Selection of and Evidentiary Considerations for Wearable Devices and Their Measurements for Use in Regulatory Decision Making: Recommendations from the ePRO Consortium.

PubMed

Byrom, Bill; Watson, Chris; Doll, Helen; Coons, Stephen Joel; Eremenco, Sonya; Ballinger, Rachel; Mc Carthy, Marie; Crescioni, Mabel; O'Donohoe, Paul; Howry, Cindy

2018-06-01

Wearable devices offer huge potential to collect rich sources of data to provide insights into the effects of treatment interventions. Despite this, at the time of writing this report, limited regulatory guidance on the use of wearables in clinical trial programs has been published. To present recommendations from the Critical Path Institute's Electronic Patient-Reported Outcome Consortium regarding the selection and evaluation of wearable devices and their measurements for use in regulatory trials and to support labeling claims. The evaluation group was composed of Critical Path Institute's clinical outcome assessment (COA) scientists and COA specialists from pharmaceutical trial eCOA solution providers, including COA development and validation specialists. The resulting recommendations were drawn from a broad range of backgrounds, perspectives, and expertise that enriched the development of this report. Recommendations were developed through analysis of existing regulatory guidance relating to COA development and use in clinical trials, medical device certification/clearance regulations, literature-reported best practice, and practical experience of wearable technology application in clinical trials. We identify the essential properties of fit-for-purpose wearables and propose evidence needed to support their use. In addition, we overview the activities required to establish clinical endpoints derived from wearables data. Using this framework, we believe there is enough current understanding to promote the appropriate use of wearables in study protocols. We hope this will provide a basis for discussion among clinical trial stakeholders and catalyze the development of more robust regulatory guidance. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Ethical Considerations for Clinical Trials in Inflammatory Bowel Disease

PubMed Central

Becker, Samuel; Siegler, Mark

2014-01-01

Although advancements in the field of inflammatory bowel disease (IBD) include effective therapies for many patients with Crohn’s disease and ulcerative colitis, there remains a large unmet need, and there is a large number of investigational agents in the pipeline. Drug development through clinical trials is critical to understanding the safety and efficacy of new therapies in the affected human population, and the need for ethical trial design is of the utmost importance. This paper explores the ethical issues of clinical trials in IBD, focusing on placebo-controlled trials, vulnerable patients, exposure to monoclonal antibodies, globalization of trials, and surgical advances. PMID:24799837

Effective Recruitment of Schools for Randomized Clinical Trials: Role of School Nurses.

PubMed

Petosa, R L; Smith, L

2017-01-01

In school settings, nurses lead efforts to improve the student health and well-being to support academic success. Nurses are guided by evidenced-based practice and data to inform care decisions. The randomized controlled trial (RCT) is considered the gold standard of scientific rigor for clinical trials. RCTs are critical to the development of evidence-based health promotion programs in schools. The purpose of this article is to present practical solutions to implementing principles of randomization to RCT trials conducted in school settings. Randomization is a powerful sampling method used to build internal and external validity. The school's daily organization and educational mission provide several barriers to randomization. Based on the authors' experience in conducting school-based RCTs, they offer a host of practical solutions to working with schools to successfully implement randomization procedures. Nurses play a critical role in implementing RCTs in schools to promote rigorous science in support of evidence-based practice.

Statistical analysis plan for the Pneumatic CompREssion for PreVENting Venous Thromboembolism (PREVENT) trial: a study protocol for a randomized controlled trial.

PubMed

Arabi, Yaseen; Al-Hameed, Fahad; Burns, Karen E A; Mehta, Sangeeta; Alsolamy, Sami; Almaani, Mohammed; Mandourah, Yasser; Almekhlafi, Ghaleb A; Al Bshabshe, Ali; Finfer, Simon; Alshahrani, Mohammed; Khalid, Imran; Mehta, Yatin; Gaur, Atul; Hawa, Hassan; Buscher, Hergen; Arshad, Zia; Lababidi, Hani; Al Aithan, Abdulsalam; Jose, Jesna; Abdukahil, Sheryl Ann I; Afesh, Lara Y; Dbsawy, Maamoun; Al-Dawood, Abdulaziz

2018-03-15

The Pneumatic CompREssion for Preventing VENous Thromboembolism (PREVENT) trial evaluates the effect of adjunctive intermittent pneumatic compression (IPC) with pharmacologic thromboprophylaxis compared to pharmacologic thromboprophylaxis alone on venous thromboembolism (VTE) in critically ill adults. In this multicenter randomized trial, critically ill patients receiving pharmacologic thromboprophylaxis will be randomized to an IPC or a no IPC (control) group. The primary outcome is "incident" proximal lower-extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the lower-extremity ultrasonography will be blinded to intervention allocation, whereas the patients and treating team will be unblinded. The trial has 80% power to detect a 3% absolute risk reduction in the rate of proximal DVT from 7% to 4%. Consistent with international guidelines, we have developed a detailed plan to guide the analysis of the PREVENT trial. This plan specifies the statistical methods for the evaluation of primary and secondary outcomes, and defines covariates for adjusted analyses a priori. Application of this statistical analysis plan to the PREVENT trial will facilitate unbiased analyses of clinical data. ClinicalTrials.gov , ID: NCT02040103 . Registered on 3 November 2013; Current controlled trials, ID: ISRCTN44653506 . Registered on 30 October 2013.

Incorporating ethical principles into clinical research protocols: a tool for protocol writers and ethics committees

PubMed Central

Li, Rebecca H; Wacholtz, Mary C; Barnes, Mark; Boggs, Liam; Callery-D'Amico, Susan; Davis, Amy; Digilova, Alla; Forster, David; Heffernan, Kate; Luthin, Maeve; Lynch, Holly Fernandez; McNair, Lindsay; Miller, Jennifer E; Murphy, Jacquelyn; Van Campen, Luann; Wilenzick, Mark; Wolf, Delia; Woolston, Cris; Aldinger, Carmen; Bierer, Barbara E

2016-01-01

A novel Protocol Ethics Tool Kit (‘Ethics Tool Kit’) has been developed by a multi-stakeholder group of the Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard. The purpose of the Ethics Tool Kit is to facilitate effective recognition, consideration and deliberation of critical ethical issues in clinical trial protocols. The Ethics Tool Kit may be used by investigators and sponsors to develop a dedicated Ethics Section within a protocol to improve the consistency and transparency between clinical trial protocols and research ethics committee reviews. It may also streamline ethics review and may facilitate and expedite the review process by anticipating the concerns of ethics committee reviewers. Specific attention was given to issues arising in multinational settings. With the use of this Tool Kit, researchers have the opportunity to address critical research ethics issues proactively, potentially speeding the time and easing the process to final protocol approval. PMID:26811365

[Failure mode and effects analysis to improve quality in clinical trials].

PubMed

Mañes-Sevilla, M; Marzal-Alfaro, M B; Romero Jiménez, R; Herranz-Alonso, A; Sanchez Fresneda, M N; Benedi Gonzalez, J; Sanjurjo-Sáez, M

The failure mode and effects analysis (FMEA) has been used as a tool in risk management and quality improvement. The objective of this study is to identify the weaknesses in processes in the clinical trials area, of a Pharmacy Department (PD) with great research activity, in order to improve the safety of the usual procedures. A multidisciplinary team was created to analyse each of the critical points, identified as possible failure modes, in the development of clinical trial in the PD. For each failure mode, the possible cause and effect were identified, criticality was calculated using the risk priority number and the possible corrective actions were discussed. Six sub-processes were defined in the development of the clinical trials in PD. The FMEA identified 67 failure modes, being the dispensing and prescription/validation sub-processes the most likely to generate errors. All the improvement actions established in the AMFE were implemented in the Clinical Trials area. The FMEA is a useful tool in proactive risk management because it allows us to identify where we are making mistakes and analyze the causes that originate them, to prioritize and to adopt solutions to risk reduction. The FMEA improves process safety and quality in PD. Copyright © 2018 SECA. Publicado por Elsevier España, S.L.U. All rights reserved.

Small studies may overestimate the effect sizes in critical care meta-analyses: a meta-epidemiological study

PubMed Central

2013-01-01

Introduction Small-study effects refer to the fact that trials with limited sample sizes are more likely to report larger beneficial effects than large trials. However, this has never been investigated in critical care medicine. Thus, the present study aimed to examine the presence and extent of small-study effects in critical care medicine. Methods Critical care meta-analyses involving randomized controlled trials and reported mortality as an outcome measure were considered eligible for the study. Component trials were classified as large (≥100 patients per arm) and small (<100 patients per arm) according to their sample sizes. Ratio of odds ratio (ROR) was calculated for each meta-analysis and then RORs were combined using a meta-analytic approach. ROR<1 indicated larger beneficial effect in small trials. Small and large trials were compared in methodological qualities including sequence generating, blinding, allocation concealment, intention to treat and sample size calculation. Results A total of 27 critical care meta-analyses involving 317 trials were included. Of them, five meta-analyses showed statistically significant RORs <1, and other meta-analyses did not reach a statistical significance. Overall, the pooled ROR was 0.60 (95% CI: 0.53 to 0.68); the heterogeneity was moderate with an I2 of 50.3% (chi-squared = 52.30; P = 0.002). Large trials showed significantly better reporting quality than small trials in terms of sequence generating, allocation concealment, blinding, intention to treat, sample size calculation and incomplete follow-up data. Conclusions Small trials are more likely to report larger beneficial effects than large trials in critical care medicine, which could be partly explained by the lower methodological quality in small trials. Caution should be practiced in the interpretation of meta-analyses involving small trials. PMID:23302257

Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation--effects on physical function: study protocol for a randomized controlled trial: a substudy of the NONSEDA trial.

PubMed

Nedergaard, Helene Korvenius; Jensen, Hanne Irene; Lauridsen, Jørgen T; Sjøgaard, Gisela; Toft, Palle

2015-07-23

Critically ill patients rapidly loose much of their muscle mass and strength. This can be attributed to prolonged admission, prolonged mechanical ventilation and increased mortality, and it can have a negative impact on the degree of independence and quality of life. In the NONSEDA trial we randomize critically ill patients to non-sedation or sedation with a daily wake-up trial during mechanical ventilation in the intensive care unit. It has never been assessed whether non-sedation affects physical function. The aim of this study is to assess the effects of non-sedation versus sedation with a daily wake-up trial on physical function after discharge from intensive care unit. Investigator-initiated, randomized, clinical, parallel-group, superiority trial, including 700 patients in total, with a substudy concerning 200 of these patients. Inclusion criteria will be intubated, mechanically ventilated patients with expected duration of mechanical ventilation >24 h. Exclusion criteria will be patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO2/FiO2<9 where sedation might be necessary to ensure sufficient oxygenation or placing the patient in a prone position. The experimental intervention will be non-sedation supplemented with pain management during mechanical ventilation. The control intervention will be sedation with a daily wake-up trial. The co-primary outcome will be quality of life regarding physical function (SF-36, physical component) and degree of independence in activities of daily living (Barthel Index), and this will be assessed for all 700 patients participating in the NONSEDA trial. The secondary outcomes, which will be assessed for the subpopulation of 200 NONSEDA patients in the trial site, Kolding, will be 6-min walking distance, handgrip strength, muscle size (ultrasonographic measurement of the rectus femoris muscle cross-sectional area) and biomechanical data on lower extremity function (maximal voluntary contraction, rate of force development and endurance). This study is the first to investigate the effect of no sedation during critical illness on physical function. If an effect is found, it will add important information on how to prevent muscle weakness following critical illness. The study has been approved by the relevant scientific ethics committee and is registered at ClinicalTrials.gov (ID: NCT02034942, 9 January 2014).

Supplemental parenteral nutrition in critically ill patients: a study protocol for a phase II randomised controlled trial.

PubMed

Ridley, Emma J; Davies, Andrew R; Parke, Rachael; Bailey, Michael; McArthur, Colin; Gillanders, Lyn; Cooper, David J; McGuinness, Shay

2015-12-24

Nutrition is one of the fundamentals of care provided to critically ill adults. The volume of enteral nutrition received, however, is often much less than prescribed due to multiple functional and process issues. To deliver the prescribed volume and correct the energy deficit associated with enteral nutrition alone, parenteral nutrition can be used in combination (termed "supplemental parenteral nutrition"), but benefits of this method have not been firmly established. A multi-centre, randomised, clinical trial is currently underway to determine if prescribed energy requirements can be provided to critically ill patients by using a supplemental parenteral nutrition strategy in the critically ill. This prospective, multi-centre, randomised, stratified, parallel-group, controlled, phase II trial aims to determine whether a supplemental parenteral nutrition strategy will reliably and safely increase energy intake when compared to usual care. The study will be conducted for 100 critically ill adults with at least one organ system failure and evidence of insufficient enteral intake from six intensive care units in Australia and New Zealand. Enrolled patients will be allocated to either a supplemental parenteral nutrition strategy for 7 days post randomisation or to usual care with enteral nutrition. The primary outcome will be the average energy amount delivered from nutrition therapy over the first 7 days of the study period. Secondary outcomes include protein delivery for 7 days post randomisation; total energy and protein delivery, antibiotic use and organ failure rates (up to 28 days); duration of ventilation, length of intensive care unit and hospital stay. At both intensive care unit and hospital discharge strength and health-related quality of life assessments will be undertaken. Study participants will be followed up for health-related quality of life, resource utilisation and survival at 90 and 180 days post randomisation (unless death occurs first). This trial aims to determine if provision of a supplemental parenteral nutrition strategy to critically ill adults will increase energy intake compared to usual care in Australia and New Zealand. Trial outcomes will guide development of a subsequent larger randomised controlled trial. NCT01847534 (First registered 5 February 2013, last updated 14 October 2015).

The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.

PubMed

Guetterman, Timothy C; Fetters, Michael D; Mawocha, Samkeliso; Legocki, Laurie J; Barsan, William G; Lewis, Roger J; Berry, Donald A; Meurer, William J

2017-01-01

Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development.

Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial.

PubMed

Carcillo, Joseph A; Dean, J Michael; Holubkov, Richard; Berger, John; Meert, Kathleen L; Anand, Kanwaljeet J S; Zimmerman, Jerry J; Newth, Christopher J L; Harrison, Rick; Burr, Jeri; Willson, Douglas F; Nicholson, Carol; Bell, Michael J; Berg, Robert A; Shanley, Thomas P; Heidemann, Sabrina M; Dalton, Heidi; Jenkins, Tammara L; Doctor, Allan; Webster, Angie; Tamburro, Robert F

2017-11-01

The pediatric Critical Illness Stress-induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis. Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category. There were 134 immune-competent children without lymphopenia, 79 previously immune-competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis ( P < .05) and on the rate of nosocomial infection and sepsis per 100 patient days ( P < .05). Whey protein treatment protected immune-competent patients without lymphopenia from infection and sepsis, both nutraceutical strategies were equivalent in immune-competent patients with lymphopenia, and zinc, selenium, glutamine, and metoclopramide treatment protected immunocompromised patients from infection and sepsis. The science of immune nutrition is more complex than previously thought. Future trial design should consider immune status at the time of trial entry because differential effects of nutraceuticals may be related to this patient characteristic.

A Combined Early Cognitive and Physical Rehabilitation Program for People Who Are Critically Ill: The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) Trial

PubMed Central

Jackson, James C.; Girard, Timothy D.; Pandharipande, Pratik P.; Schiro, Elena; Work, Brittany; Pun, Brenda T.; Boehm, Leanne; Gill, Thomas M.; Ely, E. Wesley

2012-01-01

Background In the coming years, the number of survivors of critical illness is expected to increase. These survivors frequently develop newly acquired physical and cognitive impairments. Long-term cognitive impairment is common following critical illness and has dramatic effects on patients' abilities to function autonomously. Neuromuscular weakness affects similar proportions of patients and leads to equally profound life alterations. As knowledge of these short-term and long-term consequences of critical illness has come to light, interventions to prevent and rehabilitate these devastating consequences have been sought. Physical rehabilitation has been shown to improve functional outcomes in people who are critically ill, but subsequent studies of physical rehabilitation after hospital discharge have not. Post-hospital discharge cognitive rehabilitation is feasible in survivors of critical illness and is commonly used in people with other forms of acquired brain injury. The feasibility of early cognitive therapy in people who are critically ill remains unknown. Objective The purpose of this novel protocol trial will be to determine the feasibility of early and sustained cognitive rehabilitation paired with physical rehabilitation in patients who are critically ill from medical and surgical intensive care units. Design This is a randomized controlled trial. Setting The setting for this trial will be medical and surgical intensive care units of a large tertiary care referral center. Patients The participants will be patients who are critically ill with respiratory failure or shock. Intervention Patients will be randomized to groups receiving usual care, physical rehabilitation, or cognitive rehabilitation plus physical rehabilitation. Twice-daily cognitive rehabilitation sessions will be performed with patients who are noncomatose and will consist of orientation, memory, and attention exercises (eg, forward and reverse digit spans, matrix puzzles, letter-number sequences, pattern recognition). Daily physical rehabilitation sessions will advance patients from passive range of motion exercises through ambulation. Patients with cognitive or physical impairment at discharge will undergo a 12-week, in-home cognitive rehabilitation program. Measurements A battery of neurocognitive and functional outcomes will be measured 3 and 12 months after hospital discharge. Conclusions If feasible, these interventions will lay the groundwork for a larger, multicenter trial to determine their efficacy. PMID:22577067

Advancing molecular-guided surgery through probe development and testing in a moderate cost evaluation pipeline

NASA Astrophysics Data System (ADS)

Pogue, Brian W.; Paulsen, Keith D.; Hull, Sally M.; Samkoe, Kimberley S.; Gunn, Jason; Hoopes, Jack; Roberts, David W.; Strong, Theresa V.; Draney, Daniel; Feldwisch, Joachim

2015-03-01

Molecular guided oncology surgery has the potential to transform the way decisions about resection are done, and can be critically important in areas such as neurosurgery where the margins of tumor relative to critical normal tissues are not readily apparent from visual or palpable guidance. Yet there are major financial barriers to advancing agents into clinical trials with commercial backing. We observe that development of these agents in the standard biological therapeutic paradigm is not viable, due to the high up front financial investment needed and the limitations in the revenue models of contrast agents for imaging. The hypothesized solution to this problem is to develop small molecular biologicals tagged with an established fluorescent reporter, through the chemical agent approval pathway, targeting a phase 0 trials initially, such that the initial startup phase can be completely funded by a single NIH grant. In this way, fast trials can be completed to de-risk the development pipeline, and advance the idea of fluorescence-guided surgery (FGS) reporters into human testing. As with biological therapies the potential successes of each agent are still moderate, but this process will allow the field to advance in a more stable and productive manner, rather than relying upon isolated molecules developed at high cost and risk. The pathway proposed and tested here uses peptide synthesis of an epidermal growth factor receptor (EGFR)-binding Affibody molecules, uniquely conjugated to IRDye 800CW, developed and tested in academic and industrial laboratories with well-established records for GMP production, fill and finish, toxicity testing, and early phase clinical trials with image guidance.

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients. Protocol Version 9, 19 February 2007 known as SIGNET (Scottish Intensive care Glutamine or seleNium Evaluative Trial)

PubMed Central

Andrews, Peter JD; Avenell, Alison; Noble, David W; Campbell, Marion K; Battison, Claire G; Croal, Bernard L; Simpson, William G; Norrie, John; Vale, Luke D; Cook, Jonathon; de Verteuil, Robyn; Milne, Anne C

2007-01-01

Background Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826 PMID:17883854

Case studies combined with or without concept maps improve critical thinking in hospital-based nurses: a randomized-controlled trial.

PubMed

Huang, Yu-Chuan; Chen, Hsing-Hsia; Yeh, Mei-Ling; Chung, Yu-Chu

2012-06-01

Critical thinking (CT) is essential to the exercise of professional judgment. As nurses face increasingly complex health-care situations, critical thinking can promote appropriate clinical decision-making and improve the quality of nursing care. This study aimed to evaluate the effects of a program of case studies, alone (CS) or combined with concept maps (CSCM), on improving CT in clinical nurses. The study was a randomized controlled trial. The experimental group participated in a 16-week CSCM program, whereas the control group participated in a CS program of equal duration. A randomized-controlled trial with a multistage randomization process was used to select and to assign participants, ultimately resulting in 67 nurses in each group. Data were collected before and after the program using the California Critical Thinking Skill Test (CCTST) and the California Critical Thinking Disposition Inventory (CCTDI). After the programs, there were significant differences between the two groups in the critical thinking skills of analysis, evaluation, inference, deduction, and induction. There was also an overall significant difference, and a significant difference in the specific disposition of open-mindedness. This study supports the application of case studies combined with concept maps as a hospital-based teaching strategy to promote development of critical thinking skills and encourage dispositions for nurses. The CSCM resulted in greater improvements in all critical thinking skills of as well as the overall and open-minded affective dispositions toward critical thinking, compared with the case studies alone. An obvious improvement in the CSCM participants was the analytic skill and disposition. Further longitudinal studies and data collection from multisite evaluations in a range of geographic locales are warranted. Copyright © 2012 Elsevier Ltd. All rights reserved.

Development of Allocentric Spatial Recall from New Viewpoints in Virtual Reality

ERIC Educational Resources Information Center

Negen, James; Heywood-Everett, Edward; Roome, Hannah E.; Nardini, Marko

2018-01-01

Using landmarks and other scene features to recall locations from new viewpoints is a critical skill in spatial cognition. In an immersive virtual reality task, we asked children 3.5-4.5 years old to remember the location of a target using various cues. On some trials they could use information from their own self-motion. On some trials they could…

Ethical Challenges of Randomized Violence Intervention Trials: Examining the SHARE intervention in Rakai, Uganda

PubMed Central

Wagman, Jennifer A.; Paul, Amy; Namatovu, Fredinah; Ssekubugu, Robert; Nalugoda, Fred

2016-01-01

Objective We identify complexities encountered, including unanticipated crossover between trial arms and inadequate ‘standard of care’ violence services, during a cluster randomized trial (CRT) of a community-level intimate partner violence (IPV) and HIV prevention intervention in Uganda. Methods Concepts in public health ethics - beneficence, social value of research, fairness, standard of care, and researcher responsibilities for post-trial benefits - are used to critically reflect on lessons learned and guide discussion on practical and ethical challenges of violence intervention CRTs. Results Existing ethical guidelines provide incomplete guidance for responding to unexpected crossover in CRTs providing IPV services. We struggled to balance duty of care with upholding trial integrity, and identifying and providing appropriate standard of care. While we ultimately offered short-term IPV services to controls, we faced additional challenges related to sustaining services beyond the ‘short-term’ and post-trial. Conclusion Studies evaluating community-level violence interventions, including those combined with HIV reduction strategies, are limited yet critical for developing evidence-based approaches for effectively preventing IPV. Although CRTs are a promising design, further guidance is needed to implement trials that avoid introducing tensions between validity of findings, researchers’ responsibilities to protect participants, and equitable distribution of CRT benefits. PMID:27453794

Malaria vaccine clinical trials: what’s on the horizon

PubMed Central

Moreno, Alberto; Joyner, Chester

2015-01-01

Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been made in the past few years with the completion of numerous clinical trials. Each trial has utilized a unique combination of antigens, delivery platforms, and adjuvants, and the data that has been obtained provides critical information that has poises the research community for the development of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P. vivax vaccine research requires more momentum and additional investigations to identify novel vaccine candidates. In this review, recently completed and ongoing malaria vaccine clinical trials as well as vaccine candidates that are in the development pipeline are reviewed. Perspectives for future research using post-genomic mining, nonhuman primate models, and systems biology are also discussed. PMID:26172291

Measuring Critical Education Processes and Outcomes: Illustration from a Cluster Randomized Trial in the Democratic Republic of the Congo

ERIC Educational Resources Information Center

Halpin, Peter F.; Torrente, Catalina

2014-01-01

Using reliable and valid measures of students' outcomes which are sensitive to change is critical for obtaining interpretable and therefore useful results from evaluations of school-based interventions. While measurement development for use in experimental evaluations receives a great deal of attention in the U.S., it lags behind in low-income…

CONSORT item reporting quality in the top ten ranked journals of critical care medicine in 2011: a retrospective analysis.

PubMed

Stevanovic, Ana; Schmitz, Sabine; Rossaint, Rolf; Schürholz, Tobias; Coburn, Mark

2015-01-01

Reporting randomised controlled trials is a key element in order to disseminate research findings. The CONSORT statement was introduced to improve the reporting quality. We assessed the adherence to the CONSORT statement of randomised controlled trials published 2011 in the top ten ranked journals of critical care medicine (ISI Web of Knowledge 2011, Thomson Reuters, London UK). Design. We performed a retrospective cross sectional data analysis. Setting. This study was executed at the University Hospital of RWTH, Aachen. Participants. We selected the following top ten listed journals according to ISI Web of Knowledge (Thomson Reuters, London, UK) critical care medicine ranking in the year 2011: American Journal of Respiratory and Critical Care Medicine, Critical Care Medicine, Intensive Care Medicine, CHEST, Critical Care, Journal of Neurotrauma, Resuscitation, Pediatric Critical Care Medicine, Shock and Minerva Anestesiologica. Main outcome measures. We screened the online table of contents of each included journal, to identify the randomised controlled trials. The adherence to the items of the CONSORT Checklist in each trial was evaluated. Additionally we correlated the citation frequency of the articles and the impact factor of the respective journal with the amount of reported items per trial. We analysed 119 randomised controlled trials and found, 15 years after the implementation of the CONSORT statement, that a median of 61,1% of the checklist-items were reported. Only 55.5% of the articles were identified as randomised trials in their titles. The citation frequency of the trials correlated significantly (rs = 0,433; p<0,001 and r = 0,331; p<0,001) to the CONSORT statement adherence. The impact factor showed also a significant correlation to the CONSORT adherence (r = 0,386; p<0,001). The reporting quality of randomised controlled trials in the field of critical care medicine remains poor and needs considerable improvement.

Basket Studies: Redefining Clinical Trials in the Era of Genome-Driven Oncology.

PubMed

Tao, Jessica J; Schram, Alison M; Hyman, David M

2018-01-29

Understanding a tumor's detailed molecular profile has become increasingly necessary to deliver the standard of care for patients with advanced cancer. Innovations in both tumor genomic sequencing technology and the development of drugs that target molecular alterations have fueled recent gains in genome-driven oncology care. "Basket studies," or histology-agnostic clinical trials in genomically selected patients, represent one important research tool to continue making progress in this field. We review key aspects of genome-driven oncology care, including the purpose and utility of basket studies, biostatistical considerations in trial design, genomic knowledgebase development, and patient matching and enrollment models, which are critical for translating our genomic knowledge into clinically meaningful outcomes.

Incorporating ethical principles into clinical research protocols: a tool for protocol writers and ethics committees.

PubMed

Li, Rebecca H; Wacholtz, Mary C; Barnes, Mark; Boggs, Liam; Callery-D'Amico, Susan; Davis, Amy; Digilova, Alla; Forster, David; Heffernan, Kate; Luthin, Maeve; Lynch, Holly Fernandez; McNair, Lindsay; Miller, Jennifer E; Murphy, Jacquelyn; Van Campen, Luann; Wilenzick, Mark; Wolf, Delia; Woolston, Cris; Aldinger, Carmen; Bierer, Barbara E

2016-04-01

A novel Protocol Ethics Tool Kit ('Ethics Tool Kit') has been developed by a multi-stakeholder group of the Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard. The purpose of the Ethics Tool Kit is to facilitate effective recognition, consideration and deliberation of critical ethical issues in clinical trial protocols. The Ethics Tool Kit may be used by investigators and sponsors to develop a dedicated Ethics Section within a protocol to improve the consistency and transparency between clinical trial protocols and research ethics committee reviews. It may also streamline ethics review and may facilitate and expedite the review process by anticipating the concerns of ethics committee reviewers. Specific attention was given to issues arising in multinational settings. With the use of this Tool Kit, researchers have the opportunity to address critical research ethics issues proactively, potentially speeding the time and easing the process to final protocol approval. 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/

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients. Protocol Version 9, 19 February 2007 known as SIGNET (Scottish Intensive care Glutamine or seleNium Evaluative Trial).

PubMed

Andrews, Peter J D; Avenell, Alison; Noble, David W; Campbell, Marion K; Battison, Claire G; Croal, Bernard L; Simpson, William G; Norrie, John; Vale, Luke D; Cook, Jonathon; de Verteuil, Robyn; Milne, Anne C

2007-09-20

Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2-3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. 2 x 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrollment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826.

The next generation of sepsis trials: What’s next after the demise of recombinant human activated Protein C?

PubMed Central

Opal, Steven M.; Dellinger, R. Phillip; Vincent, Jean-Louis; Masur, Henry; Angus, Derek C.

2014-01-01

Progress in the development of novel therapeutics to treat sepsis has come to virtual standstill. While enormous strides have been made in the understanding of basic molecular mechanisms that underlie the pathophysiology of sepsis, a distressingly long list of novel therapeutic agents have been tested in large clinical trials over the past 25 years without a single, specific, immunomodulating agent showing consistent benefit in sepsis trials. The only novel anti-sepsis agent to successfully complete a phase 3 sepsis trial, human recombinant activated protein C, was recently taken off the market after a follow up placebo-controlled trial (PROWESS SHOCK) failed to replicate the results of the initial registration trial (PROWESS) performed 10 yr earlier. We must critically re-examine our basic approach in the preclinical and clinical evaluation of new sepsis therapies. We propose 12 specific recommendations that if implemented could improve the outlook for developing new drugs for sepsis. PMID:24717456

Latino recruitment to cancer prevention/screening trials in the Southwest: setting a research agenda.

PubMed

Larkey, Linda K; Ogden, Sheryl L; Tenorio, Sally; Ewell, Teresa

2008-02-01

Examples of cancer prevention and screening trials in the Southwest are reviewed as a platform for highlighting gaps in research on Latino recruitment. Three trials are described, using "message/source/channel" categories as a framework. Each trial engaged community members to facilitate recruitment and developed tailored strategies to meet challenges emerging after recruitment began. Although we affirm that culturally relevant messages, community member referral networks, and adjustment to community realities seem important to Latino recruitment, current anecdotal and research findings do not allow evidence-based recommendations to be made. We suggest a research agenda to further illuminate critical factors for successful Latino recruitment.

Improving clinical trials in the critically ill.

PubMed

Angus, Derek C; Mira, Jean-Paul; Vincent, Jean-Louis

2010-02-01

To propose ways in which clinical trials in intensive care can be improved. An international roundtable conference was convened focused on improvement in three broad areas: translation of new knowledge from bench to bedside; design and conduct of clinical trials; and clinical trial infrastructure and environment. The roundtable recommendations were: improvement in clinical trials is a multistep process from better preclinical studies to better clinical trial methodology; new technologies should be used to improve models of critical illness; diseasomes and theragnostics will aid inpatient population selection and more appropriate targeting of interventions; broader study end points should include morbidity as well as mortality; more multicenter studies should be conducted by national and international networks or clinical trials groups; and better collaboration is needed with the industry. There was broad agreement among the roundtable participants regarding a number of explicit opportunities for the improvement of clinical trials in critical care.

The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project

PubMed Central

Guetterman, Timothy C; Fetters, Michael D; Mawocha, Samkeliso; Legocki, Laurie J; Barsan, William G; Lewis, Roger J; Berry, Donald A; Meurer, William J

2017-01-01

Objectives: Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. Methods: To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. Results: The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. Conclusion: Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development. PMID:29085638

Better infrastructure for critical care trials: nomenclature, etymology, and informatics.

PubMed

Singh, Jeffrey M; Ferguson, Niall D

2009-01-01

The goals of this review article are to review the importance and value of standardized definitions in clinical research, as well as to propose the necessary tools and infrastructure needed to advance nosology and medial taxonomy to improve the quality of clinical trials in the field of critical care. We searched MEDLINE for relevant articles, reviewed those selected and their reference lists, and consulted personal files for relevant information. When the pathobiology of diseases is well understood, standard disease definitions can be extremely specific and precise; however, when the pathobiology of the disease is less well understood or more complex, biological markers may not be diagnostically useful or even available. In these cases, syndromic definitions effectively classify and group illnesses with similar symptoms and clinical signs. There is no clear gold standard for the diagnosis of many clinical entities in the intensive care unit, including notably both acute respiratory distress syndrome and sepsis. There are several types of consensus methods that can be used to explicate the judgmental approach that is often needed in these cases, including interactive or consensus groups, the nominal group technique, and the Delphi technique. Ideally, the definition development process will create clear and unambiguous language in which each definition accurately reflects the current understanding of the disease state. The development, implementation, evaluation, revision, and reevaluation of standardized definitions are keys for advancing the quality of clinical trials in the critical care arena.

Extra Physiotherapy in Critical Care (EPICC) Trial Protocol: a randomised controlled trial of intensive versus standard physical rehabilitation therapy in the critically ill.

PubMed

Thomas, Kirsty; Wright, Stephen E; Watson, Gillian; Baker, Catherine; Stafford, Victoria; Wade, Clare; Chadwick, Thomas J; Mansfield, Leigh; Wilkinson, Jennifer; Shen, Jing; Deverill, Mark; Bonner, Stephen; Hugill, Keith; Howard, Philip; Henderson, Andrea; Roy, Alistair; Furneval, Julie; Baudouin, Simon V

2015-05-25

Patients discharged from Critical Care suffer from excessive longer term morbidity and mortality. Physical and mental health measures of quality of life show a marked and immediate fall after admission to Critical Care with some recovery over time. However, physical function is still significantly reduced at 6 months. The National Institute for Health and Care Excellence clinical guideline on rehabilitation after critical illness, identified the need for high-quality randomised controlled trials to determine the most effective rehabilitation strategy for critically ill patients at risk of critical illness-associated physical morbidity. In response to this, we will conduct a randomised controlled trial, comparing physiotherapy aimed at early and intensive patient mobilisation with routine care. We hypothesise that this intervention will improve physical outcomes and the mental health and functional well-being of survivors of critical illness. 308 adult patients who have received more than 48 h of non-invasive or invasive ventilation in Critical Care will be recruited to a patient-randomised, parallel group, controlled trial, comparing two intensities of physiotherapy. Participants will be randomised to receive either standard or intensive physiotherapy for the duration of their Critical Care admission. Outcomes will be recorded on Critical Care discharge, at 3 and 6 months following initial recruitment to the study. The primary outcome measure is physical health at 6 months, as measured by the SF-36 Physical Component Summary. Secondary outcomes include assessment of mental health, activities of daily living, delirium and ventilator-free days. We will also include a health economic analysis. The trial has ethical approval from Newcastle and North Tyneside 2 Research Ethics Committee (11/NE/0206). There is a Trial Oversight Committee including an independent chair. The results of the study will be submitted for publication in peer-reviewed journals and presented at national and international scientific meetings. ISRCTN20436833. 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.

A Critical Evaluation of the Representation of Black Patients With Heart Failure and Preserved Ejection Fraction in Clinical Trials: A Literature Review.

PubMed

Lekavich, Carolyn L; Barksdale, Debra J

2016-01-01

In the United States, heart failure costs $34.4 billion annually and is associated with a mortality rate of 20% within 5 years of diagnosis. Heart failure preserved ejection fraction (HFpEF) accounts for 50% of all hospital admissions for heart failure. Black patients develop HFpEF at a significantly earlier age than do white patients, and the 5-year mortality rate for blacks with HFpEF is 30% to 44% higher compared with white patients. Current trials may not represent black patients proportionately to the general population. The primary aim of this literature review was to critically evaluate the representation of black patients in HFpEF trials and propose solutions for future research. PubMed and CINAHL were queried for peer-reviewed journal articles from 1997 to 2014 using 2 sets of search terms that included HFpEF or preserved left ventricular function and all relevant search terms for black patients. Initially, 182 articles were identified; however, after exclusionary criteria were applied, 22 articles remained. After critical review of each article for relevance, a total of 9 articles remained for the review. For the 9 trials reviewed including a total of 63,065 patients with HFpEF, 10,436 (17%) of the patients were black. Three of the 9 trials included less than 10% black patients, 4 trials included 10% to 20% black patients, and 2 trials included greater than 20% black patients. In 2 studies, the percentage of black patients in the HFpEF trial (13% and 17%) was significantly less than the percentage of black patients in the general regional population (53% and 39%), respectively. Although the mortality rate for black patients with HFpEF is 30% to 45% higher than the rate for white patients, 2 of the 9 studies did not have a representative sample of the general HFpEF population and none of the studies reported the objective of establishing a representative study population.

A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension.

PubMed

Hylands, Mathieu; Moller, Morten Hylander; Asfar, Pierre; Toma, Augustin; Frenette, Anne Julie; Beaudoin, Nicolas; Belley-Côté, Émilie; D'Aragon, Frédérick; Laake, Jon Henrik; Siemieniuk, Reed Alexander; Charbonney, Emmanuel; Lauzier, François; Kwong, Joey; Rochwerg, Bram; Vandvik, Per Olav; Guyatt, Gordon; Lamontagne, François

2017-07-01

Clinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients. We searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects. Of 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01). Current evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.

A path to precision in the ICU.

PubMed

Maslove, David M; Lamontagne, Francois; Marshall, John C; Heyland, Daren K

2017-04-03

Precision medicine is increasingly touted as a groundbreaking new paradigm in biomedicine. In the ICU, the complexity and ambiguity of critical illness syndromes have been identified as fundamental justifications for the adoption of a precision approach to research and practice. Inherently protean diseases states such as sepsis and acute respiratory distress syndrome have manifestations that are physiologically and anatomically diffuse, and that fluctuate over short periods of time. This leads to considerable heterogeneity among patients, and conditions in which a "one size fits all" approach to therapy can lead to widely divergent results. Current ICU therapy can thus be seen as imprecise, with the potential to realize substantial gains from the adoption of precision medicine approaches. A number of challenges still face the development and adoption of precision critical care, a transition that may occur incrementally rather than wholesale. This article describes a few concrete approaches to addressing these challenges.First, novel clinical trial designs, including registry randomized controlled trials and platform trials, suggest ways in which conventional trials can be adapted to better accommodate the physiologic heterogeneity of critical illness. Second, beyond the "omics" technologies already synonymous with precision medicine, the data-rich environment of the ICU can generate complex physiologic signatures that could fuel precision-minded research and practice. Third, the role of computing infrastructure and modern informatics methods will be central to the pursuit of precision medicine in the ICU, necessitating close collaboration with data scientists. As work toward precision critical care continues, small proof-of-concept studies may prove useful in highlighting the potential of this approach.

Considerations and caveats in anti-virulence drug development

PubMed Central

Maura, Damien; Ballok, Alicia E.; Rahme, Laurence G.

2016-01-01

As antibiotic resistance remains a major public health threat, anti-virulence therapy research is gaining interest. Hundreds of potential anti-virulence compounds have been examined, but very few have made it to clinical trials and none have been approved. This review surveys the current anti-virulence research field with a focus on the highly resistant and deadly ESKAPE pathogens, especially Pseudomonas aeruginosa. We discuss timely considerations and caveats in anti-virulence drug development, including target identification, administration, preclinical development, and metrics for success in clinical trials. Development of a defined pipeline for anti-virulence agents, which differs in important ways from conventional antibiotics, is imperative for the future success of these critically needed drugs. PMID:27318551

Evaluation of a multi-center randomised clinical trial on prophylactic transfusion of fresh frozen plasma: implications for future trials.

PubMed

Müller, M C A; de Haan, R J; Vroom, M B; Juffermans, N P

2014-10-01

Prophylactic use of fresh frozen plasma (FFP) in critically ill patients with a coagulopathy is common. However, a lack of evidence of efficacy has resulted in a call for trials on the benefit of FFP in these patients. To date, conducting a trial on this subject has not been successful. Recently, a multi-center randomised trial was stopped prematurely due to slow inclusion. To assess clinicians' opinions regarding a trial on prophylactic administration of FFP in coagulopathic critically ill patients who need to undergo an intervention. A survey among 55 intensivists who all participated in a randomised trial on the risks and benefits of FFP in critically ill patients. Response rate was 84%. Majority of respondents indicated that international normalised ratio (INR) should be assessed before insertion of a central venous catheter (CVC) (61%), chest tube (89%) or tracheostomy (91%). Reasons to withhold transfusion of FFP to non-bleeding critically ill patients are risk of transfusion-related acute lung injury (TRALI) (46%), fluid overload (39%) and allergic reaction (24%). Although, the majority of respondents expressed the opinion that the trial was clinically relevant, 56% indicated that ≥1 patient subgroups should have been excluded from participation. Intensivists express the need for more evidence on the prophylactic use of FFP in coagulopathic critically ill patients. However, lack of knowledge about FFP and personal beliefs about the preferable transfusion strategy among clinicians, resulted in premature termination of a clinical trial on this topic. © 2014 British Blood Transfusion Society.

Rett Syndrome: Crossing the Threshold to Clinical Translation

PubMed Central

Katz, David M.; Bird, Adrian; Coenraads, Monica; Gray, Steven J.; Menon, Debashish U.; Philpot, Benjamin D.; Tarquinio, Daniel C.

2016-01-01

Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders. PMID:26830113

First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

PubMed

Baylis, Francoise; McLeod, Marcus

2017-01-01

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Using "clinical trial diaries" to track patterns of participation for serial healthy volunteers in U.S. phase I studies.

PubMed

Edelblute, Heather B; Fisher, Jill A

2015-02-01

Phase I testing of investigational drugs relies on healthy volunteers as research participants. Many U.S. healthy volunteers enroll repeatedly in clinical trials for the financial compensation. Serial participants are incentivized to ignore restrictions on their participation, and no centralized clinical trial registry prevents dual enrollment. Little is currently known about how healthy volunteers participate in studies over time, hampering the development of policies to protect this group. We detail a methodology developed as part of a longitudinal study to track in real-time healthy volunteers' Phase I participation. Illustrating these data through three case studies, we document how healthy volunteers use strategies, such as qualifying for studies at more than one clinic and traveling significant distances, to maximize their participation. Our findings suggest that "clinical trial diaries" can generate critical information about serial research participation and point to ethical issues unique to healthy volunteers' involvement in Phase I clinical trials. © The Author(s) 2015.

Innovative strategies for early clinical R&D.

PubMed

Butz, Robert F; Morelli, Gaetano

2008-01-01

Developments in translational medicine and regulatory initiatives associated with the FDA's Critical Path Initiative are creating new opportunities for innovation in early clinical R&D. The introduction of the exploratory IND process allows small, 'phase 0' clinical trials to be conducted prior to traditional phase I trials - sometimes requiring considerably less chemistry, manufacturing and controls, or preclinical support. Phase 0 clinical trials involving subtherapeutic, yet pharmacologically active, dose levels can provide an early demonstration of clinical proof of concept; such demonstration is of particular importance to small pharmaceutical and early-stage biotechnology companies. However, these opportunities for rapid entry into the clinic must be balanced by a consideration of the unique risks associated with first-in-human clinical trials, and by accounting for public concerns regarding drug safety in general. This feature review discusses how innovative clinical strategies can be used effectively in early drug development.

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression

PubMed Central

2012-01-01

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

Inclusion of adolescents in preventive HIV vaccine trials: public health policy and research design at a crossroads.

PubMed

Jaspan, Heather B; Cunningham, Coleen K; Tucker, Tim J P; Wright, Peter F; Self, Steve G; Sheets, Rebecca L; Rogers, Audrey S; Bekker, Linda-Gail; Wilson, Craig M; Duerr, Ann; Wasserheit, Judith N

2008-01-01

The search for a safe effective HIV vaccine has been a centerpiece of HIV research for almost 2 decades. More than 60 clinical HIV vaccine trials have been conducted to date. Several promising candidate HIV vaccines are in advanced clinical development. To date, however, no trial has included adolescents, one of the most important target groups for any preventive HIV vaccine. To license a vaccine for use in this age group, efficacy data or, at a minimum, bridging safety and immunogenicity data in this population are needed. To accomplish this, several critical issues and special challenges in the development and implementation of HIV vaccine trials in adolescents must be addressed, including regulatory considerations, potential differentials in safety and immunogenicity, alternative trial design strategies, recruitment and retention challenges, community involvement models, and approaches to informed consent/assent. This article examines these issues and proposes specific next steps to facilitate the routine inclusion of this high-priority population in preventive HIV vaccine trials as early and seamlessly as possible.

The role of nutritional support in the physical and functional recovery of critically ill patients: a narrative review.

PubMed

Bear, Danielle E; Wandrag, Liesl; Merriweather, Judith L; Connolly, Bronwen; Hart, Nicholas; Grocott, Michael P W

2017-08-26

The lack of benefit from randomised controlled trials has resulted in significant controversy regarding the role of nutrition during critical illness in terms of long-term recovery and outcome. Although methodological caveats with a failure to adequately appreciate biological mechanisms may explain these disappointing results, it must be acknowledged that nutritional support during early critical illness, when considered alone, may have limited long-term functional impact.This narrative review focuses specifically on recent clinical trials and evaluates the impact of nutrition during critical illness on long-term physical and functional recovery.Specific focus on the trial design and methodological limitations has been considered in detail. Limitations include delivery of caloric and protein targets, patient heterogeneity, short duration of intervention, inappropriate clinical outcomes and a disregard for baseline nutritional status and nutritional intake in the post-ICU period.With survivorship at the forefront of critical care research, it is imperative that nutrition studies carefully consider biological mechanisms and trial design because these factors can strongly influence outcomes, in particular long-term physical and functional outcome. Failure to do so may lead to inconclusive clinical trials and consequent rejection of the potentially beneficial effects of nutrition interventions during critical illness.

The effectiveness of problem-based learning on development of nursing students' critical thinking: a systematic review and meta-analysis.

PubMed

Kong, Ling-Na; Qin, Bo; Zhou, Ying-qing; Mou, Shao-yu; Gao, Hui-Ming

2014-03-01

The objective of this systematic review and meta-analysis was to estimate the effectiveness of problem-based learning in developing nursing students' critical thinking. Searches of PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Proquest, Cochrane Central Register of Controlled Trials (CENTRAL) and China National Knowledge Infrastructure (CNKI) were undertaken to identify randomized controlled trails from 1965 to December 2012, comparing problem-based learning with traditional lectures on the effectiveness of development of nursing students' critical thinking, with no language limitation. The mesh-terms or key words used in the search were problem-based learning, thinking, critical thinking, nursing, nursing education, nurse education, nurse students, nursing students and pupil nurse. Two reviewers independently assessed eligibility and extracted data. Quality assessment was conducted independently by two reviewers using the Cochrane Collaboration's Risk of Bias Tool. We analyzed critical thinking scores (continuous outcomes) using a standardized mean difference (SMD) or weighted mean difference (WMD) with a 95% confidence intervals (CIs). Heterogeneity was assessed using the Cochran's Q statistic and I(2) statistic. Publication bias was assessed by means of funnel plot and Egger's test of asymmetry. Nine articles representing eight randomized controlled trials were included in the meta-analysis. Most studies were of low risk of bias. The pooled effect size showed problem-based learning was able to improve nursing students' critical thinking (overall critical thinking scores SMD=0.33, 95%CI=0.13-0.52, P=0.0009), compared with traditional lectures. There was low heterogeneity (overall critical thinking scores I(2)=45%, P=0.07) in the meta-analysis. No significant publication bias was observed regarding overall critical thinking scores (P=0.536). Sensitivity analysis showed that the result of our meta-analysis was reliable. Most effect sizes for subscales of the California Critical Thinking Dispositions Inventory (CCTDI) and Bloom's Taxonomy favored problem-based learning, while effect sizes for all subscales of the California Critical Thinking Skills Test (CCTST) and most subscales of the Watson-Glaser Critical Thinking Appraisal (WCGTA) were inconclusive. The results of the current meta-analysis indicate that problem-based learning might help nursing students to improve their critical thinking. More research with larger sample size and high quality in different nursing educational contexts are required. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Mock Trial: A Dynamic Exercise for Thinking Critically about Management Theories, Topics, and Practices

ERIC Educational Resources Information Center

Farmer, Kevin; Meisel, Steven I.; Seltzer, Joe; Kane, Kathleen

2013-01-01

The Mock Trial is an experiential exercise adapted from a law school process that encourages students to think critically about theories, topics, and the practice of management in an innovative classroom experience. Playing the role of attorneys and witnesses, learners ask questions and challenge assumptions by playing roles in a trial with…

Effects of an Integrative Nursing Intervention on Pain in Critically Ill Patients: A Pilot Clinical Trial.

PubMed

Papathanassoglou, Elizabeth D E; Hadjibalassi, Maria; Miltiadous, Panagiota; Lambrinou, Ekaterini; Papastavrou, Evridiki; Paikousis, Lefkios; Kyprianou, Theodoros

2018-05-01

Pain, a persistent problem in critically ill patients, adversely affects outcomes. Despite recommendations, no evidence-based nonpharmacological approaches for pain treatment in critically ill patients have been developed. To investigate the effects of a multimodal integrative intervention on the incidence of pain and on secondary outcomes: intensity of pain, hemodynamic indices (systolic and mean arterial pressure, heart rate), anxiety, fear, relaxation, optimism, and sleep quality. A randomized, controlled, double-blinded repeated-measures trial with predetermined eligibility criteria was conducted. The intervention included relaxation, guided imagery, moderate pressure massage, and listening to music. The primary outcome was incidence of pain (score on Critical Care Pain Observation Tool > 2). Other outcomes included pain ratings, hemodynamic measurements, self-reported psychological outcomes, and quality of sleep. Repeated-measures models with adjustments (baseline levels, confounders) were used. Among the 60 randomized critically ill adults in the sample, the intervention group experienced significant decreases in the incidence ( P = .003) and ratings of pain ( P < .001). Adjusted models revealed a significant trend for lower incidence ( P = .002) and ratings ( P < .001) of pain, systolic arterial pressure ( P < .001), anxiety ( P = .01), and improved quality of sleep ( P = .02). A multimodal integrative intervention may be effective in decreasing pain and improving pain-related outcomes in critically ill patients. © 2018 American Association of Critical-Care Nurses.

Selenium and glutamine supplements: where are we heading? A critical care perspective.

