analysis, single-level multiple imputation that ignores the clustering, multiple imputation with a fixed effect for each cluster and multilevel multiple imputation. We contrasted the alternative approaches to handling missing data in a cost-effectiveness analysis that uses data from a cluster randomised trial to evaluate an exercise intervention for care home residents. We then conducted a simulation study to assess the performance of these approaches on bivariate continuous outcomes, in terms of confidence interval coverage and empirical bias in the estimated treatment effects. Missing-at-random clustered data scenarios were simulated following a full-factorial design. Across all the missing data mechanisms considered, the multiple imputation methods provided estimators with negligible bias, while complete case analysis resulted in biased treatment effect estimates in scenarios where the randomised treatment arm was associated with missingness. Confidence interval coverage was generally in excess of nominal levels (up to 99.8%) following fixed-effects multiple imputation and too low following single-level multiple imputation. Multilevel multiple imputation led to coverage levels of approximately 95% throughout. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

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

ERIC Educational Resources Information Center

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,…

LapTrain: multi-modality training curriculum for laparoscopic cholecystectomy-results of a randomized controlled trial.

PubMed

Kowalewski, K F; Garrow, C R; Proctor, T; Preukschas, A A; Friedrich, M; Müller, P C; Kenngott, H G; Fischer, L; Müller-Stich, B P; Nickel, F

2018-02-12

Multiple training modalities for laparoscopy have different advantages, but little research has been conducted on the benefit of a training program that includes multiple different training methods compared to one method only. This study aimed to evaluate benefits of a combined multi-modality training program for surgical residents. Laparoscopic cholecystectomy (LC) was performed on a porcine liver as the pre-test. Randomization was stratified for experience to the multi-modality Training group (12 h of training on Virtual Reality (VR) and box trainer) or Control group (no training). The post-test consisted of a VR LC and porcine LC. Performance was rated with the Global Operative Assessment of Laparoscopic Skills (GOALS) score by blinded experts. Training (n = 33) and Control (n = 31) were similar in the pre-test (GOALS: 13.7 ± 3.4 vs. 14.7 ± 2.6; p = 0.198; operation time 57.0 ± 18.1 vs. 63.4 ± 17.5 min; p = 0.191). In the post-test porcine LC, Training had improved GOALS scores (+ 2.84 ± 2.85 points, p < 0.001), while Control did not (+ 0.55 ± 2.34 points, p = 0.154). Operation time in the post-test was shorter for Training vs. Control (40.0 ± 17.0 vs. 55.0 ± 22.2 min; p = 0.012). Junior residents improved GOALS scores to the level of senior residents (pre-test: 13.7 ± 2.7 vs. 18.3 ± 2.9; p = 0.010; post-test: 15.5 ± 3.4 vs. 18.8 ± 3.8; p = 0.120) but senior residents remained faster (50.1 ± 20.6 vs. 25.0 ± 1.9 min; p < 0.001). No differences were found between groups on the post-test VR trainer. Structured multi-modality training is beneficial for novices to improve basics and overcome the initial learning curve in laparoscopy as well as to decrease operation time for LCs in different stages of experience. Future studies should evaluate multi-modality training in comparison with single modalities. German Clinical Trials Register DRKS00011040.

Addressing the targeting range of the ABILHAND-56 in relapsing-remitting multiple sclerosis: A mixed methods psychometric study.

PubMed

Cleanthous, Sophie; Strzok, Sara; Pompilus, Farrah; Cano, Stefan; Marquis, Patrick; Cohan, Stanley; Goldman, Myla D; Kresa-Reahl, Kiren; Petrillo, Jennifer; Castrillo-Viguera, Carmen; Cadavid, Diego; Chen, Shih-Yin

2018-01-01

ABILHAND, a manual ability patient-reported outcome instrument originally developed for stroke patients, has been used in multiple sclerosis clinical trials; however, psychometric analyses indicated the measure's limited measurement range and precision in higher-functioning multiple sclerosis patients. The purpose of this study was to identify candidate items to expand the measurement range of the ABILHAND-56, thus improving its ability to detect differences in manual ability in higher-functioning multiple sclerosis patients. A step-wise mixed methods design strategy was used, comprising two waves of patient interviews, a combination of qualitative (concept elicitation and cognitive debriefing) and quantitative (Rasch measurement theory) analytic techniques, and consultation interviews with three clinical neurologists specializing in multiple sclerosis. Original ABILHAND was well understood in this context of use. Eighty-two new manual ability concepts were identified. Draft supplementary items were generated and refined with patient and neurologist input. Rasch measurement theory psychometric analysis indicated supplementary items improved targeting to higher-functioning multiple sclerosis patients and measurement precision. The final pool of Early Multiple Sclerosis Manual Ability items comprises 20 items. The synthesis of qualitative and quantitative methods used in this study improves the ABILHAND content validity to more effectively identify manual ability changes in early multiple sclerosis and potentially help determine treatment effect in higher-functioning patients in clinical trials.

Social Cognition Psychometric Evaluation: Results of the Final Validation Study.

PubMed

Pinkham, Amy E; Harvey, Philip D; Penn, David L

2018-06-06

Social cognition is increasingly recognized as an important treatment target in schizophrenia; however, the dearth of well-validated measures that are suitable for use in clinical trials remains a significant limitation. The Social Cognition Psychometric Evaluation (SCOPE) study addresses this need by systematically evaluating the psychometric properties of promising measures. In this final phase of SCOPE, eight new or modified tasks were evaluated. Stable outpatients with schizophrenia (n = 218) and healthy controls (n = 154) completed the battery at baseline and 2-4 weeks later across three sites. Tasks included the Bell Lysaker Emotion Recognition Task (BLERT), Penn Emotion Recognition Task (ER-40), Reading the Mind in the Eyes Task (Eyes), The Awareness of Social Inferences Test (TASIT), Hinting Task, Mini Profile of Nonverbal Sensitivity (MiniPONS), Social Attribution Task-Multiple Choice (SAT-MC), and Intentionality Bias Task (IBT). BLERT and ER-40 modifications included response time and confidence ratings. The Eyes task was modified to include definitions of terms and TASIT to include response time. Hinting was scored with more stringent criteria. MiniPONS, SAT-MC, and IBT were new to this phase. Tasks were evaluated on (1) test-retest reliability, (2) utility as a repeated measure, (3) relationship to functional outcome, (4) practicality and tolerability, (5) sensitivity to group differences, and (6) internal consistency. Hinting, BLERT, and ER-40 showed the strongest psychometric properties and are recommended for use in clinical trials. Eyes, TASIT, and IBT showed somewhat weaker psychometric properties and require further study. MiniPONS and SAT-MC showed poorer psychometric properties that suggest caution for their use in clinical trials.

Evaluation of a novel supplement to reduce blood glucose through the use of a modified oral glucose tolerance test

PubMed Central

Smith, Adam J; Giunta, Brian; Shytle, R Douglas; Blum, James M

2011-01-01

Elevated blood glucose is a major component in metabolic syndrome and pre-diabetes, sometimes leading to type 2 diabetes mellitus (DM II). Additionally, it may lead to adipose deposits when left elevated for long periods. The epidemiology of DM II clearly shows that uncontrolled blood glucose levels leads to many adverse conditions including heart disease, retinal damage, renal failure, erectile dysfunction, and other significant medical conditions. Here we conducted a single-center, prospective, randomized, double-blinded, placebo-controlled, parallel-group- clinical trial of a nutraceutical supplement vs. placebo to measure its glucose lowering effect in generally healthy adults before and after a simple sugars meal. Subjects reported to the test clinic on multiple days to receive placebo or treatment, a simple sugars meal, as well as pre-and postprandial blood glucose measurement (modified oral glucose tolerance test). Each subject served as his or her own control and thirty-one subjects completed the trial with at least one oral glucose tolerance test (OGTT) with the nutraceutical supplement and placebo. Statistical analysis revealed the nutraceutical supplement significantly lowered postprandial glucose levels by 36% and 59% at 45 and 60 minutes, respectively (***P<.001). The study was limited by its composition of primarily overweight females. Future studies will be required over longer periods in more heterogeneous and larger groups to determine the long-term effect of this supplement on blood glucose levels in terms of prophylaxis or treatment for DM II. PMID:21416063

Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation

PubMed Central

Dallaku, Kastriot; Shakur, Haleema; Edwards, Phil; Beaumont, Danielle; Roberts, Ian; Huque, Sumaya; Delius, Maria; Mansmann, Ulrich

2017-01-01

Background. Postpartum haemorrhage (PPH) is a potentially life-threatening complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin. Methods. WOMAN ETAPlaT is a sub-study of the World Maternal Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate® tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma. Results. Recruitment to WOMAN ETAPlaT started on 04 November 2013 and closed on 13 January 2015, during this time  188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data.   Conclusion. The data from this study will provide evidence for the effect of TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Trial registration: ClinicalTrials.gov Identifier: NCT00872469; ISRCTN76912190 PMID:28413832

The Social Attribution Task-Multiple Choice (SAT-MC): A Psychometric and Equivalence Study of an Alternate Form

PubMed Central

Johannesen, Jason K.; Lurie, Jessica B.; Fiszdon, Joanna M.; Bell, Morris D.

2013-01-01

The Social Attribution Task-Multiple Choice (SAT-MC) uses a 64-second video of geometric shapes set in motion to portray themes of social relatedness and intentions. Considered a test of “Theory of Mind,” the SAT-MC assesses implicit social attribution formation while reducing verbal and basic cognitive demands required of other common measures. We present a comparability analysis of the SAT-MC and the new SAT-MC-II, an alternate form created for repeat testing, in a university sample (n = 92). Score distributions and patterns of association with external validation measures were nearly identical between the two forms, with convergent and discriminant validity supported by association with affect recognition ability and lack of association with basic visual reasoning. Internal consistency of the SAT-MC-II was superior (alpha = .81) to the SAT-MC (alpha = .56). Results support the use of SAT-MC and new SAT-MC-II as equivalent test forms. Demonstrating relatively higher association to social cognitive than basic cognitive abilities, the SAT-MC may provide enhanced sensitivity as an outcome measure of social cognitive intervention trials. PMID:23864984

Development and Psychometric Evaluation of the HPV Clinical Trial Survey for Parents (CTSP‐HPV) Using Traditional Survey Development Methods and Community Engagement Principles

PubMed Central

Wallston, Kenneth A.; Wilkins, Consuelo H.; Hull, Pamela C.; Miller, Stephania T.

2015-01-01

Abstract Objective This study describes the development and psychometric evaluation of HPV Clinical Trial Survey for Parents with Children Aged 9 to 15 (CTSP‐HPV) using traditional instrument development methods and community engagement principles. Methods An expert panel and parental input informed survey content and parents recommended study design changes (e.g., flyer wording). A convenience sample of 256 parents completed the final survey measuring parental willingness to consent to HPV clinical trial (CT) participation and other factors hypothesized to influence willingness (e.g., HPV vaccine benefits). Cronbach's a, Spearman correlations, and multiple linear regression were used to estimate internal consistency, convergent and discriminant validity, and predictively validity, respectively. Results Internal reliability was confirmed for all scales (a ≥ 0.70.). Parental willingness was positively associated (p < 0.05) with trust in medical researchers, adolescent CT knowledge, HPV vaccine benefits, advantages of adolescent CTs (r range 0.33–0.42), supporting convergent validity. Moderate discriminant construct validity was also demonstrated. Regression results indicate reasonable predictive validity with the six scales accounting for 31% of the variance in parents’ willingness. Conclusions This instrument can inform interventions based on factors that influence parental willingness, which may lead to the eventual increase in trial participation. Further psychometric testing is warranted. PMID:26530324

Closing the Loop on Deep Brain Stimulation for Treatment-Resistant Depression

PubMed Central

Widge, Alik S.; Malone, Donald A.; Dougherty, Darin D.

2018-01-01

Major depressive episodes are the largest cause of psychiatric disability, and can often resist treatment with medication and psychotherapy. Advances in the understanding of the neural circuit basis of depression, combined with the success of deep brain stimulation (DBS) in movement disorders, spurred several groups to test DBS for treatment-resistant depression. Multiple brain sites have now been stimulated in open-label and blinded studies. Initial open-label results were dramatic, but follow-on controlled/blinded clinical trials produced inconsistent results, with both successes and failures to meet endpoints. Data from follow-on studies suggest that this is because DBS in these trials was not targeted to achieve physiologic responses. We review these results within a technology-lifecycle framework, in which these early trial “failures” are a natural consequence of over-enthusiasm for an immature technology. That framework predicts that from this “valley of disillusionment,” DBS may be nearing a “slope of enlightenment.” Specifically, by combining recent mechanistic insights and the maturing technology of brain-computer interfaces (BCI), the next generation of trials will be better able to target pathophysiology. Key to that will be the development of closed-loop systems that semi-autonomously alter stimulation strategies based on a patient's individual phenotype. Such next-generation DBS approaches hold great promise for improving psychiatric care. PMID:29618967

Optimizing Educational Video through Comparative Trials in Clinical Environments

ERIC Educational Resources Information Center

Aronson, Ian David; Plass, Jan L.; Bania, Theodore C.

2012-01-01

Although video is increasingly used in public health education, studies generally do not implement randomized trials of multiple video segments in clinical environments. Therefore, the specific configurations of educational videos that will have the greatest impact on outcome measures ranging from increased knowledge of important public health…

Forensic analysis of explosives using isotope ratio mass spectrometry (IRMS)--part 2: forensic inter-laboratory trial: bulk carbon and nitrogen stable isotopes in a range of chemical compounds (Australia and New Zealand).

PubMed

Benson, Sarah J; Lennard, Christopher J; Maynard, Philip; Hill, David M; Andrew, Anita S; Neal, Ken; Stuart-Williams, Hilary; Hope, Janet; Walker, G Stewart; Roux, Claude

2010-01-01

Comparability of data over time and between laboratories is a key issue for consideration in the development of global databases, and more broadly for quality assurance in general. One mechanism that can be utilized for evaluating traceability is an inter-laboratory trial. This paper addresses an inter-laboratory trial conducted across a number of Australian and New Zealand isotope ratio mass spectrometry (IRMS) laboratories. The main objective of this trial was to determine whether IRMS laboratories in these countries would record comparable values for the distributed samples. Four carbon containing and four nitrogen containing compounds were distributed to seven laboratories in Australia and one in New Zealand. The laboratories were requested to analyze the samples using their standard procedures. The data from each laboratory was evaluated collectively using International Standard ISO 13528 (Statistical methods for use in proficiency testing by inter-laboratory comparisons). "Warning signals" were raised against one participant in this trial. "Action signals" requiring corrective action were raised against four participants. These participants reviewed the data and possible sources for the discrepancies. This inter-laboratory trial was successful in providing an initial snapshot of the potential for traceability between the participating laboratories. The statistical methods described in this article could be used as a model for others needing to evaluate stable isotope results derived from multiple laboratories, e.g., inter-laboratory trials/proficiency testing. Ongoing trials will be conducted to improve traceability across the Australian and New Zealand IRMS community.

Multiple Testing in the Context of Gene Discovery in Sickle Cell Disease Using Genome-Wide Association Studies.

PubMed

Kuo, Kevin H M

2017-01-01

The issue of multiple testing, also termed multiplicity, is ubiquitous in studies where multiple hypotheses are tested simultaneously. Genome-wide association study (GWAS), a type of genetic association study that has gained popularity in the past decade, is most susceptible to the issue of multiple testing. Different methodologies have been employed to address the issue of multiple testing in GWAS. The purpose of the review is to examine the methodologies employed in dealing with multiple testing in the context of gene discovery using GWAS in sickle cell disease complications.

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial.

PubMed

Moe, Sharon M; Abdalla, Safa; Chertow, Glenn M; Parfrey, Patrick S; Block, Geoffrey A; Correa-Rotter, Ricardo; Floege, Jürgen; Herzog, Charles A; London, Gerard M; Mahaffey, Kenneth W; Wheeler, David C; Dehmel, Bastian; Goodman, William G; Drüeke, Tilman B

2015-06-01

Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%. Copyright © 2015 by the American Society of Nephrology.

Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials.

PubMed

Glass, Jonathan D; Hertzberg, Vicki S; Boulis, Nicholas M; Riley, Jonathan; Federici, Thais; Polak, Meraida; Bordeau, Jane; Fournier, Christina; Johe, Karl; Hazel, Tom; Cudkowicz, Merit; Atassi, Nazem; Borges, Lawrence F; Rutkove, Seward B; Duell, Jayna; Patil, Parag G; Goutman, Stephen A; Feldman, Eva L

2016-07-26

To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale-Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression. Intraspinal transplantation of human spinal cord-derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers. This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues. © 2016 American Academy of Neurology.

A Systems Approach to Designing Effective Clinical Trials Using Simulations

PubMed Central

Fusaro, Vincent A.; Patil, Prasad; Chi, Chih-Lin; Contant, Charles F.; Tonellato, Peter J.

2013-01-01

Background Pharmacogenetics in warfarin clinical trials have failed to show a significant benefit compared to standard clinical therapy. This study demonstrates a computational framework to systematically evaluate pre-clinical trial design of target population, pharmacogenetic algorithms, and dosing protocols to optimize primary outcomes. Methods and Results We programmatically created an end-to-end framework that systematically evaluates warfarin clinical trial designs. The framework includes options to create a patient population, multiple dosing strategies including genetic-based and non-genetic clinical-based, multiple dose adjustment protocols, pharmacokinetic/pharmacodynamics (PK/PD) modeling and international normalization ratio (INR) prediction, as well as various types of outcome measures. We validated the framework by conducting 1,000 simulations of the CoumaGen clinical trial primary endpoints. The simulation predicted a mean time in therapeutic range (TTR) of 70.6% and 72.2% (P = 0.47) in the standard and pharmacogenetic arms, respectively. Then, we evaluated another dosing protocol under the same original conditions and found a significant difference in TTR between the pharmacogenetic and standard arm (78.8% vs. 73.8%; P = 0.0065), respectively. Conclusions We demonstrate that this simulation framework is useful in the pre-clinical assessment phase to study and evaluate design options and provide evidence to optimize the clinical trial for patient efficacy and reduced risk. PMID:23261867

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

Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial.

PubMed

Poewe, Werner; Seppi, Klaus; Fitzer-Attas, Cheryl J; Wenning, Gregor K; Gilman, Sid; Low, Phillip A; Giladi, Nir; Barone, Paolo; Sampaio, Cristina; Eyal, Eli; Rascol, Olivier

2015-02-01

Multiple system atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of multiple system atrophy. We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with multiple systemic atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant multiple system atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7·2 (SE 1·2) total UMSARS units versus 7·8 (1·1) units in those in the placebo group. This treatment difference of -0·60 (95% CI -3·68 to 2·47; p=0·70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]). In this population of patients with the parkinsonian variant of multiple system atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for multiple system atrophy to detect clinically significant decline, even in individuals with early disease. Teva Pharmaceutical Industries and H Lundbeck A/S. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of a Mobile Web App on Kidney Transplant Candidates' Knowledge About Increased Risk Donor Kidneys: A Randomized Controlled Trial.

PubMed

Gordon, Elisa J; Sohn, Min-Woong; Chang, Chih-Hung; McNatt, Gwen; Vera, Karina; Beauvais, Nicole; Warren, Emily; Mannon, Roslyn B; Ison, Michael G

2017-06-01

Kidney transplant candidates (KTCs) must provide informed consent to accept kidneys from increased risk donors (IRD), but poorly understand them. We conducted a multisite, randomized controlled trial to evaluate the efficacy of a mobile Web application, Inform Me, for increasing knowledge about IRDs. Kidney transplant candidates undergoing transplant evaluation at 2 transplant centers were randomized to use Inform Me after routine transplant education (intervention) or routine transplant education alone (control). Computer adaptive learning method reinforced learning by embedding educational material, and initial (test 1) and additional test questions (test 2) into each chapter. Knowledge (primary outcome) was assessed in person after education (tests 1 and 2), and 1 week later by telephone (test 3). Controls did not receive test 2. Willingness to accept an IRD kidney (secondary outcome) was assessed after tests 1 and 3. Linear regression test 1 knowledge scores were used to test the significance of Inform Me exposure after controlling for covariates. Multiple imputation was used for intention-to-treat analysis. Two hundred eighty-eight KTCs participated. Intervention participants had higher test 1 knowledge scores (mean difference, 6.61; 95% confidence interval [95% CI], 5.37-7.86) than control participants, representing a 44% higher score than control participants' scores. Intervention participants' knowledge scores increased with educational reinforcement (test 2) compared with control arm test 1 scores (mean difference, 9.50; 95% CI, 8.27-10.73). After 1 week, intervention participants' knowledge remained greater than controls' knowledge (mean difference, 3.63; 95% CI, 2.49-4.78) (test 3). Willingness to accept an IRD kidney did not differ between study arms at tests 1 and 3. Inform Me use was associated with greater KTC knowledge about IRD kidneys above routine transplant education alone.

Speech Perception by 6- to 8-Month-Olds in the Presence of Distracting Sounds

ERIC Educational Resources Information Center

Polka, Linda; Rvachew, Susan; Molnar, Monika

2008-01-01

The role of selective attention in infant phonetic perception was examined using a distraction masker paradigm. We compared perception of /bu/ versus /gu/ in 6- to 8-month-olds using a visual fixation procedure. Infants were habituated to multiple natural productions of 1 syllable type and then presented 4 test trials (old-new-old-new). Perception…

A combined intervention of zinc, multiple micronutrients, and albendazole does not ameliorate environmental enteric dysfunction or stunting in rural Malawian children in a double-blind randomized controlled trial

USDA-ARS?s Scientific Manuscript database

Environmental enteric dysfunction (EED) and linear growth stunting affect many rural agrarian children in the developing world and contribute to the persistently high rates of stunting that are observed worldwide. Effective interventions to consistently ameliorate EED are lacking. We tested whether ...

Using Multiple Types of Studies in Systematic Reviews of Health Care Interventions – A Systematic Review

PubMed Central

Peinemann, Frank; Tushabe, Doreen Allen; Kleijnen, Jos

2013-01-01

Background A systematic review may evaluate different aspects of a health care intervention. To accommodate the evaluation of various research questions, the inclusion of more than one study design may be necessary. One aim of this study is to find and describe articles on methodological issues concerning the incorporation of multiple types of study designs in systematic reviews on health care interventions. Another aim is to evaluate methods studies that have assessed whether reported effects differ by study types. Methods and Findings We searched PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Methodology Register on 31 March 2012 and identified 42 articles that reported on the integration of single or multiple study designs in systematic reviews. We summarized the contents of the articles qualitatively and assessed theoretical and empirical evidence. We found that many examples of reviews incorporating multiple types of studies exist and that every study design can serve a specific purpose. The clinical questions of a systematic review determine the types of design that are necessary or sufficient to provide the best possible answers. In a second independent search, we identified 49 studies, 31 systematic reviews and 18 trials that compared the effect sizes between randomized and nonrandomized controlled trials, which were statistically different in 35%, and not different in 53%. Twelve percent of studies reported both, different and non-different effect sizes. Conclusions Different study designs addressing the same question yielded varying results, with differences in about half of all examples. The risk of presenting uncertain results without knowing for sure the direction and magnitude of the effect holds true for both nonrandomized and randomized controlled trials. The integration of multiple study designs in systematic reviews is required if patients should be informed on the many facets of patient relevant issues of health care interventions. PMID:24416098

The recolonization hypothesis in a full-mouth or multiple-session treatment protocol: a blinded, randomized clinical trial.

PubMed

Zijnge, Vincent; Meijer, Henriette F; Lie, Mady-Ann; Tromp, Jan A H; Degener, John E; Harmsen, Hermie J M; Abbas, Frank

2010-06-01

To test recolonization of periodontal lesions after full-mouth scaling and root planing (FM-SRP) or multiple session-SRP (MS-SRP) in a randomized clinical trial and whether FM-SRP and MS-SRP result in different clinical outcomes. Thirty-nine subjects were randomly assigned to FM-SRP or MS-SRP groups. At baseline and after 3 months, probing pocket depth (PPD), plaque index (PlI) and bleeding on probing (BoP) were recorded. At baseline, immediately after treatment, after 1, 2, 7, 14 and 90 days, paper point samples from a single site from the maxillary right quadrant were collected for microbiological analysis of five putative pathogens by polymerase chain reaction. FM-SRP and MS-SRP resulted in significant reductions in PPD, BoP and PlI and the overall detection frequencies of the five species after 3 months without significant differences between treatments. Compared with MS-SRP, FM-SRP resulted in less recolonization of the five species, significantly for Treponema denticola, in the tested sites. FM-SRP and MS-SRP result in overall clinically and microbiologically comparable outcomes where recolonization of periodontal lesions may be better prevented by FM-SRP.