PubMed

Andrews, Peter J D

2010-03-01

There is considerable interest in glutamine and selenium in critical care as both offer the potential to enhance host defences, through different but complimentary mechanisms and may reduce subsequent infections and mortality. The SIGNET trial (randomized controlled factorial trial) is the largest, critical care study of both supplements. The data have been presented publicly, but the data are not published or available for review and will therefore not be discussed fully in this update. In the present review I will explore the recently available (past 1-2 years) published literature. The current literature demonstrates that there are currently insufficient data to enable confident recommendations on the optimal route, timing, duration and dosage of each of these nutritional supplements. The pending results of SIGNET, the largest critical care trial of parenteral nutrition supplemented by glutamine and or selenium promises to clarify some of the current ambiguities and inform future practice. To be able to confidently establish or refute the hypothesis that either glutamine or selenium alone or in combination improves outcome in critical care requires a well designed prospective randomized controlled trial. To design such a trial we require the optimal dose and duration of the nutritional supplement (balancing efficacy and toxicity, ease of administration and cost) and then conduct an adequately powered trial. Such a trial is still lacking for these two agents. There are some supportive data for selenium but the case is less strong for parenteral glutamine and weakest for enteral glutamine.

A review of evidence of health benefit from artificial neural networks in medical intervention.

PubMed

Lisboa, P J G

2002-01-01

The purpose of this review is to assess the evidence of healthcare benefits involving the application of artificial neural networks to the clinical functions of diagnosis, prognosis and survival analysis, in the medical domains of oncology, critical care and cardiovascular medicine. The primary source of publications is PUBMED listings under Randomised Controlled Trials and Clinical Trials. The rĵle of neural networks is introduced within the context of advances in medical decision support arising from parallel developments in statistics and artificial intelligence. This is followed by a survey of published Randomised Controlled Trials and Clinical Trials, leading to recommendations for good practice in the design and evaluation of neural networks for use in medical intervention.

Validation of Immunohistochemical Assays for Integral Biomarkers in the NCI-MATCH EAY131 Clinical Trial.

PubMed

Khoury, Joseph D; Wang, Wei-Lien; Prieto, Victor G; Medeiros, L Jeffrey; Kalhor, Neda; Hameed, Meera; Broaddus, Russell; Hamilton, Stanley R

2018-02-01

Biomarkers that guide therapy selection are gaining unprecedented importance as targeted therapy options increase in scope and complexity. In conjunction with high-throughput molecular techniques, therapy-guiding biomarker assays based upon immunohistochemistry (IHC) have a critical role in cancer care in that they inform about the expression status of a protein target. Here, we describe the validation procedures for four clinical IHC biomarker assays-PTEN, RB, MLH1, and MSH2-for use as integral biomarkers in the nationwide NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) EAY131 clinical trial. Validation procedures were developed through an iterative process based on collective experience and adaptation of broad guidelines from the FDA. The steps included primary antibody selection; assay optimization; development of assay interpretation criteria incorporating biological considerations; and expected staining patterns, including indeterminate results, orthogonal validation, and tissue validation. Following assay lockdown, patient samples and cell lines were used for analytic and clinical validation. The assays were then approved as laboratory-developed tests and used for clinical trial decisions for treatment selection. Calculations of sensitivity and specificity were undertaken using various definitions of gold-standard references, and external validation was required for the PTEN IHC assay. In conclusion, validation of IHC biomarker assays critical for guiding therapy in clinical trials is feasible using comprehensive preanalytic, analytic, and postanalytic steps. Implementation of standardized guidelines provides a useful framework for validating IHC biomarker assays that allow for reproducibility across institutions for routine clinical use. Clin Cancer Res; 24(3); 521-31. ©2017 AACR . ©2017 American Association for Cancer Research.

Understanding health economic analysis in critical care: insights from recent randomized controlled trials.

PubMed

Sud, Sachin; Cuthbertson, Brian H

2011-10-01

The article reviews the methods of health economic analysis (HEA) in clinical trials of critically ill patients. Emphasis is placed on the usefulness of HEA in the context of positive and 'no effect' studies, with recent examples. The need to control costs and promote effective spending in caring for the critically ill has garnered considerable attention due to the high cost of critical illness. Many clinical trials focus on short-term mortality, ignoring costs and quality of life, and fail to change clinical practice or promote efficient use of resources. Incorporating HEA into clinical trials is a possible solution. Such studies have shown some interventions, although expensive, provide good value, whereas others should be withdrawn from clinical practice. Incorporating HEA into randomized controlled trials (RCTs) requires careful attention to collect all relevant costs. Decision trees, modeling assumptions and methods for collecting costs and measuring outcomes should be planned and published beforehand to minimize bias. Costs and cost-effectiveness are potentially useful outcomes in RCTs of critically ill patients. Future RCTs should incorporate parallel HEA to provide both economic outcomes, which are important to the community, alongside patient-centered outcomes, which are important to individuals.

Physical rehabilitation interventions for adult patients during critical illness: an overview of systematic reviews

PubMed Central

Connolly, Bronwen; O'Neill, Brenda; Salisbury, Lisa; Blackwood, Bronagh

2016-01-01

Background Physical rehabilitation interventions aim to ameliorate the effects of critical illness-associated muscle dysfunction in survivors. We conducted an overview of systematic reviews (SR) evaluating the effect of these interventions across the continuum of recovery. Methods Six electronic databases (Cochrane Library, CENTRAL, DARE, Medline, Embase, and Cinahl) were searched. Two review authors independently screened articles for eligibility and conducted data extraction and quality appraisal. Reporting quality was assessed and the Grading of Recommendations Assessment, Development and Evaluation approach applied to summarise overall quality of evidence. Results Five eligible SR were included in this overview, of which three included meta-analyses. Reporting quality of the reviews was judged as medium to high. Two reviews reported moderate-to-high quality evidence of the beneficial effects of physical therapy commencing during intensive care unit (ICU) admission in improving critical illness polyneuropathy/myopathy, quality of life, mortality and healthcare utilisation. These interventions included early mobilisation, cycle ergometry and electrical muscle stimulation. Two reviews reported very low to low quality evidence of the beneficial effects of electrical muscle stimulation delivered in the ICU for improving muscle strength, muscle structure and critical illness polyneuropathy/myopathy. One review reported that due to a lack of good quality randomised controlled trials and inconsistency in measuring outcomes, there was insufficient evidence to support beneficial effects from physical rehabilitation delivered post-ICU discharge. Conclusions Patients derive short-term benefits from physical rehabilitation delivered during ICU admission. Further robust trials of electrical muscle stimulation in the ICU and rehabilitation delivered following ICU discharge are needed to determine the long-term impact on patient care. This overview provides recommendations for design of future interventional trials and SR. Trial registration number CRD42015001068. PMID:27220357

Hot topics in parenteral nutrition. Current evidence and ongoing trials on the use of glutamine in critically-ill patients and patients undergoing surgery.

PubMed

Avenell, Alison

2009-08-01

The amino acid glutamine has numerous important roles including particularly antioxidant defence, immune function, the inflammatory response, acid-base balance and N economy. The present systematic review of randomised controlled trials of nutrition support with glutamine up to August 2008 has found that parenteral glutamine in critical illness is associated with a non-significant reduction in mortality (risk ratio 0.71 (95% CI 0.49, 1.03)) and may reduce infections. However, poor study quality and the possibility of publication bias mean that these results should be interpreted with caution. There is no evidence to suggest that glutamine is harmful in terms of organ failure and parenteral glutamine may reduce the development of organ failure.

Effects of Scenery, Lighting, Glideslope, and Experience on Timing the Landing Flare

ERIC Educational Resources Information Center

Palmisano, Stephen; Favelle, Simone; Sachtler, W. L.

2008-01-01

This study examined three visual strategies for timing the initiation of the landing flare based on perceptions of either: (a) a critical height above ground level; (b) a critical runway width angle ([psi]); or (c) a critical time-to-contact (TTC) with the runway. Visual displays simulated landing approaches with trial-to-trial variations in…

Mobile critical care recovery program (m-CCRP) for acute respiratory failure survivors: study protocol for a randomized controlled trial.

PubMed

Khan, Sikandar; Biju, Ashok; Wang, Sophia; Gao, Sujuan; Irfan, Omar; Harrawood, Amanda; Martinez, Stephanie; Brewer, Emily; Perkins, Anthony; Unverzagt, Frederick W; Lasiter, Sue; Zarzaur, Ben; Rahman, Omar; Boustani, Malaz; Khan, Babar

2018-02-07

Patients admitted to intensive care units (ICU) with acute respiratory failure (ARF) face chronic complications that can impede return to normal daily function. A mobile, collaborative critical care model may enhance the recovery of ARF survivors. The Mobile Critical Care Recovery Program (m-CCRP) study is a two arm, randomized clinical trial. We will randomize 620 patients admitted to the ICU with acute respiratory failure requiring mechanical ventilation in a 1:1 ratio to one of two arms (310 patients per arm) - m-CCRP intervention versus attention control. Those in the intervention group will meet with a care coordinator after hospital discharge in predetermined intervals to aid in the recovery process. Baseline assessments and personalized goal setting will be used to develop an individualized care plan for each patient after discussion with an interdisciplinary team. The attention control arm will receive printed material and telephone reminders emphasizing mobility and management of chronic conditions. Duration of the intervention and follow-up is 12 months post-randomization. Our primary aim is to assess the efficacy of m-CCRP in improving the quality of life of ARF survivors at 12 months. Secondary aims of the study are to evaluate the efficacy of m-CCRP in improving function (cognitive, physical, and psychological) of ARF survivors and to determine the efficacy of m-CCRP in reducing acute healthcare utilization. The proposed randomized controlled trial will evaluate the efficacy of a collaborative critical care recovery program in accomplishing the Institute of Healthcare Improvement's triple aims of better health, better care, at lower cost. We have developed a collaborative critical care model to promote ARF survivors' recovery from the physical, psychological, and cognitive impacts of critical illness. In contrast to a single disease focus and clinic-based access, m-CCRP represents a comprehensive, accessible, mobile, ahead of the curve intervention, focused on the multiple aspects of the unique recovery needs of ARF survivors. NCT03053245 , clinicaltrials.gov, registered February 1, 2017.

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.

Highly effective cystic fibrosis clinical research teams: critical success factors.

PubMed

Retsch-Bogart, George Z; Van Dalfsen, Jill M; Marshall, Bruce C; George, Cynthia; Pilewski, Joseph M; Nelson, Eugene C; Goss, Christopher H; Ramsey, Bonnie W

2014-08-01

Bringing new therapies to patients with rare diseases depends in part on optimizing clinical trial conduct through efficient study start-up processes and rapid enrollment. Suboptimal execution of clinical trials in academic medical centers not only results in high cost to institutions and sponsors, but also delays the availability of new therapies. Addressing the factors that contribute to poor outcomes requires novel, systematic approaches tailored to the institution and disease under study. To use clinical trial performance metrics data analysis to select high-performing cystic fibrosis (CF) clinical research teams and then identify factors contributing to their success. Mixed-methods research, including semi-structured qualitative interviews of high-performing research teams. CF research teams at nine clinical centers from the CF Foundation Therapeutics Development Network. Survey of site characteristics, direct observation of team meetings and facilities, and semi-structured interviews with clinical research team members and institutional program managers and leaders in clinical research. Critical success factors noted at all nine high-performing centers were: 1) strong leadership, 2) established and effective communication within the research team and with the clinical care team, and 3) adequate staff. Other frequent characteristics included a mature culture of research, customer service orientation in interactions with study participants, shared efficient processes, continuous process improvement activities, and a businesslike approach to clinical research. Clinical research metrics allowed identification of high-performing clinical research teams. Site visits identified several critical factors leading to highly successful teams that may help other clinical research teams improve clinical trial performance.

Global Collaboration in Acute Care Clinical Research: Opportunities, Challenges, and Needs.

PubMed

Marshall, John C

2017-02-01

The most impactful research in critical care comes from trials groups led by clinician-investigators who study questions arising through the day-to-day care of critically ill patients. The success of this model reflects both "necessity"-the paucity of new therapies introduced through industry-led research-and "clinical reality"-nuanced modulation of standard practice can have substantial impact on clinically important outcomes. Success in a few countries has fueled efforts to build similar models around the world and to collaborate on an unprecedented scale in large international trials. International collaboration brings opportunity-the more rapid completion of clinical trials, enhanced generalizability of the results of these trials, and a focus on questions that have evoked international curiosity. It has changed practice, improved outcomes, and enabled an international response to pandemic threats. It also brings challenges. Investigators may feel threatened by the loss of autonomy inherent in collaboration, and appropriate models of academic credit are yet to be developed. Differences in culture, practice, ethical frameworks, research experience, and resource availability create additional imbalances. Patient and family engagement in research is variable and typically inadequate. Funders are poorly equipped to evaluate and fund international collaborative efforts. Yet despite or perhaps because of these challenges, the discipline of critical care is leading the world in crafting new models of clinical research collaboration that hold the promise of not only improving the care of the most vulnerable patients in the healthcare system but also transforming the way that we conduct clinical research.

Development and Pilot Trial of an Intervention to Reduce Disclosure Recipients Negative Social Reactions and Victims Psychological Distress and Problem Drinking

ClinicalTrials.gov

2018-04-06

Social Skills; Self-Criticism; Post-traumatic Stress Disorder; Depression; Alcohol Abuse; Drinking, College; Alcohol Drinking; Alcohol; Harmful Use; Social Stigma; Social Norms; Social Responsibility; Social Behavior; Empathy; Coping Skills; Coping Behavior

Rationale, timeline, study design, and protocol overview of the therapeutic hypothermia after pediatric cardiac arrest trials.

PubMed

Moler, Frank W; Silverstein, Faye S; Meert, Kathleen L; Clark, Amy E; Holubkov, Richard; Browning, Brittan; Slomine, Beth S; Christensen, James R; Dean, J Michael

2013-09-01

To describe the rationale, timeline, study design, and protocol overview of the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Multicenter randomized controlled trials. Pediatric intensive care and cardiac ICUs in the United States and Canada. Children from 48 hours to 18 years old, who have return of circulation after cardiac arrest, who meet trial eligibility criteria, and whose guardians provide written consent. Therapeutic hypothermia or therapeutic normothermia. From concept inception in 2002 until trial initiation in 2009, 7 years were required to plan and operationalize the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Two National Institute of Child Health and Human Development clinical trial planning grants (R21 and R34) supported feasibility assessment and protocol development. Two clinical research networks, Pediatric Emergency Care Applied Research Network and Collaborative Pediatric Critical Care Research Network, provided infrastructure resources. Two National Heart Lung Blood Institute U01 awards provided funding to conduct separate trials of in-hospital and out-of-hospital cardiac arrest. A pilot vanguard phase that included half the clinical sites began on March 9, 2009, and this was followed by full trial funding through 2015. Over a decade will have been required to plan, design, operationalize, and conduct the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Details described in this report, such as participation of clinical research networks and clinical trial planning grants utilization, may be of utility for individuals who are planning investigator-initiated, federally supported clinical trials.

Inadequate safety reporting in pre-eclampsia trials: a systematic evaluation.

PubMed

Duffy, Jmn; Hirsch, M; Pealing, L; Showell, M; Khan, K S; Ziebland, S; McManus, R J

2018-06-01

Randomised trials and their syntheses in meta-analyses offer a unique opportunity to assess the frequency and severity of adverse reactions. To assess safety reporting in pre-eclampsia trials. Systematic search using bibliographic databases, including Cochrane Central Register of Controlled Trials, Embase, and MEDLINE, from inception to August 2017. Randomised trials evaluating anticonvulsant or antihypertensive medication for pre-eclampsia. Descriptive statistics appraising the adequacy of adverse reaction and toxicity reporting. We included 60 randomised trials. Six trials (10%) were registered with the International Clinical Trials Registry Platform, two registry records referred to adverse reactions, stating 'safety and toleration' and 'possible side effects' would be collected. Twenty-six trials (43%) stated the frequency of withdrawals within each study arm, and five trials (8%) adequately reported these withdrawals. Adverse reactions were inconsistently reported across eligible trials: 24 (40%) reported no serious adverse reactions and 36 (60%) reported no mild adverse reactions. The methods of definition or measurement of adverse reactions were infrequently reported within published trial reports. Pre-eclampsia trials regularly omit critical information related to safety. Despite the paucity of reporting, randomised trials collect an enormous amount of safety data. Developing and implementing a minimum data set could help to improve safety reporting, permitting a more balanced assessment of interventions by considering the trade-off between the benefits and harms. National Institute for Health Research (DRF-2014-07-051), UK; Maternity Forum, Royal Society of Medicine, UK. Developing @coreoutcomes could help to improve safety reporting in #preeclampsia trials. @NIHR_DC. © 2017 Royal College of Obstetricians and Gynaecologists.

Informed consent for inclusion into clinical trials: a serious subject to note in the developing world.

PubMed

Izadi, Morteza; Fazel, Mozhgan; Nasiri-Vanashi, Taha; Saadat, Seyed Hasan; Taheri, Saeed

2012-05-01

Informed consent is a critical issue especially in conducting clinical trials that expose human life to medical or surgical interventions. It necessitates a long and complex process through which the participant is presented with all potential favorable and non-favorable consequences upon getting enrolled in the study. The process of taking informed consent is well-understood in developed countries, with every effort taken to enhance and maintain the autonomy of patients and their right to make an informed choice of whether to participate or not. This may not be the case in the developing world.The information given to patients before the trial might not be properly developed and presented, an issue that can result in serious threat to the decision-making process. On the other hand, investigators should remember that enrolling people into a trial with no potential benefit for themselves cannot be considered ethical. In the current debate, we aim to address the issue of how respectfully and ethically clinical research trials can be done on human subjects and what we can do to enhance the practice in an ethical context. Development of a system through which we could warrant all rights of study participants in all cases around the world seems far from view. However, if we are in doubt about the ethics of a clinical trial, we can ask ourselves: "what would we do, if we were in the same position our patients are in now?"

Developing translational research infrastructure and capabilities associated with cancer clinical trials.

PubMed

Hall, Jacqueline A; Brown, Robert

2013-09-27

The integration of molecular information in clinical decision making is becoming a reality. These changes are shaping the way clinical research is conducted, and as reality sets in, the challenges in conducting, managing and organising multi-disciplinary research become apparent. Clinical trials provide a platform to conduct translational research (TR) within the context of high quality clinical data accrual. Integrating TR objectives in trials allows the execution of pivotal studies that provide clinical evidence for biomarker-driven treatment strategies, targeting early drug development trials to a homogeneous and well defined patient population, supports the development of companion diagnostics and provides an opportunity for deepening our understanding of cancer biology and mechanisms of drug action. To achieve these goals within a clinical trial, developing translational research infrastructure and capabilities (TRIC) plays a critical catalytic role for translating preclinical data into successful clinical research and development. TRIC represents a technical platform, dedicated resources and access to expertise promoting high quality standards, logistical and operational support and unified streamlined procedures under an appropriate governance framework. TRIC promotes integration of multiple disciplines including biobanking, laboratory analysis, molecular data, informatics, statistical analysis and dissemination of results which are all required for successful TR projects and scientific progress. Such a supporting infrastructure is absolutely essential in order to promote high quality robust research, avoid duplication and coordinate resources. Lack of such infrastructure, we would argue, is one reason for the limited effect of TR in clinical practice beyond clinical trials.

Bayesian methodology for the design and interpretation of clinical trials in critical care medicine: a primer for clinicians.

PubMed

Kalil, Andre C; Sun, Junfeng

2014-10-01

To review Bayesian methodology and its utility to clinical decision making and research in the critical care field. Clinical, epidemiological, and biostatistical studies on Bayesian methods in PubMed and Embase from their inception to December 2013. Bayesian methods have been extensively used by a wide range of scientific fields, including astronomy, engineering, chemistry, genetics, physics, geology, paleontology, climatology, cryptography, linguistics, ecology, and computational sciences. The application of medical knowledge in clinical research is analogous to the application of medical knowledge in clinical practice. Bedside physicians have to make most diagnostic and treatment decisions on critically ill patients every day without clear-cut evidence-based medicine (more subjective than objective evidence). Similarly, clinical researchers have to make most decisions about trial design with limited available data. Bayesian methodology allows both subjective and objective aspects of knowledge to be formally measured and transparently incorporated into the design, execution, and interpretation of clinical trials. In addition, various degrees of knowledge and several hypotheses can be tested at the same time in a single clinical trial without the risk of multiplicity. Notably, the Bayesian technology is naturally suited for the interpretation of clinical trial findings for the individualized care of critically ill patients and for the optimization of public health policies. We propose that the application of the versatile Bayesian methodology in conjunction with the conventional statistical methods is not only ripe for actual use in critical care clinical research but it is also a necessary step to maximize the performance of clinical trials and its translation to the practice of critical care medicine.

Assessing the detection, reporting and investigation of adverse events in clinical trial protocols implemented in Cameroon: a documentary review of clinical trial protocols.

PubMed

Ebile, Akoh Walter; Ateudjieu, Jerome; Yakum, Martin Ndinakie; Djuidje, Marceline Ngounoue; Watcho, Pierre

2015-09-29

International guidelines recommend ethical and scientific quality standards for managing and reporting adverse events occurring during clinical trials to competent research ethics committees and regulatory authorities. The purpose of this study was to determine whether clinical trial protocols in Cameroon are developed in line with national requirements and international guidelines as far as detecting, reporting and investigating of adverse events is concerned. It was a documentary review of all approved clinical trial protocols that were submitted at the Cameroon National Ethics Committee for evaluation from 1997 through 2012. Data were extracted using a preconceived and validated grid. Protocol review process targeted the title, abstract, objectives, methodology, resources, and the chapter on safety. In total, 106 (4.9 %) clinical trial protocols were identified from 2173 protocols seen in the archive and 104 (4.8 %) included for review. Seventy six (73.1 %) trials did not include the surveillance of adverse events as part of their objective. A total of 91 (87.5 %) protocols did not budget for adverse event surveillance, 76 (73.1 %) did not have a data safety management board (DSMB), 11(10.6 %) included insurance for participants, 47 (45.2 %) did not include a case definition for serious adverse events, 33 (31.7 %) described procedures to detect adverse events, 33 (31.7 %) described procedure for reporting and 22 (21.2 %) described procedure for investigating adverse events. Most clinical trial protocols in Cameroon are developed to focus on benefits and pay little attention to harms. The development of national guidelines can improve the surveillance of adverse events in clinical trial research conducted in Cameroon. Adverse events surveillance tools and a budget are critical for an adequate planning for adverse event surveillance when developing trial protocols. Clinical trial protocols submitted in the Cameroon National Ethics Committee do not adequately plan to assess adverse events in clinical trial protocols. In order to improve on the safety of participants and marketed drug, there is a need to develop national guidelines for clinical trials by the government, and to improve evaluation procedures and monitoring of ongoing trials by the ethics committee.

The development of an innovative music therapy treatment method: trial competency through music.

PubMed

Sammons, Andrew

2014-01-01

Competence to stand trial is necessary for a defendant in criminal adjudication. Recent estimates indicate that between 50,000 and 60,000 defendants in the United States raise the question of competence each year, with approximately 20 percent found incompetent to stand trial (IST). Most of these defendants are committed to an inpatient facility for competence restoration. Although psychopharmacological intervention is a critical component of restoration, as most defendants are found incompetent because of a psychotic disorder, many other modalities of treatment are used. Traditional treatment methods include the use of standardized testing and psychoeducational group sessions. This article discusses the development of an innovative intervention using music therapy. Music as the catalyst provides a forum in which psychiatric patients are engaged and observed within a structured environment designed to address both their factual and rational knowledge and abilities to assist their attorneys in their defense. Trial competency training through a specific music therapy method called Competency Through Music (CTM) is presented, including examples of how music can be used to educate patients and assess trial competence. © 2014 American Academy of Psychiatry and the Law.

Rebuilding immunity with Remune.

PubMed

Whitfield, L

1998-01-01

Remune, an immune response therapy composed of inactivated HIV, is designed to enhance the immune system's ability to recognize and kill HIV proteins. Developed by Dr. Jonas Salk, researchers hope Remune's actions can alter the course of HIV infection and slow disease progression. Remune has gained Food and Drug Administration (FDA) approval to enter the critical Phase III trial stage. Two clinical trials are tracking Remune's immunogenicity (ability to provoke an immune response), its immunogenicity relative to dose level, and its effect on viral load. An ongoing trial, approved in February of 1996, enrolled 2,500 patients at 74 sites. The manufacturer, Immune Response Corporation (IRC), announced earlier this year that treatment with Remune induces an immune response to HIV that cross-reacts with different strains of the virus. This immune response is crucial for developing an effective worldwide treatment. Remune decreases levels of tumor necrosis factor alpha (TNF-a). IRC recently began a Phase I clinical trial in Great Britain that combines Remune with a protease inhibitor, two antiviral nucleoside analogues, and Interleukin-2. The trial is designed to determine the role that the drug may play in restoring immune response.

A Review of Clinical Trials in Spinal Cord Injury including Biomarkers.

PubMed

Badhiwala, Jetan H; Wilson, Jefferson R; Kwon, Brian K; Casha, Steve; Fehlings, Michael G

2018-06-11

Acute traumatic spinal cord injury (SCI) entered the arena of prospective randomized clinical trials almost 40 years ago, with the undertaking of the National Acute Spinal Cord Study (NASCIS) I trial. Since then, a number of clinical trials have been conducted in the field, spurred by the devastating physical, social, and economic consequences of acute SCI for patients, families, and society at large. Many of these have been controversial and attracted criticism. The current review provides a critical summary of select past and current clinical trials in SCI, focusing in particular on the findings of prospective randomized controlled trials (RCTs), the challenges and barriers encountered, and the valuable lessons learned that can be applied to future trials.

Clinical effectiveness of a silicone foam dressing for the prevention of heel pressure ulcers in critically ill patients: Border II Trial.

PubMed

Santamaria, N; Gerdtz, M; Liu, W; Rakis, S; Sage, S; Ng, A W; Tudor, H; McCann, J; Vassiliou, T; Morrow, F; Smith, K; Knott, J; Liew, D

2015-08-01

Critically ill patients are at high risk of developing pressure ulcers (PU), with the sacrum and heels being highly susceptible to pressure injuries. The objective of our study was to evaluate the clinical effectiveness of a new multi-layer, self-adhesive soft silicone foam heel dressing to prevent PU development in trauma and critically ill patients in the intensive care unit (ICU). A cohort of critically ill patients were enrolled at the Royal Melbourne Hospital. Each patient had the multi-layer soft silicone foam dressing applied to each heel on admission to the emergency department. The dressings were retained with a tubular bandage for the duration of the patients' stay in the ICU. The skin under the dressings was examined daily and the dressings were replaced every three days. The comparator for our cohort study was the control group from the recently completed Border Trial. Of the 191 patients in the initial cohort, excluding deaths, loss to follow-up and transfers to another ward, 150 patients were included in the final analysis. There was no difference in key demographic or physiological variables between the cohorts, apart from a longer ICU length of stay for our current cohort. No PUs developed in any of our intervention cohort patients compared with 14 patients in the control cohort (n=152; p<0.001) who developed a total of 19 heel PUs. We conclude, based on our results, that the multi-layer soft silicone foam dressing under investigation was clinically effective in reducing ICU-acquired heel PUs. The findings also support previous research on the clinical effectiveness of multi-layer soft silicone foam dressings for PU prevention in the ICU.

A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial

PubMed Central

2011-01-01

Background Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes. Methods/Design A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates. Discussion Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic. Trial Registration Number ISRCTN45190901 PMID:21388549

Ensuring Quality in AFRINEST and SATT

PubMed Central

2013-01-01

Background: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. Methods: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Conclusions: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials’ results. PMID:23945575

Adverse event reporting in cancer clinical trial publications.

PubMed

Sivendran, Shanthi; Latif, Asma; McBride, Russell B; Stensland, Kristian D; Wisnivesky, Juan; Haines, Lindsay; Oh, William K; Galsky, Matthew D

2014-01-10

Reporting adverse events is a critical element of a clinical trial publication. In 2003, the Consolidated Standards of Reporting Trials (CONSORT) group generated recommendations regarding the appropriate reporting of adverse events. The degree to which these recommendations are followed in oncology publications has not been comprehensively evaluated. A review of citations from PubMed, Medline, and Embase published between Jan 1, 2009 and December 31, 2011, identified eligible randomized, controlled phase III trials in metastatic solid malignancies. Publications were assessed for 14 adverse event-reporting elements derived from the CONSORT harms extension statement; a completeness score (range, 0 to 14) was calculated by adding the number of elements reported. Linear regression analysis identified which publication characteristics associated with reporting completeness. A total of 175 publications, with data for 96,125 patients, were included in the analysis. The median completeness score was eight (range, three to 12). Most publications (96%) reported only adverse events occurring above a threshold rate or severity, 37% did not specify the criteria used to select which adverse events were reported, and 88% grouped together adverse events of varying severity. Regression analysis revealed that trials without a stated funding source and with an earlier year of publication had significantly lower completeness scores. Reporting of adverse events in oncology publications of randomized trials is suboptimal and characterized by substantial selectivity and heterogeneity. The development of oncology-specific standards for adverse event reporting should be established to ensure consistency and provide critical information required for medical decision-making.

Thromboprophylaxis using combined intermittent pneumatic compression and pharmacologic prophylaxis versus pharmacologic prophylaxis alone in critically ill patients: study protocol for a randomized controlled trial.

PubMed

Arabi, Yaseen M; Alsolamy, Sami; Al-Dawood, Abdulaziz; Al-Omari, Awad; Al-Hameed, Fahad; Burns, Karen E A; Almaani, Mohammed; Lababidi, Hani; Al Bshabshe, Ali; Mehta, Sangeeta; Al-Aithan, Abdulsalam M; Mandourah, Yasser; Almekhlafi, Ghaleb; Finfer, Simon; Abdukahil, Sheryl Ann I; Afesh, Lara Y; Dbsawy, Maamoun; Sadat, Musharaf

2016-08-03

Venous thromboembolism (VTE) remains a common problem in critically ill patients. Pharmacologic prophylaxis is currently the standard of care based on high-level evidence from randomized controlled trials. However, limited evidence exists regarding the effectiveness of intermittent pneumatic compression (IPC) devices. The Pneumatic compREssion for preventing VENous Thromboembolism (PREVENT trial) aims to determine whether the adjunct use of IPC with pharmacologic prophylaxis compared to pharmacologic prophylaxis alone in critically ill patients reduces the risk of VTE. The PREVENT trial is a multicenter randomized controlled trial, which will recruit 2000 critically ill patients from over 20 hospitals in three countries. The primary outcome is the incidence of proximal lower extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the scans are blinded to intervention allocation, whereas the patients and caregivers are unblinded. The trial has 80 % power to detect a 3 % absolute risk reduction in proximal DVT from 7 to 4 %. The first patient was enrolled in July 2014. As of May 2015, a total of 650 patients have been enrolled from 13 centers in Saudi Arabia, Canada and Australia. The first interim analysis is anticipated in July 2016. We expect to complete recruitment by 2018. Clinicaltrials.gov: NCT02040103 (registered on 3 November 2013). Current controlled trials: ISRCTN44653506 (registered on 30 October 2013).

Measuring symptoms as a critical component of drug development and evaluation in hematological diseases

PubMed Central

Williams, Loretta A; Yucel, Emre; Cortes, Jorge E; Cleeland, Charles S

2014-01-01

With the rapid development of new therapies for patients with hematological malignancies, there is an increasing need for patient report of symptom status during all phases of drug testing. The patient’s perspective on new treatments reflects treatment tolerability as well as symptom benefit, and may assist patients and clinicians in choosing treatments. Inclusion of patient-reported outcomes, more common in solid-tumor than hematological trials, provides early information about symptoms to guide decisions about appropriate dosing and supportive care needs. We provide a historical overview of the use of patient-reported outcomes and symptom assessment in solid-tumor and hematological drug development, and offer recommendations about methodological issues in the monitoring of symptoms in the drug development process in hematological clinical trials. PMID:24910769

The role of occupational and physiotherapy in multi-modal approach to tackling delirium in the intensive care

PubMed Central

Chee, Nigel

2017-01-01

The presence of delirium within critical care remains a long-standing challenge for patients and clinicians alike. A myriad of pre-disposing and precipitating factors lead to this patient cohort being high risk for developing delirium during their critical care stay. Until now, non-pharmacological management of these patients usually encompasses a ‘bundle’ of principles to reduce delirium days. These bundles have limited focus on the entire multi-disciplinary team (including occupational therapists and physiotherapists) who could assist with the reduction of delirium. The purpose of this analysis is to review the current literature and develop a mnemonic, which may help facilitate collaborative working for patients with delirium. Electronic databases were searched for non-pharmacological managements of delirium within intensive care settings, after 2006. Critical appraisal using Critical Appraisal Skills Programme methodology was completed by the author. Multi-intervention approaches and bundles are successful at reducing delirium days, and in some cases, reducing hospital length of stay. The key components of these bundles include spontaneous breathing trials, daily sedation holds, addressing pain relief, early mobilisation and to a small extent normalisation of a daily routine. There is limited research into the role of therapy within this patient group, but there is a role for cognitive therapy, functional tasks, and a greater rehab emphasis within other patient populations such as stroke and elderly care. The critical care population have similar rehabilitation needs to these groups, and therefore would benefit from similar treatment plans. Critical care patients with delirium may benefit from a range of additional therapeutic activities to reduce the duration of delirium. The D.E.L.I.R.I.U.M mnemonic has been developed to encompass all the key elements of current delirium research in a simplistic memorable fashion. Further work is needed to trial the usefulness of the mnemonic in clinical practice to enable the entire multi-disciplinary team work collaboratively to reduce delirium with the intensive care. PMID:29123562

Practice Guidelines for Nutrition in Critically Ill Patients: A Relook for Indian Scenario.

PubMed

Mehta, Yatin; Sunavala, J D; Zirpe, Kapil; Tyagi, Niraj; Garg, Sunil; Sinha, Saswati; Shankar, Bhuvaneshwari; Chakravarti, Sanghamitra; Sivakumar, M N; Sahu, Sambit; Rangappa, Pradeep; Banerjee, Tanmay; Joshi, Anshu; Kadhe, Ganesh

2018-04-01

Intensive-care practices and settings may differ for India in comparison to other countries. While international guidelines are available to direct the use of enteral nutrition (EN), there are no recommendations specific to Indian settings. Advisory board meetings were arranged to develop the practice guidelines specific to Indian context, for the use of EN in critically ill patients and to overcome challenges in this field. Various existing guidelines, meta-analyses, randomized controlled trials, controlled trials, and review articles were reviewed for their contextual relevance and strength. A systematic grading of practice guidelines by advisory board was done based on strength of the supporting evidence. Wherever Indian studies were not available, references were taken from the international guidelines. Based on the literature review, the recommendations for developing the practice guidelines were made as per the grading criteria agreed upon by the advisory board. The recommendations were to address challenges regarding EN versus parenteral nutrition; nutrition screening and assessment; nutrition in hemodynamically unstable; route of nutrition; tube feeding and challenges; tolerance; optimum calorie-protein requirements; selection of appropriate enteral feeding formula; micronutrients and immune-nutrients; standard nutrition in hepatic, renal, and respiratory diseases and documentation of nutrition practices. This paper summarizes the optimum nutrition practices for critically ill patients. The possible solutions to overcome the challenges in this field are presented as practice guidelines at the end of each section. These guidelines are expected to provide guidance in critical care settings regarding appropriate critical-care nutrition practices and to set up Intensive Care Unit nutrition protocols.

Practice Guidelines for Nutrition in Critically Ill Patients: A Relook for Indian Scenario

PubMed Central

Mehta, Yatin; Sunavala, J. D.; Zirpe, Kapil; Tyagi, Niraj; Garg, Sunil; Sinha, Saswati; Shankar, Bhuvaneshwari; Chakravarti, Sanghamitra; Sivakumar, M. N.; Sahu, Sambit; Rangappa, Pradeep; Banerjee, Tanmay; Joshi, Anshu; Kadhe, Ganesh

2018-01-01

Background and Aim: Intensive-care practices and settings may differ for India in comparison to other countries. While international guidelines are available to direct the use of enteral nutrition (EN), there are no recommendations specific to Indian settings. Advisory board meetings were arranged to develop the practice guidelines specific to Indian context, for the use of EN in critically ill patients and to overcome challenges in this field. Methods: Various existing guidelines, meta-analyses, randomized controlled trials, controlled trials, and review articles were reviewed for their contextual relevance and strength. A systematic grading of practice guidelines by advisory board was done based on strength of the supporting evidence. Wherever Indian studies were not available, references were taken from the international guidelines. Results: Based on the literature review, the recommendations for developing the practice guidelines were made as per the grading criteria agreed upon by the advisory board. The recommendations were to address challenges regarding EN versus parenteral nutrition; nutrition screening and assessment; nutrition in hemodynamically unstable; route of nutrition; tube feeding and challenges; tolerance; optimum calorie-protein requirements; selection of appropriate enteral feeding formula; micronutrients and immune-nutrients; standard nutrition in hepatic, renal, and respiratory diseases and documentation of nutrition practices. Conclusion: This paper summarizes the optimum nutrition practices for critically ill patients. The possible solutions to overcome the challenges in this field are presented as practice guidelines at the end of each section. These guidelines are expected to provide guidance in critical care settings regarding appropriate critical-care nutrition practices and to set up Intensive Care Unit nutrition protocols. PMID:29743765

Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis.

PubMed

Alhazzani, Waleed; Alenezi, Farhan; Jaeschke, Roman Z; Moayyedi, Paul; Cook, Deborah J

2013-03-01

Critically ill patients may develop bleeding caused by stress ulceration. Acid suppression is commonly prescribed for patients at risk of stress ulcer bleeding. Whether proton pump inhibitors are more effective than histamine 2 receptor antagonists is unclear. To determine the efficacy and safety of proton pump inhibitors vs. histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in the ICU. We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ACPJC, CINHAL, online trials registries (clinicaltrials.gov, ISRCTN Register, WHO ICTRP), conference proceedings databases, and reference lists of relevant articles. Randomized controlled parallel group trials comparing proton pump inhibitors to histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in critically ill patients, published before March 2012. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were clinically important upper gastrointestinal bleeding and overt upper gastrointestinal bleeding; secondary outcomes were nosocomial pneumonia, ICU mortality, ICU length of stay, and Clostridium difficile infection. Trial authors were contacted for additional or clarifying information. Fourteen trials enrolling a total of 1,720 patients were included. Proton pump inhibitors were more effective than histamine 2 receptor antagonists at reducing clinically important upper gastrointestinal bleeding (relative risk 0.36; 95% confidence interval 0.19-0.68; p = 0.002; I = 0%) and overt upper gastrointestinal bleeding (relative risk 0.35; 95% confidence interval 0.21-0.59; p < 0.0001; I = 15%). There were no differences between proton pump inhibitors and histamine 2 receptor antagonists in the risk of nosocomial pneumonia (relative risk 1.06; 95% confidence interval 0.73-1.52; p = 0.76; I = 0%), ICU mortality (relative risk 1.01; 95% confidence interval 0.83-1.24; p = 0.91; I = 0%), or ICU length of stay (mean difference -0.54 days; 95% confidence interval -2.20 to 1.13; p = 0.53; I = 39%). No trials reported on C. difficile infection. In critically ill patients, proton pump inhibitors seem to be more effective than histamine 2 receptor antagonists in preventing clinically important and overt upper gastrointestinal bleeding. The robustness of this conclusion is limited by the trial methodology, differences between lower and higher quality trials, sparse data, and possible publication bias. We observed no differences between drugs in the risk of pneumonia, death, or ICU length of stay.

Assessment of Suicidal Ideation and Behavior: Report of the International Society for CNS Clinical Trials and Methodology Consensus Meeting.

PubMed

Chappell, Phillip B; Stewart, Michelle; Alphs, Larry; DiCesare, Franco; DuBrava, Sarah; Harkavy-Friedman, Jill; Lim, Pilar; Ratcliffe, Sian; Silverman, Morton M; Targum, Steven D; Marder, Stephen R

2017-06-01

To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials. Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17-18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting. Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting. Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded. All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions. © Copyright 2017 Physicians Postgraduate Press, Inc.

Impressions of Early Mobilization of Critically Ill Children-Clinician, Patient, and Family Perspectives.

PubMed

Zheng, Katina; Sarti, Aimee; Boles, Sama; Cameron, Saoirse; Carlisi, Robert; Clark, Heather; Khawaji, Adeeb; Awladthani, Saif; Al-Harbi, Samah; Choong, Karen

2018-04-11

To understand patient, family caregiver, and clinician impressions of early mobilization, the perceived barriers and facilitators to its implementation, and the use of in-bed cycling as a method of mobilization. A qualitative study, conducted as part of the Early Exercise in Critically ill Youth and Children, a preliminary Evaluation (wEECYCLE) Pilot randomized controlled trial. McMaster Children's Hospital PICU, Hamilton, ON, Canada. Clinicians (i.e., physicians, nurses, and physiotherapists), family caregivers, and capable patients age greater than or equal to 8 years old who were enrolled in a clinical trial of early mobilization in critically ill children (wEECYCLE). Semistructured, face-to-face interviews using a customized interview guide for clinicians, caregivers, and patients respectively, conducted after exposure to the early mobilization intervention. Thirty-seven participants were interviewed (19 family caregivers, four patients, and 14 clinicians). Family caregivers and clinicians described similar interrelated themes representing barriers to mobilization, namely low prioritization of mobilization by the medical team, safety concerns, the lack of physiotherapy resources, and low patient motivation. Key facilitators were family trust in the healthcare team, team engagement, an a priori belief that physical activity is important, and participation in research. Increased familiarity and specific features such as the virtual reality component and ability to execute passive and or active mobilization helped to engage critically ill children in in-bed cycling. Clinicians, patients, and families were highly supportive of mobilization in critically ill children; however, concerns were identified with respect to how and when to execute this practice. Understanding key stakeholder perspectives enables the development of strategies to facilitate the implementation of early mobilization and in-bed cycling, not just in the context of a clinical trial but also within the culture of practice in a PICU.

An Interaction-Based Approach to Enhancing Secondary School Instruction and Student Achievement

ERIC Educational Resources Information Center

Allen, Joseph; Pianta, Robert; Gregory, Anne; Mikami, Amori; Lun, Janetta

2011-01-01

Improving teaching quality is widely recognized as critical to addressing deficiencies in secondary school education, yet the field has struggled to identify rigorously evaluated teacher-development approaches that can produce reliable gains in student achievement. A randomized controlled trial of My Teaching Partner-Secondary--a Web-mediated…

Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Pediatric Critically Ill Patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition.

PubMed

Mehta, Nilesh M; Skillman, Heather E; Irving, Sharon Y; Coss-Bu, Jorge A; Vermilyea, Sarah; Farrington, Elizabeth Anne; McKeever, Liam; Hall, Amber M; Goday, Praveen S; Braunschweig, Carol

2017-07-01

This document represents the first collaboration between 2 organizations-the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine-to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and <18 years) expected to require a length of stay >2-3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.

Porous silicon for drug delivery applications and theranostics: recent advances, critical review and perspectives.

PubMed

Kumeria, Tushar; McInnes, Steven J P; Maher, Shaheer; Santos, Abel

2017-12-01

Porous silicon (pSi) engineered by electrochemical etching has been used as a drug delivery vehicle to address the intrinsic limitations of traditional therapeutics. Biodegradability, biocompatibility, and optoelectronic properties make pSi a unique candidate for developing biomaterials for theranostics and photodynamic therapies. This review presents an updated overview about the recent therapeutic systems based on pSi, with a critical analysis on the problems and opportunities that this technology faces as well as highlighting pSi's growing potential. Areas covered: Recent progress in pSi-based research includes drug delivery systems, including biocompatibility studies, drug delivery, theranostics, and clinical trials with the most relevant examples of pSi-based systems presented here. A critical analysis about the technical advantages and disadvantages of these systems is provided along with an assessment on the challenges that this technology faces, including clinical trials and investors' support. Expert opinion: pSi is an outstanding material that could improve existing drug delivery and photodynamic therapies in different areas, paving the way for developing advanced theranostic nanomedicines and incorporating payloads of therapeutics with imaging capabilities. However, more extensive in-vivo studies are needed to assess the feasibility and reliability of this technology for clinical practice. The technical and commercial challenges that this technology face are still uncertain.

Rationale, Timeline, Study Design, and Protocol Overview of the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials

PubMed Central

Moler, Frank W.; Silverstein, Faye S.; Meert, Kathleen L.; Clark, Amy E.; Holubkov, Richard; Browning, Brittan; Slomine, Beth S.; Christensen, James R.; Dean, Michael

2014-01-01

Objective To describe the rationale, timeline, study design, and protocol overview of the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Design Multicenter randomized controlled trials. Setting Pediatric intensive care and cardiac ICUs in the United States and Canada. Patients Children from 48 hours to 18 years old, who have return of circulation after cardiac arrest, who meet trial eligibility criteria, and whose guardians provide written consent. Interventions Therapeutic hypothermia or therapeutic normothermia. Measurements and Main Results From concept inception in 2002 until trial initiation in 2009, 7 years were required to plan and operationalize the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Two National Institute of Child Health and Human Development clinical trial planning grants (R21 and R34) supported feasibility assessment and protocol development. Two clinical research networks, Pediatric Emergency Care Applied Research Network and Collaborative Pediatric Critical Care Research Network, provided infrastructure resources. Two National Heart Lung Blood Institute U01 awards provided funding to conduct separate trials of in-hospital and out-of-hospital cardiac arrest. A pilot vanguard phase that included half the clinical sites began on March 9, 2009, and this was followed by full trial funding through 2015. Conclusions Over a decade will have been required to plan, design, operationalize, and conduct the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Details described in this report, such as participation of clinical research networks and clinical trial planning grants utilization, may be of utility for individuals who are planning investigator-initiated, federally supported clinical trials. PMID:23842585

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations

PubMed Central

Butler, Javed; Hamo, Carine E.; Udelson, James E.; O’Connor, Christopher; Sabbah, Hani N.; Metra, Marco; Shah, Sanjiv J.; Kitzman, Dalane W.; Teerlink, John; Bernstein, Harold S.; Brooks, Gabriel; Depre, Christophe; DeSouza, Mary M.; Dinh, Wilfried; Donovan, Mark; Frische-Danielson, Regina; Frost, Robert J.; Garza, Dahlia; Gohring, Udo-Michael; Hellawell, Jennifer; Hsia, Judith; Ishihara, Shiro; Kay-Mugford, Patricia; Koglin, Joerg; Kozinn, Marc; Larson, Christopher J.; Mayo, Martha; Gan, Li-Ming; Mugnier, Pierrre; Mushonga, Sekayi; Roessig, Lothar; Russo, Cesare; Salsali, Afshin; Satler, Carol; Shi, Victor; Ticho, Barry; van der Laan, Michael; Yancy, Clyde; Stockbridge, Norman; Gheorghiade, Mihai

2017-01-01

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue regarding the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17th 2016 represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions. PMID:28356300

Real-Time Enrollment Dashboard For Multisite Clinical Trials.

PubMed

Mattingly, William A; Kelley, Robert R; Wiemken, Timothy L; Chariker, Julia H; Peyrani, Paula; Guinn, Brian E; Binford, Laura E; Buckner, Kimberley; Ramirez, Julio

2015-10-30

Achieving patient recruitment goals are critical for the successful completion of a clinical trial. We designed and developed a web-based dashboard for assisting in the management of clinical trial screening and enrollment. We use the dashboard to assist in the management of two observational studies of community-acquired pneumonia. Clinical research associates and managers using the dashboard were surveyed to determine its effectiveness as compared with traditional direct communication. The dashboard has been in use since it was first introduced in May of 2014. Of the 23 staff responding to the survey, 77% felt that it was easier or much easier to use the dashboard for communication than to use direct communication. We have designed and implemented a visualization dashboard for managing multi-site clinical trial enrollment in two community acquired pneumonia studies. Information dashboards are a useful tool for clinical trial management. They can be used as a standalone trial information tool or included into a larger management system.

The effect of glutamine therapy on outcomes in critically ill patients: a meta-analysis of randomized controlled trials

PubMed Central

2014-01-01

Introduction Glutamine supplementation is supposed to reduce mortality and nosocomial infections in critically ill patients. However, the recently published reducing deaths due to oxidative stress (REDOX) trials did not provide evidence supporting this. This study investigated the impact of glutamine-supplemented nutrition on the outcomes of critically ill patients using a meta-analysis. Methods We searched for and gathered data from the Cochrane Central Register of Controlled Trials, MEDLINE, Elsevier, Web of Science and ClinicalTrials.gov databases reporting the effects of glutamine supplementation on outcomes in critically ill patients. We produced subgroup analyses of the trials according to specific patient populations, modes of nutrition and glutamine dosages. Results Among 823 related articles, eighteen Randomized Controlled Trials (RCTs) met all inclusion criteria. Mortality events among 3,383 patients were reported in 17 RCTs. Mortality showed no significant difference between glutamine group and control group. In the high dosage subgroup (above 0.5 g/kg/d), the mortality rate in the glutamine group was significantly higher than that of the control group (relative risk (RR) 1.18; 95% confidence interval (CI), 1.02 to 1.38; P = 0.03). In 15 trials, which included a total of 2,862 patients, glutamine supplementation reportedly affected the incidence of nosocomial infections in the critically ill patients observed. The incidence of nosocomial infections in the glutamine group was significantly lower than that of the control group (RR 0.85; 95% CI, 0.74 to 0.97; P = 0.02). In the surgical ICU subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.70; 95% CI, 0.52 to 0.94; P = 0.04). In the parental nutrition subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.83; 95% CI, 0.70 to 0.98; P = 0.03). The length of hospital stay was reported in 14 trials, in which a total of 2,777 patients were enrolled; however, the patient length of stay was not affected by glutamine supplementation. Conclusions Glutamine supplementation conferred no overall mortality and length of hospital stay benefit in critically ill patients. However, this therapy reduced nosocomial infections among critically ill patients, which differed according to patient populations, modes of nutrition and glutamine dosages. PMID:24401636

Identifying patients for clinical trials using fuzzy ternary logic expressions on HL7 messages.

PubMed

Majeed, Raphael W; Röhrig, Rainer

2011-01-01

Identifying eligible patients is one of the most critical parts of any clinical trial. The process of recruiting patients for the third phase of any clinical trial is usually done manually, informing relevant physicians or putting notes on bulletin boards. While most necessary information is already available in electronic hospital information systems, required data still has to be looked up individually. Most university hospitals make use of a dedicated communication server to distribute information from independent information systems, e.g. laboratory information systems, electronic health records, surgery planning systems. Thus, a theoretical model is developed to formally describe inclusion and exclusion criteria for each clinical trial using a fuzzy ternary logic expression. These expressions will then be used to process HL7 messages from a communication server in order to identify eligible patients.