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

Oral paracetamol versus oral ibuprofen for closure of haemodynamically significant patent ductus arteriosus in preterm neonates (<32 weeks): a blinded, randomised, active-controlled, non-inferiority trial

PubMed Central

Kumar, Ashutosh; Sundaram, Venkataseshan; Yadav, Rahul; Oleti, Tejo Pratap; Murki, Srinivas; Krishna, Arun; Sundaram, Mangalabharathi; Saini, Shiv Sajan; Dutta, Sourabh

2017-01-01

Introduction Haemodynamically significant patent ductus arteriosus (hsPDA) is a common cause of mortality and morbidity in preterm infants. Existing medical therapies with ibuprofen or indomethacin have multiple adverse effects. Hence, an alternative drug like paracetamol given through oral route with less side effects need to be tested in an appropriate study design with least risk of bias to arrive at a conclusion. Methods and analysis Multisite, randomised, active-controlled, non-inferiority design. The primary objective is to study the efficacy of oral paracetamol for closure of hsPDA in comparison to oral ibuprofen in preterm neonates of <32 weeks’ gestation. Randomisation web-based and allocation concealment would be done; the treating team, investigators, outcome assessors and laboratory personnel would be blinded from the intervention. Echocardiography images would be coded for independent review. Closure of PDA by the end of last dose of study drug or earlier would be the study endpoint. A sample size of 196 neonates would be enrolled with a non-inferiority margin of 15%. Both intention-to-treat and per-protocol analysis will be done to assess the effect of contamination and protocol violations in the primary outcome. Ethics and dissemination The trial would follow international code of ethics for clinical trial. The trial protocol was approved by the Institute Ethics Committee of all three centres. All serious adverse events would be reported in detail to the Institute Ethics Committee. A written informed consent would be obtained from one of the parents. No plan has been made for dissemination. Trial registration number CTRI/2014/08/004805. PMID:29637155

Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement†‡.

PubMed

Legro, Richard S; Wu, Xiaoke; Barnhart, Kurt T; Farquhar, Cynthia; Fauser, Bart C J M; Mol, Ben

2014-10-10

Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor on the harms, including maternal risks during pregnancy and fetal anomalies. This is complicated by the multiple participants in infertility trials which may include a woman (mother), a man (father), and result in a third individual if successful, their offspring (child), who is also the desired outcome of treatment. The primary outcome of interest and many adverse events occur after cessation of infertility treatment and during pregnancy and the puerperium, which create a unique burden of follow-up for clinical trial investigators and participants. In 2013, because of the inconsistencies in trial reporting and the unique aspects of infertility trials not adequately addressed by existing Consolidated Standards of Reporting Trials (CONSORT) statements, we convened a consensus conference in Harbin, China, with the aim of planning modifications to the CONSORT checklist to improve the quality of reporting of clinical trials testing infertility treatment. The consensus group recommended that the preferred primary outcome of all infertility trials is live birth (defined as any delivery of a live infant ≥20 weeks gestations) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles). In addition, harms to all participants should be systematically collected and reported, including during the intervention, any resulting pregnancy, and during the neonatal period. Routine information should be collected and reported on both male and female participants in the trial. We propose to track the change in quality that these guidelines may produce in published trials testing infertility treatments. Our ultimate goal is to increase the transparency of benefits and risks of infertility treatments to provide better medical care to affected individuals and couples. © The Author 2014. 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.

Virtual patients in the acquisition of clinical reasoning skills: does presentation mode matter? A quasi-randomized controlled trial.

PubMed

Schubach, Fabian; Goos, Matthias; Fabry, Götz; Vach, Werner; Boeker, Martin

2017-09-15

The objective of this study is to compare two different instructional methods in the curricular use of computerized virtual patients in undergraduate medical education. We aim to investigate whether using many short and focused cases - the key feature principle - is more effective for the learning of clinical reasoning skills than using few long and systematic cases. We conducted a quasi-randomized, non-blinded, controlled parallel-group intervention trial in a large medical school in Southwestern Germany. During two seminar sessions, fourth- and fifth-year medical students (n = 56) worked on the differential diagnosis of the acute abdomen. The educational tool - virtual patients - was the same, but the instructional method differed: In one trial arm, students worked on multiple short cases, with the instruction being focused only on important elements ("key feature arm", n = 30). In the other trial arm, students worked on few long cases, with the instruction being comprehensive and systematic ("systematic arm", n = 26). The overall training time was the same in both arms. The students' clinical reasoning capacity was measured by a specifically developed instrument, a script concordance test. Their motivation and the perceived effectiveness of the instruction were assessed using a structured evaluation questionnaire. Upon completion of the script concordance test with a reference score of 80 points and a standard deviation of 5 for experts, students in the key feature arm attained a mean of 57.4 points (95% confidence interval: 50.9-63.9), and in the systematic arm, 62.7 points (57.2-68.2), with Cohen's d at 0.337. The difference is statistically non-significant (p = 0.214). In the evaluation survey, students in the key feature arm indicated that they experienced more time pressure and perceived the material as more difficult. In this study powered for a medium effect, we could not provide empirical evidence for the hypothesis that a key feature-based instruction on multiple short cases is superior to a systematic instruction on few long cases in the curricular implementation of virtual patients. The results of the evaluation survey suggest that learners should be given enough time to work through case examples, and that caution should be taken to prevent cognitive overload.

Dietary approaches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls Elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: study protocol for a randomized controlled trial.

PubMed

Wahls, Terry; Scott, Maria O; Alshare, Zaidoon; Rubenstein, Linda; Darling, Warren; Carr, Lucas; Smith, Karen; Chenard, Catherine A; LaRocca, Nicholas; Snetselaar, Linda

2018-06-04

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS) and contributes to diminishing quality of life. Although currently available interventions have had limited success in relieving MS-related fatigue, clinically significant reductions in perceived fatigue severity have been reported in a multimodal intervention pilot study that included a Paleolithic diet in addition to stress reduction, exercise, and electrical muscle stimulation. An optimal dietary approach to reducing MS-related fatigue has not been identified. To establish the specific effects of diet on MS symptoms, this study focuses on diet only instead of the previously tested multimodal intervention by comparing the effectiveness of two dietary patterns for the treatment of MS-related fatigue. The purpose of this study is to determine the impact of a modified Paleolithic and low saturated fat diet on perceived fatigue (primary outcome), cognitive and motor symptoms, and quality of life in persons with relapsing-remitting multiple sclerosis (RRMS). This 36-week randomized clinical trial consists of three 12-week periods during which assessments of perceived fatigue, quality of life, motor and cognitive function, physical activity and sleep, diet quality, and social support for eating will be collected. The three 12-week periods will consist of the following: 1. Participants continue eating their usual diet. 2. Participants will be randomized to a modified Paleolithic or low saturated fat diet for the intervention period. Participants will receive support from a registered dietitian (RD) through in-person coaching, telephone calls, and emails. 3. Participants will continue the study diet for an additional 12 weeks with minimal RD support to assess the ability of the participants to sustain the study diet on their own. Because fatigue is one of the most common and disabling symptoms of MS, effective management and reduction of MS-related fatigue has the potential to increase quality of life in this population. The results of this study will add to the evidence base for providing dietary recommendations to treat MS-related fatigue and other symptoms associated with this disease. ClinicalTrials.gov, NCT02914964 . Registered on 24 August 2016.

The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis.

PubMed

Morgan, Gareth J; Gregory, Walter M; Davies, Faith E; Bell, Sue E; Szubert, Alexander J; Brown, Julia M; Coy, Nuria N; Cook, Gordon; Russell, Nigel H; Rudin, Claudius; Roddie, Huw; Drayson, Mark T; Owen, Roger G; Ross, Fiona M; Jackson, Graham H; Child, J Anthony

2012-01-05

Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

Participant recruitment into a randomised controlled trial of exercise therapy for people with multiple sclerosis.

PubMed

Carter, Anouska; Humphreys, Liam; Snowdon, Nicky; Sharrack, Basil; Daley, Amanda; Petty, Jane; Woodroofe, Nicola; Saxton, John

2015-10-15

The success of a clinical trial is often dependant on whether recruitment targets can be met in the required time frame. Despite an increase in research into the benefits of exercise in people with multiple sclerosis (PwMS), no trial has reported detailed data on effective recruitment strategies for large-scale randomised controlled trials. The main purpose of this report is to provide a detailed outline of recruitment strategies, rates and estimated costs in the Exercise Intervention for Multiple Sclerosis (ExIMS) trial to identify best practices for future trials involving multiple sclerosis (MS) patient recruitment. The ExIMS researchers recruited 120 PwMS to participate in a 12-week exercise intervention. Participants were randomly allocated to either exercise or usual-care control groups. Participants were sedentary, aged 18-65 years and had Expanded Disability Status Scale scores of 1.0-6.5. Recruitment strategies included attendance at MS outpatient clinics, consultant mail-out and trial awareness-raising activities. A total of 120 participants were recruited over the course of 34 months. To achieve this target, 369 potentially eligible and interested participants were identified. A total of 60 % of participants were recruited via MS clinics, 29.2 % from consultant mail-outs and 10.8 % through trial awareness. The randomisation yields were 33.2 %, 31.0 % and 68.4 % for MS clinic, consultant mail-outs and trial awareness strategies, respectively. The main reason for ineligibility was being too active (69.2 %), whilst for eligible participants the most common reason for non-participation was the need to travel to the study site (15.8 %). Recruitment via consultant mail-out was the most cost-effective strategy, with MS clinics being the most time-consuming and most costly. To reach recruitment targets in a timely fashion, a variety of methods were employed. Although consultant mail-outs were the most cost-effective recruitment strategy, use of this method alone would not have allowed us to obtain the predetermined number of participants in the required time period, thus leading to costly extensions of the project or failure to reach the number of participants required for sufficient statistical power. Thus, a multifaceted approach to recruitment is recommended for future trials. International Standard Randomised Controlled Trial Registry number: ISRCTN41541516 ; date registered: 5 February 2009.

Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.

PubMed

Paltamaa, Jaana; Sjögren, Tuulikki; Peurala, Sinikka H; Heinonen, Ari

2012-10-01

To determine the effects of physiotherapy interventions on balance in people with multiple sclerosis. A systematic literature search was conducted in Medline, Cinahl, Embase, PEDro, both electronically and by manual search up to March 2011. Randomized controlled trials of physiotherapy interventions in people with multiple sclerosis, with an outcome measure linked to the International Classification of Functioning, Disability and Health (ICF) category of "Changing and maintaining body position", were included. The quality of studies was determined by the van Tulder criteria. Meta-analyses were performed in subgroups according to the intervention. After screening 233 full-text papers, 11 studies were included in a qualitative analysis and 7 in a meta-analysis. The methodological quality of the studies ranged from poor to moderate. Low evidence was found for the efficacy of specific balance exercises, physical therapy based on an individualized problem-solving approach, and resistance and aerobic exercises on improving balance among ambulatory people with multiple sclerosis. These findings indicate small, but significant, effects of physiotherapy on balance in people with multiple sclerosis who have a mild to moderate level of disability. However, evidence for severely disabled people is lacking, and further research is needed.

Multiple-level stakeholder engagement in malaria clinical trials: addressing the challenges of conducting clinical research in resource-limited settings.