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients.

PubMed

Andrews, Peter J D; Avenell, Alison; Noble, David W; Campbell, Marion K; Croal, Bernard L; Simpson, William G; Vale, Luke D; Battison, Claire G; Jenkinson, David J; Cook, Jonathan A

2011-03-17

To determine whether inclusion of glutamine, selenium, or both in a standard isonitrogenous, isocaloric preparation of parenteral nutrition influenced new infections and mortality among critically ill patients. Randomised, double blinded, factorial, controlled trial. Level 2 and 3 (or combined) critical care units in Scotland. All 22 units were invited, and 10 participated. 502 adults in intensive care units and high dependency units for ≥ 48 hours, with gastrointestinal failure and requiring parenteral nutrition. Parenteral glutamine (20.2 g/day) or selenium (500 μg/day), or both, for up to seven days. Primary outcomes were participants with new infections in the first 14 days and mortality. An intention to treat analysis and a prespecified analysis of patients who received ≥ 5 days of the trial intervention are presented. Secondary outcomes included critical care unit and acute hospital lengths of stay, days of antibiotic use, and modified SOFA (Sepsis-related Organ Failure Assessment) score. Selenium supplementation did not significantly affect patients developing a new infection (126/251 v 139/251, odds ratio 0.81 (95% CI 0.57 to 1.15)), except for those who had received ≥ 5 days of supplementation (odds ratio 0.53 (0.30 to 0.93)). There was no overall effect of glutamine on new infections (134/250 v 131/252, odds ratio 1.07 (0.75 to 1.53)), even if patients received ≥ 5 days of supplementation (odds ratio 0.99 (0.56 to 1.75)). Six month mortality was not significantly different for selenium (107/251 v 114/251, odds ratio 0.89 (0.62 to 1.29)) or glutamine (115/250 v 106/252, 1.18 (0.82 to 1.70)). Length of stay, days of antibiotic use, and modified SOFA score were not significantly affected by selenium or glutamine supplementation. The primary (intention to treat) analysis showed no effect on new infections or on mortality when parenteral nutrition was supplemented with glutamine or selenium. Patients who received parenteral nutrition supplemented with selenium for ≥ 5 days did show a reduction in new infections. This finding requires confirmation. Trial registration Current Controlled Trials ISRCTN87144826.

Effectiveness of a programme of exercise on physical function in survivors of critical illness following discharge from the ICU: study protocol for a randomised controlled trial (REVIVE)

PubMed Central

2014-01-01

Background Following discharge home from the ICU, patients often suffer from reduced physical function, exercise capacity, health-related quality of life and social functioning. There is usually no support to address these longer term problems, and there has been limited research carried out into interventions which could improve patient outcomes. The aim of this study is to investigate the effectiveness and cost-effectiveness of a 6-week programme of exercise on physical function in patients discharged from hospital following critical illness compared to standard care. Methods/Design The study design is a multicentre prospective phase II, allocation-concealed, assessor-blinded, randomised controlled clinical trial. Participants randomised to the intervention group will complete three exercise sessions per week (two sessions of supervised exercise and one unsupervised session) for 6 weeks. Supervised sessions will take place in a hospital gymnasium or, if this is not possible, in the participants home and the unsupervised session will take place at home. Blinded outcome assessment will be conducted at baseline after hospital discharge, following the exercise intervention, and at 6 months following baseline assessment (or equivalent time points for the standard care group). The primary outcome measure is physical function as measured by the physical functioning subscale of the Short-Form-36 health survey following the exercise programme. Secondary outcomes are health-related quality of life, exercise capacity, anxiety and depression, self efficacy to exercise and healthcare resource use. In addition, semi-structured interviews will be conducted to explore participants’ perceptions of the exercise programme, and the feasibility (safety, practicality and acceptability) of providing the exercise programme will be assessed. A within-trial cost-utility analysis to assess the cost-effectiveness of the intervention compared to standard care will also be conducted. Discussion If the exercise programme is found to be effective, this study will improve outcomes that are meaningful to patients and their families. It will inform the design of a future multicentre phase III clinical trial of exercise following recovery from critical illness. It will provide useful information which will help the development of services for patients after critical illness. Trial registration ClinicalTrials.gov NCT01463579 PMID:24767671

Effect of Omega-3 and -6 Supplementation on Language in Preterm Toddlers Exhibiting Autism Spectrum Disorder Symptoms.

PubMed

Sheppard, Kelly W; Boone, Kelly M; Gracious, Barbara; Klebanoff, Mark A; Rogers, Lynette K; Rausch, Joseph; Bartlett, Christopher; Coury, Daniel L; Keim, Sarah A

2017-11-01

Delayed language development may be an early indicator of autism spectrum disorder (ASD). Early intervention is critical for children with ASD, and the present study presents pilot data on a clinical trial of omega-3 and -6 fatty acid supplementation and language development, a secondary trial outcome, in children at risk for ASD. We randomized 31 children to receive an omega-3 and -6 supplement or a placebo for 3 months, and measured their language abilities at baseline and after supplementation. Gesture use, but not word production, increased for children in the treatment group more than children in the placebo group. These results suggest possible effectiveness of omega-3 and -6 supplementation for language development in children at risk for ASD.

Dialogues on Diversifying Clinical Trials: Successful Strategies for Engaging Women and Minorities in Clinical Trials

PubMed Central

Fadiran, Emmanuel Olutayo; Parrish, L. Jo; Griffith, Rachel A.; Weiss, Eleanor; Carter, Christine

2012-01-01

Abstract There is mounting scientific evidence pointing to genetic or physiologic distinctions between genders and among racial and ethnic groups that influence disease risk and severity and response to treatment. The diverse enrollment of subjects engaged in clinical trials research is, thus, critical to developing safer and more effective drugs and medical devices. However, in the United States, there are striking disparities in clinical trial participation. To address this problem, the Food and Drug Administration (FDA) Office of Women's Health and the Society for Women's Health Research (SWHR) together convened the 2-day meeting, Dialogues on Diversifying Clinical Trials. The conference was held in Washington, DC, on September 22–23, 2011, and brought together a wide range of speakers from clinical research, industry, and regulatory agencies. Here, we present the major findings discussed at this meeting about female and minority patients and physicians and their willingness to participate in clinical trials and the barriers that sponsors face in recruiting a diverse trial population. We also discuss some recommendations for improving trial diversity through new technologies and greater efficiency in trial regulation and review. PMID:22747427

Chemopreventive Agent Development Clinical Trials | Division of Cancer Prevention

Cancer.gov

The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

Efficacy of Language Intervention in the Early Years

ERIC Educational Resources Information Center

Fricke, Silke; Bowyer-Crane, Claudine; Haley, Allyson J.; Hulme, Charles; Snowling, Margaret J.

2013-01-01

Background: Oral language skills in the preschool and early school years are critical to educational success and provide the foundations for the later development of reading comprehension. Methods: In a randomized controlled trial, 180 children from 15 UK nursery schools ("n" = 12 from each setting; M[subscript age] = 4;0) were randomly…

DTkid: Interactive Simulation Software for Training Tutors of Children with Autism

ERIC Educational Resources Information Center

Randell, Tom; Hall, Martin; Bizo, Lewis; Remington, Bob

2007-01-01

Discrete-trial training (DTT) relies critically on implementation by trained tutors. We report three experiments carried out in the development of "DTkid"--interactive computer simulation software that presents "SIMon", a realistic virtual child with whom novice tutors can learn and practise DTT techniques. Experiments 1 and 2 exposed groups of…

Embodying self-compassion within virtual reality and its effects on patients with depression.

PubMed

Falconer, Caroline J; Rovira, Aitor; King, John A; Gilbert, Paul; Antley, Angus; Fearon, Pasco; Ralph, Neil; Slater, Mel; Brewin, Chris R

2016-01-01

Self-criticism is a ubiquitous feature of psychopathology and can be combatted by increasing levels of self-compassion. However, some patients are resistant to self-compassion. To investigate whether the effects of self-identification with virtual bodies within immersive virtual reality could be exploited to increase self-compassion in patients with depression. We developed an 8-minute scenario in which 15 patients practised delivering compassion in one virtual body and then experienced receiving it from themselves in another virtual body. In an open trial, three repetitions of this scenario led to significant reductions in depression severity and self-criticism, as well as to a significant increase in self-compassion, from baseline to 4-week follow-up. Four patients showed clinically significant improvement. The results indicate that interventions using immersive virtual reality may have considerable clinical potential and that further development of these methods preparatory to a controlled trial is now warranted. None. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) licence.

Adding value to clinical trial registries: insights from Australian Cancer Trials Online, a website for consumers.

PubMed

Dear, Rachel; Barratt, Alexandra; Askie, Lisa; McGeechan, Kevin; Arora, Sheena; Crossing, Sally; Currow, David; Tattersall, Martin

2011-02-01

Clinical trials registries are now operating in the USA, Europe, Australia, China, and India and more are planned. Trial registries could be an excellent source of information about clinical trials for patients and others affected by cancer as well as health care professionals, but may be difficult for patients to navigate and use. An opportunity arose in Australia to develop a consumer friendly cancer clinical trials website (Australian Cancer Trials Online (ACTO), www.australiancancertrials.gov.au) using an automated data feed from two large clinical trial registries. In this article, we describe aspects of this new website, and explore ways in which such a website may add value to clinical trial data which are already collected and held by trial registries. The development of ACTO was completed by a Web company working in close association with staff at the Australian New Zealand Clinical Trials Registry (ANZCTR), and with consumer representatives. Data for the website were sourced directly and only from clinical trial registries, thus avoiding the creation of an additional trials database. It receives an automated, daily data feed of newly registered cancer clinical trials from both the ANZCTR and Clinical Trials.gov. The development of ACTO exemplifies the advantage of a local clinical trial registry working with consumers to provide accessible information about cancer clinical trials to meet consumers' information needs. We found that the inclusion of a lay summary added substantial value for consumers, and recommend that consideration be given to adding a lay summary to the mandatory data items collected by all trial registries. Furthermore, improved navigation, decision support tools, and consistency in data collection between clinical trial registries will also enable consumer websites to provide additional value for users. Clinical trial registration is not compulsory in Australia. If the additional cancer items (including a lay summary) are not provided by registrants of cancer trials on ANZCTR, this can compromise the quality and usefulness of the data for the end-user, in this case consumers, as they may encounter gaps in the data. Expanding the World Health Organization Trial Registration Data Set to include this additional information, particularly the lay summary, would be valuable. A well-coordinated system of clinical trial registration is critical to the success of efforts to provide better access for all to inform about clinical trials.

Augmented real-time navigation with critical structure proximity alerts for endoscopic skull base surgery.

PubMed

Dixon, Benjamin J; Daly, Michael J; Chan, Harley; Vescan, Allan; Witterick, Ian J; Irish, Jonathan C

2014-04-01

Image-guided surgery (IGS) systems are frequently utilized during cranial base surgery to aid in orientation and facilitate targeted surgery. We wished to assess the performance of our recently developed localized intraoperative virtual endoscopy (LIVE)-IGS prototype in a preclinical setting prior to deployment in the operating room. This system combines real-time ablative instrument tracking, critical structure proximity alerts, three-dimensional virtual endoscopic views, and intraoperative cone-beam computed tomographic image updates. Randomized-controlled trial plus qualitative analysis. Skull base procedures were performed on 14 cadaver specimens by seven fellowship-trained skull base surgeons. Each subject performed two endoscopic transclival approaches; one with LIVE-IGS and one using a conventional IGS system in random order. National Aeronautics and Space Administration Task Load Index (NASA-TLX) scores were documented for each dissection, and a semistructured interview was recorded for qualitative assessment. The NASA-TLX scores for mental demand, effort, and frustration were significantly reduced with the LIVE-IGS system in comparison to conventional navigation (P < .05). The system interface was judged to be intuitive and most useful when there was a combination of high spatial demand, reduced or absent surface landmarks, and proximity to critical structures. The development of auditory icons for proximity alerts during the trial better informed the surgeon while limiting distraction. The LIVE-IGS system provided accurate, intuitive, and dynamic feedback to the operating surgeon. Further refinements to proximity alerts and visualization settings will enhance orientation while limiting distraction. The system is currently being deployed in a prospective clinical trial in skull base surgery. © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib

PubMed Central

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L.

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug’s known mechanism of action. Also, the models predict each drug’s potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets. PMID:26107615

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib.

PubMed

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.

Scientific publications in critical care medicine journals from Chinese authors: a 10-year survey of the literature.

PubMed

Li, Zhi; Liao, Zhuan; Wu, Fei-Xiang; Yang, Li-Qun; Sun, Yu-Ming; Yu, Wei-Feng

2010-10-01

People of Chinese ethnicity are the largest population in the world. Critical care medicine in China is developing rapidly and has achieved great advances in recent 20 years. The research contribution in critical care medicine among Chinese individuals in the three major regions of China--Mainland (ML), Hong Kong (HK), and Taiwan (TW)--is unknown. Articles published in 18 journals on critical care medicine originating from ML, TW, and HK from 1999 to 2008 were retrieved from the PubMed database and Science Citation Index Expanded. Quantity and quality analyses were conducted for the total numbers of articles, clinical trials, randomized controlled trials, impact factors (IF), citations, and articles published in high-impact journals. There were 932 articles from ML (268), TW (506), and HK (158) from 1999 to 2008. The annual total numbers of articles of the three regions increased gradually from 1999 to 2008 (from 57 to 157). From 2002 onward, the number of articles published from ML exceeded that from HK, but TW still has the dominance in both annual and total number of articles published compared with ML and HK. The accumulated IF of articles from TW (1676.67) was higher than that from ML (708.25) and HK (449.51). TW had the highest average IF of 3.31 followed by HK of 2.85 and ML of 2.64. HK had the highest average citations of each article of 10.73, followed by TW of 6.74 and ML of 5.34. The Journal of Trauma was the most popular journal in the three regions. The total numbers of articles in China increased markedly from 1999 to 2008. TW published the most number of articles, clinical trials, and randomised controlled trials among the three regions. The Journal of Trauma was the most popular journal in the three regions.

Co-enrollment of critically ill patients into multiple studies: patterns, predictors and consequences

PubMed Central

2013-01-01

Introduction Research on co-enrollment practices and their impact are limited in the ICU setting. The objectives of this study were: 1) to describe patterns and predictors of co-enrollment of patients in a thromboprophylaxis trial, and 2) to examine the consequences of co-enrollment on clinical and trial outcomes. Methods In an observational analysis of an international thromboprophylaxis trial in 67 ICUs, we examined the co-enrollment of critically ill medical-surgical patients into more than one study, and examined the clinical and trial outcomes among co-enrolled and non-co-enrolled patients. Results Among 3,746 patients enrolled in PROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial), 713 (19.0%) were co-enrolled in at least one other study (53.6% in a randomized trial, 37.0% in an observational study and 9.4% in both). Six factors independently associated with co-enrollment (all P < 0.001) were illness severity (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.19 to 1.53 for each 10-point Acute Physiology and Chronic Health Evaluation (APACHE) II score increase), substitute decision-makers providing consent, rather than patients (OR 3.31, 2.03 to 5.41), experience of persons inviting consent (OR 2.67, 1.74 to 4.11 for persons with > 10 years' experience compared to persons with none), center size (all ORs > 10 for ICUs with > 15 beds), affiliation with trials groups (OR 5.59, 3.49 to 8.95), and main trial rather than pilot phase (all ORs > 8 for recruitment year beyond the pilot). Co-enrollment did not influence clinical or trial outcomes or risk of adverse events. Conclusions Co-enrollment was strongly associated with features of the patients, research personnel, setting and study. Co-enrollment had no impact on trial results, and appeared safe, acceptable and feasible. Transparent reporting, scholarly discourse, ethical analysis and further research are needed on the complex topic of co-enrollment during critical illness. PMID:23298553

Co-enrollment of critically ill patients into multiple studies: patterns, predictors and consequences.

PubMed

Cook, Deborah; McDonald, Ellen; Smith, Orla; Zytaruk, Nicole; Heels-Ansdell, Diane; Watpool, Irene; McArdle, Tracy; Matte, Andrea; Clarke, France; Vallance, Shirley; Finfer, Simon; Galt, Pauline; Crozier, Tim; Fowler, Rob; Arabi, Yaseen; Woolfe, Clive; Orford, Neil; Hall, Richard; Adhikari, Neill K J; Ferland, Marie-Clauide; Marshall, John; Meade, Maureen

2013-01-08

Research on co-enrollment practices and their impact are limited in the ICU setting. The objectives of this study were: 1) to describe patterns and predictors of co-enrollment of patients in a thromboprophylaxis trial, and 2) to examine the consequences of co-enrollment on clinical and trial outcomes. In an observational analysis of an international thromboprophylaxis trial in 67 ICUs, we examined the co-enrollment of critically ill medical-surgical patients into more than one study, and examined the clinical and trial outcomes among co-enrolled and non-co-enrolled patients. Among 3,746 patients enrolled in PROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial), 713 (19.0%) were co-enrolled in at least one other study (53.6% in a randomized trial, 37.0% in an observational study and 9.4% in both). Six factors independently associated with co-enrollment (all P < 0.001) were illness severity (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.19 to 1.53 for each 10-point Acute Physiology and Chronic Health Evaluation (APACHE) II score increase), substitute decision-makers providing consent, rather than patients (OR 3.31, 2.03 to 5.41), experience of persons inviting consent (OR 2.67, 1.74 to 4.11 for persons with > 10 years' experience compared to persons with none), center size (all ORs > 10 for ICUs with > 15 beds), affiliation with trials groups (OR 5.59, 3.49 to 8.95), and main trial rather than pilot phase (all ORs > 8 for recruitment year beyond the pilot). Co-enrollment did not influence clinical or trial outcomes or risk of adverse events. Co-enrollment was strongly associated with features of the patients, research personnel, setting and study. Co-enrollment had no impact on trial results, and appeared safe, acceptable and feasible. Transparent reporting, scholarly discourse, ethical analysis and further research are needed on the complex topic of co-enrollment during critical illness.

[Development of competency to stand trial rating scale in offenders with mental disorders].

PubMed

Chen, Xiao-Bing; Cai, Wei-Xiong

2013-04-01

According with Chinese legal system, to develop a competency to stand trial rating scale in offenders with mental disorders. Proceeding from the juristical elements, 15 items were extracted and formulated a preliminary instrument named the competency to stand trial rating scale in offenders with mental disorders. The item analysis included six aspects, which were critical ratio, item-total correlation, corrected item-total correlation, alpha value if item deleted, communalities of items, and factor loading. The Logistic regression equation and cut-off score of ROC curve were used to explore the diagnostic efficiency. The data of critical ratio of extreme group were 18.390-46.763; item-total correlation, 0.639-0.952; corrected item-total correlation, 0.582-0.944; communalities of items, 0.377-0.916; and factor loadings, 0.614-0.957. Seven items were included in the regression equation and the accuracy of back substitution test was 96.0%. The score of 33 was ascertained as the cut-off score by ROC fitting curve, the overlapping ratio compared with the expertise was 95.8%. The sensibility and the specificity were 0.938 and 0.966, respectively, while the positive and negative likelihood ratios were 27.67 and 0.06, respectively. With all items satisfied the requirement of homogeneity test, the rating scale has a reasonable construct and excellent diagnostic efficiency.

Edgewood Chemical Biological Center In-House Laboratory Independent Research Program Annual Report FY11

DTIC Science & Technology

2011-01-01

flow rates which were held constant from trial to trial by critical orifices, were checked with several different calibrated mass flow meters. None of...processes or products in mind”. ECBC views the ILIR program as a critical part of its efforts to ensure a high level of basic science, foster innovation in...missions. The ILIR program solicits innovative proposals from the Center’s principal investigators (PI) that correspond to ECBC’s critical core

HIV vaccine research--South Africa's ethical-legal framework and its ability to promote the welfare of trial participants.

PubMed

Strode, Ann; Slack, Catherine; Mushariwa, Muriel

2005-08-01

An effective ethical-legal framework for the conduct of research is critical. We describe five essential components of such a system, review the extent to which these components have been realised in South Africa, present brief implications for the ethical conduct of clinical trials of HIV vaccines in South Africa and make recommendations. The components of an effective ethical-legal system that we propose are the existence of scientific ethical and policy-making structures that regulate research; research ethics committees (RECs) that ethically review research; national ethical guidelines and standards; laws protecting research participants; and mechanisms to enforce and monitor legal rights and ethical standards. We conclude that the ethical-legal framework has, for the most part, the necessary institutions, and certain necessary guidelines but does not have many of the laws needed to protect and promote the rights of persons participating in research, including HIV vaccine trials. Recommendations made include advocacy measures to finalise and implement legislation, development of regulations, analysis and comparison of ethical guidelines, and the development of measures to monitor ethical-legal rights at trial sites.

Use of the PiCCO system in critically ill patients with septic shock and acute respiratory distress syndrome: a study protocol for a randomized controlled trial.

PubMed

Zhang, Zhongheng; Xu, Xiao; Yao, Min; Chen, Huilan; Ni, Hongying; Fan, Haozhe

2013-02-01

Hemodynamic monitoring is very important in critically ill patients with shock or acute respiratory distress syndrome(ARDS). The PiCCO (Pulse index Contour Continuous Cardiac Output, Pulsion Medical Systems, Germany) system has been developed and used in critical care settings for several years. However, its impact on clinical outcomes remains unknown. The study is a randomized controlled multi-center trial. A total of 708 patients with ARDS, septic shock or both will be included from January 2012 to January 2014. Subjects will be randomized to receive PiCCO monitoring or not. Our primary end point is 30-day mortality, and secondary outcome measures include ICU length of stay, days on mechanical ventilation, days of vasoactive agent support, ICU-free survival days during a 30-day period, mechanical-ventilation-free survival days during a 30-day period, and maximum SOFA score during the first 7 days. We investigate whether the use of PiCCO monitoring will improve patient outcomes in critically ill patients with ARDS or septic shock. This will provide additional data on hemodynamic monitoring and help clinicians to make decisions on the use of PiCCO. http://www.clinicaltrials.gov NCT01526382.

Current trials to reduce surgical intervention in ductal carcinoma in situ of the breast: Critical review.

PubMed

Toss, M; Miligy, I; Thompson, A M; Khout, H; Green, A R; Ellis, I O; Rakha, E A

2017-10-01

The high proportion of ductal carcinoma in situ (DCIS) presented in mammographic screening and the relatively low risk of progression to invasive disease have raised questions related to overtreatment. Following a review of current DCIS management protocols a more conservative approach has been suggested. Clinical trials have been introduced to evaluate the option of avoiding surgical intervention in a proportion of patients with DCIS defined as "low-risk" using certain clinicopathological criteria. These trials can potentially provide evidence-based models of active surveillance (with or without endocrine therapy) as a future management approach. Despite the undisputable fact of our need to address the obvious overtreatment of screen-detected DCIS, some important questions need to be considered regarding these trials including the eligibility criteria and definition of risk, the proportion of patient eligible for inclusion, and the length of time required for proper analysis of the trials' outcome in view of the long-term natural history of DCIS progression particularly the low-risk group. These factors can potentially affect the practicality and future impact of such trials. This review provides critical analysis of current DCIS management trials and highlights critical issues related to their practicality and the expected outcome. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bayesian hierarchical modeling for detecting safety signals in clinical trials.

PubMed

Xia, H Amy; Ma, Haijun; Carlin, Bradley P

2011-09-01

Detection of safety signals from clinical trial adverse event data is critical in drug development, but carries a challenging statistical multiplicity problem. Bayesian hierarchical mixture modeling is appealing for its ability to borrow strength across subgroups in the data, as well as moderate extreme findings most likely due merely to chance. We implement such a model for subject incidence (Berry and Berry, 2004 ) using a binomial likelihood, and extend it to subject-year adjusted incidence rate estimation under a Poisson likelihood. We use simulation to choose a signal detection threshold, and illustrate some effective graphics for displaying the flagged signals.

Implementing post-trial access plans for HIV prevention research.

PubMed

Paul, Amy; Merritt, Maria W; Sugarman, Jeremy

2018-05-01

Ethics guidance increasingly recognises that researchers and sponsors have obligations to consider provisions for post-trial access (PTA) to interventions that are found to be beneficial in research. Yet, there is little information regarding whether and how such plans can actually be implemented. Understanding practical experiences of developing and implementing these plans is critical to both optimising their implementation and informing conceptual work related to PTA. This viewpoint is informed by experiences with developing and implementing PTA plans for six large-scale multicentre HIV prevention trials supported by the HIV Prevention Trials Network. These experiences suggest that planning and implementing PTA often involve challenges of planning under uncertainty and confronting practical barriers to accessing healthcare systems. Even in relatively favourable circumstances where a tested intervention medication is approved and available in the local healthcare system, system-level barriers can threaten the viability of PTA plans. The aggregate experience across these HIV prevention trials suggests that simply referring participants to local healthcare systems for PTA will not necessarily result in continued access to beneficial interventions for trial participants. Serious commitments to PTA will require additional efforts to learn from future approaches, measuring the success of PTA plans with dedicated follow-up and further developing normative guidance to help research stakeholders navigate the complex practical challenges of realising PTA. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Failures in Phase III: Causes and Consequences.

PubMed

Seruga, Bostjan; Ocana, Alberto; Amir, Eitan; Tannock, Ian F

2015-10-15

Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients. ©2015 American Association for Cancer Research.

Developing Consensus-Based Priority Outcome Domains for Trials in Kidney Transplantation: A Multinational Delphi Survey With Patients, Caregivers, and Health Professionals.

PubMed

Sautenet, Bénédicte; Tong, Allison; Manera, Karine E; Chapman, Jeremy R; Warrens, Anthony N; Rosenbloom, David; Wong, Germaine; Gill, John; Budde, Klemens; Rostaing, Lionel; Marson, Lorna; Josephson, Michelle A; Reese, Peter P; Pruett, Timothy L; Hanson, Camilla S; O'Donoghue, Donal; Tam-Tham, Helen; Halimi, Jean-Michel; Shen, Jenny I; Kanellis, John; Scandling, John D; Howard, Kirsten; Howell, Martin; Cross, Nick; Evangelidis, Nicole; Masson, Philip; Oberbauer, Rainer; Fung, Samuel; Jesudason, Shilpa; Knight, Simon; Mandayam, Sreedhar; McDonald, Stephen P; Chadban, Steve; Rajan, Tasleem; Craig, Jonathan C

2017-08-01

Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondents' scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically. One thousand eighteen participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, ≥7.5; median, ≥8; proportion, >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin), and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified 5 themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.

What attitudes and beliefs underlie patients' decisions about participating in chemotherapy trials?

PubMed

Sutherland, H J; da Cunha, R; Lockwood, G A; Till, J E

1998-01-01

The theory of reasoned action, which postulates that personal attitudes and external social influences predict intentions to undertake a behavior, was used as a conceptual framework for developing a questionnaire to elicit beliefs and attitudes associated with the decision to participate in a hypothetical cancer chemotherapy trial. After completing the questionnaire, two-thirds of the 150 respondents indicated they would enroll in such a trial if it were available. Considerable variation existed in both "universal" and "trial-specific" beliefs and attitudes underpinning their intentions. A substantial amount of the variance in "intention" to participate was explained by "attitude" alone (75%). Social influences, although statistically significant, made a mere 1% additional contribution. One interpretation is that subjective expected-utility theory, which essentially predicts beliefs or "attitude," is a better model. The authors conclude that both theories may be criticized regarding how well they capture the rationality and nuances of decision behavior.

Major publications in the critical care pharmacotherapy literature: January-December 2017.

PubMed

Hammond, Drayton A; Baumgartner, Laura; Cooper, Craig; Donahey, Elisabeth; Harris, Serena A; Mercer, Jessica M; Morris, Mandy; Patel, Mona K; Plewa-Rusiecki, Angela M; Poore, Alia A; Szaniawski, Ryan; Horner, Deanna

2018-06-01

To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2017. The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 32 journals monthly for impactful articles and reviewed 115 during 2017. Two meta-analyses and eight original research trials were reviewed here from those included in the monthly CCPLU. Meta-analyses on early, goal-directed therapy for septic shock and statin therapy for acute respiratory distress syndrome were summarized. Original research trials that were included evaluate thrombolytic therapy in severe stroke, hyperoxia and hypertonic saline in septic shock, intraoperative ketamine for prevention of post-operative delirium, intravenous ketorolac dosing regimens for acute pain, angiotensin II for vasodilatory shock, dabigatran reversal with idarucizumab, bivalirudin versus heparin monotherapy for myocardial infarction, and balanced crystalloids versus saline fluid resuscitation. This clinical review provides perspectives on impactful critical care pharmacotherapy publications in 2017. Copyright © 2018 Elsevier Inc. All rights reserved.

Animal research as a basis for clinical trials.

PubMed

Faggion, Clovis M

2015-04-01

Animal experiments are critical for the development of new human therapeutics because they provide mechanistic information, as well as important information on efficacy and safety. Some evidence suggests that authors of animal research in dentistry do not observe important methodological issues when planning animal experiments, for example sample-size calculation. Low-quality animal research directly interferes with development of the research process in which multiple levels of research are interconnected. For example, high-quality animal experiments generate sound information for the further planning and development of randomized controlled trials in humans. These randomized controlled trials are the main source for the development of systematic reviews and meta-analyses, which will generate the best evidence for the development of clinical guidelines. Therefore, adequate planning of animal research is a sine qua non condition for increasing efficacy and efficiency in research. Ethical concerns arise when animal research is not performed with high standards. This Focus article presents the latest information on the standards of animal research in dentistry, more precisely in the field of implant dentistry. Issues on precision and risk of bias are discussed, and strategies to reduce risk of bias in animal research are reported. © 2015 Eur J Oral Sci.

A brief history of the global effort to develop a preventive HIV vaccine.

PubMed

Esparza, José

2013-08-02

Soon after HIV was discovered as the cause of AIDS in 1983-1984, there was an expectation that a preventive vaccine would be rapidly developed. In trying to achieve that goal, three successive scientific paradigms have been explored: induction of neutralizing antibodies, induction of cell mediated immunity, and exploration of combination approaches and novel concepts. Although major progress has been made in understanding the scientific basis for HIV vaccine development, efficacy trials have been critical in moving the field forward. In 2009, the field was reinvigorated with the modest results obtained from the RV144 trial conducted in Thailand. Here, we review those vaccine development efforts, with an emphasis on events that occurred during the earlier years. The goal is to provide younger generations of scientists with information and inspiration to continue the search for an HIV vaccine. Copyright © 2013 The Author. Published by Elsevier Ltd.. All rights reserved.

Clinical Trials in Late Life: New Science in Old Paradigms

ERIC Educational Resources Information Center

Lebowitz, Barry D.

2004-01-01

This article, based on a Lawton Award Lecture, addresses the subject of the need to enhance the evidence base in our field in order to influence processes of policy development. Four issues are identified as critical to this: theory-driven targets of public health significance, use of appropriate and sophisticated approaches to research design and…

Preventing Adolescent Social Anxiety and Depression and Reducing Peer Victimization: Intervention Development and Open Trial

ERIC Educational Resources Information Center

La Greca, Annette M.; Ehrenreich-May, Jill; Mufson, Laura; Chan, Sherilynn

2016-01-01

Background: Social anxiety disorder (SAD) and depression are common among adolescents, frequently comorbid, and resistant to change. Prevention programs for adolescent SAD are scant, and depression prevention programs do not fully address peer-risk factors. One critical peer-risk factor for SAD and depression is peer victimization. We describe the…

Reliability of Eye Tracking and Pupillometry Measures in Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Farzin, Faraz; Scaggs, Felicia; Hervey, Crystal; Berry-Kravis, Elizabeth; Hessl, David

2011-01-01

Recent insight into the underlying molecular and cellular mechanisms of fragile X syndrome (FXS) has led to the proposal and development of new pharmaceutical treatment strategies, and the initiation of clinical trials aimed at correcting core symptoms of the developmental disorder. Consequently, there is an urgent and critical need for outcome…

Justice by the People. Teacher's Guide.

ERIC Educational Resources Information Center

Hart, Diane; Alderson, Jan, Ed.

This interactive curriculum has been developed to teach students about one of their most important rights as citizens, trial by jury. Knowledge about this right is critical since most of today's students will be called to serve on juries at some point in their lives. The curriculum's goal is to help students understand the history and value of…

Levosimendan in Critical Illness: A Literature Review

PubMed Central

Pierrakos, Charalampos; Velissaris, Dimitrios; Franchi, Federico; Muzzi, Luigi; Karanikolas, Menelaos; Scolletta, Sabino

2014-01-01

Levosimendan, the active enantiomer of simendan, is a calcium sensitizer developed for treatment of decompensated heart failure, exerts its effects independently of the beta adrenergic receptor and seems beneficial in cases of severe, intractable heart failure. Levosimendan is usually administered as 24-h infusion, with or without a loading dose, but dosing needs adjustment in patients with severe liver or renal dysfunction. Despite several promising reports, the role of levosimendan in critical illness has not been thoroughly evaluated. Available evidence suggests that levosimendan is a safe treatment option in critically ill patients and may reduce mortality from cardiac failure. However, data from well-designed randomized controlled trials in critically ill patients are needed to validate or refute these preliminary conclusions. This literature review is an attempt to synthesize available evidence on the role and possible benefits of levosimendan in critically ill patients with severe heart failure. PMID:24578748

Competency to stand trial evaluations: a study of actual practice in two states.

PubMed

Robbins, E; Waters, J; Herbert, P

1997-01-01

A criminal defendant must be competent to stand trial (CST) to safeguard the fundamental right to a fair trial. If there is a question as to a defendant's ability to assist in his or her own defense, a mental health professional is asked to perform a CST evaluation. Forensic assessment is a growing field, and CST is the most frequent evaluation requested. Over the years, forensic examiners' reports to the courts have been criticized for lack of relevance, insufficiency, and invading the province of the judge. If mental health professionals wish to advance the field of forensic assessment and respond to these criticisms, research on current practice with suggestions for advancement are necessary. A total of 66 CST reports conducted within the last five years in two states were compared to a proposed model for CST assessment. Results indicated that although forensic examiners are maintaining legal relevance, some CST reports may lack thoroughness and/or provide information that exceeds their role responsibilities. The findings support the need for the development of a standardized method of conducting and writing CST evaluations that should improve the quality of such reports.

Barriers to investigator-initiated deep brain stimulation and device research

PubMed Central

Malone, Donald; Okun, Michael S.; Booth, Joan; Machado, Andre G.

2014-01-01

The success of device-based research in the clinical neurosciences has overshadowed a critical and emerging problem in the biomedical research environment in the United States. Neuroprosthetic devices, such as deep brain stimulation (DBS), have been shown in humans to be promising technologies for scientific exploration of neural pathways and as powerful treatments. Large device companies have, over the past several decades, funded and developed major research programs. However, both the structure of clinical trial funding and the current regulation of device research threaten investigator-initiated efforts in neurologic disorders. The current atmosphere dissuades clinical investigators from pursuing formal and prospective research with novel devices or novel indications. We review our experience in conducting a federally funded, investigator-initiated, device-based clinical trial that utilized DBS for thalamic pain syndrome. We also explore barriers that clinical investigators face in conducting device-based clinical trials, particularly in early-stage studies or small disease populations. We discuss 5 specific areas for potential reform and integration: (1) alternative pathways for device approval; (2) eliminating right of reference requirements; (3) combining federal grant awards with regulatory approval; (4) consolidation of oversight for human subjects research; and (5) private insurance coverage for clinical trials. Careful reformulation of regulatory policy and funding mechanisms is critical for expanding investigator-initiated device research, which has great potential to benefit science, industry, and, most importantly, patients. PMID:24670888

No child left behind: Enrolling children and adults simultaneously in critical care randomized trials*

PubMed Central

Halpern, Scott D.; Randolph, Adrienne G.; Angus, Derek C.

2010-01-01

Objective Randomized clinical trials of novel critical care interventions are currently tested in children only after documenting their safety in adults. Although this practice may protect children from research risks, it may paradoxically threaten children’s well-being by depriving them of evidence to guide their care. We sought to evaluate the ethical, methodologic, and practical arguments for and against studying critical care interventions in adults and children simultaneously rather than sequentially. Data Source Empirical studies and conceptual arguments germane to the objective were reviewed. Data Extraction and Synthesis Children are traditionally viewed as “participants of last resort” due to their vulnerability and decisional incapacity. However, critically ill adults commonly share similar features. Thus, structured risk assessments used by Institutional Review Boards to determine the adequacy of research protections for critically ill adults can also help protect children. From a methodologic perspective, interventions may be tested simultaneously in children and adults by enrolling children as a prespecified subgroup within a larger adult randomized clinical trial or by enrolling children in a separate trial conducted in parallel. Both approaches raise practical and analytical challenges that can frequently be met. For example, investigators might choose outcome measures that are appropriate for both adults and children. Additionally, using Bayesian approaches to link the estimates of treatment effects in children to the values observed in adults may enhance the statistical power to detect pediatric-specific effects. Finally, centralized Institutional Review Boards and data monitoring centers may alleviate practical concerns with conducting trials among adults and children simultaneously. Conclusions The current standard of testing critical care interventions in adults before children rests on tenuous ethical arguments and is entrenched by the methodologic and logistic barriers encountered with alternative approaches. However, these barriers will frequently be surmountable. We therefore propose that the default paradigm be changed such that interventions are examined routinely in critically ill children and adults simultaneously unless unique reasons exist to the contrary. PMID:19602971

Vaccine trials in the developing world: operational lessons learnt from a phase IV poliomyelitis vaccine trial in South Africa.

PubMed

Geldenhuys, H; Waggie, Z; Jacks, M; Geldenhuys, M; Traut, L; Tameris, M; Hatherill, M; Hanekom, W A; Sutter, R; Hussey, G; Mahomed, H

2012-08-31

Conducting vaccine trials in developing nations is necessary but operationally complex. We describe operational lessons learnt from a phase IV poliomyelitis vaccine trial in a semi-rural region of South Africa. We reviewed operational data collected over the duration of the trial with respect to staff recruitment and training, participant recruitment and retention, and cold chain maintenance. RESULTS-LESSONS LEARNT: The recruitment model we used that relied on the 24h physical presence of a team member in the birthing unit was expensive and challenging to manage. Forecasting of enrolment rates was complicated by incomplete baseline data and by the linear nature of forecasts that do not take into account changing variables. We found that analyzing key operational data to monitor progress of the trial enabled us to identify problem areas timeously, and to facilitate a collegial problem-solving process by the extended trial team. Pro-actively nurturing a working relationship with the public sector health care system and the community was critical to our success. Despite the wide geographical area and lack of fixed addresses, we maintained an excellent retention rate through community assistance and the use of descriptive residential information. Training needs of team members were ongoing and dynamic and we discovered that these needs that were best met by an in-house, targeted and systemized training programme. The use of vaccine refrigerators instead of standard frost-free refrigerators is cost-effective and necessary to maintain the cold-chain. Operational challenges of a vaccine trial in developing world populations include inexperienced staff, the close liaison required between researchers and public health care services, impoverished participants that require complex recruitment and retention strategies, and challenges of distance and access. These challenges can be overcome by innovative strategies that allow for the unique characteristics of the setting, trial population, and trial team. Copyright © 2012 Elsevier Ltd. All rights reserved.

A systematic review assessing non-pharmacological conservative treatment studies for people with non-inflammatory multi-joint pain: clinical outcomes and research design considerations.

PubMed

Comer, C; Smith, T O; Drew, B; Raja, R; Kingsbury, S R; Conaghan, Philip G

2018-03-01

To systematically review the evidence to determine the clinical outcomes and the important methodological quality features of interventional studies on adults with non-inflammatory multi-joint pain (MJP). Systematic search of published and unpublished literature using the databases: AMED, CINAHL, MEDLINE, EMBASE, psycINFO, SPORTDiscus, PEDro, OpenGrey, the EU Clinical Trials Register, World Health Organization International Clinical Trial Registry Platform, ClinicalTrials.gov and the ISRCTN registry (search: inception to 19th October 2017). All papers reporting the clinical outcomes of non-pharmacological interventions for people with non-inflammatory MJP were included. Studies were critically appraised using the Downs and Black Critical Appraisal and the TIDieR reporting checklists. Data were analysed using a Best Evidence Synthesis approach. From 3824 citations, four papers satisfied the eligibility criteria. Three studies reported outcomes from multidisciplinary rehabilitation programmes and one study reported the findings of a spa therapy intervention. All interventions significantly improved pain, function and quality of life in the short-term. There was limited reporting of measures for absenteeism, presenteeism and psychosocial outcomes. The evidence was 'weak', and due to a lack of controlled trials, there is limited evidence to ascertain treatment effectiveness. Design consideration for future trials surround improved reporting of participant characteristics, interventions and the standardisation of core outcome measures. There is insufficient high-quality trial data to determine the effectiveness of treatments for non-inflammatory MJP. Given the significant health burden which this condition presents on both individuals and wider society, developing and testing interventions and accurately reporting these, should be a research priority. Registration PROSPERO (CRD42013005888).

TU-G-BRB-04: Digital Phantoms for Developing Protocols in Particle Therapy

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

Lee, C.

2015-06-15

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. Themore » lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial development and support. Research reported in this presentation is supported by the National Cancer Institute of the National; Institutes of Health under Award Number P20CA183640.« less

A critical appraisal of once-daily topical luliconazole for the treatment of superficial fungal infections

PubMed Central

Gupta, Aditya K; Daigle, Deanne

2016-01-01

Luliconazole is a novel imidazole derivative, which has demonstrated in vitro efficacy against dermatophytes and Candida. The results from Phase III trials show that luliconazole 1% cream applied once daily for 2 weeks successfully resolved the clinical signs and symptoms as well as eradicated the pathologic fungi, which cause tinea pedis. A 1-week treatment with luliconazole 1% cream also produced favorable clinical and mycological results in clinical trials for tinea corporis and tinea cruris. Across trials, adverse events consisted mainly of localized reactions following application. The development of a new antifungal agent is timely due to mounting resistance among existing treatments. Because luliconazole requires a short duration of treatment, it may assist in reducing disease recurrence as a result of patient nonadherence. PMID:26848272

Estimating Single-Trial Responses in EEG

NASA Technical Reports Server (NTRS)

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

2002-01-01

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

Designing trials for pressure ulcer risk assessment research: methodological challenges.

PubMed

Balzer, K; Köpke, S; Lühmann, D; Haastert, B; Kottner, J; Meyer, G

2013-08-01

For decades various pressure ulcer risk assessment scales (PURAS) have been developed and implemented into nursing practice despite uncertainty whether use of these tools helps to prevent pressure ulcers. According to current methodological standards, randomised controlled trials (RCTs) are required to conclusively determine the clinical efficacy and safety of this risk assessment strategy. In these trials, PURAS-aided risk assessment has to be compared to nurses' clinical judgment alone in terms of its impact on pressure ulcer incidence and adverse outcomes. However, RCTs evaluating diagnostic procedures are prone to specific risks of bias and threats to the statistical power which may challenge their validity and feasibility. This discussion paper critically reflects on the rigour and feasibility of experimental research needed to substantiate the clinical efficacy of PURAS-aided risk assessment. Based on reflections of the methodological literature, a critical appraisal of available trials on this subject and an analysis of a protocol developed for a methodologically robust cluster-RCT, this paper arrives at the following conclusions: First, available trials do not provide reliable estimates of the impact of PURAS-aided risk assessment on pressure ulcer incidence compared to nurses' clinical judgement alone due to serious risks of bias and insufficient sample size. Second, it seems infeasible to assess this impact by means of rigorous experimental studies since sample size would become extremely high if likely threats to validity and power are properly taken into account. Third, means of evidence linkages seem to currently be the most promising approaches for evaluating the clinical efficacy and safety of PURAS-aided risk assessment. With this kind of secondary research, the downstream effect of use of PURAS on pressure ulcer incidence could be modelled by combining best available evidence for single parts of this pathway. However, to yield reliable modelling results, more robust experimental research evaluating specific parts of the pressure ulcer risk assessment-prevention pathway is needed. Copyright © 2013 Elsevier Ltd. All rights reserved.

HIV vaccine trials: critical issues in informed consent.

PubMed

Lindegger, G; Richter, L M

2000-06-01

Informed consent (IC), a fundamental principle of ethics in medical research, is recognized as a vital component of HIV vaccine trials. There are different notions of IC, some legally based and others based on ethics. It is argued that, though legal indemnity is necessary, vaccine trials should be founded on fully ethical considerations. Various contentious aspects of IC are examined, especially the problem of social desirability and of adequate comprehension. The need for sensitivity to cultural norms in implementing IC procedures is critically reviewed, and some of the potential conflict between ethos and ethics is considered. The transmission of information is examined as a particular aspect of IC in HIV vaccine trials.

Missing data in trial-based cost-effectiveness analysis: An incomplete journey.

PubMed

Leurent, Baptiste; Gomes, Manuel; Carpenter, James R

2018-06-01

Cost-effectiveness analyses (CEA) conducted alongside randomised trials provide key evidence for informing healthcare decision making, but missing data pose substantive challenges. Recently, there have been a number of developments in methods and guidelines addressing missing data in trials. However, it is unclear whether these developments have permeated CEA practice. This paper critically reviews the extent of and methods used to address missing data in recently published trial-based CEA. Issues of the Health Technology Assessment journal from 2013 to 2015 were searched. Fifty-two eligible studies were identified. Missing data were very common; the median proportion of trial participants with complete cost-effectiveness data was 63% (interquartile range: 47%-81%). The most common approach for the primary analysis was to restrict analysis to those with complete data (43%), followed by multiple imputation (30%). Half of the studies conducted some sort of sensitivity analyses, but only 2 (4%) considered possible departures from the missing-at-random assumption. Further improvements are needed to address missing data in cost-effectiveness analyses conducted alongside randomised trials. These should focus on limiting the extent of missing data, choosing an appropriate method for the primary analysis that is valid under contextually plausible assumptions, and conducting sensitivity analyses to departures from the missing-at-random assumption. © 2018 The Authors Health Economics published by John Wiley & Sons Ltd.

Knowledge, Attitudes, and Experiences of HIV Pre-Exposure Prophylaxis (PrEP) Trial Participants in Botswana.

PubMed

Toledo, Lauren; McLellan-Lemal, Eleanor; Henderson, Faith L; Kebaabetswe, Poloko M

2015-03-01

Recent clinical trials have shown that a daily dose of oral TDF/FTC pre-exposure prophylaxis (PrEP) is effective in reducing human immunodeficiency (HIV) risk. Understanding trial participants' perspectives about retention and PrEP adherence is critical to inform future PrEP trials and the scale-up and implementation of PrEP programs. We analyzed 53 in-depth interviews conducted in April 2010 with participants in the TDF2 study, a Phase 3, randomized, double-blind, placebo-controlled clinical trial of daily oral TDF/FTC with heterosexual men and women in Francistown and Gaborone, Botswana. We examined participants' knowledge, attitudes, and experiences of the trial, identified facilitators and barriers to enrollment and retention, and compared participant responses by study site, sex, and study drug adherence. Our findings point to several factors to consider for participant retention and adherence in PrEP trials and programs, including conducting pre-enrollment education and myth reduction counseling, providing accurate estimates of participant obligations and side effect symptoms, ensuring participant understanding of the effects of non-adherence, gauging personal commitment and interest in study outcomes, and developing a strong external social support network for participants.

Formative research methods for designing culturally appropriate, integrated child nutrition and development interventions: An overview

PubMed Central

Bentley, Margaret E.; Johnson, Susan L.; Wasser, Heather; Creed-Kanashiro, Hilary; Shroff, Monal; Fernandez-Rao, Sylvia; Cunningham, Melissa

2014-01-01

Nutritional and developmental insults in the first few years of life have profound public health implications, including substantial contributions to neonatal, infant, and early childhood morbidity and mortality, as well as longer term impacts on cognitive development, school achievement, and worker productivity. Optimal development that can lead to the attainment of the individual's fullest potential therefore requires a combination of genetic capacity, adequate nutrition, psychosocial stimulation, and safe, clean physical environments. Researchers and policymakers have called for integrated child nutrition and development interventions for more than twenty years, yet there are only a handful of efficacy trials and even fewer examples of integrated interventions that have been taken to scale. While a critical component to the design of such interventions is formative research, there is a dearth of information in both the literature and policy arenas to guide this phase of the process. To move the field forward, this paper first provides an overview of formative research methods with a focus on qualitative inquiry, a description of the critical domains to be assessed (infant and young child feeding, responsive feeding, and child development), and currently available resources. Application of these methods is provided through a real-world case study—the design of an integrated nutrition and child development efficacy trial in Andhra Pradesh, India. Recommendations for next steps are discussed, the most important of which is the need for a comprehensive set of formative guidelines for designing locally tailored, culturally appropriate integrated interventions. PMID:24673167

Thinking outside the Randomized Controlled Trials Experimental Box: Strategies for Enhancing Credibility and Social Justice

ERIC Educational Resources Information Center

Hesse-Biber, Sharlene

2013-01-01

Some evaluators employ randomized controlled trials (RCTs) as the gold standard of evidence-based practice (EBP). Critics of RCT designs argue that RCTs do not include the complexity of program participants' experiences or clinical expertise, and couple this with criticisms that it is difficult to transfer RCT findings from the laboratory to…

The Role of Time-Limited Trials in Dialysis Decision Making in Critically Ill Patients.

PubMed

Scherer, Jennifer S; Holley, Jean L

2016-02-05

Technologic advances, such as continuous RRT, provide lifesaving therapy for many patients. AKI in the critically ill patient, a fatal diagnosis in the past, is now often a survivable condition. Dialysis decision making for the critically ill patient with AKI is complex. What was once a question solely of survival now is nuanced by an individual's definition of quality of life, personal values, and short- and long-term prognoses. Clinical evaluation of AKI in the critically ill is multifaceted. Treatment decision making requires consideration of the natural evolution of the patient's AKI within the context of the global prognosis. Situations are often marked by prognostic uncertainty and clinical unknowns. In the face of these uncertainties, establishment of patient-directed therapies is imperative. A time-limited trial of continuous RRT in this setting is often appropriate but difficult to execute. Using patient preferences as a clinical guide, a proper time-limited trial requires assessment of prognosis, elicitation of patient values, strong communication skills, clear documentation, and often, appropriate integration of palliative care services. A well conducted time-limited trial can avoid interprofessional conflict and provide support for the patient, family, and staff. Copyright © 2016 by the American Society of Nephrology.