PubMed

Mtove, George; Kimani, Joshua; Kisinza, William; Makenga, Geofrey; Mangesho, Peter; Duparc, Stephan; Nakalembe, Miriam; Phiri, Kamija S; Orrico, Russell; Rojo, Ricardo; Vandenbroucke, Pol

2018-03-22

Multinational clinical trials are logistically complex and require close coordination between various stakeholders. They must comply with global clinical standards and are accountable to multiple regulatory and ethical bodies. In resource-limited settings, it is challenging to understand how to apply global clinical standards to international, national, and local factors in clinical trials, making multiple-level stakeholder engagement an important element in the successful conduct of these clinical trials. During the planning and implementation of a large multinational clinical trial for intermittent preventive treatment of malaria in pregnancy in resource-limited areas of sub-Saharan Africa, we encountered numerous challenges, which required implementation of a range of engagement measures to ensure compliance with global clinical and regulatory standards. These challenges included coordination with ongoing global malaria efforts, heterogeneity in national regulatory structures, sub-optimal healthcare infrastructure, local practices and beliefs, and perspectives that view healthcare providers with undue trust or suspicion. In addition to engagement with international bodies, such as the World Health Organization, the Malaria in Pregnancy Consortium, the Steve Biko Centre for Bioethics, and the London School of Hygiene and Tropical Medicine, in order to address the challenges just described, Pfizer Inc. and Medicines for Malaria Venture (the "Sponsoring Entities" for these studies) and investigators liaised with national- and district-level stakeholders such as health ministers and regional/local community health workers. Community engagement measures undertaken by investigators included local meetings with community leaders to explain the research aims and answer questions and concerns voiced by the community. The investigators also engaged with family members of prospective trial participants in order to be sensitive to local practices and beliefs. Engagement with key stakeholders at international and national levels enabled the Sponsoring Entities to address challenges by aligning the study design with the requirements of health and regulatory agencies and to understand and address healthcare infrastructure needs prior to trial initiation. Local stakeholder engagement, including community members, study participants, and family enabled the investigators to address challenges by ensuring that study design and conduct were adapted to local considerations and ensuring accurate information about the study aims was shared with the public. ClinicalTrials.gov, ID: NCT01103063 . Registered on 7 April 2010.

Respiratory viruses among children with non-severe community-acquired pneumonia: A prospective cohort study.

PubMed

Nascimento-Carvalho, Amanda C; Vilas-Boas, Ana-Luisa; Fontoura, Maria-Socorro H; Vuorinen, Tytti; Nascimento-Carvalho, Cristiana M

2018-06-06

Community-acquired pneumonia (CAP) causes a major burden to the health care system among children under-5 years worldwide. Information on respiratory viruses in non-severe CAP cases is scarce. To estimate the frequency of respiratory viruses among non-severe CAP cases. Prospective study conducted in Salvador, Brazil. Out of 820 children aged 2-59 months with non-severe CAP diagnosed by pediatricians (respiratory complaints and radiographic pulmonary infiltrate/consolidation), recruited in a clinical trial (ClinicalTrials.gov Identifier NCT01200706), nasopharyngeal aspirate samples were obtained from 774 (94.4%) patients and tested for 16 respiratory viruses by PCRs. Viruses were detected in 708 (91.5%; 95%CI: 89.3-93.3) cases, out of which 491 (69.4%; 95%CI: 65.9-72.7) harbored multiple viruses. Rhinovirus (46.1%; 95%CI: 42.6-49.6), adenovirus (38.4%; 95%CI: 35.0-41.8), and enterovirus (26.5%; 95%CI: 23.5-29.7) were the most commonly found viruses. The most frequent combination comprised rhinovirus plus adenovirus. No difference was found in the frequency of RSVA (16.1% vs. 14.6%; P = 0.6), RSVB (10.9% vs. 13.2%; P = 0.4) influenza (Flu) A (6.3% vs. 5.1%; P = 0.5), FluB (4.5% vs. 1.8%; P = 0.09), parainfluenza virus (PIV) 1 (5.1% vs. 2.8%; P = 0.2), or PIV4 (7.7% vs. 4.1%; P = 0.08), when children with multiple or sole virus detection were compared. Conversely, rhinovirus, adenovirus, enterovirus, bocavirus, PIV2, PIV3, metapneumovirus, coronavirus OC43, NL63, 229E were significantly more frequent among cases with multiple virus detection. Respiratory viruses were detected in over 90% of the cases, out of which 70% had multiple viruses. Several viruses are more commonly found in multiple virus detection whereas other viruses are similarly found in sole and in multiple virus detection. Copyright © 2018 Elsevier B.V. All rights reserved.

BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation–Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group

PubMed Central

Alsop, Kathryn; Fereday, Sian; Meldrum, Cliff; deFazio, Anna; Emmanuel, Catherine; George, Joshy; Dobrovic, Alexander; Birrer, Michael J.; Webb, Penelope M.; Stewart, Colin; Friedlander, Michael; Fox, Stephen; Bowtell, David; Mitchell, Gillian

2012-01-01

Purpose The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. Patients and Methods Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. Results Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. Conclusion BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history. PMID:22711857

Self-directed learning can outperform direct instruction in the course of a modern German medical curriculum - results of a mixed methods trial.

PubMed

Peine, Arne; Kabino, Klaus; Spreckelsen, Cord

2016-06-03

Modernised medical curricula in Germany (so called "reformed study programs") rely increasingly on alternative self-instructed learning forms such as e-learning and curriculum-guided self-study. However, there is a lack of evidence that these methods can outperform conventional teaching methods such as lectures and seminars. This study was conducted in order to compare extant traditional teaching methods with new instruction forms in terms of learning effect and student satisfaction. In a randomised trial, 244 students of medicine in their third academic year were assigned to one of four study branches representing self-instructed learning forms (e-learning and curriculum-based self-study) and instructed learning forms (lectures and seminars). All groups participated in their respective learning module with standardised materials and instructions. Learning effect was measured with pre-test and post-test multiple-choice questionnaires. Student satisfaction and learning style were examined via self-assessment. Of 244 initial participants, 223 completed the respective module and were included in the study. In the pre-test, the groups showed relatively homogenous scores. All students showed notable improvements compared with the pre-test results. Participants in the non-self-instructed learning groups reached scores of 14.71 (seminar) and 14.37 (lecture), while the groups of self-instructed learners reached higher scores with 17.23 (e-learning) and 15.81 (self-study). All groups improved significantly (p < .001) in the post-test regarding their self-assessment, led by the e-learning group, whose self-assessment improved by 2.36. The study shows that students in modern study curricula learn better through modern self-instructed methods than through conventional methods. These methods should be used more, as they also show good levels of student acceptance and higher scores in personal self-assessment of knowledge.

Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial.

PubMed

Grieve, Stuart M; Korgaonkar, Mayuresh S; Etkin, Amit; Harris, Anthony; Koslow, Stephen H; Wisniewski, Stephen; Schatzberg, Alan F; Nemeroff, Charles B; Gordon, Evian; Williams, Leanne M

2013-07-18

Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD. The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n=102), test the findings in the second half, and then extend the analyses to the total sample. International Study to Predict Optimized Treatment--in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849.

Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics.

PubMed

Collongues, Nicolas; Patte-Mensah, Christine; De Seze, Jérôme; Mensah-Nyagan, Ayikoe-Guy; Derfuss, Tobias

2018-06-01

Neuroprotection and remyelination are two unmet needs in the treatment of multiple sclerosis (MS). Therapeutic potential has been identified with sexual hormones, supported in women by a decrease in MS activity during the pregnancy, in men by a greater severity of symptoms and a faster progression than in women. Areas covered: The therapeutic effect of testosterone and estrogens is reviewed. Both hormones have demonstrated an anti-inflammatory effect. Testosterone has an effect in protecting neurons in culture against glutamate-induced toxicity and oxidative stress, and stimulates myelin formation and regeneration mediated through the neural androgen receptor. In experimental autoimmune encephalomyelitis model, estrogens significantly decrease inflammation in the central nervous system via ERα, while its action on ERβ leads to myelin and axon reparation. Estriol therapy in two phase 2 trials showed a decrease in clinical disease activity and inflammatory parameters in MRI. However, evidence of a therapeutic effect of testosterone is scarce. Expert commentary: Phase 3 trials with estriol as an add-on supplementation are now mandatory. Testosterone is another candidate to be tested in phase 2 trials. These hormones should be considered as an adjunctive therapy. New validated tools are needed to assess their effect on neuroprotection and remyelination.

The role of calcium in the prevention of cardiovascular disease--a review of observational studies and randomized clinical trials.

PubMed

Rautiainen, Susanne; Wang, Lu; Manson, JoAnn E; Sesso, Howard D

2013-11-01

Calcium is a mineral that is important for bone health and has also been suggested to play a role in the prevention of cardiovascular disease (CVD). Lately, the potential effects of both inadequate and excessive calcium intake have received growing attention. In this review, we summarize the evidence from experimental, epidemiologic, and clinical studies investigating the role of calcium intake, either from the diet or from supplements, as well as blood concentrations, in relation to the risk of CVD in adults. In vitro and in vivo laboratory studies suggest that calcium may be involved in CVD development through multiple pathways, including blood cholesterol, insulin secretion and sensitivity, vasodilation, inflammatory profile, thrombosis, obesity, and vascular calcification. Several prospective epidemiologic studies have examined how dietary or supplemental calcium intake is associated with CVD incidence or mortality in middle-aged and older adults, and the results are inconsistent. Prospective studies investigating blood concentrations of calcium have also reported mixed results. However, changes in blood calcium concentrations may reflect a disturbed calcium phosphate balance, which is associated with increased risk of CVD. To date there is no randomized clinical trial that has been designed specifically to test the effect of calcium supplementation on the risk of CVD as the primary end point. Existing trials have performed secondary analyses, and most of them have been conducted among postmenopausal women. These trials suggest that calcium supplementation has no effect on CVD development; however, they do not allow a definitive conclusion to be drawn. The average daily intake of calcium is low in many populations; however, the evidence for a potential role of dietary or supplemental calcium in the prevention of CVD remains insufficient and inconclusive. Only large-scale randomized trials designed to investigate the effects of calcium supplementation on CVD events as the primary end point, as well as short-term trials investigating the effect on coronary biomarkers, can provide a definitive answer.

A cluster randomised controlled trial of a comprehensive accreditation intervention to reduce alcohol consumption at community sports clubs: study protocol

PubMed Central

Wolfenden, Luke; Rowland, Bosco C; Tindall, Jennifer; Gillham, Karen E; McElduff, Patrick; Rogerson, John C; Wiggers, John H

2011-01-01

Introduction Excessive alcohol consumption is responsible for considerable harm from chronic disease and injury. Within most developed countries, members of sporting clubs consume alcohol at levels above that of communities generally. Despite the potential benefits of interventions to address alcohol consumption in sporting clubs, there have been no randomised controlled trials to test the effectiveness of these interventions. The aim of this study is to examine the effectiveness of a comprehensive accreditation intervention with community football clubs (Rugby League, Rugby Union, soccer/association football and Australian Rules football) in reducing excessive alcohol consumption by club members. Methods and analysis The study will be conducted in New South Wales, Australia, and employ a cluster randomised controlled trial design. Half of the football clubs recruited to the trial will be randomised to receive an intervention implemented over two and a half winter sporting seasons. The intervention is based on social ecology theory and is comprehensive in nature, containing multiple elements designed to decrease the supply of alcohol to intoxicated members, cease the provision of cheap and free alcohol, increase the availability and cost-attractiveness of non-alcoholic and low-alcoholic beverages, remove high alcohol drinks and cease drinking games. The intervention utilises a three-tiered accreditation framework designed to motivate intervention implementation. Football clubs in the control group will receive printed materials on topics unrelated to alcohol. Outcome data will be collected pre- and postintervention through cross-sectional telephone surveys of club members. The primary outcome measure will be alcohol consumption by club members at the club, assessed using a graduated frequency index and a seven day diary. Ethics and dissemination The study was approved by The University of Newcastle Human Research Ethics Committee (reference: H-2008-0432). Study findings will be disseminated widely through peer-reviewed publications and conference presentations. Trial registration number Australian New Zealand Clinical Trials Registry: ACTRN12609000224224. PMID:22021867

Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes

PubMed Central

Greenbaum, Carla J.; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg; Battelino, Tadej; Haastert, Burkhard; Ludvigsson, Johnny; Pozzilli, Paolo; Lachin, John M.; Kolb, Hubert

2008-01-01

OBJECTIVE—β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS—In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. RESULTS—Among individuals with up to 4 years’ duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R2 = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. CONCLUSIONS—The MMTT is preferred for the assessment of β-cell function in therapeutic trials in type 1 diabetes. PMID:18628574

Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

PubMed

Greenbaum, Carla J; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg; Battelino, Tadej; Haastert, Burkhard; Ludvigsson, Johnny; Pozzilli, Paolo; Lachin, John M; Kolb, Hubert

2008-10-01

Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R(2) = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. The MMTT is preferred for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

A multiple imputation strategy for sequential multiple assignment randomized trials

PubMed Central

Shortreed, Susan M.; Laber, Eric; Stroup, T. Scott; Pineau, Joelle; Murphy, Susan A.