Application of the Actor-Critic Architecture to Functional Electrical Stimulation Control of a Human Arm.

PubMed

Thomas, Philip; Branicky, Michael; van den Bogert, Antonie; Jagodnik, Kathleen

2009-01-01

Clinical tests have shown that the dynamics of a human arm, controlled using Functional Electrical Stimulation (FES), can vary significantly between and during trials. In this paper, we study the application of the actor-critic architecture, with neural networks for the both the actor and the critic, as a controller that can adapt to these changing dynamics of a human arm. Development and tests were done in simulation using a planar arm model and Hill-based muscle dynamics. We begin by training it using a Proportional Derivative (PD) controller as a supervisor. We then make clinically relevant changes to the dynamics of the arm and test the actor-critic's ability to adapt without supervision in a reasonable number of episodes. Finally, we devise methods for achieving both rapid learning and long-term stability.

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.

The effect of deworming on early childhood development in Peru: A randomized controlled trial.

PubMed

Joseph, Serene A; Casapía, Martín; Lazarte, Fabiola; Rahme, Elham; Pezo, Lidsky; Blouin, Brittany; Gyorkos, Theresa W

2015-12-01

There is a knowledge gap on the effect of early childhood deworming on development in low- and middle-income countries. This evidence is important in the critical window of growth and development before two years of age. A randomized controlled trial of the benefit, and optimal timing and frequency, of deworming on development was conducted in Iquitos, Peru. Children were enrolled during routine 12-month growth and development visits and randomly allocated to: (1) deworming at the 12-month visit and placebo at the 18-month visit; (2) placebo at the 12-month visit and deworming at the 18-month visit; (3) deworming at the 12 and 18-month visits; or (4) placebo at the 12 and 18-month visits. The Bayley Scales of Infant Development III was used to assess cognitive, language and motor skills at the 12 and 24-month visits. One-way ANOVA analyses used an intention-to-treat approach. Between September 2011 and June 2012, 1760 children were enrolled. Attendance at the 24-month visit was 88.8% ( n =1563). Raw scores on all subtests increased over 12 months; however, cognitive and expressive language scaled scores decreased. There was no statistically significant benefit of deworming, or effect of timing or frequency, on any of the development scores. Baseline height and weight and maternal education were associated with development scores at 24 months. After 12 months of follow-up, an overall benefit of deworming on cognition, language or fine motor development was not detected. Additional integrated child and maternal interventions should be considered to prevent developmental deficits in this critical period.

Critical early thrombolytic and endovascular reperfusion therapy for acute ischemic stroke victims: a call for adjunct neuroprotection.

PubMed

Lapchak, Paul A

2015-10-01

Today, there is an enormous amount of excitement in the field of stroke victim care due to the recent success of MR. CLEAN, SWIFT PRIME, ESCAPE, EXTEND-IA, and REVASCAT endovascular trials. Successful intravenous (IV) recombinant tissue plasminogen activator (rt-PA) clinical trials [i.e., National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial, Third European Cooperative Acute Stroke Study (ECASSIII), and Third International Stroke study (IST-3)] also need to be emphasized. In the recent endovascular and thrombolytic trials, there is statistically significant improvement using both the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Score (mRS) scale, but neither approach promotes complete recovery in patients enrolled within any particular NIHSS or mRS score tier. Absolute improvement (mRS 0-2 at 90 days) with endovascular therapy is 13.5-31 %, whereas thrombolytics alone also significantly improve patient functional independence, but to a lesser degree (NINDS rt-PA trial 13 %). This article has 3 main goals: (1) first to emphasize the utility and cost-effectiveness of rt-PA to treat stroke; (2) second to review the recent endovascular trials with respect to efficacy, safety, and cost-effectiveness as a stroke treatment; and (3) to further consider and evaluate strategies to develop novel neuroprotective drugs. A thesis will be put forth so that future stroke trials and therapy development can optimally promote recovery so that stroke victims can return to "normal" life.

TU-G-BRB-05: Panel Discussion: Clinical Trials in Proton and Ion Therapy - Are We Ready?

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

Schulte, R.

2015-06-15

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. Themore » lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial development and support. Research reported in this presentation is supported by the National Cancer Institute of the National; Institutes of Health under Award Number P20CA183640.« less

TU-G-BRB-02: Clinical Trials in Particle Therapy - Open Questions

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

Choy, H.

2015-06-15

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. Themore » lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial development and support. Research reported in this presentation is supported by the National Cancer Institute of the National; Institutes of Health under Award Number P20CA183640.« less

TU-G-BRB-03: IROC Houston’s Proton Beam Validation for Clinical Trials

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

Taylor, P.

2015-06-15

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. Themore » lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial development and support. Research reported in this presentation is supported by the National Cancer Institute of the National; Institutes of Health under Award Number P20CA183640.« less

TU-G-BRB-00: Clinical Trials in Proton and Particle Therapy

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

NONE

2015-06-15

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. Themore » lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial development and support. Research reported in this presentation is supported by the National Cancer Institute of the National; Institutes of Health under Award Number P20CA183640.« less

Recommendations for clinical biomarker specimen preservation and stability assessments.

PubMed

Dakappagari, Naveen; Zhang, Hui; Stephen, Laurie; Amaravadi, Lakshmi; Khan, Masood U

2017-04-01

With the wide use of biomarkers to enable critical drug-development decisions, there is a growing concern from scientific community on the need for a 'standardized process' for ensuring biomarker specimen stability and hence, a strong desire to share best practices on preserving the integrity of biomarker specimens in clinical trials and the design of studies to evaluate analyte stability. By leveraging representative industry experience, we have attempted to provide an overview of critical aspects of biomarker specimen stability commonly encountered during clinical development, including: planning of clinical sample collection procedures, clinical site training, selection of sample preservation buffers, shipping logistics, fit-for-purpose stability assessments in the analytical laboratory and presentation of case studies covering widely utilized biomarker specimen types.

Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa.

PubMed

Mamotte, Nicole; Wassenaar, Douglas; Koen, Jennifer; Essack, Zaynab

2010-03-09

Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields.

'It looks like you just want them when things get rough': civil society perspectives on negative trial results and stakeholder engagement in HIV prevention trials.

PubMed

Koen, Jennifer; Essack, Zaynab; Slack, Catherine; Lindegger, Graham; Newman, Peter A

2013-12-01

Civil society organizations (CSOs) have significantly impacted on the politics of health research and the field of bioethics. In the global HIV epidemic, CSOs have served a pivotal stakeholder role. The dire need for development of new prevention technologies has raised critical challenges for the ethical engagement of community stakeholders in HIV research. This study explored the perspectives of CSO representatives involved in HIV prevention trials (HPTs) on the impact of premature trial closures on stakeholder engagement. Fourteen respondents from South African and international CSOs representing activist and advocacy groups, community mobilisation initiatives, and human and legal rights groups were purposively sampled based on involvement in HPTs. Interviews were conducted from February-May 2010. Descriptive analysis was undertaken across interviews and key themes were developed inductively. CSO representatives largely described positive outcomes of recent microbicide and HIV vaccine trial terminations, particularly in South Africa, which they attributed to improvements in stakeholder engagement. Ongoing challenges to community engagement included the need for principled justifications for selective stakeholder engagement at strategic time-points, as well as the need for legitimate alternatives to CABs as mechanisms for engagement. Key issues for CSOs in relation to research were also raised. © 2012 John Wiley & Sons Ltd.

Intrinsic development of choroidal and thalamic collaterals in hemorrhagic-onset moyamoya disease: case-control study of the Japan Adult Moyamoya Trial.

PubMed

Fujimura, Miki; Funaki, Takeshi; Houkin, Kiyohiro; Takahashi, Jun C; Kuroda, Satoshi; Tomata, Yasutake; Tominaga, Teiji; Miyamoto, Susumu

2018-05-04

OBJECTIVE This study was performed to identify the angiographic features of hemorrhagic-onset moyamoya disease (MMD) in comparison with those of patients with ischemic-onset MMD. METHODS This case-control study compared the data set of the Japan Adult Moyamoya (JAM) Trial with the angiographic data of adult patients with ischemic-onset MMD. The authors analyzed angiograms obtained at onset, classifying the collaterals into 3 subtypes: lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis. They then compared the extent of these collaterals, as indicated by the collateral development grade from 0 to 2 in each subtype, between the JAM Trial group and the ischemic-onset group. They also compared the involvement of the posterior cerebral artery (PCA) and Suzuki's angiographic staging between each group. RESULTS Among 89 ischemic-onset patients, 103 symptomatic hemispheres in 80 patients were analyzed and compared with 75 hemorrhagic hemispheres from the JAM Trial. The hemorrhagic-onset patients showed a significantly higher proportion of thalamic anastomosis (p = 0.043) and choroidal anastomosis (< 0.001), as indicated by grade 2 in each subtype, compared with ischemic-onset patients. Suzuki's angiographic staging was significantly higher in the hemorrhagic group (< 0.038). There was no difference in the extent of lenticulostriate anastomosis and PCA involvement between the groups. CONCLUSIONS In adult MMD, the characteristic pattern of the abnormal vascular networks at the base of the brain is different between each onset type. In light of the more prominent development of thalamic and choroidal anastomosis in the JAM Trial group in the present study, development of these collaterals, especially the choroidal collateral extending beyond the lateral ventricle, may play a critical role in hemorrhagic presentation in MMD. Clinical trial registration no. C000000166 ( http://www.umin.ac.jp/ctr/index.htm ).

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/1st communication: The contribution of clinical pharmacology].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture; genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/2nd communication: promising strategies].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture, genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

Clinical research and the development of medical therapeutics.

PubMed

Antman, Elliott M

2014-01-01

Clinical research plays a central role in the development of medical therapeutics, but the current system is estimated to take 10-15 years from initial discovery to regulatory approval, at a cost of approximately US$1 billion. Contrast the paths by which 2 anticoagulant options for atrial fibrillation were discovered and ultimately established as treatment options in clinical medicine. Warfarin was discovered by serendipity and compared with placebo in relatively small trials; this was associated with a low cost of development. The new oral anticoagulants were synthesized to provide highly specific, targeted inhibition of critical steps in the coagulation system. They were compared with warfarin for prevention of stroke and systemic embolic events in large, phase 3 trials; this resulted in very expensive development programs. Neither of these paths is desirable for future development of therapeutics. We need to focus on innovative approaches at the preclinical level (systems approach, greater use of inducible pluripotent stem cells, use of novel bioengineering platforms) and clinical trial level (adaptive design, greater use of new and emerging technology). Focusing on disruptive innovations for development of medical therapeutics has the potential to bring us closer to the goal of precision medicine where safer, more effective treatments are discovered in a more efficient system.

Risk of bias assessment of randomised controlled trials in high-impact ophthalmology journals and general medical journals: a systematic review.

PubMed

Joksimovic, Lazar; Koucheki, Robert; Popovic, Marko; Ahmed, Yusuf; Schlenker, Matthew B; Ahmed, Iqbal Ike K

2017-10-01

Evidence-based treatments in ophthalmology are often based on the results of randomised controlled trials. Biased conclusions from randomised controlled trials may lead to inappropriate management recommendations. This systematic review investigates the prevalence of bias risk in randomised controlled trials published in high-impact ophthalmology journals and ophthalmology trials from general medical journals. Using Ovid MEDLINE, randomised controlled trials in the top 10 high-impact ophthalmology journals in 2015 were systematically identified and critically appraised for the prevalence of bias risk. Included randomised controlled trials were assessed in all domains of bias as defined by the Cochrane Collaboration. In addition, the prevalence of conflict of interest and industry sponsorship was investigated. A comparison with ophthalmology articles from high-impact general medical journals was performed. Of the 259 records that were screened from ophthalmology-specific journals, 119 trials met all inclusion criteria and were critically appraised. In total, 29.4% of domains had an unclear risk, 13.8% had a high risk and 56.8% had a low risk of bias. In comparison, ophthalmology articles from general medical journals had a lower prevalence of unclear risk (17.1%), higher prevalence of high risk (21.9%) and a higher prevalence of low risk domains (61.9%). Furthermore, 64.7% of critically appraised trials from ophthalmology-specific journals did not report any conflicts of interest, while 70.6% did not report an industry sponsor of their trial. In closing, it is essential that authors, peer reviewers and readers closely follow published risk of bias guidelines. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Bench-to-bedside review: Avoiding pitfalls in critical care meta-analysis – funnel plots, risk estimates, types of heterogeneity, baseline risk and the ecologic fallacy

PubMed Central

Reade, Michael C; Delaney, Anthony; Bailey, Michael J; Angus, Derek C

2008-01-01

Meta-analysis can be a powerful tool for demonstrating the applicability of a concept beyond the context of individual clinical trials and observational studies, including exploration of effects across different subgroups. Meta-analysis avoids Simpson's paradox, in which a consistent effect in constituent trials is reversed when results are simply pooled. Meta-analysis in critical care medicine is made more complicated, however, by the heterogeneous nature of critically ill patients and the contexts within which they are treated. Failure to properly adjust for this heterogeneity risks missing important subgroup effects in, for example, the interaction of treatment with varying levels of baseline risk. When subgroups are defined by characteristics that vary within constituent trials (such as age) rather than features constant within each trial (such as drug dose), there is the additional risk of incorrect conclusions due to the ecological fallacy. The present review explains these problems and the strategies by which they are overcome. PMID:18671838

Using Computerized Games to Teach Face Recognition Skills to Children with Autism Spectrum Disorder: The "Let's Face It!" Program

ERIC Educational Resources Information Center

Tanaka, James W.; Wolf, Julie M.; Klaiman, Cheryl; Koenig, Kathleen; Cockburn, Jeffrey; Herlihy, Lauren; Brown, Carla; Stahl, Sherin; Kaiser, Martha D.; Schultz, Robert T.

2010-01-01

Background: An emerging body of evidence indicates that relative to typically developing children, children with autism are selectively impaired in their ability to recognize facial identity. A critical question is whether face recognition skills can be enhanced through a direct training intervention. Methods: In a randomized clinical trial,…

Effectiveness of a programme of exercise on physical function in survivors of critical illness following discharge from the ICU: study protocol for a randomised controlled trial (REVIVE).

PubMed

O'Neill, Brenda; McDowell, Kathryn; Bradley, Judy; Blackwood, Bronagh; Mullan, Brian; Lavery, Gavin; Agus, Ashley; Murphy, Sally; Gardner, Evie; McAuley, Daniel F

2014-04-27

Following discharge home from the ICU, patients often suffer from reduced physical function, exercise capacity, health-related quality of life and social functioning. There is usually no support to address these longer term problems, and there has been limited research carried out into interventions which could improve patient outcomes. The aim of this study is to investigate the effectiveness and cost-effectiveness of a 6-week programme of exercise on physical function in patients discharged from hospital following critical illness compared to standard care. The study design is a multicentre prospective phase II, allocation-concealed, assessor-blinded, randomised controlled clinical trial. Participants randomised to the intervention group will complete three exercise sessions per week (two sessions of supervised exercise and one unsupervised session) for 6 weeks. Supervised sessions will take place in a hospital gymnasium or, if this is not possible, in the participants home and the unsupervised session will take place at home. Blinded outcome assessment will be conducted at baseline after hospital discharge, following the exercise intervention, and at 6 months following baseline assessment (or equivalent time points for the standard care group). The primary outcome measure is physical function as measured by the physical functioning subscale of the Short-Form-36 health survey following the exercise programme. Secondary outcomes are health-related quality of life, exercise capacity, anxiety and depression, self efficacy to exercise and healthcare resource use. In addition, semi-structured interviews will be conducted to explore participants' perceptions of the exercise programme, and the feasibility (safety, practicality and acceptability) of providing the exercise programme will be assessed. A within-trial cost-utility analysis to assess the cost-effectiveness of the intervention compared to standard care will also be conducted. If the exercise programme is found to be effective, this study will improve outcomes that are meaningful to patients and their families. It will inform the design of a future multicentre phase III clinical trial of exercise following recovery from critical illness. It will provide useful information which will help the development of services for patients after critical illness. ClinicalTrials.gov NCT01463579.

Embodying self-compassion within virtual reality and its effects on patients with depression

PubMed Central

Falconer, Caroline J.; Rovira, Aitor; King, John A.; Gilbert, Paul; Antley, Angus; Fearon, Pasco; Ralph, Neil; Slater, Mel

2016-01-01

Background Self-criticism is a ubiquitous feature of psychopathology and can be combatted by increasing levels of self-compassion. However, some patients are resistant to self-compassion. Aims To investigate whether the effects of self-identification with virtual bodies within immersive virtual reality could be exploited to increase self-compassion in patients with depression. Method We developed an 8-minute scenario in which 15 patients practised delivering compassion in one virtual body and then experienced receiving it from themselves in another virtual body. Results In an open trial, three repetitions of this scenario led to significant reductions in depression severity and self-criticism, as well as to a significant increase in self-compassion, from baseline to 4-week follow-up. Four patients showed clinically significant improvement. Conclusions The results indicate that interventions using immersive virtual reality may have considerable clinical potential and that further development of these methods preparatory to a controlled trial is now warranted. Declaration of interest None. Copyright and usage © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) licence. PMID:27703757

Targeted full energy and protein delivery in critically ill patients: a study protocol for a pilot randomised control trial (FEED Trial).

PubMed

Fetterplace, Kate; Deane, Adam M; Tierney, Audrey; Beach, Lisa; Knight, Laura D; Rechnitzer, Thomas; Forsyth, Adrienne; Mourtzakis, Marina; Presneill, Jeffrey; MacIsaac, Christopher

2018-01-01

Current guidelines for the provision of protein for critically ill patients are based on incomplete evidence, due to limited data from randomised controlled trials. The present pilot randomised controlled trial is part of a program of work to expand knowledge about the clinical effects of protein delivery to critically ill patients. The primary aim of this pilot study is to determine whether an enteral feeding protocol using a volume target, with additional protein supplementation, delivers a greater amount of protein and energy to mechanically ventilated critically ill patients than a standard nutrition protocol. The secondary aims are to evaluate the potential effects of this feeding strategy on muscle mass and other patient-centred outcomes. This prospective, single-centred, pilot, randomised control trial will include 60 participants who are mechanically ventilated and can be enterally fed. Following informed consent, the participants receiving enteral nutrition in the intensive care unit (ICU) will be allocated using a randomisation algorithm in a 1:1 ratio to the intervention (high-protein daily volume-based feeding protocol, providing 25 kcal/kg and 1.5 g/kg protein) or standard care (hourly rate-based feeding protocol providing 25 kcal/kg and 1 g/kg protein). The co-primary outcomes are the average daily protein and energy delivered to the end of day 15 following randomisation. The secondary outcomes include change in quadriceps muscle layer thickness (QMLT) from baseline (prior to randomisation) to ICU discharge and other nutritional and patient-centred outcomes. This trial aims to examine whether a volume-based feeding protocol with supplemental protein increases protein and energy delivery. The potential effect of such increases on muscle mass loss will be explored. These outcomes will assist in formulating larger randomised control trials to assess mortality and morbidity. Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: 12615000876594 UTN: U1111-1172-8563.

Antibiotics or probiotics as preventive measures against ventilator-associated pneumonia: a literature review

PubMed Central

2011-01-01

Introduction Mechanically ventilated critically ill patients frequently develop ventilator-associated pneumonia (VAP), a life-threatening complication. Proposed preventive measures against VAP include, but are not restricted to, selective decontamination of the digestive tract (SDD), selective oropharyngeal decontamination (SOD) and the use of probiotics. Probiotics are live bacteria that could have beneficial effects on the host by altering gastrointestinal flora. Similar to SDD and SOD, a prescription of probiotics aims at the prevention of secondary colonization of the upper and/or lower digestive tract. Methods We performed a literature review to describe the differences and similarities between SDD/SOD and probiotic preventive strategies, focusing on (a) efficacy, (b) risks, and (c) the routing of these strategies. Results Reductions in the incidence of VAP have been achieved with SDD and SOD. Two large randomized controlled trials even showed reduced mortality with these preventive strategies. Randomized controlled trials of probiotic strategies also showed a reduction of the incidence of VAP, but trials were too small to draw firm conclusions. Preventive strategies with antibiotics and probiotics may be limited due to the risk of emerging resistance to the locally applied antibiotics and the risk of probiotic-related infections, respectively. The majority of trials of SDD and SOD did not exhaustively address the issue of emerging resistance. Likewise, trials of probiotic strategies did not adequately address the risk of colonization with probiotics and probiotic-related infection. In studies of SDD and SOD the preventive strategy aimed at decontamination of the oral cavity, throat, stomach and intestines, and the oral cavity and throat, respectively. In the vast majority of studies of probiotic therapy the preventive strategy aimed at decontamination of the stomach and intestines. Conclusions Prophylactic use of antibiotics in critically ill patients is effective in reducing the incidence of VAP. Probiotic strategies deserve consideration in future well-powered trials. Future studies are needed to determine if preventive antibiotic and probiotic strategies are safe with regard to development of antibiotic resistance and probiotic infections. It should be determined whether the efficacy of probiotics improves when these agents are provided to the mouth and the intestines simultaneously. PMID:21232110

Probabilistic Structural Analysis Theory Development

NASA Technical Reports Server (NTRS)

Burnside, O. H.

1985-01-01

The objective of the Probabilistic Structural Analysis Methods (PSAM) project is to develop analysis techniques and computer programs for predicting the probabilistic response of critical structural components for current and future space propulsion systems. This technology will play a central role in establishing system performance and durability. The first year's technical activity is concentrating on probabilistic finite element formulation strategy and code development. Work is also in progress to survey critical materials and space shuttle mian engine components. The probabilistic finite element computer program NESSUS (Numerical Evaluation of Stochastic Structures Under Stress) is being developed. The final probabilistic code will have, in the general case, the capability of performing nonlinear dynamic of stochastic structures. It is the goal of the approximate methods effort to increase problem solving efficiency relative to finite element methods by using energy methods to generate trial solutions which satisfy the structural boundary conditions. These approximate methods will be less computer intensive relative to the finite element approach.

Effects of yoga on chronic neck pain: a systematic review of randomized controlled trials

PubMed Central

Kim, Sang-Dol

2016-01-01

[Purpose] The aim of this study was to investigate the effectiveness of yoga in the management of chronic neck pain. [Subjects and Methods] Five electronic databases were searched to identify randomized controlled trials (RCTs) of yoga intervention on chronic neck pain. The trials were published in the English language between January 1966 and December 2015. The Cochrane Risk of Bias Tool was used to assess the quality of the trials. [Results] Three trials were identified and included in this review. A critical appraisal was performed on the trials, and the result indicated a high risk of bias. A narrative description was processed because of the small number of RCTs. Neck pain intensity and functional disability were significantly lower in the yoga groups than in the control groups. [Conclusion] Evidence from the 3 randomly controlled trials shows that yoga may be beneficial for chronic neck pain. The low-quality result of the critical appraisal and the small number of trials suggest that high-quality RCTs are required to examine further the effects of yoga intervention on chronic neck pain relief. PMID:27512290

Strategic Planning for Research in Pediatric Critical Care.

PubMed

Tamburro, Robert F; Jenkins, Tammara L; Kochanek, Patrick M

2016-11-01

To summarize the scientific priorities and potential future research directions for pediatric critical care research discussed by a panel of experts at the inaugural Strategic Planning Conference of the Pediatric Trauma and Critical Illness Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Expert opinion expressed during the Strategic Planning Conference. Not applicable. Chaired by an experienced expert from the field, issues relevant to the conduct of pediatric critical care research were discussed and debated by the invited participants. Common themes and suggested priorities were identified and coalesced. Of the many pathophysiologic conditions discussed, the multiple organ dysfunction syndrome emerged as a topic in need of more study that is most relevant to the field. Additionally, the experts offered that the interrelationship and impact of critical illness on child development and family functioning are important research priorities. Consequently, long-term outcomes research was encouraged. The expert group also suggested that multidisciplinary conferences are needed to help identify key knowledge gaps to advance and direct research in the field. The Pediatric Critical Care and Trauma Scientist Development National K12 Program and the Collaborative Pediatric Critical Care Research Network were recognized as successful and important programs supported by the branch. The development of core data resources including biorepositories with robust phenotypic data using common data elements was also suggested to foster data sharing among investigators and to enhance disease diagnosis and discovery. Multicenter clinical trials and innovative study designs to address understudied and poorly understood conditions were considered important for field advancement. Finally, the growth of the pediatric critical care research workforce was offered as a priority that could be spawned in many ways including by expanded transdisciplinary and multiprofessional collaboration and diversity representation.

Strategic Planning for Research in Pediatric Critical Care

PubMed Central

Tamburro, Robert F.; Jenkins, Tammara L.; Kochanek, Patrick M.

2016-01-01

Objective To summarize the scientific priorities and potential future research directions for pediatric critical care research discussed by a panel of experts at the inaugural Strategic Planning Conference of the Pediatric Trauma and Critical Illness Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Data Sources Expert opinion expressed during the Strategic Planning Conference. Study Selection Not applicable Data Extraction Chaired by an experienced expert from the field, issues relevant to the conduct of pediatric critical care research were discussed and debated by the invited participants. Data Synthesis Common themes and suggested priorities were identified and coalesced. Conclusions Of the many pathophysiological conditions discussed, the multiple organ dysfunction syndrome emerged as a topic in need of more study that is most relevant to the field. Additionally, the experts offered that the inter-relationship and impact of critical illness on child development and family functioning are important research priorities. Consequently, long-term outcomes research was encouraged. The expert group also suggested that multidisciplinary conferences are needed to help identify key knowledge gaps to advance and direct research in the field. The Pediatric Critical Care and Trauma Scientist Development National K12 Program and the Collaborative Pediatric Critical Care Research Network were recognized as successful and important programs supported by the branch. The development of core data resources including biorepositories with robust phenotypic data using common data elements was also suggested to foster data sharing among investigators and to enhance disease diagnosis and discovery. Multicenter clinical trials and innovative study designs to address understudied and poorly understood conditions were considered important for field advancement. Finally, the growth of the pediatric critical care research workforce was offered as a priority that could be spawned in many ways including by expanded transdisciplinary and multiprofessional collaboration and diversity representation. PMID:27679964

Pathophysiology of Septic Shock: From Bench to Bedside

PubMed Central

McConnell, Kevin W.; Coopersmith, Craig M.

2016-01-01

Our understanding of sepsis and its resultant outcomes remains a paradox. On the one hand, we know more about the pathophysiology of sepsis than ever before. However, this knowledge has not successfully translated to the bedside, as the vast majority of clinical trials for sepsis have been negative. Yet even in the general absence of positive clinical trials, mortality from sepsis has fallen to its lowest point in history, in large part due to educational campaigns that stress timely antibiotics and hemodynamic support. While additional improvements in outcome will assuredly result from further compliance with evidence based practices, a deeper understanding of the science that underlies the host response in sepsis is critical to the development of novel therapeutics. In this review, we outline immunopathologic abnormalities in sepsis, and then look at potential approaches to therapeutically modulate them. Ultimately, an understanding of the science underlying sepsis should allow the critical care community to utilize precision medicine to combat this devastating disease on an individual basis leading to improved outcomes. PMID:27085986

Physiotherapy for adult patients with critical illness: recommendations of the European Respiratory Society and European Society of Intensive Care Medicine Task Force on Physiotherapy for Critically Ill Patients.

PubMed

Gosselink, R; Bott, J; Johnson, M; Dean, E; Nava, S; Norrenberg, M; Schönhofer, B; Stiller, K; van de Leur, H; Vincent, J L

2008-07-01

The Task Force reviewed and discussed the available literature on the effectiveness of physiotherapy for acute and chronic critically ill adult patients. Evidence from randomized controlled trials or meta-analyses was limited and most of the recommendations were level C (evidence from uncontrolled or nonrandomized trials, or from observational studies) and D (expert opinion). However, the following evidence-based targets for physiotherapy were identified: deconditioning, impaired airway clearance, atelectasis, intubation avoidance, and weaning failure. Discrepancies and lack of data on the efficacy of physiotherapy in clinical trials support the need to identify guidelines for physiotherapy assessments, in particular to identify patient characteristics that enable treatments to be prescribed and modified on an individual basis. There is a need to standardize pathways for clinical decision-making and education, to define the professional profile of physiotherapists, and increase the awareness of the benefits of prevention and treatment of immobility and deconditioning for critically ill adult patients.

Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial.

PubMed

Doig, Gordon S; Simpson, Fiona; Heighes, Philippa T; Bellomo, Rinaldo; Chesher, Douglas; Caterson, Ian D; Reade, Michael C; Harrigan, Peter W J

2015-12-01

Equipoise exists regarding the benefits of restricting caloric intake during electrolyte replacement for refeeding syndrome, with half of intensive care specialists choosing to continue normal caloric intake. We aimed to assess whether energy restriction affects the duration of critical illness, and other measures of morbidity, compared with standard care. We did a randomised, multicentre, single-blind clinical trial in 13 hospital intensive care units (ICUs) in Australia (11 sites) and New Zealand (two sites). Adult critically ill patients who developed refeeding syndrome within 72 h of commencing nutritional support in the ICU were enrolled and allocated to receive continued standard nutritional support or protocolised caloric restriction. 1:1 computer-based randomisation was done in blocks of variable size, stratified by enrolment serum phosphate concentration (>0·32 mmol/L vs ≤0·32 mmol/L) and body-mass index (BMI; >18 kg/m(2)vs ≤18 kg/m(2)). The primary outcome was the number of days alive after ICU discharge, with 60 day follow-up, in a modified intention-to-treat population of all randomly allocated patients except those mistakenly enrolled. Days alive after ICU discharge was a composite outcome based on ICU length of stay, overall survival time, and mortality. The Refeeding Syndrome Trial was registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR number 12609001043224). Between Dec 3, 2010, and Aug 13, 2014, we enrolled 339 adult critically ill patients: 170 were randomly allocated to continued standard nutritional support and 169 to protocolised caloric restriction. During the 60 day follow-up, the mean number of days alive after ICU discharge in 165 assessable patients in the standard care group was 39·9 (95% CI 36·4-43·7) compared with 44·8 (95% CI 40·9-49·1) in 166 assessable patients in the caloric restriction group (difference 4·9 days, 95% CI -2·3 to 13·6, p=0·19). Nevertheless, protocolised caloric restriction improved key individual components of the primary outcome: more patients were alive at day 60 (128 [78%] of 163 vs 149 [91%] of 164, p=0·002) and overall survival time was increased (48·9 [SD 1·46] days vs 53·65 [0·97] days, log-rank p=0·002). Protocolised caloric restriction is a suitable therapeutic option for critically ill adults who develop refeeding syndrome. We did not identify any safety concerns associated with the use of protocolised caloric restriction. National Health and Medical Research Council of Australia. Copyright © 2015 Elsevier Ltd. All rights reserved.

Integrating evidence-based treatments for common mental disorders in routine primary care: feasibility and acceptability of the MANAS intervention in Goa, India

PubMed Central

CHATTERJEE, SUDIPTO; CHOWDHARY, NEERJA; PEDNEKAR, SULOCHANA; COHEN, ALEX; ANDREW, GRACY; ANDREW, GRACY; ARAYA, RICARDO; SIMON, GREGORY; KING, MICHAEL; TELLES, SHIRLEY; VERDELI, HELENA; CLOUGHERTY, KATHLEEN; KIRKWOOD, BETTY; PATEL, VIKRAM

2008-01-01

Common mental disorders, such as depression and anxiety, pose a major public health burden in developing countries. Although these disorders are thought to be best managed in primary care settings, there is a dearth of evidence about how this can be achieved in low resource settings. The MANAS project is an attempt to integrate an evidence based package of treatments into routine public and private primary care settings in Goa, India. Before initiating the trial, we carried out extensive preparatory work, over a period of 15 months, to examine the feasibility and acceptability of the planned intervention. This paper describes the systematic development and evaluation of the intervention through this preparatory phase. The preparatory stage, which was implemented in three phases, utilized quantitative and qualitative methods to inform our understanding of the potential problems and possible solutions in implementing the trial and led to critical modifications of the original intervention plan. Investing in systematic formative work prior to conducting expensive trials of the effectiveness of complex interventions is a useful exercise which potentially improves the likelihood of a positive result of such trials. PMID:18458786

Cellular Therapies Clinical Research Roadmap: Lessons learned on how to move a cellular therapy into a clinical trial

PubMed Central

Ouseph, Stacy; Tappitake, Darah; Armant, Myriam; Wesselschmidt, Robin; Derecho, Ivy; Draxler, Rebecca; Wood, Deborah; Centanni, John M.

2014-01-01

A clinical research roadmap has been developed as a resource for researchers to identify critical areas and potential pitfalls when transitioning a cellular therapy product from the research laboratory, via and Investigational New Drug (IND) application, into early phase clinical trials. The roadmap describes four key areas; basic and preclinical research, resource development, translational research and good manufacturing practice (GMP), and IND assembly and submission. Basic and preclinical research identifies a new therapeutic concept and demonstrates its potential value using a model of the relevant disease. During resource development the appropriate specialists and the required expertise to bring this product into the clinic are identified (e.g., researchers, regulatory specialists, GMP manufacturing staff, clinicians, and clinical trials staff, etc.). Additionally, the funds required to achieve this goal (or a plan to procure them) are identified. In the next phase the plan to translate the research product into a clinical grade therapeutic is developed. Finally regulatory approval to start the trial must be obtained. In the United States this is done by filing an IND application with the Food and Drug Administration. The NHLBI-funded Production Assistance for Cellular Therapies (PACT) program has facilitated the transition of a variety of cellular therapy products from the laboratory into Phase1/2 trials. The five PACT facilities have assisted investigators by performing translational studies and GMP manufacturing to ensure that cellular products met release specifications and were manufactured safely, reproducibly, and at the appropriate scale. The roadmap resulting from this experience is the focus of this article. PMID:25484311

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial – challenges, enablers and lessons learned

PubMed Central

Anguzu, Ronald; Akun, Pamela R; Ogwang, Rodney; Shour, Abdul Rahman; Sekibira, Rogers; Ningwa, Albert; Nakamya, Phellister; Abbo, Catherine; Mwaka, Amos D; Opar, Bernard; Idro, Richard

2018-01-01

ABSTRACT A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research. PMID:29382251

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial - challenges, enablers and lessons learned.

PubMed

Anguzu, Ronald; Akun, Pamela R; Ogwang, Rodney; Shour, Abdul Rahman; Sekibira, Rogers; Ningwa, Albert; Nakamya, Phellister; Abbo, Catherine; Mwaka, Amos D; Opar, Bernard; Idro, Richard

2018-01-01

A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research.

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.

In Defense of the Randomized Controlled Trial for Health Promotion Research

PubMed Central

Rosen, Laura; Manor, Orly; Engelhard, Dan; Zucker, David

2006-01-01

The overwhelming evidence about the role lifestyle plays in mortality, morbidity, and quality of life has pushed the young field of modern health promotion to center stage. The field is beset with intense debate about appropriate evaluation methodologies. Increasingly, randomized designs are considered inappropriate for health promotion research. We have reviewed criticisms against randomized trials that raise philosophical and practical issues, and we will show how most of these criticisms can be overcome with minor design modifications. By providing rebuttal to arguments against randomized trials, our work contributes to building a sound methodological base for health promotion research. PMID:16735622

Critical Appraisal Toolkit (CAT) for assessing multiple types of evidence

PubMed Central

Moralejo, D; Ogunremi, T; Dunn, K

2017-01-01

Healthcare professionals are often expected to critically appraise research evidence in order to make recommendations for practice and policy development. Here we describe the Critical Appraisal Toolkit (CAT) currently used by the Public Health Agency of Canada. The CAT consists of: algorithms to identify the type of study design, three separate tools (for appraisal of analytic studies, descriptive studies and literature reviews), additional tools to support the appraisal process, and guidance for summarizing evidence and drawing conclusions about a body of evidence. Although the toolkit was created to assist in the development of national guidelines related to infection prevention and control, clinicians, policy makers and students can use it to guide appraisal of any health-related quantitative research. Participants in a pilot test completed a total of 101 critical appraisals and found that the CAT was user-friendly and helpful in the process of critical appraisal. Feedback from participants of the pilot test of the CAT informed further revisions prior to its release. The CAT adds to the arsenal of available tools and can be especially useful when the best available evidence comes from non-clinical trials and/or studies with weak designs, where other tools may not be easily applied. PMID:29770086

Implications of Heterogeneity of Treatment Effect for Reporting and Analysis of Randomized Trials in Critical Care.

PubMed

Iwashyna, Theodore J; Burke, James F; Sussman, Jeremy B; Prescott, Hallie C; Hayward, Rodney A; Angus, Derek C

2015-11-01

Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called "heterogeneity of treatment effect" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.

Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

PubMed

Nixon, Nancy A; Khan, Omar F; Imam, Hasiba; Tang, Patricia A; Monzon, Jose; Li, Haocheng; Sun, Gavin; Ezeife, Doreen; Parimi, Sunil; Dowden, Scot; Tam, Vincent C

2017-12-01

Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society. © 2017 American Cancer Society.

Integrating ADNI Results into Alzheimer’s Disease Drug Development Programs

PubMed Central

Cummings, Jeffrey L.

2010-01-01

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is providing critical new information on biomarkers in cognitively normal elderly, persons with mild cognitive impairment (MCI), and patients with mild Alzheimer’s disease (AD). The data provide insights into the progression of the pathology of AD over time, assist in understanding which biomarkers might be most useful in clinical trials, and facilitate development of disease-modifying treatments. ADNI results are intended to support new AD Treatments development; this paper considers how ADNI information can be integrated in AD drug development programs. Cerebrospinal fluid (CSF) amyloid beta protein (Aβ) measures can be used in Phase I studies to detect any short term effects on Aβ levels in the CSF. Phase II studies may benefit most from biomarker measures that can inform decisions about Phase III. CSF Aβ levels, CSF total tau and phospotau measures, fluorodexoyglucose positron emission tomography (FDG PET), Pittsburgh Compound B (PIB) amyloid imaging, or magnetic resonance imaging (MRI) may be employed to select patient in enriched trials or as outcomes for specific disease-modifying interventions. Use of biomarkers may allow Phase II trials to be conducted more efficiently with smaller populations of patients or shorted treatment times. New drug applications (NDA) may include biomarker outcomes of phase III trials. ADNI patients are highly educated and are nearly all of Caucasian ethnicity limiting the generalizability of the results to other populations commonly included in global clinical trials. ADNI has inspired or collaborates with biomarker investigations worldwide and together these studies will provide biomarker information that can reduce development times and costs, improve drug safety, optimize drug efficacy, and bring new treatments to patients with or at risk for AD. PMID:20447734

Global Epidemiology of Pediatric Severe Sepsis: The Sepsis Prevalence, Outcomes, and Therapies Study

PubMed Central

Weiss, Scott L.; Pappachan, John; Wheeler, Derek; Jaramillo-Bustamante, Juan C.; Salloo, Asma; Singhi, Sunit C.; Erickson, Simon; Roy, Jason A.; Bush, Jenny L.; Nadkarni, Vinay M.; Thomas, Neal J.

2015-01-01

Rationale: Limited data exist about the international burden of severe sepsis in critically ill children. Objectives: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. Methods: A point prevalence study was conducted on 5 days throughout 2013–2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. Measurements and Main Results: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6–8.9%). The patients’ median age was 3.0 (interquartile range [IQR], 0.7–11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0–25), and vasoactive-free days were 23 (IQR, 12–28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5–10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group. Conclusions: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted. PMID:25734408

Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.

PubMed

Fitzgerald, Julie C; Weiss, Scott L; Maude, Shannon L; Barrett, David M; Lacey, Simon F; Melenhorst, J Joseph; Shaw, Pamela; Berg, Robert A; June, Carl H; Porter, David L; Frey, Noelle V; Grupp, Stephan A; Teachey, David T

2017-02-01

Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy. Retrospective cohort study. Academic children's hospital. Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab. Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.

Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.

PubMed

Weiss, Scott L; Fitzgerald, Julie C; Pappachan, John; Wheeler, Derek; Jaramillo-Bustamante, Juan C; Salloo, Asma; Singhi, Sunit C; Erickson, Simon; Roy, Jason A; Bush, Jenny L; Nadkarni, Vinay M; Thomas, Neal J

2015-05-15

Limited data exist about the international burden of severe sepsis in critically ill children. To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

PubMed

Opal, Steven M; Dellinger, R Phillip; Vincent, Jean-Louis; Masur, Henry; Angus, Derek C

2014-07-01

The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

Lessons for Successful Study Enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

PubMed Central

Crowley, Susan T.; Chertow, Glenn M.; Vitale, Joseph; O'Connor, Theresa; Zhang, Jane; Schein, Roland M.H.; Choudhury, Devasmita; Finkel, Kevin; Vijayan, Anitha; Paganini, Emil; Palevsky, Paul M.

2008-01-01

Background and objectives: Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. Design, setting, participants, & measurements: Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. Results: 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. Conclusions: The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury. PMID:18385390

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study.

PubMed

Crowley, Susan T; Chertow, Glenn M; Vitale, Joseph; O'Connor, Theresa; Zhang, Jane; Schein, Roland M H; Choudhury, Devasmita; Finkel, Kevin; Vijayan, Anitha; Paganini, Emil; Palevsky, Paul M

2008-07-01

Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Preventing ARDS

PubMed Central

Beitler, Jeremy R.; Schoenfeld, David A.

2014-01-01

Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high. Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges. ARDS has not been validated as an end point for pivotal clinical trials, and caution is needed when testing toxic therapies that may prevent ARDS yet potentially increase mortality. PMID:25288000

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

Schulte, R.

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. Themore » lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial development and support. Research reported in this presentation is supported by the National Cancer Institute of the National; Institutes of Health under Award Number P20CA183640.« less

The Trial Using Motivational Interviewing and Positive Affect and Self-Affirmation in African-Americans with Hypertension (TRIUMPH): From Theory to Clinical Trial Implementation

PubMed Central

Boutin-Foster, Carla; Scott, Ebony; Rodriguez, Anna; Ramos, Rosio; Kanna, Balavenkatesh; Michelen, Walid; Charlson, Mary; Gbenga, Ogedegbe

2014-01-01

This paper describes the application of a translational research model in developing The Trial Using Motivational Interviewing and Positive Affect and Self-Affirmation in African-Americans with Hypertension (TRIUMPH), a theoretically-based, randomized controlled trial. TRIUMPH targets blood pressure control among African-Americans with hypertension in a community health center and public hospital setting. TRIUMPH applies positive affect, self-affirmation, and motivational interviewing as strategies to increase medication adherence and blood pressure control. A total of 220 participants were recruited in TRIUMPH and are currently being followed. This paper provides a detailed description of the theoretical framework and study design of TRIUMPH and concludes with a critical reflection of the lessons learned in the process of implementing a health behavior intervention in a community-based setting. TRIUMPH provides a model for incorporating the translational science research paradigm to conducting pragmatic behavioral trials in a real-world setting in a vulnerable population. Lessons learned through interactions with our community partners reinforce the value of community engagement in research. PMID:23403073

The application of active side arm controllers in helicopters

NASA Technical Reports Server (NTRS)

Knorr, R.; Melz, C.; Faulkner, A.; Obermayer, M.

1993-01-01

Eurocopter Deutschland (ECD) started simulation trials to investigate the particular problems of Side Arm Controllers (SAC) applied to helicopters. Two simulation trials have been performed. In the first trial, the handling characteristics of a 'passive' SAC and the basic requirements for the application of an 'active' SAC were evaluated in pilot-in-the-loop simulations, performing the tasks in a realistic scenario representing typical phases of a transport mission. The second simulation trial investigated the general control characteristics of the 'active' in comparison to the 'passive' control principle. A description of the SACs developed by ECD and the principle of the 'passive' and 'active' control concept is given, as well as specific ratings for the investigated dynamic and ergonomic parameters effecting SAC characteristics. The experimental arrangements, as well as the trials procedures of both simulation phases, are described and the results achieved are discussed emphasizing the advantages of the 'active' as opposed to the 'passive' SAC concept. This also includes the presentation of some critical aspects still to be improved and proposals to solve them.

COMBAT: Initial experience with a randomized clinical trial of plasma-based resuscitation in the field for traumatic hemorrhagic shock

PubMed Central

Chapman, Michael P.; Moore, Ernest E.; Chin, Theresa L; Ghasabyan, Arsen; Chandler, James; Stringham, John; Gonzalez, Eduardo; Moore, Hunter B.; Banerjee, Anirban; Silliman, Christopher C; Sauaia, Angela

2015-01-01

The existing evidence shows great promise for plasma as the first resuscitation fluid in both civilian and military trauma. We embarked on the Control of Major Bleeding After Trauma (COMBAT) trial with the support of the Department of Defense, in order to determine if plasma-first resuscitation yields hemostatic and survival benefits. The methodology of the COMBAT study represents not only three years of development work, but the integration of nearly two-decades of technical experience with the design and implementation of other clinical trials and studies. Herein, we describe the key features of the study design, critical personnel and infrastructural elements, and key innovations. We will also briefly outline the systems engineering challenges entailed by this study. COMBAT is a randomized, placebo controlled, semi-blinded prospective Phase IIB clinical trial, conducted in a ground ambulance fleet based at a Level I trauma center, and part of a multicenter collaboration. The primary objective of COMBAT is to determine the efficacy of field resuscitation with plasma first, compared to standard of care (normal saline). To date we have enrolled 30 subjects in the COMBAT study. The ability to achieve intervention with a hemostatic resuscitation agent in the closest possible temporal proximity to injury is critical and represents an opportunity to forestall the evolution of the “bloody vicious cycle”. Thus, the COMBAT model for deploying plasma in first response units should serve as a model for RCTs of other hemostatic resuscitative agents. PMID:25784527

Barriers and Solutions to Smart Water Grid Development.

PubMed

Cheong, So-Min; Choi, Gye-Woon; Lee, Ho-Sun

2016-03-01

This limited review of smart water grid (SWG) development, challenges, and solutions provides an initial assessment of early attempts at operating SWGs. Though the cost and adoption issues are critical, potential benefits of SWGs such as efficient water conservation and distribution sustain the development of SWGs around the world. The review finds that the keys to success are the new regulations concerning data access and ownership to solve problems of security and privacy; consumer literacy to accept and use SWGs; active private sector involvement to coordinate SWG development; government-funded pilot projects and trial centers; and integration with sustainable water management.

Barriers and Solutions to Smart Water Grid Development

NASA Astrophysics Data System (ADS)

Cheong, So-Min; Choi, Gye-Woon; Lee, Ho-Sun

2016-03-01

This limited review of smart water grid (SWG) development, challenges, and solutions provides an initial assessment of early attempts at operating SWGs. Though the cost and adoption issues are critical, potential benefits of SWGs such as efficient water conservation and distribution sustain the development of SWGs around the world. The review finds that the keys to success are the new regulations concerning data access and ownership to solve problems of security and privacy; consumer literacy to accept and use SWGs; active private sector involvement to coordinate SWG development; government-funded pilot projects and trial centers; and integration with sustainable water management.

Negative mood and mind wandering increase long-range temporal correlations in attention fluctuations.

PubMed

Irrmischer, Mona; van der Wal, C Natalie; Mansvelder, Huibert D; Linkenkaer-Hansen, Klaus

2018-01-01

There is growing evidence that the intermittent nature of mind wandering episodes and mood have a pronounced influence on trial-to-trial variability in performance. Nevertheless, the temporal dynamics and significance of such lapses in attention remains inadequately understood. Here, we hypothesize that the dynamics of fluctuations in sustained attention between external and internal sources of information obey so-called critical-state dynamics, characterized by trial-to-trial dependencies with long-range temporal correlations. To test this, we performed behavioral investigations measuring reaction times in a visual sustained attention task and cued introspection in probe-caught reports of mind wandering. We show that trial-to-trial variability in reaction times exhibit long-range temporal correlations in agreement with the criticality hypothesis. Interestingly, we observed the fastest responses in subjects with the weakest long-range temporal correlations and show the vital effect of mind wandering and bad mood on this response variability. The implications of these results stress the importance of future research to increase focus on behavioral variability.

Negative mood and mind wandering increase long-range temporal correlations in attention fluctuations

PubMed Central

van der Wal, C. Natalie; Mansvelder, Huibert D.; Linkenkaer-Hansen, Klaus

2018-01-01

There is growing evidence that the intermittent nature of mind wandering episodes and mood have a pronounced influence on trial-to-trial variability in performance. Nevertheless, the temporal dynamics and significance of such lapses in attention remains inadequately understood. Here, we hypothesize that the dynamics of fluctuations in sustained attention between external and internal sources of information obey so-called critical-state dynamics, characterized by trial-to-trial dependencies with long-range temporal correlations. To test this, we performed behavioral investigations measuring reaction times in a visual sustained attention task and cued introspection in probe-caught reports of mind wandering. We show that trial-to-trial variability in reaction times exhibit long-range temporal correlations in agreement with the criticality hypothesis. Interestingly, we observed the fastest responses in subjects with the weakest long-range temporal correlations and show the vital effect of mind wandering and bad mood on this response variability. The implications of these results stress the importance of future research to increase focus on behavioral variability. PMID:29746529

First-in-human cell transplant trials in Parkinson's disease: The need for an improved informed consent process.

PubMed

de Melo-Martín, Inmaculada; Hellmers, Natalie; Henchcliffe, Claire

2015-08-01

First-in-human clinical trials of innovative medical procedures, such as cell transplantation for Parkinson's disease, present a variety of ethical challenges. In an era of rapidly developing stem cell technologies likely to be translated into clinical trials over the next few years, it is critical that ethical concerns be fully considered. One important undertaking is ensuring that research participants give free and truly informed consent. This will necessitate adequate disclosure of risks and benefits at a time when these are incompletely defined; ensuring understanding of a complex research protocol when there is significant possibility of therapeutic misconception; and careful determination of capacity for informed consent in patients with a neurodegenerative disorder that is known to affect cognition. Here we call attention to the ethical issues that researchers conducting these types of trials will face when trying to obtain a genuinely informed consent, and we suggest possible solutions. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Drug trials in humans. Risks in the light of the London catastrophe].