2014-01-01

Sequential multiple assignment randomized trials (SMARTs) are increasingly being used to inform clinical and intervention science. In a SMART, each patient is repeatedly randomized over time. Each randomization occurs at a critical decision point in the treatment course. These critical decision points often correspond to milestones in the disease process or other changes in a patient’s health status. Thus, the timing and number of randomizations may vary across patients and depend on evolving patient-specific information. This presents unique challenges when analyzing data from a SMART in the presence of missing data. This paper presents the first comprehensive discussion of missing data issues typical of SMART studies: we describe five specific challenges, and propose a flexible imputation strategy to facilitate valid statistical estimation and inference using incomplete data from a SMART. To illustrate these contributions, we consider data from the Clinical Antipsychotic Trial of Intervention and Effectiveness (CATIE), one of the most well-known SMARTs to date. PMID:24919867

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study

PubMed Central

Snowdon, Claire; Elbourne, Diana R; Garcia, Jo; Campbell, Marion K; Entwistle, Vikki A; Francis, David; Grant, Adrian M; Knight, Rosemary C; McDonald, Alison M; Roberts, Ian

2006-01-01

Background Securing and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS). Methods In-depth semi-structured telephone interviews were conducted in 2003–04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti. Results The data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA. Conclusion This study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research. PMID:17184521

Web-based versus in-person methods for training lay community health advisors to implement health promotion workshops: participant outcomes from a cluster-randomized trial.

PubMed

Holt, Cheryl L; Tagai, Erin K; Santos, Sherie Lou Zara; Scheirer, Mary Ann; Bowie, Janice; Haider, Muhiuddin; Slade, Jimmie

2018-06-28

Project HEAL (Health through Early Awareness and Learning) is an implementation trial that compared two methods of training lay peer community health advisors (CHAs)-in-person ("Traditional") versus web-based ("Technology")-to conduct a series of three evidence-based cancer educational workshops in African American churches. This analysis reports on participant outcomes from Project HEAL. Fifteen churches were randomized to the two CHA training methods and the intervention impact was examined over 24 months. This study was conducted in Prince George's County, MD, and enrolled 375 church members age 40-75. Participants reported on knowledge and screening behaviors for breast, prostate, and colorectal cancer. Overall, cancer knowledge in all areas increased during the study period (p < .001). There were significant increases in digital rectal exam (p < .05), fecal occult blood test (p < .001), and colonoscopy (p < .01) at 24 months; however, this did not differ by study group. Mammography maintenance (56% overall) was evidenced by women reporting multiple mammograms within the study period. Participants attending all three workshops were more likely to report a fecal occult blood test or colonoscopy at 24 months (p < .05) than those who attended only one. These findings suggest that lay individuals can receive web-based training to successfully implement an evidence-based health promotion intervention that results in participant-level outcomes comparable with (a) people trained using the traditional classroom method and (b) previous efficacy trials. Findings have implications for resources and use of technology to increase widespread dissemination of evidence-based health promotion interventions through training lay persons in community settings.

Testing the effects of brief intervention in primary care for problem drug use in a randomized controlled trial: rationale, design, and methods.

PubMed

Krupski, Antoinette; Joesch, Jutta M; Dunn, Chris; Donovan, Dennis; Bumgardner, Kristin; Lord, Sarah Peregrine; Ries, Richard; Roy-Byrne, Peter

2012-12-14

A substantial body of research has established the effectiveness of brief interventions for problem alcohol use. Following these studies, national dissemination projects of screening, brief intervention (BI), and referral to treatment (SBIRT) for alcohol and drugs have been implemented on a widespread scale in multiple states despite little existing evidence for the impact of BI on drug use for non-treatment seekers. This article describes the design of a study testing the impact of SBIRT on individuals with drug problems, its contributions to the existing literature, and its potential to inform drug policy. The study is a randomized controlled trial of an SBIRT intervention carried out in a primary care setting within a safety net system of care. Approximately 1,000 individuals presenting for scheduled medical care at one of seven designated primary care clinics who endorse problematic drug use when screened are randomized in a 1:1 ratio to BI versus enhanced care as usual (ECAU). Individuals in both groups are reassessed at 3, 6, 9, and 12 months after baseline. Self-reported drug use and other psychosocial measures collected at each data point are supplemented by urine analysis and public health-related data from administrative databases. This study will contribute to the existing literature by providing evidence for the impact of BI on problem drug use based on a broad range of measures including self-reported drug use, urine analysis, admission to drug abuse treatment, and changes in utilization and costs of health care services, arrests, and death with the intent of informing policy and program planning for problem drug use at the local, state, and national levels. ClinicalTrials.gov NCT00877331.

A systematic review of nonsurgical single-visit versus multiple-visit endodontic treatment

PubMed Central

Wong, Amy WY; Zhang, Chengfei; Chu, Chun-hung

2014-01-01

Conventional endodontic treatment used to require multiple visits, but some clinicians have suggested that single-visit treatment is superior. Single-visit endodontic treatment and multiple-visit endodontic treatment both have their advantages and disadvantages. This paper is a literature review of the research on nonsurgical single-visit versus multiple-visit endodontic treatment. The PubMed database was searched using the keywords (endodontic treatment OR endodontic therapy OR root canal treatment OR root canal therapy) AND (single-visit OR one-visit OR 1-visit). Review papers, case reports, data studies, and irrelevant reports were excluded, and 47 papers on clinical trials were reviewed. The studies generally had small sample sizes, and the endodontic procedures varied among the studies. Meta-analysis on the selected studies was performed, and the results showed that the postoperative complications of the single-visit and multiple-visit endodontic treatment were similar. Furthermore, neither single-visit endodontic treatment nor multiple-visit treatment had superior results over the other in terms of healing or success rate. Results of limited studies on disinfection of the root canals using low-energy laser photodynamic therapy is inconclusive, and further studies are necessary to show whether laser should be used in endodontic treatment. This review also found that that neither single-visit endodontic treatment nor multiple-visit treatment could guarantee the absence of postoperative pain. Since the study design of many studies displayed significant limitation and the materials and equipment used in endodontic treatment have dramatically changed in recent years, prospective randomized clinical trials are needed to further verify the postoperative pain and success rates of single-visit versus multiple-visit endodontic treatment. PMID:24855389

Self-arranged exposure for overcoming blood-injection-injury Phobia: a case study

PubMed Central

Pitkin, Michelle R.; Malouff, John M.

2014-01-01

Blood-injection-injury (BII) phobia is both common and dangerous, because it can lead to avoidance of medical procedures for diagnosis and treatment. It also tends to prevent individuals from donating blood for use in the healthcare of others. BII phobia often has an unusual characteristic for a type of phobia – fainting. The typical treatment for BII phobia involves teaching the client how to avoid fainting and staging multiple gradual-exposure trials for the client. In this case report, an adult with the phobia obtained initial, mostly written, guidance from a psychologist, arranged her own applied muscle-tension practice sessions to learn how to keep from fainting, created her own fear hierarchy, and staged exposure trials herself, ending years of avoidance of blood withdrawal. By the end of the trials, she was able to give blood for a medical test and to donate blood for the first time in her life and to work as a volunteer at a blood-donation center. The results provide the first evidence that adults with BII phobia can end the phobia by arranging their own sessions of applied-tension practice and gradual self-exposure. The results suggest a new option for treating specific phobias in general with some adults: initial professional guidance followed by self-arranged gradual-exposure trials. PMID:25750809

Achieving high-value cardiac imaging: challenges and opportunities.

PubMed

Wiener, David H

2014-01-01

Cardiac imaging is under intense scrutiny as a contributor to health care costs, with multiple initiatives under way to reduce and eliminate inappropriate testing. Appropriate use criteria are valuable guides to selecting imaging studies but until recently have focused on the test rather than the patient. Patient-centered means are needed to define the true value of imaging for patients in specific clinical situations. This article provides a definition of high-value cardiac imaging. A paradigm to judge the efficacy of echocardiography in the absence of randomized controlled trials is presented. Candidate clinical scenarios are proposed in which echocardiography constitutes high-value imaging, as well as stratagems to increase the likelihood that high-value cardiac imaging takes place in those circumstances. Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

A feasibility study and pilot randomised trial of a tailored prevention program to reduce falls in older people with mild dementia

PubMed Central

2013-01-01

Background People with dementia have a disproportionately high rate of falls and fractures and poorer outcomes, yet there is currently no evidence to guide falls prevention in this population. Methods A randomised trial design was used to test feasibility of study components and acceptability of a home hazard reduction and balance and strength exercise fall prevention program. The program was tailored to participant’s individual cognitive levels and implemented as a carer-supported intervention. Feasibility of recruitment, retention and implementation of intervention were recorded through observation and documented in field notes. Adherence, carer burden and use of task simplification strategies were also monitored. Outcome measures, collected at 12 weeks included physiological, fear of falling, cognitive and functional measures. Results Recruitment was achievable but may be more challenging in a multisite trial. Twenty two dyads of persons with mild dementia and their carers were randomised to intervention or usual care control group. Of 38 dyads referred to the study, there was a high rate of willingness to participate, with 6 (16%) declining and 10 (26%) not meeting inclusion criteria. The intervention was well received by participants and carers and adherence to both program components was very good. All participants implemented some home safety recommendations (range 19-80%) with half implementing 50% or more. At the end of 12 weeks, 72% of the intervention group were exercising. Both the rate of falling and the risk of a fall were lower in the intervention group but these findings were not significant (RR= 0.50 (95% CI 0.11-2.19). There were no differences in physiological outcome measures between the control and intervention groups. However results were influenced by the small study size and incomplete data primarily in the intervention group at follow up. Conclusions The pilot study was feasible and acceptable to people with mild dementia and their carers. The lessons learnt included: recruitment for a larger trial will require multiple approaches; home safety recommendations should provide a greater emphasis on environmental use compared with behavioural change; strategies to ensure an adequate dosage of exercise should be further explored. We recommend that intervention delivery incorporate an integrated occupational therapy and physiotherapy approach and that carers be provided with an individualised session to enhance dementia-specific skills in management and communication. A refined intervention should be tested in a randomised trial with an adequately powered sample size. Trial registration Australia and New Zealand Clinical Trials Registry 126100001049066 PMID:24004682

Multi-EMR Structured Data Entry Form: User-Acceptance Testing of a Prototype.

PubMed

Zavar, Abbas; Keshavjee, Karim

2017-01-01

Capturing standardized data from multiple EMRs at the point of care is highly desirable for a variety of uses, including quality improvement programs, multi-centered clinical trials and clinical decision support. In this paper, we describe the design, development and user acceptance testing of a prototype web-based form (the Form) that can integrate with multiple EMRs. We used the validated UTAUT questionnaire to assess the likelihood of uptake of the Form into clinical practice. The Form was found to be easy to use, elicits low anxiety, supports productivity and is perceived to have good support. Users would benefit from training and from better social signaling about the importance of using the Form in their practice. Making the Form more fun and interesting could help increase uptake.

Spatial Working Memory Deficits in Male Rats Following Neonatal Hypoxic Ischemic Brain Injury Can Be Attenuated by Task Modifications

PubMed Central

Smith, Amanda L.; Hill, Courtney A.; Alexander, Michelle; Szalkowski, Caitlin E.; Chrobak, James J.; Rosenkrantz, Ted S.; Fitch, R. Holly

2014-01-01

Hypoxia-ischemia (HI; reduction in blood/oxygen supply) is common in infants with serious birth complications, such as prolonged labor and cord prolapse, as well as in infants born prematurely (<37 weeks gestational age; GA). Most often, HI can lead to brain injury in the form of cortical and subcortical damage, as well as later cognitive/behavioral deficits. A common domain of impairment is working memory, which can be associated with heightened incidence of developmental disorders. To further characterize these clinical issues, the current investigation describes data from a rodent model of HI induced on postnatal (P)7, an age comparable to a term (GA 36–38) human. Specifically, we sought to assess working memory using an eight-arm radial water maze paradigm. Study 1 used a modified version of the paradigm, which requires a step-wise change in spatial memory via progressively more difficult tasks, as well as multiple daily trials for extra learning opportunity. Results were surprising and revealed a small HI deficit only for the final and most difficult condition, when a delay before test trial was introduced. Study 2 again used the modified radial arm maze, but presented the most difficult condition from the start, and only one daily test trial. Here, results were expected and revealed a robust and consistent HI deficit across all weeks. Combined results indicate that male HI rats can learn a difficult spatial working memory task if it is presented in a graded multi-trial format, but performance is poor and does not appear to remediate if the task is presented with high initial memory demand. Male HI rats in both studies displayed impulsive characteristics throughout testing evidenced as reduced choice latencies despite more errors. This aspect of behavioral results is consistent with impulsiveness as a core symptom of ADHD—a diagnosis common in children with HI insult. Overall findings suggest that task specific behavioral modifications are crucial to accommodating memory deficits in children suffering from cognitive impairments following neonatal HI. PMID:24961760

Effects of a Home-Based Upper Limb Training Program in Patients With Multiple Sclerosis: A Randomized Controlled Trial.