PubMed

Otte, A

2007-06-01

London's first-in-man drug trial with the monoclonal anti-CD28 antibody TGN1412 used for the treatment of oncological and autoimmune diseases resulted in a disaster with life-threatening adverse events in the volunteers triggered by an unexpected cytokine storm. Potential mistakes and consequences from this trial are highlighted in the general context of drug development and its risks. Risks in drug testing are not only found for high risk substances, such as TGN1412, or in the critical first-in-man phase, but can sometimes be detected only in later phases of the clinical testing, such as the phase 3 submission studies, or even after market authorization, as for example was the case in the cyclooxygenase-2-inhibitor rofecoxib (Vioxx) used for the treatment of rheumatic diseases and acute pain. Regulatory requirements to minimize risks in drug trials, however, have improved substantially over the last decades. Moreover, in light of the London incident these are being continuously modified with great diligence.

Ethics of phase 1 oncology studies: reexamining the arguments and data.

PubMed

Agrawal, Manish; Emanuel, Ezekiel J

2003-08-27

Phase 1 oncology trials are critical to improving the treatment of cancer. Critics have raised 2 fundamental ethical challenges about phase 1 cancer research: the paucity of benefits with substantial risks and poor-quality informed consent. Despite 3 decades of controversy about phase 1 oncology research, there is little critical analysis of the arguments or of the data relevant to these questions. Existing but old data reveal that about 5% of patients in phase 1 trials experience shrinkage of their tumor, with a 0.5% mortality rate. In some notable cases, patients in phase 1 trials have been cured or sustained long-term remissions. Limited data suggest that patients in phase 1 trials may have better quality of life than comparable patients receiving supportive care. More important, the risks and benefits of phase 1 trials are not clearly worse than risk-benefit ratios used by the US Food and Drug Administration to approve chemotherapeutic agents for clinical use. The objections based on informed consent are deficiencies of disclosure, understanding, and voluntariness. The available data do not support the claim that disclosure is deficient. Although studies evaluating patient understanding have substantial methodological problems, they demonstrate that more than 70% of patients understand that they may not directly benefit even when they hope they will personally benefit. Finally, a closer look at issues of voluntariness reveals that patients with advanced cancer who participate in phase 1 research may have a different set of values than do critics and are not coerced. Overall, it appears that phase 1 oncology trials satisfy the requirement for a favorable risk-benefit ratio and that patients who enroll provide adequate informed consent.

A Comprehensive Critique and Review of Published Measures of Acne Severity

PubMed Central

Furber, Gareth; Leach, Matthew; Segal, Leonie

2016-01-01

Objective: Acne vulgaris is a dynamic, complex condition that is notoriously difficult to evaluate. The authors set out to critically evaluate currently available measures of acne severity, particularly in terms of suitability for use in clinical trials. Design: A systematic review was conducted to identify methods used to measure acne severity, using MEDLINE, CINAHL, Scopus, and Wiley Online. Each method was critically reviewed and given a score out of 13 based on eight quality criteria under two broad groupings of psychometric testing and suitability for research and evaluation. Results: Twenty-four methods for assessing acne severity were identified. Four scales received a quality score of zero, and 11 scored ≤3. The highest rated scales achieved a total score of 6. Six scales reported strong inter-rater reliability (ICC>0.75), and four reported strong intra-rater reliability (ICC>0.75). The poor overall performance of most scales, largely characterized by the absence of reliability testing or evidence for independent assessment and validation indicates that generally, their application in clinical trials is not supported. Conclusion: This review and appraisal of instruments for measuring acne severity supports previously identified concerns regarding the quality of published measures. It highlights the need for a valid and reliable acne severity scale, especially for use in research and evaluation. The ideal scale would demonstrate adequate validation and reliability and be easily implemented for third-party analysis. The development of such a scale is critical to interpreting results of trials and facilitating the pooling of results for systematic reviews and meta-analyses. PMID:27672410

Phase 3 Oncology Clinical Trials in South Africa: Experimentation or Therapeutic Misconception?

PubMed

Malan, Tina; Moodley, Keymanthri

2016-02-01

Although clinical research in oncology is vital to improve current understanding of cancer and to validate new treatment options, voluntary informed consent is a critical component. Oncology research participants are a particularly vulnerable population; hence, therapeutic misconception often leads to ethical and legal challenges. We conducted a qualitative study administering semi-structured questionnaires on 29 adult, Phase 3, oncology clinical trial participants at three different private oncology clinical trial sites in South Africa. A descriptive content analysis was performed to identify perceptions of these participants regarding Phase 3 clinical trials. We found that most participants provided consent to be included in the trial for self-benefit. More than half of the participants had a poor understanding of Phase 3 clinical trials, and almost half the participants believed the clinical trial did not pose any significant risk to them. The word "hope" was used frequently by participants, displaying clear optimism with regard to the clinical trial and its outcome. This indicated that therapeutic misconception does occur in the South African oncology research setting and has the potential to lead to underestimation of the risks of a Phase 3 clinical trial. Emphasizing the experimental nature of a clinical trial during the consent process is critical to address therapeutic misconception in oncology research. © The Author(s) 2016.

Enhancing clinical evidence by proactively building quality into clinical trials.

PubMed

Meeker-O'Connell, Ann; Glessner, Coleen; Behm, Mark; Mulinde, Jean; Roach, Nancy; Sweeney, Fergus; Tenaerts, Pamela; Landray, Martin J

2016-08-01

Stakeholders across the clinical trial enterprise have expressed concern that the current clinical trial enterprise is unsustainable. The cost and complexity of trials have continued to increase, threatening our ability to generate reliable evidence essential for making appropriate decisions concerning the benefits and harms associated with clinical interventions. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight. The Clinical Trials Transformation Initiative convened a project to evaluate methods to prospectively build quality into the scientific and operational design of clinical trials ("quality-by-design"), such that trials are feasible to conduct and important errors are prevented rather than remediated. A working group evaluated aspects of trial design and oversight and developed the Clinical Trials Transformation Initiative quality-by-design principles document, outlining a series of factors generally relevant to the reliability of trial conclusions and to patient safety. These principles were then applied and further refined during a series of hands-on workshops to evaluate their utility in facilitating proactive, cross-functional dialogue, and decision-making about trial design and planning. Following these workshops, independent qualitative interviews were conducted with 19 workshop attendees to explore the potential challenges for implementing a quality-by-design approach to clinical trials. The Clinical Trials Transformation Initiative project team subsequently developed recommendations and an online resource guide to support implementation of this approach. The Clinical Trials Transformation Initiative quality-by-design principles provide a framework for assuring that clinical trials adequately safeguard participants and provide reliable information on which to make decisions on the effects of treatments. The quality-by-design workshops highlighted the value of active discussions incorporating the different perspectives within and external to an organization (e.g. clinical investigators, research site staff, and trial participants) in improving trial design. Workshop participants also recognized the value of focusing oversight on those aspects of the trial where errors would have a major impact on participant safety and reliability of results. Applying the Clinical Trials Transformation Initiative quality-by-design recommendations and principles should enable organizations to prioritize the most critical determinants of a trial's quality, identify non-essential activities that can be eliminated to streamline trial conduct and oversight, and formulate appropriate plans to define, avoid, mitigate, monitor, and address important errors. © The Author(s) 2016.

Critical appraisal of nonrandomized studies-A review of recommended and commonly used tools.

PubMed

Quigley, Joan M; Thompson, Juliette C; Halfpenny, Nicholas J; Scott, David A

2018-02-27

When randomized controlled trial data are limited or unavailable, or to supplement randomized controlled trial evidence, health technology assessment (HTA) agencies may rely on systematic reviews of nonrandomized studies (NRSs) for evidence of the effectiveness of health care interventions. NRS designs may introduce considerable bias into systematic reviews, and several methodologies by which to evaluate this risk of bias are available. This study aimed to identify tools commonly used to assess bias in NRS and determine those recommended by HTA bodies. Appraisal tools used in NRS were identified through a targeted search of systematic reviews (January 2013-March 2017; MEDLINE and EMBASE [OVID SP]). Recommendations for the critical appraisal of NRS by expert review groups and HTA bodies were reviewed. From the 686 studies included in the narrative synthesis, 48 critical appraisal tools were identified. Commonly used tools included the Newcastle-Ottawa Scale, the methodological index for NRS, and bespoke appraisal tools. Neither the Cochrane Handbook nor the Centre for Reviews and Dissemination recommends a particular instrument for the assessment of risk of bias in NRS, although Cochrane has recently developed their own NRS critical appraisal tool. Among HTA bodies, only the Canadian Agency for Drugs and Technologies in Health recommends use of a specific critical appraisal tool-SIGN 50 (for cohort or case-control studies). Several criteria including reporting, external validity, confounding, and power were examined. There is no consensus between HTA groups on the preferred appraisal tool. Reviewers should select from a suite of tools on the basis of the design of studies included in their review. © 2018 John Wiley & Sons, Ltd.

Clinical review: The critical care management of the burn patient

PubMed Central

2013-01-01

Between 4 and 22% of burn patients presenting to the emergency department are admitted to critical care. Burn injury is characterised by a hypermetabolic response with physiologic, catabolic and immune effects. Burn care has seen renewed interest in colloid resuscitation, a change in transfusion practice and the development of anti-catabolic therapies. A literature search was conducted with priority given to review articles, meta-analyses and well-designed large trials; paediatric studies were included where adult studies were lacking with the aim to review the advances in adult intensive care burn management and place them in the general context of day-to-day practical burn management. PMID:24093225

Formative research methods for designing culturally appropriate, integrated child nutrition and development interventions: an overview.

PubMed

Bentley, Margaret E; Johnson, Susan L; Wasser, Heather; Creed-Kanashiro, Hilary; Shroff, Monal; Fernandez Rao, Sylvia; Cunningham, Melissa

2014-01-01

Nutritional and developmental insults in the first few years of life have profound public health implications, including substantial contributions to neonatal, infant, and early childhood morbidity and mortality, as well as longer term effects on cognitive development, school achievement, and worker productivity. Optimal development that can lead to the attainment of an individual's fullest potential, therefore, requires a combination of genetic capacity, adequate nutrition, psychosocial stimulation, and safe, clean physical environments. Researchers and policymakers have called for integrated child nutrition and development interventions for more than 20 years, yet there are only a handful of efficacy trials and even fewer examples of integrated interventions that have been taken to scale. While a critical component in the design of such interventions is formative research, there is a dearth of information in both the literature and policy arenas to guide this phase of the process. To move the field forward, this paper first provides an overview of formative research methods with a focus on qualitative inquiry, a description of the critical domains to be assessed (infant and young child feeding, responsive feeding, and child development), and currently available resources. Application of these methods is provided through a real-world case study--the design of an integrated nutrition and child development efficacy trial in Andhra Pradesh, India. Recommendations for next steps are discussed, the most important of which is the need for a comprehensive set of formative guidelines for designing locally tailored, culturally appropriate, integrated interventions. © 2013 New York Academy of Sciences.

Phase 0 trials: an industry perspective.

PubMed

Eliopoulos, Helen; Giranda, Vincent; Carr, Robert; Tiehen, Rita; Leahy, Terri; Gordon, Gary

2008-06-15

Worldwide, cancer is a leading cause of morbidity and mortality. An increased understanding of the disease and its process has resulted in a multitude of new targeted therapies. The costs as well as time from drug discovery to market, however, remain staggeringly high and protracted, with the majority of compounds never reaching phase III. The concept of an exploratory or phase 0 trial was introduced as a mechanism to enhance and accelerate the overall process of new oncologic drug development. Performance of a phase 0 study allows researchers to better understand the pharmacokinetic and pharmacodynamic properties of compounds in human subjects before initiation of phase I trials. Data gleaned from a phase 0 trial are beneficial not only in prioritizing promising compounds but also in allowing the modification of phase I study design before initiation. To date, few researchers have taken advantage of the potential benefits of phase 0 trials. This review focuses on the purpose as well as the potential merits of phase 0 trials from the perspective of a pharmaceutical company. The review summarizes the experience of a team of researchers with ABT-888, a novel poly (ADP-ribose) polymerase agent that inhibits an enzyme critical for repairing damage to DNA, which is one of the first compounds to be investigated using the phase 0 clinical trial design.

The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome

PubMed Central

Dietrich, Johannes W; Stachon, Axel; Antic, Biljana; Klein, Harald H; Hering, Steffen

2008-01-01

Background Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. Although this condition is associated with significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts, is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for those inconsistencies. Objectives Primary objective of this study is the identification and differentiation of different functional states of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA) in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis. Secondary objective is observation of variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors like medication. Design The approach to a quantitative follow-up of non-thyroidal illness syndrome (AQUA FONTIS study) is designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and clinical data in additional weekly observations up to discharge. A second part of the study investigates the neuropsychological impact of NTIS and medium-term outcomes. The study design incorporates a two-module structure that covers a reduced protocol in form of an observation trial before patients give informed consent. Additional investigations are performed if and after patients agree in participation. Trial Registration ClinicalTrials.gov NCT00591032 PMID:18851740

Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke✰

PubMed Central

Liu, Ran; Yang, Shao-Hua

2013-01-01

The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. PMID:23340160

Preclinical and clinical experience in vascular gene therapy: advantages over conservative/standard therapy.

PubMed

Nikol, S; Huehns, T Y

2001-04-01

No systemic pharmacological treatment has been shown to convincingly reduce the incidence of restenosis after angioplasty or increase the formation of collaterals in ischemic tissue in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates or in inducing angiogenesis post-angioplasty and following stent implantation has encouraged the development of new technological treatment approaches. Gene therapy is a novel strategy with the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation, and to induce growth of new vessels or remodeling of pre-existing vessel branches, which may help patients with critical ischemia. Gene therapy strategies have the advantage of minimizing systemic side effects and may have a long-term effect as the encoded protein is released. Most clinical trials investigating gene therapy for vascular disease have been uncontrolled phase I and IIa trials. Gene therapy into vessels with the genes for growth factors has been demonstrated to be feasible and efficient. Local drug delivery devices have been used in combination with gene therapy in several trials to maximize safety and efficiency. Data from experimental animal work indicates that gene therapy may modify intimal hyperplasia after arterial injury, but there are few clinical trials on restenosis in patients. Preliminary clinical results show only limited success in altering restenosis rates. In vitro and experimental in vivo investigations into gene therapy for angiogenesis demonstrate increased formation of collaterals and functional improvement of limb ischemia. There is some evidence of increased collateral formation and clinical improvement in patients with critical limb ischemia. Results of placebo-controlled and double-blind trials of gene therapy for vascular disease are awaited.

Closing Arguments in the Patricia Hearst Trial: March 18-19, 1976; and Thought Control in the Patricia Hearst Trial.

ERIC Educational Resources Information Center

McDermid, Nancy Gossage; Timmis, John H., III

1976-01-01

The rhetorical criticism of the Patricia Hearst trial published in this quarterly journal consists of two articles written before a verdict was reached. The first, "Closing Arguments in the Patricia Hearst Trial," by Nancy Gossage McDermid, reflects the author's perception of stylistic and substantive differences between the arguments of…

Spinal cord injury: promising interventions and realistic goals.

PubMed

McDonald, John W; Becker, Daniel

2003-10-01

Long regarded as impossible, spinal cord repair is approaching the realm of reality as efforts to bridge the gap between bench and bedside point to novel approaches to treatment. It is important to recognize that the research playing field is rapidly changing and that new mechanisms of resource development are required to effectively make the transition from basic science discoveries to effective clinical treatments. This article reviews recent laboratory studies and phase 1 clinical trials in neural and nonneural cell transplantation, stressing that the transition from basic science to clinical applications requires a parallel rather than serial approach, with continuous, two-way feedback to most efficiently translate basic science findings, through evaluation and optimization, to clinical treatments. An example of mobilizing endogenous stem cells for repair is reviewed, with emphasis on the rapid application of basic science to clinical therapy. Successful and efficient transition from basic science to clinical applications requires (1) a parallel rather than a serial approach; (2) development of centers that integrate three spheres of science, translational, transitional, and clinical trials; and (3) development of novel resources to fund the most critically limited step of transitional to clinical trials.

Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments.

PubMed

Saas, Philippe; Daguindau, Etienne; Perruche, Sylvain

2016-06-01

The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473. © 2016 AlphaMed Press.

Treatment of pediculosis capitis: a critical appraisal of the current literature.

PubMed

Feldmeier, Hermann

2014-10-01

Pediculosis capitis is the most common ectoparasitic disease in children in industrialized countries and extremely common in resource-poor communities of the developing world. The extensive use of pediculicides with a neurotoxic mode of action has led to the development and spread of resistant head lice populations all over the world. This triggered the development of compounds with other modes of action. The current literature on treatment approaches of head lice infestation was searched, and published randomized controlled trials were critically analyzed. The following compounds/family of compounds were identified: spinosad, a novel compound with a new neurotoxic mode of action, isopropyl myristate, 1,2-octanediol, ivermectin, plant-based products, and dimeticones. The efficacy and safety of these compounds are reviewed and recommendations for the treatment of pediculosis capitis in individuals as well as the interruption of ongoing epidemics are provided.

Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa

PubMed Central

2010-01-01

Background Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. Methods In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Results Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. Conclusion The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields. PMID:20211030

Current status of pharmacokinetic and safety studies of multidrug-resistant tuberculosis treatment in children.

PubMed

Garcia-Prats, A J; Svensson, E M; Weld, E D; Schaaf, H S; Hesseling, A C

2018-05-01

After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB. There is international consensus that an efficacy trial of a novel, all-oral, shortened MDR-TB treatment trial in children is both needed and feasible. Key novel and repurposed second-line anti-tuberculosis drugs include BDQ, DLM, PTM, MFX, LVX, CFZ and LZD. The rapidly emerging PK and safety data on these medications in children with MDR-TB from studies that are underway, completed or planned, will be critical in supporting such an efficacy trial. Commitment to addressing the remaining knowledge gaps, developing child-friendly formulations of key medications, improving the design of paediatric PK and safety studies, and development of international trial capacity in children with MDR-TB are important priorities.

An evaluation of the effectiveness of a risk-based monitoring approach implemented with clinical trials involving implantable cardiac medical devices.

PubMed

Diani, Christopher A; Rock, Angie; Moll, Phil

2017-12-01

Background Risk-based monitoring is a concept endorsed by the Food and Drug Administration to improve clinical trial data quality by focusing monitoring efforts on critical data elements and higher risk investigator sites. BIOTRONIK approached this by implementing a comprehensive strategy that assesses risk and data quality through a combination of operational controls and data surveillance. This publication demonstrates the effectiveness of a data-driven risk assessment methodology when used in conjunction with a tailored monitoring plan. Methods We developed a data-driven risk assessment system to rank 133 investigator sites comprising 3442 subjects and identify those sites that pose a potential risk to the integrity of data collected in implantable cardiac device clinical trials. This included identification of specific risk factors and a weighted scoring mechanism. We conducted trend analyses for risk assessment data collected over 1 year to assess the overall impact of our data surveillance process combined with other operational monitoring efforts. Results Trending analyses of key risk factors revealed an improvement in the quality of data collected during the observation period. The three risk factors follow-up compliance rate, unavailability of critical data, and noncompliance rate correspond closely with Food and Drug Administration's risk-based monitoring guidance document. Among these three risk factors, 100% (12/12) of quantiles analyzed showed an increase in data quality. Of these, 67% (8/12) of the improving trends in worst performing quantiles had p-values less than 0.05, and 17% (2/12) had p-values between 0.05 and 0.06. Among the poorest performing site quantiles, there was a statistically significant decrease in subject follow-up noncompliance rates, protocol noncompliance rates, and incidence of missing critical data. Conclusion One year after implementation of a comprehensive strategy for risk-based monitoring, including a data-driven risk assessment methodology to target on-site monitoring visits, statistically significant improvement was seen in a majority of measurable risk factors at the worst performing site quantiles. For the three risk factors which are most critical to the overall compliance of cardiac rhythm management medical device studies: follow-up compliance rate, unavailability of critical data, and noncompliance rate, we measured significant improvement in data quality. Although the worst performing site quantiles improved but not significantly in some risk factors such as subject attrition, the data-driven risk assessment highlighted key areas on which to continue focusing both on-site and centralized monitoring efforts. Data-driven surveillance of clinical trial performance provides actionable observations that can improve site performance. Clinical trials utilizing risk-based monitoring by leveraging a data-driven quality assessment combined with specific operational procedures may lead to an improvement in data quality and resource efficiencies.

Down with Tyranny.

ERIC Educational Resources Information Center

Starr, Isidore

1985-01-01

The Zenger trial established the right of the press to criticize those in the centers of political power. The characters and events of the trial are described. The trial had all the elements of great theater and is a must for use in high school U.S. history or legal education courses. (RM)

Priorities for clinical research in intracerebral hemorrhage: report from a National Institute of Neurological Disorders and Stroke workshop.

PubMed

2005-03-01

Spontaneous intracerebral hemorrhage (ICH) is one of the most lethal stroke types. In December 2003, a National Institute of Neurological Disorders and Stroke (NINDS) workshop was convened to develop a consensus for ICH research priorities. The focus was clinical research aimed at acute ICH in patients. Workshop participants were divided into 6 groups: (1) current state of ICH research; (2) basic science; and (3) imaging, (4) medical, (5) surgical, and (6) clinical methodology. Each group formulated research priorities before the workshop. At the workshop, these were discussed and refined. Recent progress in management of hemorrhage growth, intraventricular hemorrhage, and limitations in the benefit of open craniotomy were noted. The workshop identified the importance of developing animal models to reflect human ICH, as well as the phenomena of rebleeding. More human ICH pathology is needed. Real-time, high-field magnets and 3-dimensional imaging, as well as high-resolution tissue probes, are ICH imaging priorities. Trials of acute blood pressure-lowering in ICH and coagulopathy reversal are medical priorities. The exact role of edema in human ICH pathology and its treatment requires intensive study. Trials of minimally invasive surgical techniques including mechanical and chemical surgical adjuncts are critically important. The methodologic challenges include establishing research networks and a multi-specialty approach. Waiver of consent issues and standardizing care in trials are important issues. Encouragement of young investigators from varied backgrounds to enter the ICH research field is critical. Increasing ICH research is crucial. A collaborative approach is likely to yield therapies for this devastating form of brain injury.

Critical review, with an optimistic outlook, on Boron Neutron Capture Therapy (BNCT).

PubMed

Moss, Raymond L

2014-06-01

The first BNCT trials took place in the USA in the early 1960's, yet BNCT is still far from mainstream medicine. Nonetheless, in recent years, reported results in the treatment of head and neck cancer and recurrent glioma, coupled with the progress in developing linear accelerators specifically for BNCT applications, have given some optimism to the future of BNCT. This article provides a brief reminder on the ups and downs of the history of BNCT and supports the view that controlled and prospective clinical trials with a modern design will make BNCT an evidence-based treatment modality within the coming decade. © 2013 Elsevier Ltd. All rights reserved.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics.

PubMed

Garg, Abhishek D; More, Sanket; Rufo, Nicole; Mece, Odeta; Sassano, Maria Livia; Agostinis, Patrizia; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2017-01-01

The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use.

PubMed

Nayak, Satyaprakash; Sander, Oliver; Al-Huniti, Nidal; de Alwis, Dinesh; Chain, Anne; Chenel, Marylore; Sunkaraneni, Soujanya; Agrawal, Shruti; Gupta, Neeraj; Visser, Sandra A G

2018-03-01

Quantitative pharmacology (QP) applications in translational medicine, drug-development, and therapeutic use were crowd-sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial-burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model-informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy. © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

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.

Cellular Therapies Clinical Research Roadmap: lessons learned on how to move a cellular therapy into a clinical trial.

PubMed

Ouseph, Stacy; Tappitake, Darah; Armant, Myriam; Wesselschmidt, Robin; Derecho, Ivy; Draxler, Rebecca; Wood, Deborah; Centanni, John M

2015-04-01

A clinical research roadmap has been developed as a resource for researchers to identify critical areas and potential pitfalls when transitioning a cellular therapy product from the research laboratory, by means of an Investigational New Drug (IND) application, into early-phase clinical trials. The roadmap describes four key areas: basic and preclinical research, resource development, translational research and Good Manufacturing Practice (GMP) and IND assembly and submission. Basic and preclinical research identifies a new therapeutic concept and demonstrates its potential value with the use of a model of the relevant disease. During resource development, the appropriate specialists and the required expertise to bring this product into the clinic are identified (eg, researchers, regulatory specialists, GMP manufacturing staff, clinicians and clinical trials staff, etc). Additionally, the funds required to achieve this goal (or a plan to procure them) are identified. In the next phase, the plan to translate the research product into a clinical-grade therapeutic is developed. Finally regulatory approval to start the trial must be obtained. In the United States, this is done by filing an IND application with the Food and Drug Administration. The National Heart, Lung and Blood Institute-funded Production Assistance for Cellular Therapies program has facilitated the transition of a variety of cellular therapy products from the laboratory into Phase1/2 trials. The five Production Assistance for Cellular Therapies facilities have assisted investigators by performing translational studies and GMP manufacturing to ensure that cellular products met release specifications and were manufactured safely, reproducibly and at the appropriate scale. The roadmap resulting from this experience is the focus of this article. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Multiattribute selection of acute stroke imaging software platform for Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) clinical trial.

PubMed

Churilov, Leonid; Liu, Daniel; Ma, Henry; Christensen, Soren; Nagakane, Yoshinari; Campbell, Bruce; Parsons, Mark W; Levi, Christopher R; Davis, Stephen M; Donnan, Geoffrey A

2013-04-01

The appropriateness of a software platform for rapid MRI assessment of the amount of salvageable brain tissue after stroke is critical for both the validity of the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) Clinical Trial of stroke thrombolysis beyond 4.5 hours and for stroke patient care outcomes. The objective of this research is to develop and implement a methodology for selecting the acute stroke imaging software platform most appropriate for the setting of a multi-centre clinical trial. A multi-disciplinary decision making panel formulated the set of preferentially independent evaluation attributes. Alternative Multi-Attribute Value Measurement methods were used to identify the best imaging software platform followed by sensitivity analysis to ensure the validity and robustness of the proposed solution. Four alternative imaging software platforms were identified. RApid processing of PerfusIon and Diffusion (RAPID) software was selected as the most appropriate for the needs of the EXTEND trial. A theoretically grounded generic multi-attribute selection methodology for imaging software was developed and implemented. The developed methodology assured both a high quality decision outcome and a rational and transparent decision process. This development contributes to stroke literature in the area of comprehensive evaluation of MRI clinical software. At the time of evaluation, RAPID software presented the most appropriate imaging software platform for use in the EXTEND clinical trial. The proposed multi-attribute imaging software evaluation methodology is based on sound theoretical foundations of multiple criteria decision analysis and can be successfully used for choosing the most appropriate imaging software while ensuring both robust decision process and outcomes. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Activating clinical trials: a process improvement approach.

PubMed

Martinez, Diego A; Tsalatsanis, Athanasios; Yalcin, Ali; Zayas-Castro, José L; Djulbegovic, Benjamin

2016-02-24

The administrative process associated with clinical trial activation has been criticized as costly, complex, and time-consuming. Prior research has concentrated on identifying administrative barriers and proposing various solutions to reduce activation time, and consequently associated costs. Here, we expand on previous research by incorporating social network analysis and discrete-event simulation to support process improvement decision-making. We searched for all operational data associated with the administrative process of activating industry-sponsored clinical trials at the Office of Clinical Research of the University of South Florida in Tampa, Florida. We limited the search to those trials initiated and activated between July 2011 and June 2012. We described the process using value stream mapping, studied the interactions of the various process participants using social network analysis, and modeled potential process modifications using discrete-event simulation. The administrative process comprised 5 sub-processes, 30 activities, 11 decision points, 5 loops, and 8 participants. The mean activation time was 76.6 days. Rate-limiting sub-processes were those of contract and budget development. Key participants during contract and budget development were the Office of Clinical Research, sponsors, and the principal investigator. Simulation results indicate that slight increments on the number of trials, arriving to the Office of Clinical Research, would increase activation time by 11 %. Also, incrementing the efficiency of contract and budget development would reduce the activation time by 28 %. Finally, better synchronization between contract and budget development would reduce time spent on batching documentation; however, no improvements would be attained in total activation time. The presented process improvement analytic framework not only identifies administrative barriers, but also helps to devise and evaluate potential improvement scenarios. The strength of our framework lies in its system analysis approach that recognizes the stochastic duration of the activation process and the interdependence between process activities and entities.

First-Stage Development and Validation of a Web-Based Automated Dietary Modeling Tool: Using Constraint Optimization Techniques to Streamline Food Group and Macronutrient Focused Dietary Prescriptions for Clinical Trials.

PubMed

Probst, Yasmine; Morrison, Evan; Sullivan, Emma; Dam, Hoa Khanh

2016-07-28

Standardizing the background diet of participants during a dietary randomized controlled trial is vital to trial outcomes. For this process, dietary modeling based on food groups and their target servings is employed via a dietary prescription before an intervention, often using a manual process. Partial automation has employed the use of linear programming. Validity of the modeling approach is critical to allow trial outcomes to be translated to practice. This paper describes the first-stage development of a tool to automatically perform dietary modeling using food group and macronutrient requirements as a test case. The Dietary Modeling Tool (DMT) was then compared with existing approaches to dietary modeling (manual and partially automated), which were previously available to dietitians working within a dietary intervention trial. Constraint optimization techniques were implemented to determine whether nonlinear constraints are best suited to the development of the automated dietary modeling tool using food composition and food consumption data. Dietary models were produced and compared with a manual Microsoft Excel calculator, a partially automated Excel Solver approach, and the automated DMT that was developed. The web-based DMT was produced using nonlinear constraint optimization, incorporating estimated energy requirement calculations, nutrition guidance systems, and the flexibility to amend food group targets for individuals. Percentage differences between modeling tools revealed similar results for the macronutrients. Polyunsaturated fatty acids and monounsaturated fatty acids showed greater variation between tools (practically equating to a 2-teaspoon difference), although it was not considered clinically significant when the whole diet, as opposed to targeted nutrients or energy requirements, were being addressed. Automated modeling tools can streamline the modeling process for dietary intervention trials ensuring consistency of the background diets, although appropriate constraints must be used in their development to achieve desired results. The DMT was found to be a valid automated tool producing similar results to tools with less automation. The results of this study suggest interchangeability of the modeling approaches used, although implementation should reflect the requirements of the dietary intervention trial in which it is used.

First-Stage Development and Validation of a Web-Based Automated Dietary Modeling Tool: Using Constraint Optimization Techniques to Streamline Food Group and Macronutrient Focused Dietary Prescriptions for Clinical Trials

PubMed Central

Morrison, Evan; Sullivan, Emma; Dam, Hoa Khanh

2016-01-01

Background Standardizing the background diet of participants during a dietary randomized controlled trial is vital to trial outcomes. For this process, dietary modeling based on food groups and their target servings is employed via a dietary prescription before an intervention, often using a manual process. Partial automation has employed the use of linear programming. Validity of the modeling approach is critical to allow trial outcomes to be translated to practice. Objective This paper describes the first-stage development of a tool to automatically perform dietary modeling using food group and macronutrient requirements as a test case. The Dietary Modeling Tool (DMT) was then compared with existing approaches to dietary modeling (manual and partially automated), which were previously available to dietitians working within a dietary intervention trial. Methods Constraint optimization techniques were implemented to determine whether nonlinear constraints are best suited to the development of the automated dietary modeling tool using food composition and food consumption data. Dietary models were produced and compared with a manual Microsoft Excel calculator, a partially automated Excel Solver approach, and the automated DMT that was developed. Results The web-based DMT was produced using nonlinear constraint optimization, incorporating estimated energy requirement calculations, nutrition guidance systems, and the flexibility to amend food group targets for individuals. Percentage differences between modeling tools revealed similar results for the macronutrients. Polyunsaturated fatty acids and monounsaturated fatty acids showed greater variation between tools (practically equating to a 2-teaspoon difference), although it was not considered clinically significant when the whole diet, as opposed to targeted nutrients or energy requirements, were being addressed. Conclusions Automated modeling tools can streamline the modeling process for dietary intervention trials ensuring consistency of the background diets, although appropriate constraints must be used in their development to achieve desired results. The DMT was found to be a valid automated tool producing similar results to tools with less automation. The results of this study suggest interchangeability of the modeling approaches used, although implementation should reflect the requirements of the dietary intervention trial in which it is used. PMID:27471104

Implementation fidelity of Multidimensional Family Therapy in an international trial.

PubMed

Rowe, Cynthia; Rigter, Henk; Henderson, Craig; Gantner, Andreas; Mos, Kees; Nielsen, Philip; Phan, Olivier

2013-04-01

Implementation fidelity, a critical aspect of clinical trials research that establishes adequate delivery of the treatment as prescribed in treatment manuals and protocols, is also essential to the successful implementation of effective programs into new practice settings. Although infrequently studied in the drug abuse field, stronger implementation fidelity has been linked to better outcomes in practice but appears to be more difficult to achieve with greater distance from model developers. In the INternational CAnnabis Need for Treatment (INCANT) multi-national randomized clinical trial, investigators tested the effectiveness of Multidimensional Family Therapy (MDFT) in comparison to individual psychotherapy (IP) in Brussels, Berlin, Paris, The Hague, and Geneva with 450 adolescents with a cannabis use disorder and their parents. This study reports on the implementation fidelity of MDFT across these five Western European sites in terms of treatment adherence, dose and program differentiation, and discusses possible implications for international implementation efforts. Copyright © 2013 Elsevier Inc. All rights reserved.

Ethical and practical challenges in implementing informed consent in HIV/AIDS clinical trials in developing or resource-limited countries.

PubMed

Mystakidou, Kyriaki; Panagiotou, Irene; Katsaragakis, Stelios; Tsilika, Eleni; Parpa, Efi

2009-09-01

Ethical issues regarding HIV/AIDS human research in the developing world remain under continuous evaluation; a critical area of concern includes informed consent. This paper reviews several of the most important ethical and practical aspects of informed consent in HIV research in developing countries. Enhancement of overall understanding of such key issues might promote higher ethical standards of future research. The major objective was to address informed consent in human research in non-Western societies, and specifically in HIV clinical trials of affected adults. Secondary end-points included the consent complexities in HIV research involving vulnerable patient populations in resource-limited nations, such as children, adolescents and women. A systematic review of the published literature using MEDLINE and EMBASE from 1998 until December 2008 was performed, using the search terms 'HIV/AIDS', 'informed consent', 'clinical trials', 'developing world'. Ethical complexities such as participants' diminished autonomy, coercion or monetary inducement, language difficulties, illiteracy or lack of true understanding of the entire study, cultural barriers mainly due to communitarianism and social diversities were identified in the 44 studies reviewed. Informed consent of vulnerable patient populations must be tailored to their sex and developmental age, while counselling is fundamental. Children and adolescents' assent must be ensured. Local language is to be used, while trusted community leaders and local cultural representatives may convey information. Despite the heterogeneity of studies, similarities were identified. Providing adequate and comprehensive information and assessing the true understanding of the research represent fundamental prerequisites. Potential solutions to the critical areas of concern include peer counselling and meetings with local community leaders or local cultural representatives. International investigators of HIV human research should bear in mind these ethical issues and their potential solutions, when trying to ensure ethical research conduct, based on a truly informed and culturally relevant consent.

Comparison of Alternative Evidence Summary and Presentation Formats in Clinical Guideline Development: A Mixed-Method Study

PubMed Central

Opiyo, Newton; Shepperd, Sasha; Musila, Nyokabi; Allen, Elizabeth; Nyamai, Rachel; Fretheim, Atle; English, Mike

2013-01-01

Background Best formats for summarising and presenting evidence for use in clinical guideline development remain less well defined. We aimed to assess the effectiveness of different evidence summary formats to address this gap. Methods Healthcare professionals attending a one-week Kenyan, national guideline development workshop were randomly allocated to receive evidence packaged in three different formats: systematic reviews (SRs) alone, systematic reviews with summary-of-findings tables, and ‘graded-entry’ formats (a ‘front-end’ summary and a contextually framed narrative report plus the SR). The influence of format on the proportion of correct responses to key clinical questions, the primary outcome, was assessed using a written test. The secondary outcome was a composite endpoint, measured on a 5-point scale, of the clarity of presentation and ease of locating the quality of evidence for critical neonatal outcomes. Interviews conducted within two months following completion of trial data collection explored panel members’ views on the evidence summary formats and experiences with appraisal and use of research information. Results 65 (93%) of 70 participants completed questions on the prespecified outcome measures. There were no differences between groups in the odds of correct responses to key clinical questions. ‘Graded-entry’ formats were associated with a higher mean composite score for clarity and accessibility of information about the quality of evidence for critical neonatal outcomes compared to systematic reviews alone (adjusted mean difference 0.52, 95% CI 0.06 to 0.99). There was no difference in the mean composite score between SR with SoF tables and SR alone. Findings from interviews with 16 panelists indicated that short narrative evidence reports were preferred for the improved clarity of information presentation and ease of use. Conclusions Our findings suggest that ‘graded-entry’ evidence summary formats may improve clarity and accessibility of research evidence in clinical guideline development. Trial Registration Controlled-Trials.com ISRCTN05154264 PMID:23372813

Rates and determinants of informed consent: a case study of an international thromboprophylaxis trial.

PubMed

Smith, Orla M; McDonald, Ellen; Zytaruk, Nicole; Foster, Denise; Matte, Andrea; Clarke, France; Meade, Laurie; O'Callaghan, Nicole; Vallance, Shirley; Galt, Pauline; Rajbhandari, Dorrilyn; Rocha, Marcelo; Mehta, Sangeeta; Ferguson, Niall D; Hall, Richard; Fowler, Robert; Burns, Karen; Qushmaq, Ismael; Ostermann, Marlies; Heels-Ansdell, Diane; Cook, Deborah

2013-02-01

Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials. The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143). Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily. The trial was conducted in 67 centers in 6 countries. A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P < .001 for those with >10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs, <0.5; P < .001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P < .001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P < .001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P < .001). Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial. Copyright © 2013 Elsevier Inc. All rights reserved.

Overcoming Age Limits in Cancer Clinical Trials

Cancer.gov

Adolescents, young adults, and the elderly lag far behind other age groups when it comes to enrolling in clinical trials. Their participation is critical to advancing effective therapies for these age groups.

The Role of Critical Self-Reflection of Assumptions in an Online HIV Intervention for Men Who Have Sex with Men

ERIC Educational Resources Information Center

Wilkerson, J. Michael; Danilenko, Gene P.; Smolenski, Derek J.; Myer, Bryn B.; Rosser, B. R. Simon

2011-01-01

The Men's INTernet Study II included a randomized controlled trial to develop and test an Internet-based HIV prevention intervention for U.S men who use the Internet to seek sex with men. In 2008, participants (n = 560) were randomized to an online, interactive, sexual risk-reduction intervention or to a wait list null control. After 3 months,…

A Randomised Controlled Trial to Test the Effect of Promoting Caregiver Contingent Talk on Language Development in Infants from Diverse Socioeconomic Status Backgrounds

ERIC Educational Resources Information Center

McGillion, Michelle; Pine, Julian M.; Herbert, Jane S.; Matthews, Danielle

2017-01-01

Background: Early language skills are critical for later academic success. Lower socioeconomic status (SES) children tend to start school with limited language skills compared to advantaged peers. We test the hypothesis that this is due in part to differences in caregiver contingent talk during infancy (how often the caregiver talks about what is…

Restoration planting options for limber pines impacted by mountain pine beetles and/or white pine blister rust in the Southern Rocky Mountains

Treesearch

Anne Marie Casper; William R. Jacobi; Anna W. Schoettle; Kelly S. Burns

2010-01-01

Limber Pine (Pinus flexilis) populations in the southern Rock Mountains are severely threatened by the combined impacts of mountain pine beetles and white pine blister rust. Limber pine’s critical role these high elevation ecosystems heightens the importance of mitigating impacts. To develop forest-scale planting methods six seedling planting trial sites were installed...

Missing data in trial‐based cost‐effectiveness analysis: An incomplete journey

PubMed Central

Gomes, Manuel; Carpenter, James R.

2018-01-01

SUMMARY Cost‐effectiveness analyses (CEA) conducted alongside randomised trials provide key evidence for informing healthcare decision making, but missing data pose substantive challenges. Recently, there have been a number of developments in methods and guidelines addressing missing data in trials. However, it is unclear whether these developments have permeated CEA practice. This paper critically reviews the extent of and methods used to address missing data in recently published trial‐based CEA. Issues of the Health Technology Assessment journal from 2013 to 2015 were searched. Fifty‐two eligible studies were identified. Missing data were very common; the median proportion of trial participants with complete cost‐effectiveness data was 63% (interquartile range: 47%–81%). The most common approach for the primary analysis was to restrict analysis to those with complete data (43%), followed by multiple imputation (30%). Half of the studies conducted some sort of sensitivity analyses, but only 2 (4%) considered possible departures from the missing‐at‐random assumption. Further improvements are needed to address missing data in cost‐effectiveness analyses conducted alongside randomised trials. These should focus on limiting the extent of missing data, choosing an appropriate method for the primary analysis that is valid under contextually plausible assumptions, and conducting sensitivity analyses to departures from the missing‐at‐random assumption. PMID:29573044

Development of core outcome sets for effectiveness trials of interventions to prevent and/or treat delirium (Del-COrS): study protocol.

PubMed

Rose, Louise; Agar, Meera; Burry, Lisa D; Campbell, Noll; Clarke, Mike; Lee, Jacques; Siddiqi, Najma; Page, Valerie J

2017-09-18

Delirium is a common, serious and potentially preventable condition with devastating impact on the quality of life prompting a proliferation of interventional trials. Core outcome sets aim to standardise outcome reporting by identifying outcomes perceived fundamental for measurement in trials of a specific interest area. Our aim is to develop international consensus on two core outcome sets for trials of interventions to prevent and/or treat delirium, irrespective of study population. We aim to identify additional core outcomes specific to the critically ill, acutely hospitalised patients, palliative care and older adults. We will conduct a systematic review of published and ongoing delirium trials (1980 onwards) and one-on-one interviews of patients who have experienced delirium and family members. These data will inform Delphi round 1 of a two-stage consensus process. In round 2, we will provide participants their own response, summarised group responses and those of patient/family participants for rescoring. We will randomise participants to receive feedback as proportion scoring the outcome as critical or as group mean responses. We will hold a consensus meeting using nominal group technique to finalise outcomes for inclusion. We will repeat the Delphi process and consensus meeting to select measures for each core outcome. We will recruit 240 Delphi participants giving us 80% power to detect a 1.0-1.5 point (9-point scale) difference by feedback method between rounds. We will analyse differences for subsequent scores, magnitude of opinion change, items retained and level of agreement. We are obtaining research ethics approvals according to local governance. Participation will be voluntary and data deidentified. Support from three international delirium organisations will be instrumental in dissemination and core outcome set uptake. We will disseminate through peer-reviewed open access publications and present at conferences selected to reach a wide range of knowledge users. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Should we treat fever in critically ill patients? A summary of the current evidence from three randomized controlled trials

PubMed Central

Serpa, Ary; Pereira, Victor Galvão Moura; Colombo, Giancarlo; Scarin, Farah Christina de la Cruz; Pessoa, Camila Menezes Souza; Rocha, Leonardo Lima

2014-01-01

Fever is a nonspecific response to various types of infectious or non-infectious insult and its significance in disease remains an enigma. Our aim was to summarize the current evidence for the use of antipyretic therapy in critically ill patients. We performed systematic review and meta-analysis of publications from 1966 to 2013. The MEDLINE and CENTRAL databases were searched for studies on antipyresis in critically ill patients. The meta-analysis was limited to: randomized controlled trials; adult human critically ill patients; treatment with antipyretics in one arm versus placebo or non-treatment in another arm; and report of mortality data. The outcomes assessed were overall intensive care unit mortality, changes in temperature, intensive care unit length of stay, and hospital length of stay. Three randomized controlled trials, covering 320 participants, were included. Patients treated with antipyretic agents showed similar intensive care unit mortality (risk ratio 0.91, with 95% confidence interval 0.65-1.28) when compared with controls. The only difference observed was a greater decrease in temperature after 24 hours in patients treated with antipyretics (-1.70±0.40 versus - 0.56±0.25ºC; p=0.014). There is no difference in treating or not the fever in critically ill patients. PMID:25628209

Glutamine Randomized Studies in Early Life: The Unsolved Riddle of Experimental and Clinical Studies

PubMed Central

Briassouli, Efrossini; Briassoulis, George

2012-01-01

Glutamine may have benefits during immaturity or critical illness in early life but its effects on outcome end hardpoints are controversial. Our aim was to review randomized studies on glutamine supplementation in pups, infants, and children examining whether glutamine affects outcome. Experimental work has proposed various mechanisms of glutamine action but none of the randomized studies in early life showed any effect on mortality and only a few showed some effect on inflammatory response, organ function, and a trend for infection control. Although apparently safe in animal models (pups), premature infants, and critically ill children, glutamine supplementation does not reduce mortality or late onset sepsis, and its routine use cannot be recommended in these sensitive populations. Large prospectively stratified trials are needed to better define the crucial interrelations of “glutamine-heat shock proteins-stress response” in critical illness and to identify the specific subgroups of premature neonates and critically ill infants or children who may have a greater need for glutamine and who may eventually benefit from its supplementation. The methodological problems noted in the reviewed randomized experimental and clinical trials should be seriously considered in any future well-designed large blinded randomized controlled trial involving glutamine supplementation in critical illness. PMID:23019424

Methodological Issues Surrounding the Use of Baseline Health-Related Quality of Life Data to Inform Trial-Based Economic Evaluations of Interventions Within Emergency and Critical Care Settings: A Systematic Literature Review.

PubMed

Dritsaki, Melina; Achana, Felix; Mason, James; Petrou, Stavros

2017-05-01

Trial-based cost-utility analyses require health-related quality of life data that generate utility values in order to express health outcomes in terms of quality-adjusted life years (QALYs). Assessments of baseline health-related quality of life are problematic where trial participants are incapacitated or critically ill at the time of randomisation. This review aims to identify and critique methods for handling non-availability of baseline health-related quality of life data in trial-based cost-utility analyses within emergency and critical illness settings. A systematic literature review was conducted, following PRISMA guidelines, to identify trial-based cost-utility analyses of interventions within emergency and critical care settings. Databases searched included the National Institute for Health Research (NIHR) Journals Library (1991-July 2016), Cochrane Library (all years); National Health Service (NHS) Economic Evaluation Database (all years) and Ovid MEDLINE/Embase (without time restriction). Strategies employed to handle non-availability of baseline health-related quality of life data in final QALY estimations were identified and critiqued. A total of 4224 published reports were screened, 19 of which met the study inclusion criteria (mean trial size 1670): 14 (74 %) from the UK, four (21%) from other European countries and one (5%) from India. Twelve studies (63%) were based in emergency departments and seven (37%) in intensive care units. Only one study was able to elicit patient-reported health-related quality of life at baseline. To overcome the lack of baseline data when estimating QALYs, eight studies (42%) assigned a fixed utility weight corresponding to either death, an unconscious health state or a country-specific norm to patients at baseline, four (21%) ignored baseline utilities, three (16%) applied values from another study, one (5%) generated utility values via retrospective recall and one (5%) elicited utilities from experts. A preliminary exploration of these methods shows that incremental QALY estimation is unlikely to be biased if balanced trial allocation is achieved and subsequent collection of health-related quality of life data occurs at the earliest possible opportunity following commencement of treatment, followed by an adequate number of follow-up assessments. Trial-based cost-utility analyses within emergency and critical illness settings have applied different methods for QALY estimation, employing disparate assumptions about the health-related quality of life of patients at baseline. Where baseline measurement is not practical, measurement at the earliest opportunity following commencement of treatment should minimise bias in QALY estimation.

Guidelines for the Reporting of Treatment Trials for Alcohol Use Disorders

PubMed Central

Witkiewitz, Katie; Finney, John W.; Harris, Alex H.S; Kivlahan, Daniel R.; Kranzler, Henry R.

2015-01-01

Background The primary goals in conducting clinical trials of treatments for alcohol use disorders (AUDs) is to identify efficacious treatments and determine which treatments are most efficacious for which patients. Accurate reporting of study design features and results is imperative to enable readers of research reports to evaluate to what extent a study has achieved these goals. Guidance on quality of clinical trial reporting has evolved substantially over the past two decades, primarily through the publication and widespread adoption of the Consolidated Standards of Reporting Trials (CONSORT) statement. However, there is room to improve the adoption of those standards in reporting the design and findings of treatment trials for AUD. Methods Narrative review of guidance on reporting quality in AUD treatment trials. Results Despite improvements in the reporting of results of treatment trials for AUD over the past two decades, many published reports provide insufficient information on design or methods. Conclusions The reporting of alcohol treatment trial design, analysis, and results requires improvement in four primary areas: (1) trial registration, (2) procedures for recruitment and retention, (3) procedures for randomization and intervention design considerations, and (4) statistical methods used to assess treatment efficacy. Improvements in these areas and the adoption of reporting standards by authors, reviewers, and editors are critical to an accurate assessment of the reliability and validity of treatment effects. Continued developments in this area are needed to move AUD treatment research forward via systematic reviews and meta-analyses that maximize the utility of completed studies. PMID:26259958

Cellular Therapies in Trauma and Critical Care Medicine: Forging New Frontiers

PubMed Central

Pati, Shibani; Pilia, Marcello; Grimsley, Juanita M.; Karanikas, Alexia T.; Oyeniyi, Blessing; Holcomb, John B.; Cap, Andrew P.; Rasmussen, Todd E.

2015-01-01

ABSTRACT Trauma is a leading cause of death in both military and civilian populations worldwide. Although medical advances have improved the overall morbidity and mortality often associated with trauma, additional research and innovative advancements in therapeutic interventions are needed to optimize patient outcomes. Cell-based therapies present a novel opportunity to improve trauma and critical care at both the acute and chronic phases that often follow injury. Although this field is still in its infancy, animal and human studies suggest that stem cells may hold great promise for the treatment of brain and spinal cord injuries, organ injuries, and extremity injuries such as those caused by orthopedic trauma, burns, and critical limb ischemia. However, barriers in the translation of cell therapies that include regulatory obstacles, challenges in manufacturing and clinical trial design, and a lack of funding are critical areas in need of development. In 2015, the Department of Defense Combat Casualty Care Research Program held a joint military–civilian meeting as part of its effort to inform the research community about this field and allow for effective planning and programmatic decisions regarding research and development. The objective of this article is to provide a “state of the science” review regarding cellular therapies in trauma and critical care, and to provide a foundation from which the potential of this emerging field can be harnessed to mitigate outcomes in critically ill trauma patients. PMID:26428845

Cellular Therapies in Trauma and Critical Care Medicine: Forging New Frontiers.

PubMed

Pati, Shibani; Pilia, Marcello; Grimsley, Juanita M; Karanikas, Alexia T; Oyeniyi, Blessing; Holcomb, John B; Cap, Andrew P; Rasmussen, Todd E

2015-12-01

Trauma is a leading cause of death in both military and civilian populations worldwide. Although medical advances have improved the overall morbidity and mortality often associated with trauma, additional research and innovative advancements in therapeutic interventions are needed to optimize patient outcomes. Cell-based therapies present a novel opportunity to improve trauma and critical care at both the acute and chronic phases that often follow injury. Although this field is still in its infancy, animal and human studies suggest that stem cells may hold great promise for the treatment of brain and spinal cord injuries, organ injuries, and extremity injuries such as those caused by orthopedic trauma, burns, and critical limb ischemia. However, barriers in the translation of cell therapies that include regulatory obstacles, challenges in manufacturing and clinical trial design, and a lack of funding are critical areas in need of development. In 2015, the Department of Defense Combat Casualty Care Research Program held a joint military-civilian meeting as part of its effort to inform the research community about this field and allow for effective planning and programmatic decisions regarding research and development. The objective of this article is to provide a "state of the science" review regarding cellular therapies in trauma and critical care, and to provide a foundation from which the potential of this emerging field can be harnessed to mitigate outcomes in critically ill trauma patients.

Application of the Actor-Critic Architecture to Functional Electrical Stimulation Control of a Human Arm

PubMed Central

Thomas, Philip; Branicky, Michael; van den Bogert, Antonie; Jagodnik, Kathleen

2010-01-01

Clinical tests have shown that the dynamics of a human arm, controlled using Functional Electrical Stimulation (FES), can vary significantly between and during trials. In this paper, we study the application of the actor-critic architecture, with neural networks for the both the actor and the critic, as a controller that can adapt to these changing dynamics of a human arm. Development and tests were done in simulation using a planar arm model and Hill-based muscle dynamics. We begin by training it using a Proportional Derivative (PD) controller as a supervisor. We then make clinically relevant changes to the dynamics of the arm and test the actor-critic’s ability to adapt without supervision in a reasonable number of episodes. Finally, we devise methods for achieving both rapid learning and long-term stability. PMID:20689654

Rating the methodological quality of single-subject designs and n-of-1 trials: introducing the Single-Case Experimental Design (SCED) Scale.

PubMed

Tate, Robyn L; McDonald, Skye; Perdices, Michael; Togher, Leanne; Schultz, Regina; Savage, Sharon

2008-08-01

Rating scales that assess methodological quality of clinical trials provide a means to critically appraise the literature. Scales are currently available to rate randomised and non-randomised controlled trials, but there are none that assess single-subject designs. The Single-Case Experimental Design (SCED) Scale was developed for this purpose and evaluated for reliability. Six clinical researchers who were trained and experienced in rating methodological quality of clinical trials developed the scale and participated in reliability studies. The SCED Scale is an 11-item rating scale for single-subject designs, of which 10 items are used to assess methodological quality and use of statistical analysis. The scale was developed and refined over a 3-year period. Content validity was addressed by identifying items to reduce the main sources of bias in single-case methodology as stipulated by authorities in the field, which were empirically tested against 85 published reports. Inter-rater reliability was assessed using a random sample of 20/312 single-subject reports archived in the Psychological Database of Brain Impairment Treatment Efficacy (PsycBITE). Inter-rater reliability for the total score was excellent, both for individual raters (overall ICC = 0.84; 95% confidence interval 0.73-0.92) and for consensus ratings between pairs of raters (overall ICC = 0.88; 95% confidence interval 0.78-0.95). Item reliability was fair to excellent for consensus ratings between pairs of raters (range k = 0.48 to 1.00). The results were replicated with two independent novice raters who were trained in the use of the scale (ICC = 0.88, 95% confidence interval 0.73-0.95). The SCED Scale thus provides a brief and valid evaluation of methodological quality of single-subject designs, with the total score demonstrating excellent inter-rater reliability using both individual and consensus ratings. Items from the scale can also be used as a checklist in the design, reporting and critical appraisal of single-subject designs, thereby assisting to improve standards of single-case methodology.

Pragmatic clinical trials embedded in healthcare systems: generalizable lessons from the NIH Collaboratory.

PubMed

Weinfurt, Kevin P; Hernandez, Adrian F; Coronado, Gloria D; DeBar, Lynn L; Dember, Laura M; Green, Beverly B; Heagerty, Patrick J; Huang, Susan S; James, Kathryn T; Jarvik, Jeffrey G; Larson, Eric B; Mor, Vincent; Platt, Richard; Rosenthal, Gary E; Septimus, Edward J; Simon, Gregory E; Staman, Karen L; Sugarman, Jeremy; Vazquez, Miguel; Zatzick, Douglas; Curtis, Lesley H

2017-09-18

The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped. To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design. In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs. A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.

Pathophysiology of septic shock: From bench to bedside.

PubMed

McConnell, Kevin W; Coopersmith, Craig M

2016-04-01

Our understanding of sepsis and its resultant outcomes remains a paradox. On the one hand, we know more about the pathophysiology of sepsis than ever before. However, this knowledge has not been successfully translated to the bedside, as the vast majority of clinical trials for sepsis have been negative. Yet even in the general absence of positive clinical trials, mortality from sepsis has fallen to its lowest point in history, in large part due to educational campaigns that stress timely antibiotics and hemodynamic support. While additional improvements in outcome will assuredly result from further compliance with evidence based practices, a deeper understanding of the science that underlies the host response in sepsis is critical to the development of novel therapeutics. In this review, we outline immunopathologic abnormalities in sepsis, and then look at potential approaches to therapeutically modulate them. Ultimately, an understanding of the science underlying sepsis should allow the critical care community to utilize precision medicine to combat this devastating disease on an individual basis leading to improved outcomes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Pharmacotherapy of anxiety disorders: a critical review

PubMed Central

Koen, Nastassja; Stein, Dan J.

2011-01-01

Given the enormous contribution of anxiety disorders to the burden of disease, it is key to optimize their prevention and treatment. In this critical review we assess advances in the pharmacotherapy of anxiety disorders, as well as remaining challenges, in recent decades, the field has seen rigorous clinical trial methods to quantify the efficacy and safety of serendipitously discovered agents, more focused development of medications with selective mechanisms of action, and the gradual translation of insights from laboratory research into proof-of-principle clinical trials. On the positive side, a considerable database of studies shows efficacy and relative tolerability of the selective serotonin reuptake inhibitors in the major anxiety disorders, and secondary analyses of such datasets have informed questions such as optimal definition of response and remission, optimal dose and duration, and comparative efficacy of different agents. Significant challenges in the field include barriers to appropriate diagnosis and treatment of anxiety disorders, failure of a significant proportion of patients to respond to first-line pharmacotherapy agents, and a limited database of efficacy or effectiveness studies to guide treatment in such cases. PMID:22275848

[Pharmaconutrition with parenteral selenium in sepsis].

PubMed

Langlois, P L; de Oliveira Figliolino, L F; Hardy, G; Manzanares, W

2014-04-01

Critical illness is characterized by oxidative stress which leads to multiple organ failure, and sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit. Over the last 2 decades, different antioxidant therapies have been developed to improve outcomes in septic patients. According to recent evidence, selenium therapy should be considered the cornerstone of the antioxidant strategies. Selenium given as selenious acid or sodium selenite should be considered as a drug or pharmaconutrient with prooxidant and cytotoxic effects when a loading dose in intravenous bolus form is administered, particularly in the early stage of severe sepsis/septic shock. To date, several phase ii trials have demonstrated that selenium therapy may be able to decrease mortality, improve organ dysfunction and reduce infections in critically ill septic patients. The effect of selenium therapy in sepsis syndrome must be confirmed by large, well designed phase iii clinical trials. The purpose of this review is to discuss current evidence on selenium pharmaconutrition in sepsis syndrome. Copyright © 2013 Elsevier España, S.L. and SEMICYUC. All rights reserved.

Development and application of a unified balancing approach with multiple constraints

NASA Technical Reports Server (NTRS)

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

1985-01-01

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

Guidelines on Good Clinical Laboratory Practice

PubMed Central

Ezzelle, J.; Rodriguez-Chavez, I. R.; Darden, J. M.; Stirewalt, M.; Kunwar, N.; Hitchcock, R.; Walter, T.; D’Souza, M. P.

2008-01-01

A set of Good Clinical Laboratory Practice (GCLP) standards that embraces both the research and clinical aspects of GLP were developed utilizing a variety of collected regulatory and guidance material. We describe eleven core elements that constitute the GCLP standards with the objective of filling a gap for laboratory guidance, based on IND sponsor requirements, for conducting laboratory testing using specimens from human clinical trials. These GCLP standards provide guidance on implementing GLP requirements that are critical for laboratory operations, such as performance of protocol-mandated safety assays, peripheral blood mononuclear cell processing and immunological or endpoint assays from biological interventions on IND-registered clinical trials. The expectation is that compliance with the GCLP standards, monitored annually by external audits, will allow research and development laboratories to maintain data integrity and to provide immunogenicity, safety, and product efficacy data that is repeatable, reliable, auditable and that can be easily reconstructed in a research setting. PMID:18037599

An overview of translationally informed treatments for PTSD: animal models of Pavlovian fear conditioning to human clinical trials

PubMed Central

Bowers, Mallory E.; Ressler, Kerry J.

2015-01-01

Posttraumatic stress disorder (PTSD) manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Pre-clinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory, which have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for PTSD that have been developed via a bench to bedside translational model. PMID:26238379

Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation

PubMed Central

Griffiths, John; Barber, Vicki S; Morgan, Lesley; Young, J Duncan

2005-01-01

Objective To compare outcomes in critically ill patients undergoing artificial ventilation who received a tracheostomy early or late in their treatment. Data sources The Cochrane Central Register of Clinical Trials, Medline, Embase, CINAHL, the National Research Register, the NHS Trusts Clinical Trials Register, the Medical Research Council UK database, the NHS Research and Development Health Technology Assessment Programme, the British Heart Foundation database, citation review of relevant primary and review articles, and expert informants. Study selection Randomised and quasi-randomised controlled studies that compared early tracheostomy with either late tracheostomy or prolonged endotracheal intubation. From 15 950 articles screened, 12 were identified as “randomised or quasi-randomised” controlled trials, and five were included for data extraction. Data extraction Five studies with 406 participants were analysed. Descriptive and outcome data were extracted. The main outcome measure was mortality in hospital. The incidence of hospital acquired pneumonia, length of stay in a critical care unit, and duration of artificial ventilation were also recorded. Random effects meta-analyses were performed. Results Early tracheostomy did not significantly alter mortality (relative risk 0.79, 95% confidence interval 0.45 to 1.39). The risk of pneumonia was also unaltered by the timing of tracheostomy (0.90, 0.66 to 1.21). Early tracheostomy significantly reduced duration of artificial ventilation (weighted mean difference –8.5 days, 95% confidence interval –15.3 to –1.7) and length of stay in intensive care (–15.3 days, –24.6 to –6.1). Conclusions In critically ill adult patients who require prolonged mechanical ventilation, performing a tracheostomy at an earlier stage than is currently practised may shorten the duration of artificial ventilation and length of stay in intensive care. PMID:15901643

The current role of systemic chemotherapy in the primary treatment of head and neck cancer.

PubMed

Busch, C-J; Tribius, S; Schafhausen, P; Knecht, R

2015-03-01

The treatment of patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) is still evolving into the perfect combination of the different multidisciplinary approaches. Induction chemotherapy (ICT) prior to planned definitive local therapy is widely used in this patient population for over 30 years but it is still unclear how to incorporate ICT into multimodality treatment the best. It appears to have a role in selected clinical situations especially for those patients with high risk for distant metastasis. However, since ICT protocols in different studies varies a lot, a comparative and consistent statement of benefits is difficult. We show the recent developments including randomized trials comparing radiochemotherapy (RCT) and ICT followed by definitive RCT here. This review summarizes how ICT has developed over the years, provides critical remarks of recent developments, and discusses how clinical trials including ICT should be conducted in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project.

PubMed

Hanning, Sara M; Orlu Gul, Mine; Winslade, Jackie; Baarslag, Manuel A; Neubert, Antje; Tuleu, Catherine

2016-09-25

A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project. Copyright © 2016 Elsevier B.V. All rights reserved.

A Conceptual Model Exploring the Relationship Between HIV Stigma and Implementing HIV Clinical Trials in Rural Communities of North Carolina

PubMed Central

Sengupta, Sohini; Strauss, Ronald P.; Miles, Margaret S.; Roman-Isler, Malika; Banks, Bahby; Corbie-Smith, Giselle

2011-01-01

Background HIV/AIDS disproportionately affects minority groups in the United States, especially in the rural southeastern states. Poverty and lack of access to HIV care, including clinical trials, are prevalent in these areas and contribute to HIV stigma. This is the first study to develop a conceptual model exploring the relationship between HIV stigma and the implementation of HIV clinical trials in rural contexts to help improve participation in those trials. Methods We conducted focus groups with HIV service providers and community leaders, and individual interviews with people living with HIV/AIDS in six counties in rural North Carolina. Themes related to stigma were elicited. We classified the themes into theoretical constructs and developed a conceptual model. Results HIV stigma themes were classified under the existing theoretical constructs of perceived, experienced, vicarious, and felt normative stigma. Two additional constructs emerged: causes of HIV stigma (e.g., low HIV knowledge and denial in the community) and consequences of HIV stigma (e.g., confidentiality concerns in clinical trials). The conceptual model illustrates that the causes of HIV stigma can give rise to perceived, experienced, and vicarious HIV stigma, and these types of stigma could lead to the consequences of HIV stigma that include felt normative stigma. Limitations Understanding HIV stigma in rural counties of North Carolina may not be generalizeable to other rural US southeastern states. Conclusion The conceptual model emphasizes that HIV stigma—in its many forms—is a critical barrier to HIV clinical trial implementation in rural North Carolina. PMID:20552760

A conceptual model exploring the relationship between HIV stigma and implementing HIV clinical trials in rural communities of North Carolina.

PubMed

Sengupta, Sohini; Strauss, Ronald P; Miles, Margaret S; Roman-Isler, Malika; Banks, Bahby; Corbie-Smith, Giselle

2010-01-01

HIV/AIDS disproportionately affects minority groups in the United States, especially in the rural southeastern states. Poverty and lack of access to HIV care, including clinical trials, are prevalent in these areas and contribute to HIV stigma. This is the first study to develop a conceptual model exploring the relationship between HIV stigma and the implementation of HIV clinical trials in rural contexts to help improve participation in those trials. We conducted focus groups with HIV service providers and community leaders, and individual interviews with people living with HIV/AIDS in six counties in rural North Carolina. Themes related to stigma were elicited. We classified the themes into theoretical constructs and developed a conceptual model. HIV stigma themes were classified under the existing theoretical constructs of perceived, experienced, vicarious, and felt normative stigma. Two additional constructs emerged: causes of HIV stigma (e.g., low HIV knowledge and denial in the community) and consequences of HIV stigma (e.g., confidentiality concerns in clinical trials). The conceptual model illustrates that the causes of HIV stigma can give rise to perceived, experienced, and vicarious HIV stigma, and these types of stigma could lead to the consequences of HIV stigma that include felt normative stigma. Understanding HIV stigma in rural counties of North Carolina may not be generalizeable to other rural US southeastern states. The conceptual model emphasizes that HIV stigma--in its many forms--is a critical barrier to HIV clinical trial implementation in rural North Carolina.

[Evidence-based medicine--method, critical appraisal and usefulness for professionalized business practice in medical].

PubMed

Portwich, P

2005-05-01

The concept of evidence-based medicine (EBM) describes 5 steps that lead to a scientifically based solution of clinical problems. EBM is often reduced to the search for the best evidence (randomised controlled trials, meta-analyses) or the introduction of guidelines. This causes criticism and may have consequences for medicine. But EBM also emphasizes the so-called clinical expertise of the doctor, which is important for reference to the individual patient. This point of EBM is being developed further. Connected with the theory of professionalization by U. Oevermann, stressing the importance of hermeneutical competence, EBM turns out to be a sophisticated model of professional medical practice.

Biomarker discovery and development in pediatric critical care medicine

PubMed Central

Kaplan, Jennifer M.; Wong, Hector R.

2010-01-01

Objective To frame the general process of biomarker discovery and development, and to describe a proposal for the development of a multi-biomarker based risk model for pediatric septic shock. Data Source Narrative literature review and author generated data. Main Results Biomarkers can be grouped into four broad classes, based on the intended function: diagnostic, monitoring, surrogate, and stratification. Biomarker discovery and development requires a rigorous process, which is frequently not well followed in the critical care medicine literature. Very few biomarkers have successfully transitioned from the candidate stage to the true biomarker stage. There is great interest in developing diagnostic and stratification biomarkers for sepsis. Procalcitonin is currently the most promising diagnostic biomarker for sepsis. Recent evidence suggests that interleukin-8 can be used to stratify children with septic shock having a high likelihood of survival with standard care. Currently, there is a multi-institutional effort to develop a multi-biomarker based sepsis risk model intended to predict outcome and illness severity for individual children with septic shock. Conclusions Biomarker discovery and development is an important portion of the pediatric critical care medicine translational research agenda. This effort will require collaboration across multiple institutions and investigators. Rigorous conduct of biomarker-focused research holds the promise of transforming our ability to care for individual patients and our ability to conduct clinical trials in a more effective manner. PMID:20473243

Enhancing the informed consent process for critical care research: strategies from a thromboprophylaxis trial.

PubMed

Smith, Orla M; McDonald, Ellen; Zytaruk, Nicole; Foster, Denise; Matte, Andrea; Clarke, France; Fleury, Suzie; Krause, Katie; McArdle, Tracey; Skrobik, Yoanna; Cook, Deborah J

2013-12-01

Critically ill patients lack capacity for decisions about research participation. Consent to enrol these patients in studies is typically obtained from substitute decision-makers. To present strategies that may optimise the process of obtaining informed consent from substitute decision-makers for participation of critically ill patients in trials. We use examples from a randomised trial of heparin thromboprophylaxis in the intensive care unit (PROTECT, clinicaltrials.gov NCT00182143). 3764 patients were randomised, with an informed consent rate of 82%; 90% of consents were obtained from substitute decision-makers. North American PROTECT research coordinators attended three meetings to discuss enrolment: (1) Trial start-up (January 2006); (2) Near trial closure (January 2010); and (3) Post-publication (April 2011). Data were derived from slide presentations, field notes from break-out groups and plenary discussions, then analysed inductively. We derived three phases for the informed consent process: (1) Preparation for the Consent Encounter; (2) The Consent Encounter; and (3) Follow-up to the Consent Encounter. Specific strategies emerged for each phase: Phase 1 (four strategies); Phase 2 (six strategies); and Phase 3 (three strategies). We identified 13 strategies that may improve the process of obtaining informed consent from substitute decision-makers and be generalisable to other settings and studies. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials.

PubMed

Verma, Nishant; Beretvas, S Natasha; Pascual, Belen; Masdeu, Joseph C; Markey, Mia K

2018-03-14

Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL study): study protocol for a randomized controlled trial.

PubMed

Muscedere, John; Maslove, David; Boyd, John Gordon; O'Callaghan, Nicole; Lamontagne, Francois; Reynolds, Steven; Albert, Martin; Hall, Rick; McGolrick, Danielle; Jiang, Xuran; Day, Andrew G

2016-09-29

Nosocomial infections remain an important source of morbidity, mortality, and increased health care costs in hospitalized patients. This is particularly problematic in intensive care units (ICUs) because of increased patient vulnerability due to the underlying severity of illness and increased susceptibility from utilization of invasive therapeutic and monitoring devices. Lactoferrin (LF) and the products of its breakdown have multiple biological effects, which make its utilization of interest for the prevention of nosocomial infections in the critically ill. This is a phase II randomized, multicenter, double-blinded trial to determine the effect of LF on antibiotic-free days in mechanically ventilated, critically ill, adult patients in the ICU. Eligible, consenting patients will be randomized to receive either LF or placebo. The treating clinician will remain blinded to allocation during the study; blinding will be maintained by using opaque syringes and containers. The primary outcome will be antibiotic-free days, defined as the number of days alive and free of antibiotics 28 days after randomization. Secondary outcomes will include: antibiotic utilization, adjudicated diagnosis of nosocomial infection (longer than 72 h of admission to ICU), hospital and ICU length of stay, change in organ function after randomization, hospital and 90-day mortality, incidence of tracheal colonization, changes in gastrointestinal permeability, and immune function. Outcomes to inform the conduct of a larger definitive trial will also be evaluated, including feasibility as determined by recruitment rates and protocol adherence. The results from this study are expected to provide insight into a potential novel therapeutic use for LF in critically ill adult patients. Further, analysis of study outcomes will inform a future, large-scale phase III randomized controlled trial powered on clinically important outcomes related to the use of LF. The trial was registered at www.ClinicalTrials.gov on 18 November 2013. NCT01996579 .

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

PubMed Central

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

2015-01-01

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

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness: executive summary of a Cochrane Collaboration systematic review.

PubMed

Connolly, Bronwen; Salisbury, Lisa; O'Neill, Brenda; Geneen, Louise; Douiri, Abdel; Grocott, Michael P W; Hart, Nicholas; Walsh, Timothy S; Blackwood, Bronagh

2016-12-01

Skeletal muscle wasting and weakness are major complications of critical illness and underlie the profound physical and functional impairments experienced by survivors after discharge from the intensive care unit (ICU). Exercise-based rehabilitation has been shown to be beneficial when delivered during ICU admission. This review aimed to determine the effectiveness of exercise rehabilitation initiated after ICU discharge on primary outcomes of functional exercise capacity and health-related quality of life. We sought randomized controlled trials, quasi-randomized controlled trials, and controlled clinical trials comparing an exercise intervention commenced after ICU discharge vs. any other intervention or a control or 'usual care' programme in adult survivors of critical illness. Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database, and Cumulative Index to Nursing and Allied Health Literature databases were searched up to February 2015. Dual, independent screening of results, data extraction, and quality appraisal were performed. We included six trials involving 483 patients. Overall quality of evidence for both outcomes was very low. All studies evaluated functional exercise capacity, with three reporting positive effects in favour of the intervention. Only two studies evaluated health-related quality of life and neither reported differences between intervention and control groups. Meta-analyses of data were precluded due to variation in study design, types of interventions, and selection and reporting of outcome measurements. We were unable to determine an overall effect on functional exercise capacity or health-related quality of life of interventions initiated after ICU discharge for survivors of critical illness. Findings from ongoing studies are awaited. Future studies need to address methodological aspects of study design and conduct to enhance rigour, quality, and synthesis.

Key Items to Get Right When Conducting a Randomized Controlled Trial in Education

ERIC Educational Resources Information Center

Coalition for Evidence-Based Policy, 2005

2005-01-01

This is a checklist of key items to get right when conducting a randomized controlled trial to evaluate an educational program or practice ("intervention"). It is intended as a practical resource for researchers and sponsors of research, describing items that are often critical to the success of a randomized controlled trial. A significant…

Research on Trial: A Pedagogy for Research Methods Instruction.

ERIC Educational Resources Information Center

Britt, Michael A.

The Research on Trial technique is designed to enable students to think critically about psychological research, to help them apply what they have learned in class in an in-depth way to this research, and to create a classroom environment in which research issues are debated. The technique employs a courtroom trial role-play, with students…

Clinical Trials Methods for Evaluation of Potential Reduced Exposure Products

PubMed Central

Hatsukami, Dorothy K.; Hanson, Karen; Briggs, Anna; Parascandola, Mark; Genkinger, Jeanine M.; O'Connor, Richard; Shields, Peter

2009-01-01

Potential reduced exposure tobacco products (PREPs) may have promise in reducing tobacco-related morbidity or mortality or may promote greater harm to individuals or the population. Critical to determining the risks or benefits from these products are valid human clinical trial PREP assessment methods. Assessment involves determining the effects of these products on biomarkers of exposure and of effect, which serve as proxies for harm, and assessing the potential for consumer uptake and abuse of the product. This article raises the critical methodological issues associated with PREP assessment, reviews the methods that have been used to assess PREPs, and describes the strengths and limitations of these methods. Additionally, recommendations for clinical trials PREP assessment methods and future research directions in this area based on this review and on the deliberations from a National Cancer Institute sponsored Clinical Trials PREP Methods Workshop are provided. PMID:19959672

A POGIL approach to teaching engineering hydrology

NASA Astrophysics Data System (ADS)

Rutten, M.

2012-12-01

This paper presents a case study of the author's experience using Problem Guided Inquiry Learning (POGIL) in an engineering hydrology course. This course is part of an interdisciplinary Water Management program at Bachelor level in the Netherlands. The aims of this approach were to promote constructivism of knowledge, activate critical thinking and reduce math anxiety. POGIL was developed for chemistry education in the United States. To the authors knowledge this is the first application of this approach in Europe. A first trial was done in 2010-2011 and a second trial in 2011-2012 and 55 students participated. The problems that motivated the novel approach, general information on POGIL, its implementation in the course are discussed and the results so far are evaluated.

Institutional mistrust in the organization of pharmaceutical clinical trials

PubMed Central

2010-01-01

In this paper I explore the politics of trust in the clinical testing of pharmaceuticals in the US. Specifically, I analyze trust in terms of its institutional manifestations in the pharmaceutical clinical trials industry. In the process of testing new drugs, pharmaceutical companies must (1) protect their proprietary information from the clinicians who conduct their studies, and (2) find a way to ensure human subjects' compliance to study protocols. Concern with these two critical issues leads drug companies to approach clinicians and research subjects with an attitude of mistrust and the desire to exert control over their activities. This orientation results in an institutionalization of mistrust that structures the relationships and activities required for the clinical development of new pharmaceutical products. PMID:18633728

Development of an automated analysis system for data from flow cytometric intracellular cytokine staining assays from clinical vaccine trials

PubMed Central

Shulman, Nick; Bellew, Matthew; Snelling, George; Carter, Donald; Huang, Yunda; Li, Hongli; Self, Steven G.; McElrath, M. Juliana; De Rosa, Stephen C.

2008-01-01

Background Intracellular cytokine staining (ICS) by multiparameter flow cytometry is one of the primary methods for determining T cell immunogenicity in HIV-1 clinical vaccine trials. Data analysis requires considerable expertise and time. The amount of data is quickly increasing as more and larger trials are performed, and thus there is a critical need for high throughput methods of data analysis. Methods A web based flow cytometric analysis system, LabKey Flow, was developed for analyses of data from standardized ICS assays. A gating template was created manually in commercially-available flow cytometric analysis software. Using this template, the system automatically compensated and analyzed all data sets. Quality control queries were designed to identify potentially incorrect sample collections. Results Comparison of the semi-automated analysis performed by LabKey Flow and the manual analysis performed using FlowJo software demonstrated excellent concordance (concordance correlation coefficient >0.990). Manual inspection of the analyses performed by LabKey Flow for 8-color ICS data files from several clinical vaccine trials indicates that template gates can appropriately be used for most data sets. Conclusions The semi-automated LabKey Flow analysis system can analyze accurately large ICS data files. Routine use of the system does not require specialized expertise. This high-throughput analysis will provide great utility for rapid evaluation of complex multiparameter flow cytometric measurements collected from large clinical trials. PMID:18615598

Update: the status of clinical trials with kinase inhibitors in thyroid cancer.

PubMed

Wells, Samuel A; Santoro, Massimo

2014-05-01

Thyroid cancer is usually cured by timely thyroidectomy; however, the treatment of patients with advanced disease is challenging because their tumors are mostly unresponsive to conventional therapies. Recently, the malignancy has attracted much interest for two reasons: the dramatic increase in its incidence over the last three decades, and the discovery of the genetic mutations or chromosomal rearrangements causing most histological types of thyroid cancer. This update reviews the molecular genetics of thyroid cancer and the clinical trials evaluating kinase inhibitors (KIs) in patients with locally advanced or metastatic disease. The update also reviews studies in other malignancies, which have identified mechanisms of efficacy, and also resistance, to specific KIs. This information has been critical both to the development of effective second-generation drugs and to the design of combinatorial therapeutic regimens. Finally, the update addresses the major challenges facing clinicians who seek to develop more effective therapy for patients with thyroid cancer. PubMed was searched from January 2000 to November 2013 using the following terms: thyroid cancer, treatment of thyroid cancer, clinical trials in thyroid cancer, small molecule therapeutics, kinase inhibitors, and next generation sequencing. A new era in cancer therapy has emerged based on the introduction of KIs for the treatment of patients with liquid and solid organ malignancies. Patients with thyroid cancer have benefited from this advance and will continue to do so with the development of drugs having greater specificity and with the implementation of clinical trials of combined therapeutics to overcome drug resistance.

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

PubMed

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

2017-01-01

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

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

PubMed Central

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

2017-01-01

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

Development and Preliminary Evaluation of a Telephone-based Mindfulness Training Intervention for Survivors of Critical Illness

PubMed Central

Porter, Laura S.; Buck, Pamela J.; Hoffa, Mary; Jones, Derek; Walton, Brenda; Hough, Catherine L.; Greeson, Jeffrey M.

2014-01-01

Rationale: Persistent symptoms of psychological distress represent an unmet need among intensive care unit (ICU) survivors. Objectives: We aimed to develop and pilot test a simple telephone-based mindfulness training intervention to address this population’s unique needs. Methods: Open trial involving survivors of medical and surgical critical illness and their informal caregivers, using a pretest–posttest design. Measurements and Main Results: We developed a six-session, telephone-delivered, ICU survivor–specific mindfulness intervention based on past focus groups, the medical literature, and the precedent of the most effective components of existing mindfulness programs. A total of 11 survivors of mechanical ventilation were enrolled, together with 2 informal caregivers for exploratory purposes. Three patients dropped out before intervention initiation because of progressive illness or severe social stressors. Of the 10 remaining participants, 8 (80%) completed the program within 7 weeks. Among these eight patients and caregivers who completed all study procedures, six (75%) experienced improvement in symptoms of psychological distress (anxiety, depression, or post-traumatic stress disorder). Changes in distress symptoms were correlated with improvement in mindfulness qualities, adaptive coping, and emotion regulation. Participants reported high satisfaction with the program in postintervention interviews. Conclusions: A new ICU survivor–specific mindfulness training intervention delivered by telephone was acceptable and feasible. Changes in symptoms of distress were correlated with changes in skills that were targeted by the mindfulness program. Controlled trials are needed to further evaluate this promising intervention. PMID:24303911

Practical experiences of adopting assurance as a quantitative framework to support decision making in drug development.

PubMed

Crisp, Adam; Miller, Sam; Thompson, Douglas; Best, Nicky

2018-04-10

All clinical trials are designed for success of their primary objectives. Hence, evaluating the probability of success (PoS) should be a key focus at the design stage both to support funding approval from sponsor governance boards and to inform trial design itself. Use of assurance-that is, expected success probability averaged over a prior probability distribution for the treatment effect-to quantify PoS of a planned study has grown across the industry in recent years, and has now become routine within the authors' company. In this paper, we illustrate some of the benefits of systematically adopting assurance as a quantitative framework to support decision making in drug development through several case-studies where evaluation of assurance has proved impactful in terms of trial design and in supporting governance-board reviews of project proposals. In addition, we describe specific features of how the assurance framework has been implemented within our company, highlighting the critical role that prior elicitation plays in this process, and illustrating how the overall assurance calculation may be decomposed into a sequence of conditional PoS estimates which can provide greater insight into how and when different development options are able to discharge risk. Copyright © 2018 John Wiley & Sons, Ltd.

Addressing weight stigma in physiotherapy: Development of a theory-driven approach to (re)thinking weight-related interactions.

PubMed

Setchell, J; Gard, M; Jones, L; Watson, B M

2017-08-01

In this article, we propose a theory-driven approach to developing interventions for reducing weight stigma in physiotherapy and discuss the design and exploratory trial of such an intervention. Weight stigma has been identified in physiotherapists in empirical investigations. However, there has been little consideration of how this stigma might be addressed. We highlight Goffman's work on stigma that provides social and embodied understandings of stigma. Goffman's approach, however, is notably apolitical, ahistorical and lacks mechanisms for understanding power. We suggest that post-structuralist perspectives can provide insight into these areas. Drawing on these theories, we critically examine the literature on weight stigma reduction, finding that trials have largely been unsuccessful. We argue that this may be due to overly passive and simplistic intervention designs. As context-specific understandings are desirable, we examine the nature of physiotherapy to determine what might be relevant to (re)thinking weight in this profession. We then discuss the development of a multifactorial, active weight stigma intervention we trialed with eight physiotherapists. Supported by theory, the outcomes of the exploratory study suggest that physiotherapy-specific factors such as fostering professional reflexivity and improving understandings of stigma need to be incorporated into an active intervention that considers the complex determinants of weight stigma.

Appealing to the Republic of Letters: An Autopsy of Anti-venereal Trials in Eighteenth-century Mexico.

PubMed

Clark, Fiona

2014-02-01

This study analyses the narrative elements of a little-known report into anti-venereal trials written by an Irish military physician-surgeon, Daniel O'Sullivan (1760- c .1797). It explores the way in which O'Sullivan as the narrator of the Historico-critical report creates medical heroes and anti-heroes as a means to criticise procedures initiated by staff in the Hospital General de San Andrés, Mexico City. The resulting work depicts a much less positive picture of medical trials and hospital authorities in this period than has been recorded to date, and provides a critical and complicated assessment of one of Spain's leading physicians of the nineteenth century, Francisco Javier Balmis (1753-1819).

Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

PubMed

McNally, Dayre; Amrein, Karin; O'Hearn, Katharine; Fergusson, Dean; Geier, Pavel; Henderson, Matt; Khamessan, Ali; Lawson, Margaret L; McIntyre, Lauralyn; Redpath, Stephanie; Weiler, Hope A; Menon, Kusum

2017-01-01

Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. The VITdAL-PICU pilot study is designed as a multicenter placebo-controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D < 50 nmol/L). The primary objective is to determine whether the dosing protocol normalizes vitamin D status, defined as a blood total 25(OH)D concentration above 75 nmol/L. Secondary objectives include an examination of the safety of the dosing regimen (e.g. hypercalcemia, hypercalciuria, nephrocalcinosis), measures of vitamin D axis function (e.g. calcitriol levels, immune function), and protocol feasibility (eligibility criteria, protocol deviations, blinding). Despite significant observational literature suggesting VDD to be a modifiable risk factor in the PICU setting, there is no robust clinical trial evidence evaluating the benefits of rapid normalization. This phase II clinical trial will evaluate an innovative weight-based dosing regimen intended to rapidly and safely normalize vitamin D levels in critically ill children. Study findings will be used to inform the design of a multicenter phase III trial evaluating the clinical and economic benefits to rapid normalization. Recruitment for this trial was initiated in January 2016 and is expected to continue until November 30, 2017. Clinicaltrials.gov NCT02452762.

Evaluation of internal peer-review to train nurses recruiting to a randomized controlled trial--Internal Peer-review for Recruitment Training in Trials (InterPReTiT).

PubMed

Mann, Cindy; Delgado, Debbie; Horwood, Jeremy

2014-04-01

A discussion and qualitative evaluation of the use of peer-review to train nurses and optimize recruitment practice in a randomized controlled trial. Sound recruitment processes are critical to the success of randomized controlled trials. Nurses recruiting to trials must obtain consent for an intervention that is administered for reasons other than anticipated benefit to the patient. This requires not only patients' acquiescence but also evidence that they have weighed the relevant information in reaching their decision. How trial information is explained is vital, but communication and training can be inadequate. A discussion of a new process to train nurses recruiting to a randomized controlled trial. Literature from 1999-2013 about consenting to trials is included. Over 3 months from 2009-2010, recruiting nurses reviewed recruitment interviews recorded during the pilot phase of a single-site randomized controlled trial and noted content, communication style and interactions. They discussed their findings during peer-review meetings, which were audio-recorded and analysed using qualitative methodology. Peer-review can enhance nurses' training in trial recruitment procedures by supporting development of the necessary communication skills, facilitating consistency in information provision and sharing best practice. Nurse-led peer-review can provide a forum to share communication strategies that will elicit and address participant concerns and obtain evidence of participant understanding prior to consent. Comparing practice can improve consistency and accuracy of trial information and facilitate identification of recruitment issues. Internal peer-review was well accepted and promoted team cohesion. Further evaluation is needed. © 2013 John Wiley & Sons Ltd.

Clinical trials in the Middle East and North Africa (MENA) Region: grandstanding or grandeur?

PubMed

Nair, Satish Chandrasekhar; Ibrahim, Halah; Celentano, David D

2013-11-01

Nearly 31% of the world's clinical trials are conducted outside the US and 25% of the new drug applications include data from international sites. The high population growth, demand for medication, increased prevalence of life-style related and rare genetic diseases in the MENA countries should be associated with a consequent scale-up of clinical trials in these countries. However, the region sponsors under 1% of global clinical trials. Determinants including the regulatory environment, patient protection, physician-preparedness, types of diseases, costs of trials and pace of subject recruitment, were analyzed to identify critical factors that influence barriers to the conduct clinical trials in MENA. Strategic planning by the CRO can help overcome challenges related to regulatory and oversight requirements. Barriers related to trial quality and subject protection can be mitigated by risk-based monitoring. Growing healthcare infrastructure and communication technologies provide clear advantages for subject recruitment. Low operating costs combined with the increase in pharmaceutical sales provide incentives for the future conduct of clinical trials. Although the opportunities and challenges cited are common to the MENA region, further studies are needed to assess other potential contributing variables for the conduct of clinical trials specific to each MENA country. Challenges in drug importation and site oversight can be overcome with systematic interventions. Social media network and community awareness programs can assist reductions in barriers in obtaining effective informed consents. Increasing pharmaceutical sales, population growth, high prevalence of genetic and life-style related diseases and reduced clinical trial development costs offer expanding opportunities for future clinical trials in MENA. Copyright © 2013 Elsevier Inc. All rights reserved.

Exclusion of Older Patients From Ongoing Clinical Trials for Hematological Malignancies: An Evaluation of the National Institutes of Health Clinical Trial Registry

PubMed Central

Stauder, Reinhard; van Munster, Barbara C.

2014-01-01

Introduction. Cancer societies, research cooperatives, and countless publications have urged the development of clinical trials that facilitate the inclusion of older patients and those with comorbidities. We set out to determine the characteristics of currently recruiting clinical trials with hematological patients to assess their inclusion and exclusion of elderly patients. Methods. The NIH clinical trial registry was searched on July 1, 2013, for currently recruiting phase I, II or III clinical trials with hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. Results. Although 5% of 1,207 included trials focused exclusively on elderly or unfit patients, 69% explicitly or implicitly excluded older patients. Exclusion based on age was seen in 27% of trials, exclusion based on performance status was seen in 16%, and exclusion based on stringent organ function restrictions was noted in 51%. One-third of the studies that excluded older patients based on age allowed inclusion of younger patients with poor performance status; 8% did not place any restrictions on organ function. Over time, there was a shift from exclusion based on age (p value for trend <.001) toward exclusion based on organ function (p = .2). Industry-sponsored studies were least likely to exclude older patients (p < .001). Conclusion. Notably, 27% of currently recruiting clinical trials for hematological malignancies use age-based exclusion criteria. Although physiological reserves diminish with age, the heterogeneity of the elderly population does not legitimize exclusion based on chronological age alone. Investigators should critically review whether sufficient justification exists for every exclusion criterion before incorporating it in trial protocols. PMID:25170014

Exclusion of older patients from ongoing clinical trials for hematological malignancies: an evaluation of the National Institutes of Health Clinical Trial Registry.

PubMed

Hamaker, Marije E; Stauder, Reinhard; van Munster, Barbara C

2014-10-01

Cancer societies, research cooperatives, and countless publications have urged the development of clinical trials that facilitate the inclusion of older patients and those with comorbidities. We set out to determine the characteristics of currently recruiting clinical trials with hematological patients to assess their inclusion and exclusion of elderly patients. The NIH clinical trial registry was searched on July 1, 2013, for currently recruiting phase I, II or III clinical trials with hematological malignancies. Trial characteristics and study objectives were extracted from the registry website. Although 5% of 1,207 included trials focused exclusively on elderly or unfit patients, 69% explicitly or implicitly excluded older patients. Exclusion based on age was seen in 27% of trials, exclusion based on performance status was seen in 16%, and exclusion based on stringent organ function restrictions was noted in 51%. One-third of the studies that excluded older patients based on age allowed inclusion of younger patients with poor performance status; 8% did not place any restrictions on organ function. Over time, there was a shift from exclusion based on age (p value for trend <.001) toward exclusion based on organ function (p = .2). Industry-sponsored studies were least likely to exclude older patients (p < .001). Notably, 27% of currently recruiting clinical trials for hematological malignancies use age-based exclusion criteria. Although physiological reserves diminish with age, the heterogeneity of the elderly population does not legitimize exclusion based on chronological age alone. Investigators should critically review whether sufficient justification exists for every exclusion criterion before incorporating it in trial protocols. ©AlphaMed Press.

Pharmacoeconomics of parenteral nutrition in surgical and critically ill patients receiving structured triglycerides in China.

PubMed

Wu, Guo Hao; Ehm, Alexandra; Bellone, Marco; Pradelli, Lorenzo

2017-01-01

A prior meta-analysis showed favorable metabolic effects of structured triglyceride (STG) lipid emulsions in surgical and critically ill patients compared with mixed medium-chain/long-chain triglycerides (MCT/LCT) emulsions. Limited data on clinical outcomes precluded pharmacoeconomic analysis. We performed an updated meta-analysis and developed a cost model to compare overall costs for STGs vs MCT/LCTs in Chinese hospitals. We searched Medline, Embase, Wanfang Data, the China Hospital Knowledge Database, and Google Scholar for clinical trials comparing STGs to mixed MCT/LCTs in surgical or critically ill adults published between October 10, 2013 and September 19, 2015. Newly identified studies were pooled with the prior studies and an updated meta-analysis was performed. A deterministic simulation model was used to compare the effects of STGs and mixed MCT/LCT's on Chinese hospital costs. The literature search identified six new trials, resulting in a total of 27 studies in the updated meta-analysis. Statistically significant differences favoring STGs were observed for cumulative nitrogen balance, pre- albumin and albumin concentrations, plasma triglycerides, and liver enzymes. STGs were also associated with a significant reduction in the length of hospital stay (mean difference, -1.45 days; 95% confidence interval, -2.48 to -0.43; p=0.005) versus mixed MCT/LCTs. Cost analysis demonstrated a net cost benefit of ¥675 compared with mixed MCT/LCTs. STGs are associated with improvements in metabolic function and reduced length of hospitalization in surgical and critically ill patients compared with mixed MCT/LCT emulsions. Cost analysis using data from Chinese hospitals showed a corresponding cost benefit.

[Dysphagia management of acute and long-term critically ill intensive care patients].

PubMed

Zielske, J; Bohne, S; Axer, H; Brunkhorst, F M; Guntinas-Lichius, O

2014-10-01

Dysphagia is a severe complication in critically ill patients and affects more than half the patients in an intensive care unit. Dysphagia also has a strong impact on morbidity and mortality. Risk factors for the development of dysphagia are neurological diseases, age >55-70 years, intubation >7 days and sepsis. With increasing numbers of long-term survivors chronic dysphagia is becoming an increasing problem. There is not much knowledge on the influence of specific diseases, including the direct impact of sepsis on the development of dysphagia. Fiberoptic evaluation of swallowing is a standardized tool for bedside evaluation, helping to plan swallowing training during the acute phase and to decrease the rate of chronic dysphagia. For evaluation of chronic dysphagia even more extensive diagnostic tools as well as several options of stepwise rehabilitation using restitution, compensation and adaption strategies for swallowing exist. Currently it seems that these options are not being sufficiently utilized. In general, there is a need for controlled clinical trials analyzing specific swallowing rehabilitation concepts for former critically ill patients and long-term survivors.

Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial.

PubMed

Krag, Mette; Perner, Anders; Wetterslev, Jørn; Wise, Matt P; Borthwick, Mark; Bendel, Stepani; Pelosi, Paolo; Keus, Frederik; Guttormsen, Anne Berit; Schefold, Joerg C; Møller, Morten Hylander

2016-04-19

Critically ill patients in the intensive care unit (ICU) are at risk of clinically important gastrointestinal bleeding, and acid suppressants are frequently used prophylactically. However, stress ulcer prophylaxis may increase the risk of serious adverse events and, additionally, the quantity and quality of evidence supporting the use of stress ulcer prophylaxis is low. The aim of the SUP-ICU trial is to assess the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the ICU. We hypothesise that stress ulcer prophylaxis reduces the rate of gastrointestinal bleeding, but increases rates of nosocomial infections and myocardial ischaemia. The overall effect on mortality is unpredictable. The SUP-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomised, blinded, parallel-group trial of stress ulcer prophylaxis with a proton pump inhibitor versus placebo (saline) in 3350 acutely ill ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support in the 90-day period, serious adverse reactions, 1-year mortality, and health economic analyses. The sample size will enable us to detect a 20 % relative risk difference (5 % absolute risk difference) in 90-day mortality assuming a 25 % event rate with a risk of type I error of 5 % and power of 90 %. The trial will be externally monitored according to Good Clinical Practice standards. Interim analyses will be performed after 1650 and 2500 patients. The SUP-ICU trial will provide high-quality data on the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in critically ill adult patients admitted in the ICU. ClinicalTrials.gov Identifier: NCT02467621 .

Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature

PubMed Central

Jureidini, Jon N.; Parry, Peter I.; Spielmans, Glen I.; Healy, David

2011-01-01

Background Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature. Methods and Findings We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations. Conclusions A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature. Please see later in the article for the Editors' Summary PMID:21559324

Fast, cheap, and out of control? Speculations and ethical concerns in the conduct of outsourced clinical trials in India.

PubMed

Kamat, Vinay R

2014-03-01

The globalization of biopharmaceutical clinical trials and their offshore outsourcing, from the West to low and middle-income countries, has come under increasing scrutiny from academic scholars, practitioners, regulatory agencies and the media. This article reports the results of a study conducted in Bangalore and Hyderabad between 2007 and 2009, to elicit the perspectives of stakeholders, concerning media representations of their work and the ethical issues that emanate from their engagement in the clinical trials enterprise. In acknowledging the inherently problematic nature of the outsourcing of clinical trials to low income countries, I argue that the practice of not prioritizing research on diseases that are most prevalent among communities, from which subjects are recruited, demands a coordinated and sustained critique. I propose that the critical discourse on the outsourcing of clinical trials should not only emphasize the perils of this practice, but also address some broader issues of equity and distributive justice that determine people's access to basic health care in low income countries. Close attention to the specific context of clinical trials in an increasingly neoliberal medical and health environment in emerging economies such as India can provide critical insights into the on-the-ground complexities and challenges of outsourced global clinical trials. Copyright © 2013 Elsevier Ltd. All rights reserved.

Practical issues regarding implementing a randomized clinical trial in a homeless population: strategies and lessons learned.

PubMed

Ojo-Fati, Olamide; Joseph, Anne M; Ig-Izevbekhai, Jed; Thomas, Janet L; Everson-Rose, Susan A; Pratt, Rebekah; Raymond, Nancy; Cooney, Ned L; Luo, Xianghua; Okuyemi, Kolawole S

2017-07-05

There is a critical need for objective data to guide effective health promotion and care for homeless populations. However, many investigators exclude homeless populations from clinical trials due to practical concerns about conducting research with this population. This report is based on our experience and lessons learned while conducting two large NIH-funded randomized controlled trials targeting smoking cessation among persons who are homeless. The current report also addresses challenges when conducting clinical trials among homeless populations and offers potential solutions. Homeless individuals face several challenges including the need to negotiate daily access to food, clothing, and shelter. Some of the critical issues investigators encounter include recruitment and retention obstacles; cognitive impairment, mental health and substance abuse disorders; transportation and scheduling challenges; issues pertaining to adequate study compensation; the need for safety protocols for study staff; and issues related to protecting the wellbeing of these potentially vulnerable adults. Anticipating realistic conditions in which to conduct studies with participants who are homeless will help investigators to design efficient protocols and may improve the feasibility of conducting clinical trials involving homeless populations and the quality of the data collected by the researchers. ClinicalTrials.gov, ID: NCT00786149 . Registered on 5 November 2008; ClinicalTrials.gov, ID: NCT01932996 . Registered on 20 November 2014.

The role of critical self-reflection of assumptions in an online HIV intervention for men who have sex with men.

PubMed

Wilkerson, J Michael; Danilenko, Gene P; Smolenski, Derek J; Myer, Bryn B; Rosser, B R Simon

2011-02-01

The Men's INTernet Study II included a randomized controlled trial to develop and test an Internet-based HIV prevention intervention for U.S men who use the Internet to seek sex with men. In 2008, participants (n = 560) were randomized to an online, interactive, sexual risk-reduction intervention or to a wait list null control. After 3 months, participants in both conditions reported varying degrees of change in sexual beliefs or behaviors. Using content analysis and logistic regression, this mixed-methods study sought to understand why these changes occurred. Level of critical self-reflection of assumptions appeared to facilitate the labeling of sexual beliefs and behaviors as risky, which in turn encouraged men to commit to and enact change. New HIV prevention interventions should include activities in their curriculum that foster critical self-reflection on assumptions.

Bedside to Bench: Integrating Quantitative Clinical Pharmacology and Reverse Translation to Optimize Drug Development.

PubMed

Gibbs, John P; Menon, Rajeev; Kasichayanula, Sreeneeranj

2018-02-01

With so much emphasis on reducing attrition and becoming more efficient in the delivery of healthcare, there are many opportunities to leverage existing clinical data in drug development and to foster the practice of reverse translation. The application of quantitative approaches to convert clinical trial and real-world data to knowledge will continue to drive innovation. Herein we discuss recent examples of reverse translation and consider future opportunities to capture critical clinical knowledge to inform decision-making in drug development. © 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Communicating vaccine safety during the development and introduction of vaccines.