PubMed

Ortiz-Rubio, Araceli; Cabrera-Martos, Irene; Rodríguez-Torres, Janet; Fajardo-Contreras, Waldo; Díaz-Pelegrina, Ana; Valenza, Marie Carmen

2016-12-01

To evaluate the effects of a home-based upper limb training program on arm function in patients with multiple sclerosis (MS). Additionally, the effects of this program on manual dexterity, handgrip strength, and finger prehension force were analyzed. Randomized, single-blind controlled trial. Home based. Patients with a clinical diagnosis of MS acknowledging impaired manual ability (N=37) were randomized into 2 groups. Patients in the experimental group were included in a supervised home-based upper limb training program for 8 weeks twice a week. Patients in the control group received information in the form of a leaflet with a schedule of upper limb exercise training. The primary outcome measure was arm function (motor functioning assessed using the finger tapping test and a functional measure, the Action Research Arm Test). The secondary outcome measures were manual dexterity assessed with the Purdue Pegboard Test and handgrip strength and finger prehension force evaluated with a handgrip and a pinch dynamometer, respectively. After 8 weeks, a significant between-group improvement (P<.05) was found on the Action Research Arm Test bilaterally and the finger tapping test in the most affected upper limb. The secondary outcomes also improved in the most affected limb in the experimental group. An 8-week home-based intervention program focused on upper limbs twice a week improved arm function and physiologic variables with a primary focus on the more affected extremity in patients with MS compared with the control group. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Multiplicity of mechanisms govern efficacy of anaerobic soil disinfestation for soil-borne disease control

USDA-ARS?s Scientific Manuscript database

Studies demonstrated that carbon input type influenced control of various fungi, oomycetes and plant parasitic nematodes with anaerobic soil disinfestation (ASD). Findings implicated multiple mechanisms may contribute to the overall level of disease control attained. In strawberry field trials, ASD ...

Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients.

PubMed

Mäurer, M; Ortler, S; Baier, M; Meergans, M; Scherer, P; Hofmann, We; Tracik, F

2013-04-01

Cognitive decline has been recognised as a frequent symptom in multiple sclerosis (MS). Cholinesterase inhibitors (ChEIs) are employed for the treatment of Alzheimer's disease, but there is some evidence that ChEIs might also be effective in MS patients with cognitive deficits, particularly deficits of memory function. The aim of this study was to evaluate efficacy on memory function and safety of the ChEI rivastigmine in MS patients with cognitive deficits as measured by the change from baseline of the total recall score of the selective reminding test (SRT) after 16 weeks of treatment. Efficacy and safety of rivastigmine were analysed in a 16-week, multicentre, double-blind, randomised, placebo-controlled study, followed by an optional one-year open-label treatment phase. Effects of rivastigmine and placebo were compared by an analysis of covariance. In total, 86 patients were enrolled. Patients who received rivastigmine (n = 43) showed a non-significant increase in total recall score (sum of all words immediately recalled over all six trials) over placebo (n = 38) after 16 weeks of treatment (p = 0.2576). Other outcome measures provided no evidence supporting benefits of rivastigmine. Treatment with rivastigmine was well tolerated. With the results of this study, the need for an effective therapy in cognitively impaired MS patients is still required. Thus, intensive and continued clinical research is required to explore therapeutic options for cognitive deficits in MS patients.

Web-based self-management for patients with multiple sclerosis: a practical, randomized trial.

PubMed

Miller, Deborah M; Moore, Shirley M; Fox, Robert J; Atreja, Ashish; Fu, Alex Z; Lee, Jar-Chi; Saupe, Welf; Stadtler, Maria; Chakraborty, Swati; Harris, C M; Rudick, Richard A

2011-01-01

No studies have addressed the use of electronic personal health records (e-PHRs) for self-management in complex neurological disorders. We assessed and tested an Internet-based self-management system that utilized the e-PHR and determined its impact on self-assessed well-being, clinician-assessed well-being, and healthcare utilization in patients with multiple sclerosis (MS). Subjects were randomized to usual care (a secure Web-based messaging system) or active intervention, which included secure messaging, self-monitoring, self-management of MS symptoms, and communication about upcoming clinic visits. Computers and Internet access were provided. Subjects were included if they had MS, lived within the county or region surrounding our MS center, had at least two appointments at our center in the previous 12 months, and demonstrated basic typing and computer skills. Study duration was 12 months. Of 220 subjects completing informed consent, 206 met the inclusion criteria. At the study's end, 83 subjects remained in the usual care group and 84 in the enhanced care group. Both groups used the available system components. The groups did not significantly differ on the primary endpoints or healthcare utilization. Self-management support is an emerging aspect of chronic care management. We established the feasibility of conducting a randomized, controlled trial using e-PHRs for patient self-management. We did not find that e-PHR-enabled self-management augmented multidisciplinary MS center-based care, possibly because the differences between interventions were not great enough.

Beta/Gamma Oscillations and Event-Related Potentials Indicate Aberrant Multisensory Processing in Schizophrenia

PubMed Central

Balz, Johanna; Roa Romero, Yadira; Keil, Julian; Krebber, Martin; Niedeggen, Michael; Gallinat, Jürgen; Senkowski, Daniel

2016-01-01

Recent behavioral and neuroimaging studies have suggested multisensory processing deficits in patients with schizophrenia (SCZ). Thus far, the neural mechanisms underlying these deficits are not well understood. Previous studies with unisensory stimulation have shown altered neural oscillations in SCZ. As such, altered oscillations could contribute to aberrant multisensory processing in this patient group. To test this assumption, we conducted an electroencephalography (EEG) study in 15 SCZ and 15 control participants in whom we examined neural oscillations and event-related potentials (ERPs) in the sound-induced flash illusion (SIFI). In the SIFI multiple auditory stimuli that are presented alongside a single visual stimulus can induce the illusory percept of multiple visual stimuli. In SCZ and control participants we compared ERPs and neural oscillations between trials that induced an illusion and trials that did not induce an illusion. On the behavioral level, SCZ (55.7%) and control participants (55.4%) did not significantly differ in illusion rates. The analysis of ERPs revealed diminished amplitudes and altered multisensory processing in SCZ compared to controls around 135 ms after stimulus onset. Moreover, the analysis of neural oscillations revealed altered 25–35 Hz power after 100 to 150 ms over occipital scalp for SCZ compared to controls. Our findings extend previous observations of aberrant neural oscillations in unisensory perception paradigms. They suggest that altered ERPs and altered occipital beta/gamma band power reflect aberrant multisensory processing in SCZ. PMID:27999553

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

PubMed Central

Stoops, William W.; Rush, Craig R.

2016-01-01

Cocaine use disorder is a persistent public health problem for which no widely effective medications exist. Self-administration procedures, which have shown good predictive validity in estimating the abuse potential of drugs, have been used in rodent, nonhuman primate, and human laboratory studies to screen putative medications. This review assessed the effectiveness of the medications development process regarding pharmacotherapies for cocaine use disorder. The primary objective was to determine whether data from animal and human laboratory self-administration studies predicted the results of clinical trials. In addition, the concordance between laboratory studies in animals and humans was assessed. More than 100 blinded, randomized, fully placebo-controlled studies of putative medications for cocaine use disorder were identified. Of the 64 drugs tested in these trials, only 10 had been examined in both human and well-controlled animal laboratory studies. Within all three stages, few studies had been conducted for each drug and when multiple studies had been conducted conclusions were sometimes contradictory. Overall, however, there was good concordance between animal and human laboratory results when the former assessed chronic drug treatment. Although only seven of the ten reviewed drugs showed fully concordant results across all three types of studies reviewed, the analysis revealed several subject-related, procedural, and environmental factors that differ between the laboratory and clinical trial settings that help explain the disagreement for other drugs. The review closes with several recommendations to enhance translation and communication across stages of the medications development process that will ultimately speed the progress toward effective pharmacotherapeutic strategies for cocaine use disorder. PMID:27255266

Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS).

PubMed

Langdon, D W; Amato, M P; Boringa, J; Brochet, B; Foley, F; Fredrikson, S; Hämäläinen, P; Hartung, H-P; Krupp, L; Penner, I K; Reder, A T; Benedict, R H B

2012-06-01

Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures. To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use. An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients. The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test - Second Edition and the Brief Visuospatial Memory Test - Revised learning trials if a further 10 minutes could be allocated for testing. A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced.

Can Targeted Intervention Mitigate Early Emotional and Behavioral Problems?: Generating Robust Evidence within Randomized Controlled Trials

PubMed Central

Doyle, Orla; McGlanaghy, Edel; O’Farrelly, Christine; Tremblay, Richard E.

2016-01-01

This study examined the impact of a targeted Irish early intervention program on children’s emotional and behavioral development using multiple methods to test the robustness of the results. Data on 164 Preparing for Life participants who were randomly assigned into an intervention group, involving home visits from pregnancy onwards, or a control group, was used to test the impact of the intervention on Child Behavior Checklist scores at 24-months. Using inverse probability weighting to account for differential attrition, permutation testing to address small sample size, and quantile regression to characterize the distributional impact of the intervention, we found that the few treatment effects were largely concentrated among boys most at risk of developing emotional and behavioral problems. The average treatment effect identified a 13% reduction in the likelihood of falling into the borderline clinical threshold for Total Problems. The interaction and subgroup analysis found that this main effect was driven by boys. The distributional analysis identified a 10-point reduction in the Externalizing Problems score for boys at the 90th percentile. No effects were observed for girls or for the continuous measures of Total, Internalizing, and Externalizing problems. These findings suggest that the impact of this prenatally commencing home visiting program may be limited to boys experiencing the most difficulties. Further adoption of the statistical methods applied here may help to improve the internal validity of randomized controlled trials and contribute to the field of evaluation science more generally. Trial Registration: ISRCTN Registry ISRCTN04631728 PMID:27253184

Inter-laboratory study to characterize the detection of serum antibodies against porcine epidemic diarrhoea virus.

PubMed

Strandbygaard, Bertel; Lavazza, Antonio; Lelli, Davide; Blanchard, Yannick; Grasland, Béatrice; Poder, Sophie Le; Rose, Nicolas; Steinbach, Falko; van der Poel, Wim H M; Widén, Frederik; Belsham, Graham J; Bøtner, Anette

2016-12-25

Porcine epidemic diarrhea virus (PEDV) has caused extensive economic losses to pig producers in many countries. It was recently introduced, for the first time, into North America and outbreaks have occurred again in multiple countries within Europe as well. To assess the properties of various diagnostic assays for the detection of PEDV infection, multiple panels of porcine sera have been shared and tested for the presence of antibodies against PEDV in an inter-laboratory ring trial. Different laboratories have used a variety of "in house" ELISAs and also one commercial assay. The sensitivity and specificity of each assay has been estimated using a Bayesian analysis applied to the ring trial results obtained with the different assays in the absence of a gold standard. Although different characteristics were found, it can be concluded that each of the assays used can detect infection of pigs at a herd level by either the early European strains of PEDV or the recently circulating strains (INDEL and non-INDEL). However, not all the assays seem suitable for demonstrating freedom from disease in a country. The results from individual animals, especially when the infection has occurred within an experimental situation, show more variation. Copyright © 2016. Published by Elsevier B.V.

Learning and memory performance in breast cancer survivors 2 to 6 years post-treatment: the role of encoding versus forgetting.

PubMed

Root, James C; Andreotti, Charissa; Tsu, Loretta; Ellmore, Timothy M; Ahles, Tim A

2016-06-01

Our previous retrospective analysis of clinically referred breast cancer survivors' performance on learning and memory measures found a primary weakness in initial encoding of information into working memory with intact retention and recall of this same information at a delay. This suggests that survivors may misinterpret cognitive lapses as being due to forgetting when, in actuality, they were not able to properly encode this information at the time of initial exposure. Our objective in this study was to replicate and extend this pattern of performance to a research sample to increase the generalizability of this finding in a sample in which subjects were not clinically referred for cognitive issues. We contrasted learning and memory performance between breast cancer survivors on endocrine therapy 2 to 6 years post-treatment with age- and education-matched healthy controls. We then stratified lower- and higher-performing breast cancer survivors to examine specific patterns of learning and memory performance. Contrasts were generated for four aggregate visual and verbal memory variables from the California Verbal Learning Test-2 (CVLT-2) and the Brown Location Test (BLT): Single-trial Learning: Trial 1 performance, Multiple-trial Learning: Trial 5 performance, Delayed Recall: Long-delay Recall performance, and Memory Errors: False-positive errors. As predicted, breast cancer survivors' performance as a whole was significantly lower on Single-trial Learning than the healthy control group but exhibited no significant difference in Delayed Recall. In the secondary analysis contrasting lower- and higher-performing survivors on cognitive measures, the same pattern of lower Single-trial Learning performance was exhibited in both groups, with the additional finding of significantly weaker Multiple-trial Learning performance in the lower-performing breast cancer group and intact Delayed Recall performance in both groups. As with our earlier finding of weaker initial encoding with intact recall in a cohort of clinically referred breast cancer survivors, our results indicate this same profile in a research sample of breast cancer survivors. Further, when the breast cancer group was stratified by lower and higher performance, both groups exhibited significantly lower performance on initial encoding, with more pronounced encoding weakness in the lower-performing group. As in our previous research, survivors did not lose successfully encoded information over longer delays, either in the lower- or higher-performing group, again arguing against memory decay in survivors. The finding of weaker initial encoding of information together with intact delayed recall in survivors points to specific treatment interventions in rehabilitation of cognitive dysfunction. The finding of weaker initial encoding of information together with intact delayed recall in survivors points to specific treatment interventions in rehabilitation of cognitive dysfunction and is discussed.

Two is better than one: advances in pathogen-boosted immunotherapy and adoptive T-cell therapy.

PubMed

Xin, Gang; Schauder, David M; Zander, Ryan; Cui, Weiguo

2017-09-01

The recent tremendous successes in clinical trials take cancer immunotherapy into a new era and have attracted major attention from both academia and industry. Among the variety of immunotherapy strategies developed to boost patients' own immune systems to fight against malignant cells, the pathogen-based and adoptive cell transfer therapies have shown the most promise for treating multiple types of cancer. Pathogen-based therapies could either break the immune tolerance to enhance the effectiveness of cancer vaccines or directly infect and kill cancer cells. Adoptive cell transfer can induce a strong durable antitumor response, with recent advances including engineering dual specificity into T cells to recognize multiple antigens and improving the metabolic fitness of transferred cells. In this review, we focus on the recent prospects in these two areas and summarize some ongoing studies that represent potential advancements for anticancer immunotherapy, including testing combinations of these two strategies.

Disease activity return after natalizumab cessation in multiple sclerosis.

PubMed

Rasenack, Maria; Derfuss, Tobias

2016-05-01

Natalizumab (NAT) was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis. Its considerable and sustained efficacy has been demonstrated in two phase III studies. However, there are several reasons why its use is limited in clinical practice. The main argument for stopping use of the drug is the risk of the rare but serious progressive multifocal leukencephalopathy. Other reasons are neutralizing antibodies and pregnancy. There is compelling evidence from some clinical trials and many case series that disease activity returns upon suspension or cessation of NAT. Several therapeutic strategies that have been tested to prevent or reduce the recurrence of disease activity will be reviewed in this article. Considering these data, it is evident that the decision to stop NAT treatment has different implications and consequences. A subsequent therapy after cessation of NAT is needed to reduce the risk of disease recurrence.

The organizational effects of pubertal testosterone on sexual proficiency in adult male Syrian hamsters.

PubMed

De Lorme, Kayla C; Sisk, Cheryl L

2016-10-15

Social proficiency requires making appropriate behavioral adaptations as a result of social experience. For example, male rodents become sexually proficient with experience as demonstrated by a reduction in ectopic (misdirected) mounts, mount-to-intromission ratio, and latency to ejaculation. We previously found that over a series of timed tests with a receptive female, male hamsters deprived of testosterone specifically during puberty (NoT@P) have overall lower levels of sexual behavior and continue to display high levels of ectopic mounts, compared with males that experienced endogenous testosterone during puberty (T@P). These results suggested that pubertal testosterone programs sexual proficiency in adulthood, but because NoT@P males engaged in less sexual behavior than T@P males in these tests, the amount of sexual experience may have been insufficient to improve sexual proficiency. To more rigorously test the hypothesis that pubertal testosterone is necessary for social proficiency in adulthood, the present study compared the behavior of NoT@P and T@P males in a series of 4 trials with a 48-h interval between each trial. Sexual experience was equated by limiting each trial to 5 intromissions. Sexually-naïve males were either gonadectomized prepubertally (NoT@P) or in adulthood (T@P) and received subcutaneous testosterone capsules four weeks later. Two weeks after testosterone replacement, these groups and a group of adult gonad-intact controls began sexual behavior testing. We found that NoT@P males had more ectopic mounts/min across all four tests compared to gonad-intact and T@P males. Moreover, both gonad-intact and T@P males, but not NoT@P males, showed an increase in the number of mounts and intromissions/min between trials 1 and 3. Unexpectedly, both gonad-intact and T@P, but not NoT@P, males showed a decrease in sexual behaviors during trial 4. Thus, T@P males display multiple behavioral adaptations to sexual experience that are not observed in NoT@P males: a reduction in ectopic mounts after repeated encounters with a receptive female and an inverted U-shape pattern in mounts and intromissions when these encounters do not lead to ejaculations. These results support the hypothesis that pubertal testosterone organizes neural circuits underlying behavioral flexibility and adaptability to promote sexual proficiency in adulthood. Copyright © 2016 Elsevier Inc. All rights reserved.

Preventing contamination between injections with multiple-use nozzle needle-free injectors: a safety trial.

PubMed

Kelly, Kimberly; Loskutov, Anatoly; Zehrung, Darin; Puaa, Kapaakea; LaBarre, Paul; Muller, Nancy; Guiqiang, Wang; Ding, Hui-Guo; Hu, Darong; Blackwelder, William C

2008-03-04

Multiple-use nozzle jet injectors (MUNJIs), a type of needle-free injector, use a high-pressure stream to penetrate skin and deliver medicament. Concerns for their potential to transmit blood borne pathogens led to development of a hybrid MUNJI for use in mass immunizations. The HSI-500, referred to here as a protector cap needle-free injector (PCNFI), utilizes a disposable cap as a shield between the reusable injector nozzle and the skin to reduce the risk of contamination. This study aimed to determine the presence of hepatitis B virus (HBV) contamination in post-injection ("next person") samples immediately following injection in HBV-carrier adults. Tolerability and pain were also assessed. The study ended early because the PCNFI failed to prevent contamination in the first batch tested (8.2% failure rate). The injections were very well tolerated, with most followed by no bleeding (81.2%) or mild bleeding (7.8%). 55.2% of participants experienced no pain while 42.3% experienced mild pain following injection.

A web-based intervention for abused women: the New Zealand isafe randomised controlled trial protocol.

PubMed

Koziol-McLain, Jane; Vandal, Alain C; Nada-Raja, Shyamala; Wilson, Denise; Glass, Nancy E; Eden, Karen B; McLean, Christine; Dobbs, Terry; Case, James

2015-01-31

Intimate partner violence (IPV) and its associated negative mental health consequences are significant for women in New Zealand and internationally. One of the most widely recommended interventions is safety planning. However, few women experiencing violence access specialist services for safety planning. A safety decision aid, weighing the dangers of leaving or staying in an abusive relationship, gives women the opportunity to prioritise, plan and take action to increase safety for themselves and their children. This randomised controlled trial is testing the effectiveness of an innovative, interactive web-based safety decision aid. The trial is an international collaborative concurrent replication of a USA trial (IRIS study NCT01312103), regionalised for the Aotearoa New Zealand culture and offers fully automated online trial recruitment, eligibility screening and consent. In a fully automated web-based trial (isafe) 340 abused women will be randomly assigned in equal numbers to a safety decision aid intervention or usual safety planning control website. Intervention components include: (a) safety priority setting, (b) danger assessment and (c) an individually tailored safety action plan. Self-reported outcome measures are collected at baseline and 3, 6, and 12-months post-baseline. Primary outcomes are depression (measured by Center for Epidemiologic Studies Depression Scale, Revised) and IPV exposure (measured by Severity Violence Against Women Scale) at 12 months post-baseline. Secondary outcomes include PTSD, psychological abuse, decisional conflict, safety behaviors and danger in the relationship. This trial will provide much-needed information on the potential relationships among safety planning, improved mental health, reduced violence as well as decreased decisional conflict related to safety in the abusive relationship. The novel web-based safety decision aid intervention may provide a cost-effective, easily accessed safety-planning resource that can be translated into clinical and community practice by multiple health disciplines and advocates. The trial will also provide information about how women in abusive relationships safely access safety information and resources through the Internet. Finally, the trial will inform other research teams on the feasibility and acceptability of fully automated recruitment, eligibility screening, consent and retention procedures. Trial registered on 03 July 2012 on the Australian New Zealand Clinical Trials Registry ACTRN12612000708853 .

Trial 1 versus Trial 2 of the Test of Memory Malingering: Evaluating accuracy without a "gold standard".

PubMed

Mossman, Douglas; Wygant, Dustin B; Gervais, Roger O; Hart, Kathleen J

2018-01-01

This study examines the accuracy of the Test of Memory Malingering (TOMM), a frequently administered measure for evaluating effort during neurocognitive testing. In the last few years, several authors have suggested that the initial recognition trial of the TOMM (Trial 1) might be a more useful index for detecting feigned or exaggerated impairment than Trial 2, which is the source for inference recommended by the original instruction manual (Tombaugh, 1996). We used latent class modeling (LCM) implemented in a Bayesian framework to evaluate archival Trial 1 and Trial 2 data collected from 1,198 adults who had undergone outpatient forensic evaluations. All subjects were tested with 2 other performance validity tests (the Word Memory Test and the Computerized Assessment of Response Bias), and for 70% of the subjects, data from the California Verbal Learning Test-Second Edition Forced Choice trial were also available. Our results suggest that not even a perfect score on Trial 1 or Trial 2 justifies saying that an evaluee is definitely responding genuinely, although such scores imply a lower-than-base-rate probability of feigning. If one uses a Trial 2 cut-off higher than the manual's recommendation, Trial 2 does better than Trial 1 at identifying individuals who are almost certainly feigning while maintaining a negligible false positive rate. Using scores from both trials, one can identify a group of definitely feigning and very likely feigning subjects who comprise about 2 thirds of all feigners; only 1% of the members of this group would not be feigning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Implications of clinical trial design on sample size requirements.

PubMed

Leon, Andrew C

2008-07-01

The primary goal in designing a randomized controlled clinical trial (RCT) is to minimize bias in the estimate of treatment effect. Randomized group assignment, double-blinded assessments, and control or comparison groups reduce the risk of bias. The design must also provide sufficient statistical power to detect a clinically meaningful treatment effect and maintain a nominal level of type I error. An attempt to integrate neurocognitive science into an RCT poses additional challenges. Two particularly relevant aspects of such a design often receive insufficient attention in an RCT. Multiple outcomes inflate type I error, and an unreliable assessment process introduces bias and reduces statistical power. Here we describe how both unreliability and multiple outcomes can increase the study costs and duration and reduce the feasibility of the study. The objective of this article is to consider strategies that overcome the problems of unreliability and multiplicity.

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem.

PubMed

Roehrs, Timothy A; Roth, Thomas

2016-03-01

Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. CLINCIAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. © 2016 American Academy of Sleep Medicine.

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.

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

PubMed Central

Roehrs, Timothy A.; Roth, Thomas

2016-01-01

Study Objectives: Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. Methods: To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23–70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Results: Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. Conclusions: In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. Clincial Trials Registration: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Roehrs TA, Roth T. Gender differences in the efficacy and safety of chronic nightly zolpidem. J Clin Sleep Med 2016;12(3):319–325. PMID:26446253

Repeat testing of low-level HIV-1 RNA: assay performance and implementation in clinical trials.