PubMed

Kochhar, Sonali

2015-01-01

Vaccines are the best defense available against infectious diseases. Vaccine safety is of major focus for regulatory bodies, vaccine manufacturers, public health authorities, health care providers and the public as vaccines are often given to healthy children and adults as well as to pregnant woman. Safety assessment is critical at all stages of vaccine development. Effective, clear and consistent communication of the risks and benefits of vaccines and advocacy during all stages of clinical research (including the preparation, approvals, conduct of clinical trials through the post marketing phase) is critically important. This needs to be done for all major stakeholders (e.g. community members, Study Team, Health Care Providers, Ministry of Health, Regulators, Ethics Committee members, Public Health Authorities and Policy Makers). Improved stakeholder alignment would help to address some of the concerns that may affect the clinical research, licensing of vaccines and their wide-spread use in immunization programs around the world.

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.

Short-term memory stores organized by information domain.

PubMed

Noyce, Abigail L; Cestero, Nishmar; Shinn-Cunningham, Barbara G; Somers, David C

2016-04-01

Vision and audition have complementary affinities, with vision excelling in spatial resolution and audition excelling in temporal resolution. Here, we investigated the relationships among the visual and auditory modalities and spatial and temporal short-term memory (STM) using change detection tasks. We created short sequences of visual or auditory items, such that each item within a sequence arose at a unique spatial location at a unique time. On each trial, two successive sequences were presented; subjects attended to either space (the sequence of locations) or time (the sequence of inter item intervals) and reported whether the patterns of locations or intervals were identical. Each subject completed blocks of unimodal trials (both sequences presented in the same modality) and crossmodal trials (Sequence 1 visual, Sequence 2 auditory, or vice versa) for both spatial and temporal tasks. We found a strong interaction between modality and task: Spatial performance was best on unimodal visual trials, whereas temporal performance was best on unimodal auditory trials. The order of modalities on crossmodal trials also mattered, suggesting that perceptual fidelity at encoding is critical to STM. Critically, no cost was attributable to crossmodal comparison: In both tasks, performance on crossmodal trials was as good as or better than on the weaker unimodal trials. STM representations of space and time can guide change detection in either the visual or the auditory modality, suggesting that the temporal or spatial organization of STM may supersede sensory-specific organization.

Enhancing Critical Thinking Via a Clinical Scholar Approach.

PubMed

Simpson, Vicki; McComb, Sara A; Kirkpatrick, Jane M

2017-11-01

Safety, quality improvement, and a systems perspective are vital for nurses to provide quality evidence-based care. Responding to the call to prepare nurses with these perspectives, one school of nursing used a clinical scholar approach, enhanced by systems engineering to more intentionally develop the ability to clinically reason and apply evidence-based practice. A two-group, repeated-measures control trial was used to determine the effects of systems engineering content and support on nursing students' clinical judgment and critical thinking skills. Findings indicated this approach had a positive effects on student's clinical judgment and clinical reasoning skills. This approach helped students view health care issues from a broader perspective and use evidence to guide solution development, enhancing the focus on evidence-based practice, and quality improvement. Intentional integration of an evidence-based, systems perspective by nursing faculty supports development of nurses who can function safely and effectively in the current health care system. [J Nurs Educ. 2017;56(11):679-682.]. Copyright 2017, SLACK Incorporated.

A checklist to assess the quality of reports on spa therapy and balneotherapy trials was developed using the Delphi consensus method: the SPAC checklist.

PubMed

Kamioka, Hiroharu; Kawamura, Yoichi; Tsutani, Kiichiro; Maeda, Masaharu; Hayasaka, Shinya; Okuizum, Hiroyasu; Okada, Shinpei; Honda, Takuya; Iijima, Yuichi

2013-08-01

The purpose of this study was to develop a checklist of items that describes and measures the quality of reports of interventional trials assessing spa therapy. The Delphi consensus method was used to select the number of items in the checklist. A total of eight individuals participated, including an epidemiologist, a clinical research methodologist, clinical researchers, a medical journalist, and a health fitness programmer. Participants ranked on a 9-point Likert scale whether an item should be included in the checklist. Three rounds of the Delphi method were conducted to achieve consensus. The final checklist contained 19 items, with items related to title, place of implementation (specificity of spa), care provider influence, and additional measures to minimize the potential bias from withdrawals, loss to follow-up, and low treatment adherence. This checklist is simple and quick to complete, and should help clinicians and researchers critically appraise the medical and healthcare literature, reviewers assess the quality of reports included in systematic reviews, and researchers plan interventional trials of spa therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Methodology for Knowledge Synthesis of the Management of Vaccination Pain and Needle Fear.

PubMed

Taddio, Anna; McMurtry, C Meghan; Shah, Vibhuti; Yoon, Eugene W; Uleryk, Elizabeth; Pillai Riddell, Rebecca; Lang, Eddy; Chambers, Christine T; Noel, Melanie; MacDonald, Noni E

2015-10-01

A knowledge synthesis was undertaken to inform the development of a revised and expanded clinical practice guideline about managing vaccination pain in children to include the management of pain across the lifespan and the management of fear in individuals with high levels of needle fear. This manuscript describes the methodological details of the knowledge synthesis and presents the list of included clinical questions, critical and important outcomes, search strategy, and search strategy results. The Grading of Assessments, Recommendations, Development and Evaluation (GRADE) and Cochrane methodologies provided the general framework. The project team voted on clinical questions for inclusion and critically important and important outcomes. A broad search strategy was used to identify relevant randomized-controlled trials and quasi-randomized-controlled trials. Quality of research evidence was assessed using the Cochrane risk of bias tool and quality across studies was assessed using GRADE. Multiple measures of the same construct within studies (eg, observer-rated and parent-rated infant distress) were combined before pooling. The standardized mean difference and 95% confidence intervals (CI) or relative risk and 95% CI was used to express the effects of an intervention. Altogether, 55 clinical questions were selected for inclusion in the knowledge synthesis; 49 pertained to pain management during vaccine injections and 6 pertained to fear management in individuals with high levels of needle fear. Pain, fear, and distress were typically prioritized as critically important outcomes across clinical questions. The search strategy identified 136 relevant studies. This manuscript describes the methodological details of a knowledge synthesis about pain management during vaccination and fear management in individuals with high levels of needle fear. Subsequent manuscripts in this series will present the results for the included questions.

Ultrasonic Measurements of Bore Temperature in Large Caliber Guns

NASA Astrophysics Data System (ADS)

Yuhas, Donald E.; Mutton, Mark J.; Remiasz, Jack R.; Vorres, Carol L.

2009-03-01

The Navy has a need to measure temperatures at critical areas on large caliber gun inner bore surfaces to insure appropriate action is taken in case of a misfire. Inappropriate actions could result in the loss of life and the disabling of a naval warship. In this report we describe the development of an ultrasonic-based sensor capable of non-intrusively measuring internal bore temperature. The results obtained during live fire field trials will be presented.

Ethical issues in HIV prevention research with people who inject drugs.

PubMed

Sugarman, Jeremy; Rose, Scott M; Metzger, David

2014-04-01

Injection drug use continues to significantly contribute to new infections with HIV. Moreover, conducting HIV prevention research with people who inject drugs (PWIDs) can be complicated for an array of practical, social, legal, and ethical reasons. It is critical that these research efforts are sensitive to the particular vulnerabilities associated with injection drug use as well as those related to being at risk of acquiring HIV so as to minimize harm to participants in research. To describe how we addressed some of these ethical challenges during the course of a large-scale multinational randomized HIV prevention trial involving PWIDs, which was successfully completed. The ethical issues encountered during the life cycle of the trial were cataloged by the principal investigator, study coordinator, and ethicist working on the trial. Relevant study documents were then reviewed to provide pertinent details. The ethical issues unique to the trial were then described. Before implementation, the trial faced particularly complex challenges related to the vulnerability of PWIDs, where HIV seroincidence rates in the population were high and legal policies and stigma regarding injection drug use was severe. Accordingly, a rapid policy assessment was commissioned, and a series of community engagement activities were conducted. During the trial, in addition to using careful standard operating procedures regarding all aspects of trial conduct and extensive staff training, the trial standardized informed consent procedures and assessed them. Furthermore, social harms were monitored along with physical harms and adverse events. Following the decision to close the study, it was critical to develop an orderly and safe process for closing it. The issue of post-trial access to the study medication and a complex intervention also surfaced for consideration. The issues described in this article are necessarily limited to how they manifested themselves within the context of a particular trial that was conducted in two countries. In addition, other stakeholders may have divergent views on the ethical issues described and may also have identified additional ethical issues that would warrant examination. Adopting similar approaches to addressing ethical issues in future research promises to facilitate this work so that needed strategies to prevent HIV infection among PWIDs can be safely and appropriately tested. Future trials enrolling PWIDs who are at risk of detainment should identify ways of mapping closely their experiences and perceptions in order to better apprehend some of the ethical issues at stake. In addition, scholarly and policy work needs to address the ethical issues related to post-trial access to multi-modal interventions that may be desired by participants, but are not shown to be effective in achieving the primary outcomes of the study.

Exercise rehabilitation following hospital discharge in survivors of critical illness: an integrative review

PubMed Central

2012-01-01

Although clinical trials have shown benefit from early rehabilitation within the ICU, rehabilitation of patients following critical illness is increasingly acknowledged as an area of clinical importance. However, despite recommendations from published guidelines for rehabilitation to continue following hospital discharge, there is limited evidence to underpin practice during this intermediate stage of recovery. Those patients with ICU-acquired weakness on discharge from the ICU are most likely to benefit from ongoing rehabilitation. Despite this, screening based on strength alone may fail to account for the associated level of physical functioning, which may not correlate with muscle strength, nor address non-physical complications of critical illness. The aim of this review was to consider which patients are likely to require rehabilitation following critical illness and to perform an integrative review of the available evidence of content and nature of exercise rehabilitation programmes for survivors of critical illness following hospital discharge. Literature databases and clinical trials registries were searched using appropriate terms and groups of terms. Inclusion criteria specified the reporting of rehabilitation programmes for patients following critical illness post-hospital discharge. Ten items, including data from published studies and protocols from trial registries, were included. Because of the variability in study methodology and inadequate level of detail of reported exercise prescription, at present there can be no clear recommendations for clinical practice from this review. As this area of clinical practice remains in its relative infancy, further evidence is required both to identify which patients are most likely to benefit and to determine the optimum content and format of exercise rehabilitation programmes for patients following critical illness post-hospital discharge. PMID:22713336

Immunogenicity of HPV prophylactic vaccines: Serology assays and their use in HPV vaccine evaluation and development.

PubMed

Pinto, Ligia A; Dillner, Joakim; Beddows, Simon; Unger, Elizabeth R

2018-01-17

When administered as standard three-dose schedules, the licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy. We summarize the immunogenicity of these licensed vaccines and the most commonly used serology assays, with a focus on key considerations for one-dose vaccine schedules. Although immune correlates of protection against infection are not entirely clear, both preclinical and clinical evidence point to neutralizing antibodies as the principal mechanism of protection. Thus, immunogenicity assessments in vaccine trials have focused on measurements of antibody responses to the vaccine. Non-inferiority of antibody responses after two doses of HPV vaccines separated by 6 months has been demonstrated and this evidence supported the recent WHO recommendations for two-dose vaccination schedules in both boys and girls 9-14 years of age. There is also some evidence suggesting that one dose of HPV vaccines may provide protection similar to the currently recommended two-dose regimens but robust data on efficacy and immunogenicity of one-dose vaccine schedules are lacking. In addition, immunogenicity has been assessed and reported using different methods, precluding direct comparison of results between different studies and vaccines. New head-to-head vaccine trials evaluating one-dose immunogenicity and efficacy have been initiated and an increase in the number of trials relying on immunobridging is anticipated. Therefore, standardized measurement and reporting of immunogenicity for the up to nine HPV types targeted by the current vaccines is now critical. Building on previous HPV serology assay standardization and harmonization efforts initiated by the WHO HPV LabNet in 2006, new secondary standards, critical reference reagents and testing guidelines will be generated as part of a new partnership to facilitate harmonization of the immunogenicity testing in new HPV vaccine trials. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Integration of Biology Into the Treatment of Diffuse Intrinsic Pontine Glioma: A Review of the North American Clinical Trial Perspective.

PubMed

Clymer, Jessica; Kieran, Mark W

2018-01-01

Dramatic advances in the molecular analysis of diffuse intrinsic pontine glioma have occurred over the last decade and resulted in the identification of potential therapeutic targets. In spite of these advances, no significant improvement in the outcome has been achieved and median survival remains approximately 10 months. An understanding of the approaches that have been taken to date, why they failed, and how that information can lead the field forward is critical if we are to change the status quo . In this review, we will discuss the clinical trial landscape in North America with an overview of historical approaches that failed and what might account for this failure. We will then provide a discussion of how our understanding of the genotype of this disease has led to the development of a number of trials targeting the mutations and epigenome of diffuse intrinsic pontine gliomas and the issues related to these trials. Similarly, the introduction of methodologies to address penetration across the blood-brain barrier will be considered in the context of both targeted approaches, epigenetic modification, and immune surveillance of these tumors. The comprehensive analysis of these data, generated through cooperative groups, collaborative clinical trials, and pilot studies in North America will be the focus of the IVth Memorial Alicia Pueyo international symposium in Barcelona on March 12th, 2018 and will be compared and contrasted with a similar comprehensive analysis of the European data with the goal of bringing all of these data together to develop a uniform platform on which new rational trials can be based.

A community randomised controlled trial evaluating a home-based environmental intervention package of improved stoves, solar water disinfection and kitchen sinks in rural Peru: rationale, trial design and baseline findings.

PubMed

Hartinger, S M; Lanata, C F; Hattendorf, J; Gil, A I; Verastegui, H; Ochoa, T; Mäusezahl, D

2011-11-01

Pneumonia and diarrhoea are leading causes of death in children. There is a need to develop effective interventions. We present the design and baseline findings of a community-randomised controlled trial in rural Peru to evaluate the health impact of an Integrated Home-based Intervention Package in children aged 6 to 35 months. We randomised 51 communities. The intervention was developed through a community-participatory approach prior to the trial. They comprised the construction of improved stoves and kitchen sinks, the promotion of hand washing, and solar drinking water disinfection (SODIS). To reduce the potential impact of non-blinding bias, a psychomotor stimulation intervention was implemented in the control arm. The baseline survey included anthropometric and socio-economic characteristics. In a sub-sample we determined the level of faecal contamination of drinking water, hands and kitchen utensils and the prevalence of diarrhoegenic Escherichia coli in stool specimen. We enrolled 534 children. At baseline all households used open fires and 77% had access to piped water supplies. E. coli was found in drinking water in 68% and 64% of the intervention and control households. Diarrhoegenic E. coli strains were isolated from 45/139 stool samples. The proportion of stunted children was 54%. Randomization resulted in comparable study arms. Recently, several critical reviews raised major concerns on the reliability of open health intervention trials, because of uncertain sustainability and non-blinding bias. In this regard, the presented trial featuring objective outcome measures, a simultaneous intervention in the control communities and a 12-month follow up period will provide valuable evidence. Copyright © 2011 Elsevier Inc. All rights reserved.

[Prescribing monitoring in clinical practice: from enlightened empiricism to rational strategies].

PubMed

Buclin, Thierry; Herzig, Lilli

2013-05-15

Monitoring of a medical condition is the periodic measurement of one or several physiological or biological variables to detect a signal regarding its clinical progression or its response to treatment. We distinguish different medical situations between diagnostic, clinical and therapeutic process to apply monitoring. Many clinical, variables can be used for monitoring, once their intrinsic properties (normal range, critical difference, kinetics, reactivity) and external validity (pathophysiological importance, predictive power for clinical outcomes) are established. A formal conceptualization of monitoring is being developed and should support the rational development of monitoring strategies and their validation through appropriate clinical trials.

Development of the activated diffusion brazing process for fabrication of finned shell to strut turbine blades

NASA Technical Reports Server (NTRS)

Wilbers, L. G.; Berry, T. F.; Kutchera, R. E.; Edmonson, R. E.

1971-01-01

The activated diffusion brazing process was developed for attaching TD-NiCr and U700 finned airfoil shells to matching Rene 80 struts obstructing the finned cooling passageways. Creep forming the finned shells to struts in combination with precise preplacement of brazing alloy resulted in consistently sound joints, free of cooling passageway clogging. Extensive tensile and stress rupture testing of several joint orientation at several temperatures provided a critical assessment of joint integrity of both material combinations. Trial blades of each material combination were fabricated followed by destructive metallographic examination which verified high joint integrity.

High dietary levels of biotin and zinc to improve health of foot pads in broilers exposed experimentally to litter with critical moisture content.

PubMed

Abd El-Wahab, A; Radko, D; Kamphues, J

2013-07-01

Foot pad dermatitis (FPD) is a widespread problem in poultry production and constitutes a welfare issue. The objective of this study was to test potentially prophylactic effects of higher biotin and Zn levels in the diet of broilers exposed to critical litter moisture content (35% water) on the development of FPD. Two trials were performed in each 4 groups of 1-wk-old male broilers (Ross 708) during 33 d. The pens of all groups (25 birds in each) were littered with wood shavings of critical moisture content. Two groups were fed high levels of Zn as zinc-oxide (150 mg/kg of diet), with normal levels of biotin (300 µg/kg of diet) or high biotin (2,000 µg/kg of diet). The other 2 groups were fed Zn as zinc-methionine (150 mg/kg of diet), with normal levels of biotin (300 µg/kg of diet) or high biotin (2,000 µg/kg of diet). External assessment of foot pads and measurements the moisture contents of excreta and litter were performed weekly. The signs of foot pad lesions were recorded on a 7-point scale (0 = normal skin; 7 = more than half of the foot pad is necrotic). High biotin supplementation resulted in a reduction of 30 and 18% of cases of foot pad lesions in trials 1 and 2, respectively. The combination of Zn-methionine and high biotin supplementation led to a decreased severity of FPD in a range of about 50 and 30% in trials 1 and 2, respectively. In broilers fed the diet containing zinc-oxide and normal biotin levels about 28 and 24% of the birds had the scores of 6 and 7 (= high foot pad alterations), whereas in birds fed Zn-methionine and high biotin no high alterations (score = 7) in the foot pad (0%) occurred in either trial. The presented results suggest that it is advisable to combine the maximum levels of Zn (especially of Zn-methionine) and high levels of biotin when clinically relevant alterations in the foot pad occur.

Comparison of Urine Output among Patients Treated with More Intensive Versus Less Intensive RRT: Results from the Acute Renal Failure Trial Network Study

PubMed Central

Asafu-Adjei, Josephine; Betensky, Rebecca A.; Palevsky, Paul M.; Waikar, Sushrut S.

2016-01-01

Background and objectives Intensive RRT may have adverse effects that account for the absence of benefit observed in randomized trials of more intensive versus less intensive RRT. We wished to determine the association of more intensive RRT with changes in urine output as a marker of worsening residual renal function in critically ill patients with severe AKI. Design, setting, participants, & measurements The Acute Renal Failure Trial Network Study (n=1124) was a multicenter trial that randomized critically ill patients requiring initiation of RRT to more intensive (hemodialysis or sustained low–efficiency dialysis six times per week or continuous venovenous hemodiafiltration at 35 ml/kg per hour) versus less intensive (hemodialysis or sustained low–efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20 ml/kg per hour) RRT. Mixed linear regression models were fit to estimate the association of RRT intensity with change in daily urine output in survivors through day 7 (n=871); Cox regression models were fit to determine the association of RRT intensity with time to ≥50% decline in urine output in all patients through day 28. Results Mean age of participants was 60±15 years old, 72% were men, and 30% were diabetic. In unadjusted models, among patients who survived ≥7 days, mean urine output was, on average, 31.7 ml/d higher (95% confidence interval, 8.2 to 55.2 ml/d) for the less intensive group compared with the more intensive group (P=0.01). More intensive RRT was associated with 29% greater unadjusted risk of decline in urine output of ≥50% (hazard ratio, 1.29; 95% confidence interval, 1.10 to 1.51). Conclusions More intensive versus less intensive RRT is associated with a greater reduction in urine output during the first 7 days of therapy and a greater risk of developing a decline in urine output of ≥50% in critically ill patients with severe AKI. PMID:27449661

Protocols and Hospital Mortality in Critically Ill Patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study.

PubMed

Sevransky, Jonathan E; Checkley, William; Herrera, Phabiola; Pickering, Brian W; Barr, Juliana; Brown, Samuel M; Chang, Steven Y; Chong, David; Kaufman, David; Fremont, Richard D; Girard, Timothy D; Hoag, Jeffrey; Johnson, Steven B; Kerlin, Mehta P; Liebler, Janice; O'Brien, James; O'Keefe, Terence; Park, Pauline K; Pastores, Stephen M; Patil, Namrata; Pietropaoli, Anthony P; Putman, Maryann; Rice, Todd W; Rotello, Leo; Siner, Jonathan; Sajid, Sahul; Murphy, David J; Martin, Greg S

2015-10-01

Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized ICUs have superior patient outcomes compared with less highly protocolized ICUs. Observational study in which participating ICUs completed a general assessment and enrolled new patients 1 day each week. A total of 6,179 critically ill patients. Fifty-nine ICUs in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. None. The primary exposure was the number of ICU protocols; the primary outcome was hospital mortality. A total of 5,809 participants were followed prospectively, and 5,454 patients in 57 ICUs had complete outcome data. The median number of protocols per ICU was 19 (interquartile range, 15-21.5). In single-variable analyses, there were no differences in ICU and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in ICUs with a high versus low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p = 0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between ICUs with high versus low numbers of protocols for lung protective ventilation in acute respiratory distress syndrome (47% vs 52%; p = 0.28) and for spontaneous breathing trials (55% vs 51%; p = 0.27). Clinical protocols are highly prevalent in U.S. ICUs. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality.

Biomarkers and surrogate endpoints in glaucoma clinical trials

PubMed Central

Medeiros, Felipe A

2015-01-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. PMID:25034049

Renal denervation for treatment of drug-resistant hypertension.

PubMed

Esler, Murray

2015-02-01

At the seven-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension, it is timely to reflect on the past, present, and future of the development and clinical application of this treatment. Unresolved procedural and technical questions are central: How much renal denervation is optimal? How can this level of denervation be achieved? What test for denervation can be applied in renal denervation trials? Will renal denervation show a "class effect," with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? When I have assessed renal denervation efficacy, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation was found to be incomplete and non-uniform between patients. It is probable that the degree of denervation has commonly been suboptimal in renal denervation trials; this criticism applying with special force to the Symplicity HTN-3 trial, where the proceduralists, although expert interventional cardiologists, had no prior experience with the renal denervation technique. Recently presented results from the Symplicity HTN-3 trial confirm that renal denervation was not achieved effectively or consistently. Given this, and other difficulties in the execution of the trial relating to drug adherence, an idea mooted is that the US pivotal trial of the future may be in younger, untreated patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Figures in clinical trial reports: current practice & scope for improvement.

PubMed

Pocock, Stuart J; Travison, Thomas G; Wruck, Lisa M

2007-11-19

Most clinical trial publications include figures, but there is little guidance on what results should be displayed as figures and how. To evaluate the current use of figures in Trial reports, and to make constructive suggestions for future practice. We surveyed all 77 reports of randomised controlled trials in five general medical journals during November 2006 to January 2007. The numbers and types of figures were determined, and then each Figure was assessed for its style, content, clarity and suitability. As a consequence, guidelines are developed for presenting figures, both in general and for each specific common type of Figure. Most trial reports contained one to three figures, mean 2.3 per article. The four main types were flow diagram, Kaplan Meier plot, Forest plot (for subgroup analyses) and repeated measures over time: these accounted for 92% of all figures published. For each type of figure there is a considerable diversity of practice in both style and content which we illustrate with selected examples of both good and bad practice. Some pointers on what to do, and what to avoid, are derived from our critical evaluation of these articles' use of figures. There is considerable scope for authors to improve their use of figures in clinical trial reports, as regards which figures to choose, their style of presentation and labelling, and their specific content. Particular improvements are needed for the four main types of figures commonly used.

Comparison of the effectiveness of two styles of case-based learning implemented in lectures for developing nursing students' critical thinking ability: A randomized controlled trial.

PubMed

Hong, Shaohua; Yu, Ping

2017-03-01

To explore and compare the effectiveness of two styles of case-based learning methods, unfolding nursing case and usual nursing case, implemented in lectures for developing nursing students' critical thinking ability. 122 undergraduate nursing students in four classes were taught the subject of medical nursing for one year. Two classes were randomly assigned as the experimental group and the other two the control group. The experimental group received the lectures presenting unfolding nursing cases and the control group was taught the usual cases. Nineteen case-based lectures were provided in 8 months in two semesters to each group. The two groups started with a similar level of critical thinking ability as tested by the instrument of Critical Thinking Disposition Inventory-Chinese version (CTDI-CV). After receiving 19 case-based learning lectures for 8 months, both groups of students significantly improved their critical thinking ability. The improvement in the experimental group was significantly higher than that in the control group (with the average total score of 303.77±15.24 vs. 288.34±13.94, p<0.05). The experimental group also had significantly better improvement in six out of seven dimensions whereas the control group showed improvement in only three out of seven dimensions of CTDI-CV. The study suggests the feasibility of implementing case-based learning in lectures. Unfolding nursing cases appear to be significantly more effective than the usual nursing cases in developing undergraduate nursing students' critical thinking ability in the subject of medical nursing. Further research can implement the unfolding nursing cases in other nursing subjects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stakeholder Engagement in Trial Design: Survey of Visitors to Critically Ill Patients Regarding Preferences for Outcomes and Treatment Options during Weaning from Mechanical Ventilation.

PubMed

Burns, Karen E A; Jacob, Sonu Karottaiyamvelil; Aguirre, Valeria; Gomes, Janice; Mehta, Sangeeta; Rizvi, Leena

2016-11-01

Stakeholder engagement in research is expected to provide unique insights, make research investments more accountable and transparent, and ensure that future research is applicable to patients and family members. To inform the design of a trial of strategies for weaning from mechanical ventilation, we sought to identify preferences of patient visitors regarding outcome and treatment measures. We conducted an interviewer-administered questionnaire of visitors of critically ill patients in two family waiting rooms serving three intensive care units (ICUs) in Toronto, Canada. Respondents rated the importance of general and ventilation-related outcomes in two hypothetical scenarios (before a first spontaneous breathing trial, and after a failed spontaneous breathing trial) and selected a preferred technique for the breathing trials. With regard to the patient they were visiting, respondents identified the most important outcome to them at ICU admission, during the ICU stay, and at ICU discharge. We analyzed 322 questionnaires (95.5% response rate). All outcomes were highly rated (average range: 7.82-9.74). Across scenarios, outcomes rated as most important were ICU and hospital survival (9.72, 9.70), avoiding complications (9.45), quality of life (9.394), patient comfort (9.393), and returning to previous living arrangements (9.31). Overall, the most important ventilation-related outcomes were being ventilator-free (8.95), avoiding reintubation (8.905), and passing a spontaneous breathing trial (8.903). Passing a spontaneous breathing trial assumed greater importance after an initial failed attempt. "Time to event" outcomes were less important to visitors. We did not identify a preferred spontaneous breathing trial technique. Although ICU survival was the most important outcome at ICU admission and during the ICU stay, visitors rated quality of life higher than hospital survival at ICU discharge. Visitors to critically ill patients prioritized two general outcomes (ICU and hospital survival) and three ventilation-related outcomes (being ventilator free, avoiding reintubation, passing a spontaneous breathing trial), and valued avoiding complications, maintaining quality of life, comfort, and returning to previous living arrangements. The outcomes preferences of the survey respondents evolved temporally during the ICU stay.

Appealing to the Republic of Letters: An Autopsy of Anti-venereal Trials in Eighteenth-century Mexico

PubMed Central

Clark, Fiona

2014-01-01

This study analyses the narrative elements of a little-known report into anti-venereal trials written by an Irish military physician-surgeon, Daniel O'Sullivan (1760–c.1797). It explores the way in which O'Sullivan as the narrator of the Historico-critical report creates medical heroes and anti-heroes as a means to criticise procedures initiated by staff in the Hospital General de San Andrés, Mexico City. The resulting work depicts a much less positive picture of medical trials and hospital authorities in this period than has been recorded to date, and provides a critical and complicated assessment of one of Spain's leading physicians of the nineteenth century, Francisco Javier Balmis (1753–1819). PMID:24771980

Electroencephalography (EEG) for neurological prognostication after cardiac arrest and targeted temperature management; rationale and study design.

PubMed

Westhall, Erik; Rosén, Ingmar; Rossetti, Andrea O; van Rootselaar, Anne-Fleur; Kjaer, Troels Wesenberg; Horn, Janneke; Ullén, Susann; Friberg, Hans; Nielsen, Niklas; Cronberg, Tobias

2014-08-16

Electroencephalography (EEG) is widely used to assess neurological prognosis in patients who are comatose after cardiac arrest, but its value is limited by varying definitions of pathological patterns and by inter-rater variability. The American Clinical Neurophysiology Society (ACNS) has recently proposed a standardized EEG-terminology for critical care to address these limitations. In the TTM-trial, 399 post cardiac arrest patients who remained comatose after rewarming underwent a routine EEG. The presence of clinical seizures, use of sedatives and antiepileptic drugs during the EEG-registration were prospectively documented. A well-defined terminology for interpreting post cardiac arrest EEGs is critical for the use of EEG as a prognostic tool. The TTM-trial is registered at ClinicalTrials.gov (NCT01020916).

Attitudes towards fever amongst UK paediatric intensive care staff.

PubMed

Brick, Thomas; Agbeko, Rachel S; Davies, Patrick; Davis, Peter J; Deep, Akash; Fortune, Peter-Marc; Inwald, David P; Jones, Amy; Levin, Richard; Morris, Kevin P; Pappachan, John; Ray, Samiran; Tibby, Shane M; Tume, Lyvonne N; Peters, Mark J

2017-03-01

The role played by fever in the outcome of critical illness in children is unclear. This survey of medical and nursing staff in 35 paediatric intensive care units and transport teams in the United Kingdom and Ireland established attitudes towards the management of children with fever. Four hundred sixty-two medical and nursing staff responded to a web-based survey request. Respondents answered eight questions regarding thresholds for temperature control in usual clinical practice, indications for paracetamol use, and readiness to participate in a clinical trial of permissive temperature control. The median reported threshold for treating fever in clinical practice was 38 °C (IQR 38-38.5 °C). Paracetamol was reported to be used as an analgesic and antipyretic but also for non-specific comfort indications. There was a widespread support for a clinical trial of a permissive versus a conservative approach to fever in paediatric intensive care units. Within a trial, 58% of the respondents considered a temperature of 39 °C acceptable without treatment. Staff on paediatric intensive care units in the United Kingdom and Ireland tends to treat temperatures within the febrile range. There was a willingness to conduct a randomized controlled trial of treatment of fever. What is known: • The effect of fever on the outcome in paediatric critical illness is unknown. • Paediatricians have traditionally been reluctant to allow fever in sick children. What is new: • Paediatric intensive care staff report a tendency towards treating fever, with a median reported treatment threshold of 38 °C. • There is widespread support amongst PICU staff in the UK for a randomized controlled trial of temperature in critically ill children. • Within a trial setting, PICU staff attitudes to fever are more permissive than in clinical practice.

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

Toward an information-motivation-behavioral skills model of microbicide adherence in clinical trials.

PubMed

Ferrer, Rebecca A; Morrow, Kathleen M; Fisher, William A; Fisher, Jeffrey D

2010-08-01

Unless optimal adherence in microbicide clinical trials is ensured, an efficacious microbicide may be rejected after trial completion, or development of a promising microbicide may be stopped, because low adherence rates create the illusion of poor efficacy. We provide a framework with which to conceptualize and improve microbicide adherence in clinical trials, supported by a critical review of the empirical literature. The information-motivation-behavioral skills (IMB) model of microbicide adherence conceptualizes microbicide adherence in clinical trials and highlights factors that can be addressed in behavioral interventions to increase adherence in such trials. This model asserts that microbicide adherence-related information, motivation, and behavioral skills are fundamental determinants of adherent microbicide utilization. Specifically, information consists of objective facts about microbicide use (e.g., administration and dosage) as well as heuristics that facilitate use (e.g., microbicides must be used with all partners). Motivation to adhere consists of attitudes toward personal use of microbicides (e.g., evaluating the consequences of using microbicides as good or pleasant) as well as social norms that support their use (e.g., beliefs that a sexual partner approves use of microbicides). Behavioral skills consist of objective skills necessary for microbicide adherence (e.g., the ability to apply the microbicide correctly and consistently). Empirical evidence concerning microbicide acceptability and adherence to spermicides, medication, and condom use regimens support the utility of this model for understanding and promoting microbicide adherence in clinical trials.

Equitable treatment for HIV/AIDS clinical trial participants: a focus group study of patients, clinician researchers, and administrators in Western Kenya.

PubMed

Shaffer, D N; Yebei, V N; Ballidawa, J B; Sidle, J E; Greene, J Y; Meslin, E M; Kimaiyo, S J N; Tierney, W M

2006-01-01

To describe the concerns and priorities of key stakeholders in a developing country regarding ethical obligations held by researchers and perceptions of equity or "what is fair" for study participants in an HIV/AIDS clinical drug trial. Qualitative study with focus groups. Teaching and referral hospital and rural health centre in Western Kenya. Potential HIV/AIDS clinical trial participants, clinician researchers, and administrators. Eighty nine individuals participated in a total of 11 focus groups over a four month period. The desire for continued drug therapy, most often life long, following an HIV/AIDS clinical trial was the most common priority expressed in all focus groups. Patients with and without HIV/AIDS also thought subsidizing of drug therapies and education were critical forms of compensation for clinical trial participation. Financial incentives were considered important primarily for purchasing drug therapy as well as obtaining food. Patients noted a concern for the potential mismanagement of any money offered. Clinician researchers and administrators felt strongly that researchers have a moral obligation to participants following a trial to provide continued drug therapy, adverse event monitoring, and primary care. Finally, clinician researchers and administrators stressed the need for thorough informed consent to avoid coercion of study participants. Kenyan patients, clinician researchers, and administrators believe that it would be unfair to stop antiretroviral therapy following an HIV/AIDS clinical trial and that researchers have a long term obligation to participants.

Understanding and preventing type 1 diabetes through the unique working model of TrialNet.

PubMed

Battaglia, Manuela; Anderson, Mark S; Buckner, Jane H; Geyer, Susan M; Gottlieb, Peter A; Kay, Thomas W H; Lernmark, Åke; Muller, Sarah; Pugliese, Alberto; Roep, Bart O; Greenbaum, Carla J; Peakman, Mark

2017-11-01

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches.

Understanding and preventing type 1 diabetes through the unique working model of TrialNet

PubMed Central

Anderson, Mark S.; Buckner, Jane H.; Geyer, Susan M.; Gottlieb, Peter A.; Kay, Thomas W. H.; Lernmark, Åke; Muller, Sarah; Pugliese, Alberto; Roep, Bart O.; Greenbaum, Carla J.

2018-01-01

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers. This niche opportunity is occupied by Type 1 Diabetes TrialNet, an international consortium of clinical trial centres that leads the field in intervention and prevention studies, accompanied by deep longitudinal bio-sampling. In this review, we focus on discoveries arising from this unique bioresource, comprising more than 70,000 samples, and outline the processes and science that have led to new biomarkers and mechanistic insights, as well as identifying new challenges and opportunities. We conclude that via integration of clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnership with industry, TrialNet embodies an enviable and unique working model for understanding a disease that to date has no cure and for designing new therapeutic approaches. PMID:28770323

Evidence-based guidelines for the use of tracheostomy in critically ill patients.

PubMed

Raimondi, Néstor; Vial, Macarena R; Calleja, José; Quintero, Agamenón; Cortés, Albán; Celis, Edgar; Pacheco, Clara; Ugarte, Sebastián; Añón, José M; Hernández, Gonzalo; Vidal, Erick; Chiappero, Guillermo; Ríos, Fernando; Castilleja, Fernando; Matos, Alfredo; Rodriguez, Enith; Antoniazzi, Paulo; Teles, José Mario; Dueñas, Carmelo; Sinclair, Jorge; Martínez, Lorenzo; von der Osten, Ingrid; Vergara, José; Jiménez, Edgar; Arroyo, Max; Rodríguez, Camilo; Torres, Javier; Fernandez-Bussy, Sebastián; Nates, Joseph L

2017-04-01

To provide evidence-based guidelines for tracheostomy in critically ill adult patients and identify areas needing further research. A taskforce composed of representatives of 10 member countries of the Pan-American and Iberic Federation of Societies of Critical and Intensive Therapy Medicine and of the Latin American Critical Care Trial Investigators Network developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation system. The group identified 23 relevant questions among 87 issues that were initially identified. In the initial search, 333 relevant publications were identified, of which 226 publications were chosen. The taskforce generated a total of 19 recommendations, 10 positive (1B, 3; 2C, 3; 2D, 4) and 9 negative (1B, 8; 2C, 1). A recommendation was not possible in 6 questions. Percutaneous techniques are associated with a lower risk of infections compared with surgical tracheostomy. Early tracheostomy only seems to reduce the duration of ventilator use but not the incidence of pneumonia, the length of stay, or the long-term mortality rate. The evidence does not support the use of routine bronchoscopy guidance or laryngeal masks during the procedure. Finally, proper prior training is as important or even a more significant factor in reducing complications than the technique used. Copyright © 2016 Elsevier Inc. All rights reserved.

Cognitive Behavior Therapy for Generalized Social Anxiety Disorder in Adolescents: A Randomized Controlled Trial

PubMed Central

Herbert, James D.; Gaudiano, Brandon A.; Rheingold, Alyssa A.; Moitra, Ethan; Myers, Valerie H.; Dalrymple, Kristy L.; Brandsma, Lynn L.

2010-01-01

Early identification and treatment of social anxiety disorder (SAD) is critical to prevent development of a chronic course of symptoms, persistent functional impairment, and progressive psychiatric comorbidity. A small but growing literature supports the effectiveness of cognitive behavior therapy (CBT) for anxiety disorders, including SAD, in adolescence. The present randomized controlled trial evaluated the efficacy of group vs. individual CBT for adolescents with generalized SAD in relation to an educational/supportive psychotherapy that did not contain specific CBT elements. All three treatments were associated with significant reductions in symptoms and functional impairment, and in improved social skills. No differences between treatments emerged on measures of symptoms, but the CBT conditions demonstrated greater gains on behavioral measures. The implications of the findings are discussed. PMID:18653310

[New Concept for Surviving Sepsis: from Phenomenon to Essence].

PubMed

Liao, Xue-Lian; Xie, Zhi-Chao; Kang, Yan

2016-07-01

Sepsis is a critical clinical syndrome which keep puzzling the medical profession for many years. Recently, the results from several large-scale trials challenged the necessity of early goal directed therapy (EGDT) in surviving sepsis bundle, These trials were not opposed to EGDT but bring new concept that it is essential to utilize therapy with multiple monitoring measures in order to minimize injury while guarantee the safety . Deeper understanding in the pathogenesis of sepsis gives rise to the update of its definition based on vital organ dysfunction. The importance of dynamic monitoring in defining sepsis also need to be emphasized. Developing more effective monitoring measures could provide better treatments, thus improve the prognosis of septic patients. Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).

Natural product and natural product derived drugs in clinical trials.

PubMed

Butler, Mark S; Robertson, Avril A B; Cooper, Matthew A

2014-11-01

There are a significant number of natural product (NP) drugs in development. We review the 100 NP and NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component being evaluated in clinical trials or in registration at the end of 2013. 38 of these compounds and 33 ADCs are being investigated as potential oncology treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurology. There was a spread of the NP and NP-derived compounds through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compounds were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compounds for which clinical trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analysed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compounds in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clinical trials. The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.

Effects of temperature and fatigue on the metabolism and swimming capacity of juvenile Chinese sturgeon (Acipenser sinensis).

PubMed

Yuan, Xi; Zhou, Yi-Hong; Huang, Ying-Ping; Guo, Wen-Tao; Johnson, David; Jiang, Qing; Jing, Jin-Jie; Tu, Zhi-Ying

2017-10-01

Chinese sturgeon (Acipenser sinensis) is a critically endangered species. A flume-type respirometer, with video, was used to conduct two consecutive stepped velocity tests at 10, 15, 20, and 25 °C. Extent of recovery was measured after the 60-min recovery period between trials, and the recovery ratio for critical swimming speed (U crit ) averaged 91.88% across temperatures. Temperature (T) effects were determined by comparing U crit , oxygen consumption rate (MO 2 ), and tail beat frequency (TBF) for each temperature. Results from the two trials were compared to determine the effect of exercise. The U crit occurring at 15 °C in both trials was significantly higher than that at 10 and 25 °C (p < 0.05). The U crit was plotted as a function of T and curve-fitting allowed calculation of the optimal swimming temperature 3.28 BL/s at 15.96 °C (trial 1) and 2.98 BL/s at 15.85 °C (trial 2). In trial 1, MO 2 increased rapidly with U, but then declined sharply as swimming speed approached U crit . In trial 2, MO 2 increased more slowly, but continuously, to U crit . TBF was directly proportional to U and the slope (dTBF/dU) for trial 2 was significantly lower than that for trial 1. The inverse slope (tail beats per body length, TB/BL) is a measure of swimming efficiency and the significant difference in slopes implies that the exercise training provided by trial 1 led to a significant increase in swimming efficiency in trial 2.

A Bayesian pick-the-winner design in a randomized phase II clinical trial.

PubMed

Chen, Dung-Tsa; Huang, Po-Yu; Lin, Hui-Yi; Chiappori, Alberto A; Gabrilovich, Dmitry I; Haura, Eric B; Antonia, Scott J; Gray, Jhanelle E

2017-10-24

Many phase II clinical trials evaluate unique experimental drugs/combinations through multi-arm design to expedite the screening process (early termination of ineffective drugs) and to identify the most effective drug (pick the winner) to warrant a phase III trial. Various statistical approaches have been developed for the pick-the-winner design but have been criticized for lack of objective comparison among the drug agents. We developed a Bayesian pick-the-winner design by integrating a Bayesian posterior probability with Simon two-stage design in a randomized two-arm clinical trial. The Bayesian posterior probability, as the rule to pick the winner, is defined as probability of the response rate in one arm higher than in the other arm. The posterior probability aims to determine the winner when both arms pass the second stage of the Simon two-stage design. When both arms are competitive (i.e., both passing the second stage), the Bayesian posterior probability performs better to correctly identify the winner compared with the Fisher exact test in the simulation study. In comparison to a standard two-arm randomized design, the Bayesian pick-the-winner design has a higher power to determine a clear winner. In application to two studies, the approach is able to perform statistical comparison of two treatment arms and provides a winner probability (Bayesian posterior probability) to statistically justify the winning arm. We developed an integrated design that utilizes Bayesian posterior probability, Simon two-stage design, and randomization into a unique setting. It gives objective comparisons between the arms to determine the winner.

Multisite effectiveness trials of treatments for substance abuse and co-occurring problems: have we chosen the best designs?

PubMed

Nunes, Edward V; Ball, Samuel; Booth, Robert; Brigham, Gregory; Calsyn, Donald A; Carroll, Kathleen; Feaster, Daniel J; Hien, Denise; Hubbard, Robert L; Ling, Walter; Petry, Nancy M; Rotrosen, John; Selzer, Jeffrey; Stitzer, Maxine; Tross, Susan; Wakim, Paul; Winhusen, Theresa; Woody, George

2010-06-01

Multisite effectiveness trials such as those carried out in the National Drug Abuse Treatment Clinical Trials Network (CTN) are a critical step in the development and dissemination of evidence-based treatments because they address how such treatments perform in real-world clinical settings. As Brigham et al. summarized in a recent article (G. S. Brigham, D. J. Feaster, P. G. Wakim, & C. L. Dempsey C. L., 2009), several possible experimental designs may be chosen for such effectiveness trials. These include (a) a new treatment intervention (Tx) is compared to an existing mode of community based treatment as usual (TAU): Tx versus TAU; (b) a new intervention is added to TAU and compared to TAU alone: Tx + TAU versus TAU; or (c) a new intervention is added to TAU and compared to a control condition added to TAU: Tx + TAU versus control + TAU. Each of these designs addresses a different question and has different potential strengths and weaknesses. As of December 2009, the primary outcome paper had been published for 16 of the multisite randomized clinical trials conducted in the CTN, testing various treatments for drug abuse, HIV risk behavior, or related problems. This paper systematically examines, for each of the completed trials, the experimental design type chosen and its original rationale, the main findings of the trial, and the strengths and weaknesses of the design in hindsight. Based on this review, recommendations are generated to inform the design of future effectiveness trials on treatments for substance abuse, HIV risk, and other behavioral health problems.

Core Outcome Domains for early phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus.

PubMed

Fackrell, Kathryn; Smith, Harriet; Colley, Veronica; Thacker, Brian; Horobin, Adele; Haider, Haúla F; Londero, Alain; Mazurek, Birgit; Hall, Deborah A

2017-08-23

The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is, therefore to, develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. The 'Core Outcome Measures in Tinnitus: International Delphi' (COMIT'ID) study will use a mixed-methods approach that incorporates input from health care users at the pre-Delphi stage, a modified three-round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following Core Outcome Set publication. The COMIT'ID study aims to develop a Core Outcome Domain Set that is agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the Core Outcome Set in the long term. This project has been registered (November 2014) in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative.

Controlled trials in children: quantity, methodological quality and descriptive characteristics of pediatric controlled trials published 1948-2006.

PubMed

Thomson, Denise; Hartling, Lisa; Cohen, Eyal; Vandermeer, Ben; Tjosvold, Lisa; Klassen, Terry P

2010-09-30

The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials.

Application of Biomarkers in the Development of Drugs Intended for the Treatment of Osteoarthritis

PubMed Central

Kraus, Virginia Byers; Burnett, Bruce; Coindreau, Javier; Cottrell, Susan; Eyre, David; Gendreau, Michael; Gardiner, Jennifer; Garnero, Patrick; Hardin, John; Henrotin, Yves; Heinegård, Dick; Ko, Amy; Lohmander, Stefan; Matthews, Gloria; Menetski, Joseph; Moskowitz, Roland; Persiani, Stefano; Poole, Robin; Rousseau, Jean Charles; Todman, Martin

2013-01-01

Objective Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. Methods The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007–2009 at the behest of the Osteoarthritis Research Society International (OARSI FDA initiative). Results This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. Conclusions Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within one to two years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent. PMID:21396468

Trial-dependent psychometric functions accounting for perceptual learning in 2-AFC discrimination tasks.

PubMed

Kattner, Florian; Cochrane, Aaron; Green, C Shawn

2017-09-01

The majority of theoretical models of learning consider learning to be a continuous function of experience. However, most perceptual learning studies use thresholds estimated by fitting psychometric functions to independent blocks, sometimes then fitting a parametric function to these block-wise estimated thresholds. Critically, such approaches tend to violate the basic principle that learning is continuous through time (e.g., by aggregating trials into large "blocks" for analysis that each assume stationarity, then fitting learning functions to these aggregated blocks). To address this discrepancy between base theory and analysis practice, here we instead propose fitting a parametric function to thresholds from each individual trial. In particular, we implemented a dynamic psychometric function whose parameters were allowed to change continuously with each trial, thus parameterizing nonstationarity. We fit the resulting continuous time parametric model to data from two different perceptual learning tasks. In nearly every case, the quality of the fits derived from the continuous time parametric model outperformed the fits derived from a nonparametric approach wherein separate psychometric functions were fit to blocks of trials. Because such a continuous trial-dependent model of perceptual learning also offers a number of additional advantages (e.g., the ability to extrapolate beyond the observed data; the ability to estimate performance on individual critical trials), we suggest that this technique would be a useful addition to each psychophysicist's analysis toolkit.

Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial.

PubMed

Fowler, Robert A; Mittmann, Nicole; Geerts, William H; Heels-Ansdell, Diane; Gould, Michael K; Guyatt, Gordon; Krahn, Murray; Finfer, Simon; Pinto, Ruxandra; Chan, Brian; Ormanidhi, Orges; Arabi, Yaseen; Qushmaq, Ismael; Rocha, Marcelo G; Dodek, Peter; McIntyre, Lauralyn; Hall, Richard; Ferguson, Niall D; Mehta, Sangeeta; Marshall, John C; Doig, Christopher James; Muscedere, John; Jacka, Michael J; Klinger, James R; Vlahakis, Nicholas; Orford, Neil; Seppelt, Ian; Skrobik, Yoanna K; Sud, Sachin; Cade, John F; Cooper, Jamie; Cook, Deborah

2014-12-20

Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded, randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients in the intensive care unit (ICU). E-PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial. The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect, variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial, and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acute healthcare system perspective, over a data-rich time horizon of ICU admission and hospital admission. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping. This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre-specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication. Clinicaltrials.gov Identifier: NCT00182143 . Date of registration: 10 September 2005.

Inclusion and definition of acute renal dysfunction in critically ill patients in randomized controlled trials: a systematic review.

PubMed

da Hora Passos, Rogerio; Ramos, Joao Gabriel Rosa; Gobatto, André; Caldas, Juliana; Macedo, Etienne; Batista, Paulo Benigno

2018-04-24

In evidence-based medicine, multicenter, prospective, randomized controlled trials (RCTs) are the gold standard for evaluating treatment benefits and ensuring the effectiveness of interventions. Patient-centered outcomes, such as mortality, are most often the preferred evaluated outcomes. While there is currently agreement on how to classify renal dysfunction in critically ill patients , the application frequency of this new classification system in RCTs has not previously been evaluated. In this study, we aim to assess the definition of renal dysfunction in multicenter RCTs involving critically ill patients that included mortality as a primary endpoint. A comprehensive search was conducted for publications reporting multicenter randomized controlled trials (RCTs) involving adult patients in intensive care units (ICUs) that included mortality as a primary outcome. MEDLINE and PUBMED were queried for relevant articles in core clinical journals published between May 2004 and December 2017. Of 418 articles reviewed, 46 multicenter RCTs with a primary endpoint related to mortality were included. Thirty-six (78.3%) of the trial reports provided information on renal function in the participants. Only seven articles (15.2%) included mean or median serum creatinine levels, mean creatinine clearance or estimated glomerular filtration rates. Sequential organ failure assessment (SOFA) score was the most commonly used definition of renal dysfunction (20 studies; 43.5%). Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria were used in five (10.9%) trials. In thirteen trials (28.3%), no renal dysfunction criteria were reported. Only one trial excluded patients with renal dysfunction, and it used urinary output or need for renal replacement therapy (RRT) as criteria for this diagnosis. The presence of renal dysfunction was included as a baseline patient characteristic in most RCTs. The RIFLE, AKIN and KDIGO classification systems were infrequently used; renal dysfunction was generally defined using the SOFA score.