PubMed

White, Kirsten; Garner, Will; Wei, Lilian; Eron, Joseph J; Zhong, Lijie; Miller, Michael D; Martin, Hal; Plummer, Andrew; Tran-Muchowski, Cecilia; Lindstrom, Kim; Porter, James; Piontkowsky, David; Light, Angela; Reiske, Heinz; Quirk, Erin

2018-05-15

Assess the performance of HIV-1 RNA repeat testing of stored samples in cases of low-level viremia during clinical trials. Prospective and retrospective analysis of randomized clinical trial samples and reference standards. To evaluate assay variability of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, v2.0, three separate sources of samples were utilized: the World Health Organization (WHO) HIV reference standard (assayed using 50 independent measurements at six viral loads <200 copies/ml), retrospective analysis of four to six aliquots of plasma samples from four clinical trial participants, and prospective repeat testing of 120 samples from participants in randomized trials with low-level viremia. The TaqMan assay on the WHO HIV-1 RNA standards at viral loads <200 copies/ml performed within the expected variability according to assay specifications. However, standards with low viral loads of 36 and 18 copies/ml reported values of ≥ 50 copies/ml in 66 and 18% of tests, respectively. In participants treated with antiretrovirals who had unexpected viremia of 50-200 copies/ml after achieving <50 copies/ml, retesting of multiple aliquots of stored plasma found <50 copies/ml in nearly all cases upon retesting (14/15; 93%). Repeat testing was prospectively implemented in four clinical trials for all samples with virologic rebound of 50-200 copies/ml (n = 120 samples from 92 participants) from which 42% (50/120) had a retest result of less than 50 copies/ml and 58% (70/120) retested ≥ 50 copies/ml. The TaqMan HIV-1 RNA assay shows variability around 50 copies/ml that affects clinical trial results and may impact clinical practice. In participants with a history of viral load suppression, unexpected low-level viremia may be because of assay variability rather than low drug adherence or true virologic failure. Retesting a stored aliquot of the same sample may differentiate between assay variability and virologic failure as the source of viremia. This retesting strategy could save time, money, and anxiety for patients and their providers, as well as decrease follow-up clinic visits without increasing the risk of virologic failure and resistance development.

Statistical grand rounds: a review of analysis and sample size calculation considerations for Wilcoxon tests.

PubMed

Divine, George; Norton, H James; Hunt, Ronald; Dienemann, Jacqueline

2013-09-01

When a study uses an ordinal outcome measure with unknown differences in the anchors and a small range such as 4 or 7, use of the Wilcoxon rank sum test or the Wilcoxon signed rank test may be most appropriate. However, because nonparametric methods are at best indirect functions of standard measures of location such as means or medians, the choice of the most appropriate summary measure can be difficult. The issues underlying use of these tests are discussed. The Wilcoxon-Mann-Whitney odds directly reflects the quantity that the rank sum procedure actually tests, and thus it can be a superior summary measure. Unlike the means and medians, its value will have a one-to-one correspondence with the Wilcoxon rank sum test result. The companion article appearing in this issue of Anesthesia & Analgesia ("Aromatherapy as Treatment for Postoperative Nausea: A Randomized Trial") illustrates these issues and provides an example of a situation for which the medians imply no difference between 2 groups, even though the groups are, in fact, quite different. The trial cited also provides an example of a single sample that has a median of zero, yet there is a substantial shift for much of the nonzero data, and the Wilcoxon signed rank test is quite significant. These examples highlight the potential discordance between medians and Wilcoxon test results. Along with the issues surrounding the choice of a summary measure, there are considerations for the computation of sample size and power, confidence intervals, and multiple comparison adjustment. In addition, despite the increased robustness of the Wilcoxon procedures relative to parametric tests, some circumstances in which the Wilcoxon tests may perform poorly are noted, along with alternative versions of the procedures that correct for such limitations. 

Can Early Intervention Improve Maternal Well-Being? Evidence from a Randomized Controlled Trial

PubMed Central

Doyle, Orla; Delaney, Liam; O’Farrelly, Christine; Fitzpatrick, Nick; Daly, Michael

2017-01-01

Objective This study estimates the effect of a targeted early childhood intervention program on global and experienced measures of maternal well-being utilizing a randomized controlled trial design. The primary aim of the intervention is to improve children’s school readiness skills by working directly with parents to improve their knowledge of child development and parenting behavior. One potential externality of the program is well-being benefits for parents given its direct focus on improving parental coping, self-efficacy, and problem solving skills, as well as generating an indirect effect on parental well-being by targeting child developmental problems. Methods Participants from a socio-economically disadvantaged community are randomly assigned during pregnancy to an intensive 5-year home visiting parenting program or a control group. We estimate and compare treatment effects on multiple measures of global and experienced well-being using permutation testing to account for small sample size and a stepdown procedure to account for multiple testing. Results The intervention has no impact on global well-being as measured by life satisfaction and parenting stress or experienced negative affect using episodic reports derived from the Day Reconstruction Method (DRM). Treatment effects are observed on measures of experienced positive affect derived from the DRM and a measure of mood yesterday. Conclusion The limited treatment effects suggest that early intervention programs may produce some improvements in experienced positive well-being, but no effects on negative aspects of well-being. Different findings across measures may result as experienced measures of well-being avoid the cognitive biases that impinge upon global assessments. PMID:28095505

Teaching veterinary radiography by e-learning versus structured tutorial: a randomized, single-blinded controlled trial.

PubMed

Vandeweerd, Jean-Michel E F; Davies, John C; Pinchbeck, Gina L; Cotton, Jo C

2007-01-01

Case-based e-learning may allow effective teaching of veterinary radiology in the field of equine orthopedics. The objective of this study was to investigate the effectiveness of a new case-based e-learning tool, compared with a standard structured tutorial, in altering students' knowledge and skills about interpretation of radiographs of the digit in the horse. It was also designed to assess students' attitudes toward the two educational interventions. A randomized, single-blinded, controlled trial of 96 fourth-year undergraduate veterinary students, involving an educational intervention of either structured tutorial or case-based e-learning, was performed. A multiple-choice examination based on six learning outcomes was carried out in each group after the session, followed by an evaluation of students' attitudes toward their session on a seven-point scale. Text blanks were available to students to allow them to comment on the educational interventions and on their learning outcomes. Students also rated, on a Likert scale from 1 to 7, their performance for each specific learning outcome and their general ability to use a systematic approach in interpreting radiographs. Data were analyzed using the Mann-Whitney test, the t-test, and the equivalence test. There was no significant difference in student achievement on course tests. The results of the survey suggest positive student attitudes toward the e-learning tool and illustrate the difference between objective ratings and subjective assessments by students in testing a new educational intervention.

The relational database model and multiple multicenter clinical trials.

PubMed

Blumenstein, B A

1989-12-01

The Southwest Oncology Group (SWOG) chose to use a relational database management system (RDBMS) for the management of data from multiple clinical trials because of the underlying relational model's inherent flexibility and the natural way multiple entity types (patients, studies, and participants) can be accommodated. The tradeoffs to using the relational model as compared to using the hierarchical model include added computing cycles due to deferred data linkages and added procedural complexity due to the necessity of implementing protections against referential integrity violations. The SWOG uses its RDBMS as a platform on which to build data operations software. This data operations software, which is written in a compiled computer language, allows multiple users to simultaneously update the database and is interactive with respect to the detection of conditions requiring action and the presentation of options for dealing with those conditions. The relational model facilitates the development and maintenance of data operations software.

Clinical Trials

MedlinePlus

Clinical trials are research studies that test how well new medical approaches work in people. Each study ... prevent, screen for, diagnose, or treat a disease. Clinical trials may also compare a new treatment to ...

A case study of SMART attributes: a qualitative assessment of generalizability, retention rate, and trial quality.

PubMed

Moodie, Erica E M; Karran, James C; Shortreed, Susan M

2016-05-14

Personalizing medical care is becoming increasingly popular, particularly mental health care. There is growing interest in formalizing medical decision making based on evolving patient symptoms in an evidence-based manner. To determine optimal sequencing of treatments, the sequences themselves must be studied; this may be accomplished by using a sequential multiple assignment randomized trial (SMART). It has been hypothesized that SMART studies may improve participant retention and generalizability. We examine the hypotheses that SMART studies are more generalizable and have better retention than traditional randomized clinical trials via a case study of a SMART study of antipsychotic medications. We considered the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, comparing the trial participant characteristics and overall retention to those of comparable trials found via a review of all related trials conducted from 2000 onwards. A MEDLINE search returned 6435 results for primary screening; ultimately, 48 distinct trials were retained for analysis. The study population in CATIE was similar to, although perhaps less symptomatic than, the study populations of traditional randomized clinical trials (RCTs), suggesting no large gains in generalizability despite the pragmatic nature of the trial. However, CATIE did see good month-by-month retention. SMARTs offer the possibility of studying treatment sequences in a way that a series of traditional RCTs cannot. SMARTs may offer improved retention; however, this case study did not find evidence to suggest greater generalizability using this trial design. ClinicalTrials.gov NCT00014001 . Registered on 6 April 2001.

Regulatory impediments jeopardizing the conduct of clinical trials in Europe funded by the National Institutes of Health

PubMed Central

Neaton, James D; Babiker, Abdel; Bohnhorst, Mark; Darbyshire, Janet; Denning, Eileen; Frishman, Arnie; Grarup, Jesper; Larson, Gregg; Lundgren, Jens

2011-01-01

Background A number of reports have highlighted problems of conducting publicly funded trials in Europe as a consequence of the European Union (EU) Clinical Trials Directive. The impact of the EU Directive on multi-national trials, which include sites in Europe that are funded by the US National Institutes of Health (NIH) have not been described. Methods Four problems in the conduct of two international HIV treatment trials funded by NIH in the EU are described: (1) conflicting regulations on the continuing review of protocols by Institutional Review Boards/Research Ethics Committees; (2) US regulations requiring Federalwide Assurances for sites which are only partially funded by NIH; (3) EU guidance on the designation of studies as a trial of an investigational medicinal product; and (4) EU guidance on trial sponsorship and the requirements for insurance and indemnification. Following the description of the problems, recommendations for improving global collaborations are made to the US Office of Human Research Protections, to NIH, and to the EU and its Member States. Results A lack of harmonization of regulations at multiple levels caused enrollment in one study to be interrupted for several months and delayed for one year the initiation of another study aimed at obtaining definitive evidence to guide the timing of the initiation of antiretroviral therapy for individuals infected with HIV. The delays and the purchase of insurance resulted in substantial increases in trial costs and caused substantial disruption at clinical sites among staff and study participants. Limitations The problems cited and recommendations made pertain to trials funded by NIH and conducted by sites in the EU. There are many other challenges in the conduct of international research, public and private, that global harmonization would alleviate. Conclusions Disharmony, at multiple levels, in international regulations and guidelines is stifling publicly funded global research. International scientific organizations and government groups should make the documentation and solution of these problems a priority. PMID:20729252

Driving Sodium/Potassium Pumps with an Oscillating Electric field: Effects on Muscle Fatigue

NASA Astrophysics Data System (ADS)

Lanes, Olivia; Bovyn, Matthew; Chen, Wei

2013-03-01

Dr. Chen has developed a technique called Synchronization Modulation, which has already been proven to be an effective tool in synchronizing and speeding up the sodium/potassium pumps in cell membranes. When synchronized, it is thought that these pumps are more efficient because they require less ATP. We hypothesized that if this was correct, this technique may be used to reduce muscle fatigue. To test our hypothesis, we had multiple test subjects hold a 15 lb weight for as long as they could while isolating the bicep muscle and applying an oscillating electric field. We compared the EMG data we took during these trials to the control, which was done the same way but without applying the electric field. To compare how fatigued subjects were, we did a Fast Fourier Transform on the first and last 10 seconds of each trial to measure the Fatigue Index. Our preliminary results suggest that the Fatigue Index decreased at a slower rate in the trials where the subject held the weight with Synchronization Modulation.

The effect of optokinetic stimulation on daytime sleepiness

NASA Technical Reports Server (NTRS)

Leslie, K. R.; Stickgold, R.; Dizio, P.; Lackner, J. R.; Hobson, J. A.

1997-01-01

This study examined the effect of optokinetic stimulation on objective sleepiness, as measured by the Multiple Sleep Latency Test (MSLT). The Nightcap, a portable sleep monitor, was used in a novel way to perform MSLTs, as well as record sleep in the home. Subjects wore the Nightcap for seven consecutive nights. On days 3 and 5 of the protocol, subjects came into the lab for an MSLT. On the experimental day, subjects underwent 10 minutes optokinetic stimulation (OKS), resulting in moderate motion sickness prior to each MSLT trial. Although subjects in the OKS condition reported significantly more drowsiness than controls, this did not result in significantly reduced sleep latencies.