The nature of placebo response in clinical studies of major depressive disorder.

PubMed

Papakostas, George I; Østergaard, Søren D; Iovieno, Nadia

2015-04-01

To review factors influencing placebo response and clinical trial outcome in depression, and suggest ways to optimize trial success in mood disorders. PubMed searches were conducted by cross-referencing the terms depression, depressive with placebo, clinical trial, and clinical trials for studies published in English between 1970 and September 2013. Relevant abstracts were identified in PubMed, including clinical trials, quantitative studies, and qualitative research. We obtained and reviewed relevant articles and utilized their information to synthesize the present review. Included articles were grouped in the following areas of relevance: (1) biological validity of illness, (2) baseline severity of illness, (3) chronicity of the index episode of depression, (4) age of participants, (5) medical and psychiatric comorbidity, (6) probability of receiving placebo, (7) use of prospective treatment phases (lead-in) (8) dosing schedule, (9) trial duration, (10) frequency of follow-up assessments, and (11) study outcome measure. Several key elements emerge as critical to the ultimate success of a clinical trial, including the probability of receiving placebo, study duration, dosing schedule, visit frequency, the use of blinded lead-in phases, the use of centralized raters, illness severity and duration, and comorbid anxiety. Our increasing understanding of the placebo response in clinical trials of major depressive disorder lends to a, gradually, more predictable phenomenon and, hopefully, to one that becomes lesser in magnitude and variability. Several elements have emerged that seem to play a critical role in trial success, gradually reshaping the design of clinical, translational, as well as mechanistic studies in depression. © Copyright 2015 Physicians Postgraduate Press, Inc.

The challenge of establishing treatment efficacy for cutaneous vascular manifestations of systemic sclerosis.

PubMed

Pauling, John D

2018-05-01

The cutaneous vascular manifestations of systemic sclerosis (SSc) comprise Raynaud's phenomenon, cutaneous ulceration, telangiectasia formation and critical digital ischaemia; each of which are associated with significant disease-related morbidity. Despite the availability of multiple classes of vasodilator therapy, many of which have been the subject of RCTs, a limited number of pharmacological interventions are currently approved for the management of cutaneous vascular manifestations of SSc. Areas covered: A major challenge has been demonstrating treatment efficacy with examples of promising therapies yielding contrasting results in controlled trial settings. Differences between consensus best-practice guidelines, evidence-based recommendations and marketing approvals in different jurisdictions has resulted in geographic variation in clinical practice concerning the management of cutaneous vascular manifestations of SSc. Difficulty demonstrating treatment efficacy risks waning industry engagement for drug development programmes in this field. This article highlights the key challenges in establishing treatment efficacy and barriers that must be overcome to support successful clinical trial programmes across the spectrum of cutaneous vascular manifestations of SSc. Expert commentary: The paucity of approved treatments for cutaneous vascular manifestations of SSc relates as much to challenges in clinical trial design and the need for reliable clinical trial endpoints, as to lack of therapeutic options.

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.

PubMed

Rodeghiero, Francesco; Stasi, Roberto; Gernsheimer, Terry; Michel, Marc; Provan, Drew; Arnold, Donald M; Bussel, James B; Cines, Douglas B; Chong, Beng H; Cooper, Nichola; Godeau, Bertrand; Lechner, Klaus; Mazzucconi, Maria Gabriella; McMillan, Robert; Sanz, Miguel A; Imbach, Paul; Blanchette, Victor; Kühne, Thomas; Ruggeri, Marco; George, James N

2009-03-12

Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

Community engagement in diverse populations for Alzheimer disease prevention trials.

PubMed

Romero, Heather R; Welsh-Bohmer, Kathleen A; Gwyther, Lisa P; Edmonds, Henry L; Plassman, Brenda L; Germain, Cassandra M; McCart, Michelle; Hayden, Kathleen M; Pieper, Carl; Roses, Allen D

2014-01-01

The recruitment of asymptomatic volunteers has been identified as a critical factor that is delaying the development and validation of preventive therapies for Alzheimer disease (AD). Typical recruitment strategies involve the use of convenience samples or soliciting participation of older adults with a family history of AD from clinics and outreach efforts. However, high-risk groups, such as ethnic/racial minorities, are traditionally less likely to be recruited for AD prevention studies, thus limiting the ability to generalize findings for a significant proportion of the aging population. A community-engagement approach was used to create a registry of 2311 research-ready, healthy adult volunteers who reflect the ethnically diverse local community. Furthermore, the registry's actual commitment to research was examined, through demonstrated participation rates in a clinical study. The approach had varying levels of success in establishing a large, diverse pool of individuals who are interested in participating in pharmacological prevention trials and meet the criteria for primary prevention research trials designed to delay the onset of AD. Our efforts suggest that entry criteria for the clinical trials need to be carefully considered to be inclusive of African Americans, and that sustained effort is needed to engage African Americans in pharmacological prevention approaches.

Racial and Ethnic Disparities in Parental Refusal of Consent in a Large, Multisite Pediatric Critical Care Clinical Trial.

PubMed

Natale, Joanne E; Lebet, Ruth; Joseph, Jill G; Ulysse, Christine; Ascenzi, Judith; Wypij, David; Curley, Martha A Q

2017-05-01

To evaluate whether race or ethnicity was independently associated with parental refusal of consent for their child's participation in a multisite pediatric critical care clinical trial. We performed a secondary analyses of data from Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE), a 31-center cluster randomized trial of sedation management in critically ill children with acute respiratory failure supported on mechanical ventilation. Multivariable logistic regression modeling estimated associations between patient race and ethnicity and parental refusal of study consent. Among the 3438 children meeting enrollment criteria and approached for consent, 2954 had documented race/ethnicity of non-Hispanic White (White), non-Hispanic Black (Black), or Hispanic of any race. Inability to approach for consent was more common for parents of Black (19.5%) compared with White (11.7%) or Hispanic children (13.2%). Among those offered consent, parents of Black (29.5%) and Hispanic children (25.9%) more frequently refused consent than parents of White children (18.2%, P < .0167 for each). Compared with parents of White children, parents of Black (OR 2.15, 95% CI 1.56-2.95, P < .001) and Hispanic (OR 1.44, 95% CI 1.10-1.88, P = .01) children were more likely to refuse consent. Parents of children offered participation in the intervention arm were more likely to refuse consent than parents in the control arm (OR 2.15, 95% CI 1.37-3.36, P < .001). Parents of Black and Hispanic children were less likely to be approached for, and more frequently declined consent for, their child's participation in a multisite critical care clinical trial. Ameliorating this racial disparity may improve the validity and generalizability of study findings. ClinicalTrials.gov: NCT00814099. Copyright © 2017 Elsevier Inc. All rights reserved.

Tracheal intubation in critically ill patients: a comprehensive systematic review of randomized trials.

PubMed

Cabrini, Luca; Landoni, Giovanni; Baiardo Radaelli, Martina; Saleh, Omar; Votta, Carmine D; Fominskiy, Evgeny; Putzu, Alessandro; Snak de Souza, Cézar Daniel; Antonelli, Massimo; Bellomo, Rinaldo; Pelosi, Paolo; Zangrillo, Alberto

2018-01-20

We performed a systematic review of randomized controlled studies evaluating any drug, technique or device aimed at improving the success rate or safety of tracheal intubation in the critically ill. We searched PubMed, BioMed Central, Embase and the Cochrane Central Register of Clinical Trials and references of retrieved articles. Finally, pertinent reviews were also scanned to detect further studies until May 2017. The following inclusion criteria were considered: tracheal intubation in adult critically ill patients; randomized controlled trial; study performed in Intensive Care Unit, Emergency Department or ordinary ward; and work published in the last 20 years. Exclusion criteria were pre-hospital or operating theatre settings and simulation-based studies. Two investigators selected studies for the final analysis. Extracted data included first author, publication year, characteristics of patients and clinical settings, intervention details, comparators and relevant outcomes. The risk of bias was assessed with the Cochrane Collaboration's Risk of Bias tool. We identified 22 trials on use of a pre-procedure check-list (1 study), pre-oxygenation or apneic oxygenation (6 studies), sedatives (3 studies), neuromuscular blocking agents (1 study), patient positioning (1 study), video laryngoscopy (9 studies), and post-intubation lung recruitment (1 study). Pre-oxygenation with non-invasive ventilation (NIV) and/or high-flow nasal cannula (HFNC) showed a possible beneficial role. Post-intubation recruitment improved oxygenation , while ramped position increased the number of intubation attempts and thiopental had negative hemodynamic effects. No effect was found for use of a checklist, apneic oxygenation (on oxygenation and hemodynamics), videolaryngoscopy (on number and length of intubation attempts), sedatives and neuromuscular blockers (on hemodynamics). Finally, videolaryngoscopy was associated with severe adverse effects in multiple trials. The limited available evidence supports a beneficial role of pre-oxygenation with NIV and HFNC before intubation of critically ill patients. Recruitment maneuvers may increase post-intubation oxygenation. Ramped position increased the number of intubation attempts; thiopental had negative hemodynamic effects and videolaryngoscopy might favor adverse events.

"Mississippi Trial, 1955": Tangling with Text through Reading, Discussion, and Writing

ERIC Educational Resources Information Center

Grierson, Sirpa; Thursby, Jacqueline S.; Dean, Deborah; Crowe, Chris

2007-01-01

The authors proffer practical critical-reading strategies for teaching "Mississippi Trial, 1955" to increase students' vocabulary, comprehension, and background knowledge of historical eras. They use nonfiction, a PBS documentary, the Web, folklore, and picture books among other tools for inciting thoughtful discussion and writing.

Web-Based Intervention for Women With Type 1 Diabetes in Pregnancy and Early Motherhood: Critical Analysis of Adherence to Technological Elements and Study Design.

PubMed

Berg, Marie; Linden, Karolina; Adolfsson, Annsofie; Sparud Lundin, Carina; Ranerup, Agneta

2018-05-02

Numerous Web-based interventions have been implemented to promote health and health-related behaviors in persons with chronic conditions. Using randomized controlled trials to evaluate such interventions creates a range of challenges, which in turn can influence the study outcome. Applying a critical perspective when evaluating Web-based health interventions is important. The objective of this study was to critically analyze and discuss the challenges of conducting a Web-based health intervention as a randomized controlled trial. The MODIAB-Web study was critically examined using an exploratory case study methodology and the framework for analysis offered through the Persuasive Systems Design model. Focus was on technology, study design, and Web-based support usage, with special focus on the forum for peer support. Descriptive statistics and qualitative content analysis were used. The persuasive content and technological elements in the design of the randomized controlled trial included all four categories of the Persuasive Systems Design model, but not all design principles were implemented. The study duration was extended to a period of four and a half years. Of 81 active participants in the intervention group, a maximum of 36 women were simultaneously active. User adherence varied greatly with a median of 91 individual log-ins. The forum for peer support was used by 63 participants. Although only about one-third of the participants interacted in the forum, there was a fairly rich exchange of experiences and advice between them. Thus, adherence in terms of social interactions was negatively affected by limited active participation due to prolonged recruitment process and randomization effects. Lessons learned from this critical analysis are that technology and study design matter and might mutually influence each other. In Web-based interventions, the use of design theories enables utilization of the full potential of technology and promotes adherence. The randomization element in a randomized controlled trial design can become a barrier to achieving a critical mass of user interactions in Web-based interventions, especially when social support is included. For extended study periods, the technology used may need to be adapted in line with newly available technical options to avoid the risk of becoming outdated in the user realm, which in turn might jeopardize study validity in terms of randomized controlled trial designs. On the basis of lessons learned in this randomized controlled trial, we give recommendations to consider when designing and evaluating Web-based health interventions. ©Marie Berg, Karolina Linden, Annsofie Adolfsson, Carina Sparud Lundin, Agneta Ranerup. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 02.05.2018.

Lungtech, a phase II EORTC trial of SBRT for centrally located lung tumours - a clinical physics perspective.

PubMed

Lambrecht, Marie; Melidis, Christos; Sonke, Jan-Jakob; Adebahr, Sonja; Boellaard, Ronald; Verheij, Marcel; Guckenberger, Matthias; Nestle, Ursula; Hurkmans, Coen

2016-01-20

The EORTC has launched a phase II trial to assess safety and efficacy of SBRT for centrally located NSCLC: The EORTC 22113-08113-Lungtech trial. Due to neighbouring critical structures, these tumours remain challenging to treat. To guarantee accordance to protocol and treatment safety, an RTQA procedure has been implemented within the frame of the EORTC RTQA levels. These levels are here expanded to include innovative tools beyond protocol compliance verification: the actual dose delivered to each patient will be estimated and linked to trial outcomes to enable better understanding of dose related response and toxicity. For trial participation, institutions must provide a completed facility questionnaire and beam output audit results. To insure ability to comply with protocol specifications a benchmark case is sent to all centres. After approval, institutions are allowed to recruit patients. Nonetheless, each treatment plan will be prospectively reviewed insuring trial compliance consistency over time. As new features, patient's CBCT images and applied positioning corrections will be saved for dose recalculation on patient's daily geometry. To assess RTQA along the treatment chain, institutions will be visited once during the time of the trial. Over the course of this visit, end-to-end tests will be performed using the 008ACIRS-breathing platform with two separate bodies. The first body carries EBT3 films and an ionization chamber. The other body newly developed for PET- CT evaluation is fillable with a solution of high activity. 3D or 4D PET-CT and 4D-CT scanning techniques will be evaluated to assess the impact of motion artefacts on target volume accuracy. Finally, a dosimetric evaluation in static and dynamic conditions will be performed. Previous data on mediastinal toxicity are scarce and source of cautiousness for setting-up SBRT treatments for centrally located NSCLC. Thanks to the combination of documented patient related outcomes and CBCT based dose recalculation we expect to provide improved models for dose response and dose related toxicity. We have developed a comprehensive RTQA model for trials involving modern radiotherapy. These procedures could also serve as examples of extended RTQA for future radiotherapy trials involving quantitative use of PET and tumour motion.

Exploring the experiences of substitute decision-makers with an exception to consent in a paediatric resuscitation randomised controlled trial: study protocol for a qualitative research study

PubMed Central

de Laat, Sonya; Schwartz, Lisa

2016-01-01

Introduction Prospective informed consent is required for most research involving human participants; however, this is impracticable under some circumstances. The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS) outlines the requirements for research involving human participants in Canada. The need for an exception to consent (deferred consent) is recognised and endorsed in the TCPS for research in individual medical emergencies; however, little is known about substitute decision-maker (SDM) experiences. A paediatric resuscitation trial (SQUEEZE) (NCT01973907) using an exception to consent process began enrolling at McMaster Children's Hospital in January 2014. This qualitative research study aims to generate new knowledge on SDM experiences with the exception to consent process as implemented in a randomised controlled trial. Methods and analysis The SDMs of children enrolled into the SQUEEZE pilot trial will be the sampling frame from which ethics study participants will be derived. Design: Qualitative research study involving individual interviews and grounded theory methodology. Participants: SDMs for children enrolled into the SQUEEZE pilot trial. Sample size: Up to 25 SDMs. Qualitative methodology: SDMs will be invited to participate in the qualitative ethics study. Interviews with consenting SDMs will be conducted in person or by telephone, taped and professionally transcribed. Participants will be encouraged to elaborate on their experience of being asked to consent after the fact and how this process occurred. Analysis: Data gathering and analysis will be undertaken simultaneously. The investigators will collaborate in developing the coding scheme, and data will be coded using NVivo. Emerging themes will be identified. Ethics and dissemination This research represents a rare opportunity to interview parents/guardians of critically ill children enrolled into a resuscitation trial without their knowledge or prior consent. Findings will inform implementation of the exception to consent process in the planned definitive SQUEEZE trial and support development of evidence-based ethics guidelines. PMID:27625066

Industry and Patient Perspectives on Child Participation in Clinical Trials: The Pediatric Assent Initiative Survey Report.

PubMed

Lombardi, Donald; Squires, Liza; Sjostedt, Philip; Eichler, Irmgard; Turner, Mark A; Thompson, Charles

2018-01-01

Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment-allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials. Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations' experience and policies regarding pediatric assent. Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients. An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients.

Preconditioning Shields Against Vascular Events in Surgery (SAVES), a multicentre feasibility trial of preconditioning against adverse events in major vascular surgery: study protocol for a randomised control trial.

PubMed

Healy, Donagh; Clarke-Moloney, Mary; Gaughan, Brendan; O'Daly, Siobhan; Hausenloy, Derek; Sharif, Faisal; Newell, John; O'Donnell, Martin; Grace, Pierce; Forbes, John F; Cullen, Walter; Kavanagh, Eamon; Burke, Paul; Cross, Simon; Dowdall, Joseph; McMonagle, Morgan; Fulton, Greg; Manning, Brian J; Kheirelseid, Elrasheid A H; Leahy, Austin; Moneley, Daragh; Naughton, Peter; Boyle, Emily; McHugh, Seamus; Madhaven, Prakash; O'Neill, Sean; Martin, Zenia; Courtney, Donal; Tubassam, Muhammed; Sultan, Sherif; McCartan, Damian; Medani, Mekki; Walsh, Stewart

2015-04-23

Patients undergoing vascular surgery procedures constitute a 'high-risk' group. Fatal and disabling perioperative complications are common. Complications arise via multiple aetiological pathways. This mechanistic redundancy limits techniques to reduce complications that target individual mechanisms, for example, anti-platelet agents. Remote ischaemic preconditioning (RIPC) induces a protective phenotype in at-risk tissue, conferring protection against ischaemia-reperfusion injury regardless of the trigger. RIPC is induced by repeated periods of upper limb ischaemia-reperfusion produced using a blood pressure cuff. RIPC confers some protection against cardiac and renal injury during major vascular surgery in proof-of-concept trials. Similar trials suggest benefit during cardiac surgery. Several uncertainties remain in advance of a full-scale trial to evaluate clinical efficacy. We propose a feasibility trial to fully evaluate arm-induced RIPC's ability to confer protection in major vascular surgery, assess the incidence of a proposed composite primary efficacy endpoint and evaluate the intervention's acceptability to patients and staff. Four hundred major vascular surgery patients in five Irish vascular centres will be randomised (stratified for centre and procedure) to undergo RIPC or not immediately before surgery. RIPC will be induced using a blood pressure cuff with four cycles of 5 minutes of ischaemia followed by 5 minutes of reperfusion immediately before the start of operations. There is no sham intervention. Participants will undergo serum troponin measurements pre-operatively and 1, 2, and 3 days post-operatively. Participants will undergo 12-lead electrocardiograms pre-operatively and on the second post-operative day. Predefined complications within one year of surgery will be recorded. Patient and staff experiences will be explored using qualitative techniques. The primary outcome measure is the proportion of patients who develop elevated serum troponin levels in the first 3 days post-operatively. Secondary outcome measures include length of hospital and critical care stay, unplanned critical care admissions, death, myocardial infarction, stroke, mesenteric ischaemia and need for renal replacement therapy (within 30 days of surgery). RIPC is novel intervention with the potential to significantly improve perioperative outcomes. This trial will provide the first evaluation of RIPC's ability to reduce adverse clinical events following major vascular surgery. www.clinicaltrials.gov NCT02097186 Date Registered: 24 March 2014.

Voting for image scoring and assessment (VISA)--theory and application of a 2 + 1 reader algorithm to improve accuracy of imaging endpoints in clinical trials.

PubMed

Gottlieb, Klaus; Hussain, Fez

2015-02-19

Independent central reading or off-site reading of imaging endpoints is increasingly used in clinical trials. Clinician-reported outcomes, such as endoscopic disease activity scores, have been shown to be subject to bias and random error. Central reading attempts to limit bias and improve accuracy of the assessment, two factors that are critical to trial success. Whether one central reader is sufficient and how to best integrate the input of more than one central reader into one output measure, is currently not known.In this concept paper we develop the theoretical foundations of a reading algorithm that can achieve both objectives without jeopardizing operational efficiency We examine the role of expert versus competent reader, frame scoring of imaging as a classification task, and propose a voting algorithm (VISA: Voting for Image Scoring and Assessment) as the most appropriate solution which could also be used to operationally define imaging gold standards. We propose two image readers plus an optional third reader in cases of disagreement (2 + 1) for ordinary scoring tasks. We argue that it is critical in trials with endoscopically determined endpoints to include the score determined by the site reader, at least in endoscopy clinical trials. Juries with more than 3 readers could define a reference standard that would allow a transition from measuring reader agreement to measuring reader accuracy. We support VISA by applying concepts from engineering (triple-modular redundancy) and voting theory (Condorcet's jury theorem) and illustrate our points with examples from inflammatory bowel disease trials, specifically, the endoscopy component of the Mayo Clinic Score of ulcerative colitis disease activity. Detailed flow-diagrams (pseudo-code) are provided that can inform program design.The VISA "2 + 1" reading algorithm, based on voting, can translate individual reader scores into a final score in a fashion that is both mathematically sound (by avoiding averaging of ordinal data) and in a manner that is consistent with the scoring task at hand (based on decisions about the presence or absence of features, a subjective classification task). While the VISA 2 + 1 algorithm is currently being used in clinical trials, empirical data of its performance have not yet been reported.

An official American Thoracic Society research statement: comparative effectiveness research in pulmonary, critical care, and sleep medicine.

PubMed

Carson, Shannon S; Goss, Christopher H; Patel, Sanjay R; Anzueto, Antonio; Au, David H; Elborn, Stuart; Gerald, Joe K; Gerald, Lynn B; Kahn, Jeremy M; Malhotra, Atul; Mularski, Richard A; Riekert, Kristin A; Rubenfeld, Gordon D; Weaver, Terri E; Krishnan, Jerry A

2013-11-15

Comparative effectiveness research (CER) is intended to inform decision making in clinical practice, and is central to patient-centered outcomes research (PCOR). To summarize key aspects of CER definitions and provide examples highlighting the complementary nature of efficacy and CER studies in pulmonary, critical care, and sleep medicine. An ad hoc working group of the American Thoracic Society with experience in clinical trials, health services research, quality improvement, and behavioral sciences in pulmonary, critical care, and sleep medicine was convened. The group used an iterative consensus process, including a review by American Thoracic Society committees and assemblies. The traditional efficacy paradigm relies on clinical trials with high internal validity to evaluate interventions in narrowly defined populations and in research settings. Efficacy studies address the question, "Can it work in optimal conditions?" The CER paradigm employs a wide range of study designs to understand the effects of interventions in clinical settings. CER studies address the question, "Does it work in practice?" The results of efficacy and CER studies may or may not agree. CER incorporates many attributes of outcomes research and health services research, while placing greater emphasis on meeting the expressed needs of nonresearcher stakeholders (e.g., patients, clinicians, and others). CER complements traditional efficacy research by placing greater emphasis on the effects of interventions in practice, and developing evidence to address the needs of the many stakeholders involved in health care decisions. Stakeholder engagement is an important component of CER.

The Canadian critical care nutrition guidelines in 2013: an update on current recommendations and implementation strategies.

PubMed

Dhaliwal, Rupinder; Cahill, Naomi; Lemieux, Margot; Heyland, Daren K

2014-02-01

Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioners and patient decisions about appropriate healthcare for specific clinical circumstances, and are designed to minimize practice variation, improve costs, and improve clinical outcomes. The Canadian Critical Care Practice Guidelines (CCPGs) were first published in 2003 and most recently updated in 2013. A total of 68 new randomized controlled trials were identified since the last version in 2009, 50 of them published between 2009 and 2013. The remaining articles were trials published before 2009 but were not identified in previous iterations of the CCPGs. For clinical practice guidelines to be useful to practitioners, they need to be up-to-date and be reflective of the current body of evidence. Herein we describe the process by which the CCPGs were updated. This process resulted in 10 new sections or clinical topics. Of the old clinical topics, 3 recommendations were upgraded, 4 were downgraded, and 27 remained the same. To influence decision making at the bedside, these updated guidelines need to be accompanied by active guideline implementation strategies. Optimal implementation strategies should be guided by local contextual factors including barriers and facilitators to best practice recommendations. Moreover, evaluating and monitoring performance, such as participating in the International Nutrition Survey of practice, should be part of any intensive care unit's performance improvement strategy. The active implementation of the updated CCPGs may lead to better nutrition care and improved patient outcomes in the critical care setting.

A prospective randomized trial of tapered-cuff endotracheal tubes with intermittent subglottic suctioning in preventing ventilator-associated pneumonia in critically ill patients.

PubMed

Mahmoodpoor, Ata; Hamishehkar, Hadi; Hamidi, Masoud; Shadvar, Kamran; Sanaie, Sarvin; Golzari, Samad Ej; Khan, Zahid Hussain; Nader, Nader D

2017-04-01

Endotracheal tube placement is necessary for the control of the airway in patients who are mechanically ventilated. However, prolonged duration of endotracheal tube placement contributes to the development of ventilator-associated pneumonias (VAPs). The aim of this study was to evaluate whether subglottic suctioning using TaperGuard EVAC tubes was effective in decreasing the frequency of VAP. A total of 276 mechanically ventilated patients for more than 72 hours were randomly assigned to group E (EVAC tube) and group C (conventional tube). All patients received routine care including VAP prevention measures during their intensive care unit stay. In group E, subglottic suctioning was performed every 6 hours. Outcome variables included incidence VAP, intensive care unit length of stay, and mortality. Frequency of intraluminal suction, mechanical ventilation-free days, reintubation, the ratio of arterial oxygen partial pressure to fractional inspired oxygen and mortality rate were similar between the 2 groups (P > .05). The mean cuff pressure in group E was significantly less than that in group C (P < .001). Ventilator-associated pneumonia was significantly less in group E compared with group C (P = .015). The use of intermittent subglottic secretion suctioning was associated with a significant decrease in the incidence of the VAP in critically ill patients. However, larger multicenter trials are required to arrive at a concrete decision on routine usage of TaperGuard tubes in critical care settings. Published by Elsevier Inc.

Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle.

PubMed

Liu, F; Ferreira, E; Porter, R M; Glatt, V; Schinhan, M; Shen, Z; Randolph, M A; Kirker-Head, C A; Wehling, C; Vrahas, M S; Evans, C H; Wells, J W

2015-09-21

Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.

Lower trial participation by culturally and linguistically diverse (CALD) cancer patients is largely due to language barriers.

PubMed

Smith, Allan 'Ben'; Agar, Meera; Delaney, Geoff; Descallar, Joseph; Dobell-Brown, Kelsey; Grand, Melissa; Aung, Jennifer; Patel, Pinky; Kaadan, Nasreen; Girgis, Afaf

2018-02-01

Clinical trials play a critical role in advancing cancer care, but international research shows that few cancer patients, particularly culturally and linguistically diverse (CALD) patients, participate in trials. This limits generalizability of trial results and increases health disparities. This study aimed to establish rates and correlates of trial participation among CALD patients in South Western Sydney Local Health District (SWSLHD), a highly culturally diverse area. Data from all cancer patients diagnosed and/or treated in SWSLHD from January 2006 to July 2016 were analyzed retrospectively. The primary outcome was trial enrolment among patients born in non-English speaking countries (CALD) versus English speaking countries (non-CALD). Multivariable logistic regression evaluated CALD status as a predictor of trial participation. Moderators of trial participation by the different CALD groups, namely those whose preferred language was English (CALD-PLE) or was not English (CALD-PLNE), were examined by testing interactions between CALD status and other demographic and clinical variables. A total of 19 453 patients were analyzed (54.9% non-CALD, 16.5% CALD-PLE, 18.5% CALD-PLNE). Overall, 7.4% of patients were enrolled in a trial. Trial participation was significantly lower in CALD patients than non-CALD patients (5.7% vs 8.4%; odds ratio [OR] = 0.80; 95% confidence interval [CI], 0.69-0.91; P = 0.001). CALD-PLNE patients were less likely to participate in trials than non-CALD (OR = 0.45; 95% CI, 0.36-0.56; P < 0.0001) and CALD-PLE patients (OR = 0.53; 95% CI, 0.67-0.41; P < 0.0001). Limited English proficiency seems particularly unfavorable to trial participation. Development and evaluation of strategies to overcome language barriers (e.g. simplified and translated multimedia participant information materials) is needed. © 2017 John Wiley & Sons Australia, Ltd.

Implementing a complex rehabilitation intervention in a stroke trial: a qualitative process evaluation of AVERT.

PubMed

Luker, Julie A; Craig, Louise E; Bennett, Leanne; Ellery, Fiona; Langhorne, Peter; Wu, Olivia; Bernhardt, Julie

2016-05-10

The implementation of multidisciplinary stroke rehabilitation interventions is challenging, even when the intervention is evidence-based. Very little is known about the implementation of complex interventions in rehabilitation clinical trials. The aim of study was to better understand how the implementation of a rehabilitation intervention in a clinical trial within acute stroke units is experienced by the staff involved. This qualitative process evaluation was part of a large Phase III stroke rehabilitation trial (AVERT). A descriptive qualitative approach was used. We purposively sampled 53 allied health and nursing staff from 19 acute stroke units in Australia, New Zealand and Scotland. Semi-structured interviews were conducted by phone, voice-internet, or face to face. Digitally recorded interviews were transcribed and analysed by two researchers using rigorous thematic analysis. Our analysis uncovered ten important themes that provide insight into the challenges of implementing complex new rehabilitation practices within complex care settings, plus factors and strategies that assisted implementation. Themes were grouped into three main categories: staff experience of implementing the trial intervention, barriers to implementation, and overcoming the barriers. Participation in the trial was challenging but had personal rewards and improved teamwork at some sites. Over the years that the trial ran some staff perceived a change in usual care. Barriers to trial implementation at some sites included poor teamwork, inadequate staffing, various organisational barriers, staff attitudes and beliefs, and patient-related barriers. Participants described successful implementation strategies that were built on interdisciplinary teamwork, education and strong leadership to 'get staff on board', and developing different ways of working. The AVERT stroke rehabilitation trial required commitment to deliver an intervention that needed strong collaboration between nurses and physiotherapists and was different to current care models. This qualitative process evaluation contributes unique insights into factors that may be critical to successful trials teams, and as AVERT was a pragmatic trial, success factors to delivering complex intervention in clinical practice. AVERT registered with Australian New Zealand Clinical Trials Registry ACTRN12606000185561 .

Recent interview-based measures of competency to stand trial: a critical review augmented with research data.

PubMed

Rogers, R; Grandjean, N; Tillbrook, C E; Vitacco, M J; Sewell, K W

2001-01-01

Forensic experts are frequently asked to conduct competency-to-stand trial evaluations and address the substantive prongs propounded in Dusky v. United States (1960). In understanding its application to competency evaluations, alternative conceptualizations of Dusky are critically examined. With Dusky providing the conceptual framework, three interview-based competency measures are reviewed: the Georgia Court Competency Test (GCCT), the MacArthur Competence Assessment Tool-Criminal Adjudication (Mac-CAT-CA), and the Evaluation of Competency to Stand Trial-Revised (ECST-R). This review has a twin focus on reliability of each measure and its correspondence to Dusky prongs. The current review is augmented by new factor analytic data on the MacCAT-CA and ECST-R. The article concludes with specific recommendations for competency evaluations. Copyright 2001 John Wiley & Sons, Ltd.

Emerging pharmacologic treatment options for fragile X syndrome

PubMed Central

Schaefer, Tori L; Davenport, Matthew H; Erickson, Craig A

2015-01-01

Fragile X syndrome (FXS) is the most common single gene cause of intellectual disability and autism spectrum disorder. Caused by a silenced fragile X mental retardation 1 gene and the subsequent deficiency in fragile X mental retardation protein, patients with FXS experience a range of physical, behavioral, and intellectual debilitations. The FXS field, as a whole, has recently met with some challenges, as several targeted clinical trials with high expectations of success have failed to elucidate significant improvements in a variety of symptom domains. As new clinical trials in FXS are planned, there has been much discussion about the use of the commonly used clinical outcome measures, as well as study design considerations, patient stratification, and optimal age range for treatment. The evidence that modification of these drug targets and use of these failed compounds would prove to be efficacious in human clinical study were rooted in years of basic and translational research. There are questions arising as to the use of the mouse models for studying FXS treatment development. This issue is twofold: many of the symptom domains and molecular and biochemical changes assessed and indicative of efficacy in mouse model study are not easily amenable to clinical trials in people with FXS because of the intolerability of the testing paradigm or a lack of noninvasive techniques (prepulse inhibition, sensory hypersensitivity, startle reactivity, or electrophysiologic, biochemical, or structural changes in the brain); and capturing subtle yet meaningful changes in symptom domains such as sociability, anxiety, and hyperactivity in human FXS clinical trials is challenging with the currently used measures (typically parent/caregiver rating scales). Clinicians, researchers, and the pharmaceutical industry have all had to take a step back and critically evaluate the way we think about how to best optimize future investigations into pharmacologic FXS treatments. As new clinical trials are coming down the drug discovery pipeline, it is clear that the field is moving in a direction that values the development of molecular biomarkers, less subjective quantitative measures of symptom improvement, and rating scales developed specifically for use in FXS in conjunction with drug safety. While summarizing preclinical evidence, where applicable, and discussing challenges in FXS treatment development, this review details both completed clinical trials for the targeted and symptomatic treatment of FXS and introduces novel projects on the cusp of clinical trial investigation. PMID:25897255

Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation.

PubMed

Cortjens, Bart; Royakkers, Annick A N M; Determann, Rogier M; van Suijlen, Jeroen D E; Kamphuis, Stephan S; Foppen, Jannetje; de Boer, Anita; Wieland, Cathrien W; Spronk, Peter E; Schultz, Marcus J; Bouman, Catherine S C

2012-06-01

Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation. Copyright © 2012 Elsevier Inc. All rights reserved.

Motivational Interviewing and Medication Review in Coronary Heart Disease (MIMeRiC): Intervention Development and Protocol for the Process Evaluation.

PubMed

Östbring, Malin Johansson; Eriksson, Tommy; Petersson, Göran; Hellström, Lina

2018-01-30

Trials of complex interventions are often criticized for being difficult to interpret because the effects of apparently similar interventions vary across studies dependent on context, targeted groups, and the delivery of the intervention. The Motivational Interviewing and Medication Review in Coronary heart disease (MIMeRiC) trial is a randomized controlled trial (RCT) of an intervention aimed at improving pharmacological secondary prevention. Guidelines for the development and evaluation of complex interventions have recently highlighted the need for better reporting of the development of interventions, including descriptions of how the intervention is assumed to work, how this theory informed the process evaluation, and how the process evaluation relates to the outcome evaluation. This paper aims to describe how the intervention was designed and developed. The aim of the process evaluation is to better understand how and why the intervention in the MIMeRiC trial was effective or not effective. The research questions for evaluating the process are based on the conceptual model of change processes assumed in the intervention and will be analyzed by qualitative and quantitative methods. Quantitative data are used to evaluate the medication review in terms of drug-related problems, to describe how patients' beliefs about medicines are affected by the intervention, and to evaluate the quality of motivational interviewing. Qualitative data will be used to analyze whether patients experienced the intervention as intended, how cardiologists experienced the collaboration and intervention, and how the intervention affected patients' overall experience of care after coronary heart disease. The development and piloting of the intervention are described in relation to the theoretical framework. Data for the process evaluation will be collected until March 2018. Some process evaluation questions will be analyzed before, and others will be analyzed after the outcomes of the MIMeRiC RCT are known. This paper describes the framework for the design of the intervention tested in the MIMeRiC trial, development of the intervention from the pilot stage to the complete trial intervention, and the framework and methods for the process evaluation. Providing the protocol of the process evaluation allows prespecification of the processes that will be evaluated, because we hypothesize that they will determine the outcomes of the MIMeRiC trial. This protocol also constitutes a contribution to the new field of process evaluations as made explicit in health services research and clinical trials of complex interventions. ©Malin Johansson Östbring, Tommy Eriksson, Göran Petersson, Lina Hellström. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 30.01.2018.

Protocols and Hospital Mortality in Critically ill Patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study

PubMed Central

Sevransky, Jonathan E.; Checkley, William; Herrera, Phabiola; Pickering, Brian W.; Barr, Juliana; Brown, Samuel M; Chang, Steven Y; Chong, David; Kaufman, David; Fremont, Richard D; Girard, Timothy D; Hoag, Jeffrey; Johnson, Steven B; Kerlin, Mehta P; Liebler, Janice; O'Brien, James; O'Keefe, Terence; Park, Pauline K; Pastores, Stephen M; Patil, Namrata; Pietropaoli, Anthony P; Putman, Maryann; Rice, Todd W.; Rotello, Leo; Siner, Jonathan; Sajid, Sahul; Murphy, David J; Martin, Greg S

2015-01-01

Objective Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized intensive care units have superior patient outcomes compared with less highly protocolized intensive care units. Design Observational study in which participating intensive care units completed a general assessment and enrolled new patients one day each week. Setting and Patients 6179 critically ill patients across 59 intensive care units in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study Interventions: None Measurements and Main Results The primary exposure was the number of intensive care unit protocols; the primary outcome was hospital mortality. 5809 participants were followed prospectively and 5454 patients in 57 intensive care units had complete outcome data. The median number of protocols per intensive care unit was 19 (IQR 15 to 21.5). In single variable analyses, there were no differences in intensive care unit and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in intensive care units with a high vs. low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p=0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between intensive care units with high vs. low numbers of protocols for lung protective ventilation in ARDS (47% vs. 52%; p=0.28) and for spontaneous breathing trials (55% vs. 51%; p=0.27). Conclusions Clinical protocols are highly prevalent in United States intensive care units. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality. PMID:26110488

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

PubMed

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

2016-07-01

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

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

PubMed

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

2016-06-01

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

vlPFC-vmPFC-Amygdala Interactions Underlie Age-Related Differences in Cognitive Regulation of Emotion.

PubMed

Silvers, Jennifer A; Insel, Catherine; Powers, Alisa; Franz, Peter; Helion, Chelsea; Martin, Rebecca E; Weber, Jochen; Mischel, Walter; Casey, B J; Ochsner, Kevin N

2017-07-01

Emotion regulation is a critical life skill that develops throughout childhood and adolescence. Despite this development in emotional processes, little is known about how the underlying brain systems develop with age. This study examined emotion regulation in 112 individuals (aged 6-23 years) as they viewed aversive and neutral images using a reappraisal task. On "reappraisal" trials, participants were instructed to view the images as distant, a strategy that has been previously shown to reduce negative affect. On "reactivity" trials, participants were instructed to view the images without regulating emotions to assess baseline emotional responding. During reappraisal, age predicted less negative affect, reduced amygdala responses and inverse coupling between the ventromedial prefrontal cortex (vmPFC) and amygdala. Moreover, left ventrolateral prefrontal (vlPFC) recruitment mediated the relationship between increasing age and diminishing amygdala responses. This negative vlPFC-amygdala association was stronger for individuals with inverse coupling between the amygdala and vmPFC. These data provide evidence that vmPFC-amygdala connectivity facilitates vlPFC-related amygdala modulation across development. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Nutritional support for critically ill children.

PubMed

Joffe, Ari; Anton, Natalie; Lequier, Laurance; Vandermeer, Ben; Tjosvold, Lisa; Larsen, Bodil; Hartling, Lisa

2016-05-27

Nutritional support in the critically ill child has not been well investigated and is a controversial topic within paediatric intensive care. There are no clear guidelines as to the best form or timing of nutrition in critically ill infants and children. This is an update of a review that was originally published in 2009. . The objective of this review was to assess the impact of enteral and parenteral nutrition given in the first week of illness on clinically important outcomes in critically ill children. There were two primary hypotheses:1. the mortality rate of critically ill children fed enterally or parenterally is different to that of children who are given no nutrition;2. the mortality rate of critically ill children fed enterally is different to that of children fed parenterally.We planned to conduct subgroup analyses, pending available data, to examine whether the treatment effect was altered by:a. age (infants less than one year versus children greater than or equal to one year old);b. type of patient (medical, where purpose of admission to intensive care unit (ICU) is for medical illness (without surgical intervention immediately prior to admission), versus surgical, where purpose of admission to ICU is for postoperative care or care after trauma).We also proposed the following secondary hypotheses (a priori), pending other clinical trials becoming available, to examine nutrition more distinctly:3. the mortality rate is different in children who are given enteral nutrition alone versus enteral and parenteral combined;4. the mortality rate is different in children who are given both enteral feeds and parenteral nutrition versus no nutrition. In this updated review we searched: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2); Ovid MEDLINE (1966 to February 2016); Ovid EMBASE (1988 to February 2016); OVID Evidence-Based Medicine Reviews; ISI Web of Science - Science Citation Index Expanded (1965 to February 2016); WebSPIRS Biological Abstracts (1969 to February 2016); and WebSPIRS CAB Abstracts (1972 to February 2016). We also searched trial registries, reviewed reference lists of all potentially relevant studies, handsearched relevant conference proceedings, and contacted experts in the area and manufacturers of enteral and parenteral nutrition products. We did not limit the search by language or publication status. We included studies if they were randomized controlled trials; involved paediatric patients, aged one day to 18 years of age, who were cared for in a paediatric intensive care unit setting (PICU) and had received nutrition within the first seven days of admission; and reported data for at least one of the pre-specified outcomes (30-day or PICU mortality; length of stay in PICU or hospital; number of ventilator days; and morbid complications, such as nosocomial infections). We excluded studies if they only reported nutritional outcomes, quality of life assessments, or economic implications. Furthermore, we did not address other areas of paediatric nutrition, such as immunonutrition and different routes of delivering enteral nutrition, in this review. Two authors independently screened the searches, applied the inclusion criteria, and performed 'Risk of bias' assessments. We resolved discrepancies through discussion and consensus. One author extracted data and a second checked data for accuracy and completeness. We graded the evidence based on the following domains: study limitations, consistency of effect, imprecision, indirectness, and publication bias. We identified only one trial as relevant. Seventy-seven children in intensive care with burns involving more than 25% of the total body surface area were randomized to either enteral nutrition within 24 hours or after at least 48 hours. No statistically significant differences were observed for mortality, sepsis, ventilator days, length of stay, unexpected adverse events, resting energy expenditure, nitrogen balance, or albumin levels. We assessed the trial as having unclear risk of bias. We consider the quality of the evidence to be very low due to there being only one small trial. In the most recent search update we identified a protocol for a relevant randomized controlled trial examining the impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients; no results have been published. There was only one randomized trial relevant to the review question. Research is urgently needed to identify best practices regarding the timing and forms of nutrition for critically ill infants and children.

Forging a critical alliance: Addressing the research needs of the United States critical illness and injury community.

PubMed

Cobb, J Perren; Ognibene, Frederick P; Ingbar, David H; Mann, Henry J; Hoyt, David B; Angus, Derek C; Thomas, Alvin V; Danner, Robert L; Suffredini, Anthony F

2009-12-01

Discuss the research needs of the critical illness and injury communities in the United States. Workshop session held during the 5 National Institutes of Health Symposium on the Functional Genomics of Critical Illness and Injury (November 15, 2007). The current clinical research infrastructure misses opportunities for synergy and does not address many important needs. In addition, it remains challenging to rapidly and properly implement system-wide changes based upon reproducible evidence from clinical research. Author presentations, panel discussion, attendee feedback. The critical illness and injury research communities seek better communication and interaction, both of which will improve the breadth and quality of acute care research. Success in meeting these needs should come from cooperative and strategic actions that favor collaboration, standardization of protocols, and strong leadership. An alliance framed on common goals will foster collaboration among experts to better promote clinical trials within the critically ill or injured patient population. The U.S. Critical Illness and Injury Trials Group was funded to create a clinical research framework that can reduce the barriers to investigation using an investigator-initiated, evidence-driven, inclusive approach that has proven successful elsewhere. This alliance will provide an annual venue for systematic review and strategic planning that will include framing the research agenda, raising awareness for the value of acute care research, gathering and promoting best practices, and bolstering the critical care workforce.

Creating a Reinforcement Learning Controller for Functional Electrical Stimulation of a Human Arm*

PubMed Central

Thomas, Philip S.; Branicky, Michael; van den Bogert, Antonie; Jagodnik, Kathleen

2010-01-01

Clinical tests have shown that the dynamics of a human arm, controlled using Functional Electrical Stimulation (FES), can vary significantly between and during trials. In this paper, we study the application of Reinforcement Learning to create a controller that can adapt to these changing dynamics of a human arm. Development and tests were done in simulation using a two-dimensional arm model and Hill-based muscle dynamics. An actor-critic architecture is used with artificial neural networks for both the actor and the critic. We begin by training it using a Proportional Derivative (PD) controller as a supervisor. We then make clinically relevant changes to the dynamics of the arm and test the actor-critic’s ability to adapt without supervision in a reasonable number of episodes. PMID:22081795

Neosphincter surgery for fecal incontinence: a critical and unbiased review of the relevant literature.

PubMed

Belyaev, Orlin; Müller, Christophe; Uhl, Waldemar

2006-01-01

Up until about 15 years ago the only realistic option for end-stage fecal incontinence was the creation of a permanent stoma. There have since been several developments. Dynamic graciloplasty (DGP) and artificial bowel sphincter (ABS) are well-established surgical techniques, which offer the patient a chance for continence restoration and improved quality of life; however, they are unfortunately associated with high morbidity and low success rates. Several trials have been done in an attempt to clarify the advantages and disadvantages of these methods and define their place in the second-line treatment of severe, refractory fecal incontinence. This review presents a critical and unbiased overview of the current status of neosphincter surgery according to the available data in the world literature.

Teacher Utilization of Instructional Consultation Teams

ERIC Educational Resources Information Center

Berger, Jill; Yiu, Ho Lam; Nelson, Deborah; Vaganek, Megan; Rosenfield, Sylvia; Gravois, Todd; Gottfredson, Gary; Vu, Phuong; Shanahan, Kate; Hong, Vanessa

2014-01-01

Data regarding intervention utilization among the target population are critical to interpret evidence from efficacy trials for school-based interventions. When use of the intervention is voluntary, intervention diffusion becomes a particularly critical variable. We examined the use of Instructional Consultation Teams (IC Teams), a voluntary…

Evidence to Support Tooth Brushing in Critically Ill Patients

PubMed Central

Ames, Nancy J.

2012-01-01

Tooth brushing in critically ill patients has been advocated by many as a standard of care despite the limited evidence to support this practice. Attention has been focused on oral care as the evidence accumulates to support an association between the bacteria in the oral microbiome and those respiratory pathogens that cause pneumonia. It is plausible to assume that respiratory pathogens originating in the oral cavity are aspirated into the lungs, causing infection. A recent study of the effects of a powered toothbrush on the incidence of ventilator-associated pneumonia was stopped early because of a lack of effect in the treatment group. This review summarizes the evidence that supports the effectiveness of tooth brushing in critically ill adults and children receiving mechanical ventilation. Possible reasons for the lack of benefit of tooth brushing demonstrated in clinical trials are discussed. Recommendations for future trials in critically ill patients are suggested. With increased emphasis being placed on oral care, the evidence that supports this intervention must be evaluated carefully. PMID:21532045

Evidence to support tooth brushing in critically ill patients.

PubMed

Ames, Nancy J

2011-05-01

Tooth brushing in critically ill patients has been advocated by many as a standard of care despite the limited evidence to support this practice. Attention has been focused on oral care as the evidence accumulates to support an association between the bacteria in the oral microbiome and those respiratory pathogens that cause pneumonia. It is plausible to assume that respiratory pathogens originating in the oral cavity are aspirated into the lungs, causing infection. A recent study of the effects of a powered toothbrush on the incidence of ventilator-associated pneumonia was stopped early because of a lack of effect in the treatment group. This review summarizes the evidence that supports the effectiveness of tooth brushing in critically ill adults and children receiving mechanical ventilation. Possible reasons for the lack of benefit of tooth brushing demonstrated in clinical trials are discussed. Recommendations for future trials in critically ill patients are suggested. With increased emphasis being placed on oral care, the evidence that supports this intervention must be evaluated carefully.

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team

PubMed Central

Arnerić, Stephen P.; Batrla-Utermann, Richard; Beckett, Laurel; Bittner, Tobias; Blennow, Kaj; Carter, Leslie; Dean, Robert; Engelborghs, Sebastiaan; Genius, Just; Gordon, Mark Forrest; Hitchcock, Janice; Kaplow, June; Luthman, Johan; Meibach, Richard; Raunig, David; Romero, Klaus; Samtani, Mahesh N.; Savage, Mary; Shaw, Leslie; Stephenson, Diane; Umek, Robert M.; Vanderstichele, Hugo; Willis, Brian; Yule, Susan

2016-01-01

Abstract Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development. PMID:27662307

Mitochondrial Replacement Therapy: Halachic Considerations for Enrolling in an Experimental Clinical Trial

PubMed Central

Tendler, Rabbi Moshe D.; Loike, John D.

2015-01-01

The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal. PMID:26241230

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma.

PubMed

Macha, Muzafar A; Batra, Surinder K; Ganti, Apar Kishor

2013-01-01

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

PubMed Central

Macha, Muzafar A; Batra, Surinder K; Ganti, Apar Kishor

2013-01-01

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC. PMID:23940421

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review.

PubMed

Fowler, Christopher J

2015-01-01

The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

Thermo-mechanical evaluation of carbon-carbon primary structure for SSTO vehicles

NASA Astrophysics Data System (ADS)

Croop, Harold C.; Lowndes, Holland B.; Hahn, Steven E.; Barthel, Chris A.

1998-01-01

An advanced development program to demonstrate carbon-carbon composite structure for use as primary load carrying structure has entered the experimental validation phase. The component being evaluated is a wing torque box section for a single-stage-to-orbit (SSTO) vehicle. The validation or demonstration component features an advanced carbon-carbon design incorporating 3D woven graphite preforms, integral spars, oxidation inhibited matrix, chemical vapor deposited (CVD) oxidation protection coating, and ceramic matrix composite fasteners. The validation component represents the culmination of a four phase design and fabrication development effort. Extensive developmental testing was performed to verify material properties and integrity of basic design features before committing to fabrication of the full scale box. The wing box component is now being set up for testing in the Air Force Research Laboratory Structural Test Facility at Wright-Patterson Air Force Base, Ohio. One of the important developmental tests performed in support of the design and planned testing of the full scale box was the fabrication and test of a skin/spar trial subcomponent. The trial subcomponent incorporated critical features of the full scale wing box design. This paper discusses the results of the trial subcomponent test which served as a pathfinder for the upcoming full scale box test.

Emerging Drugs and Vaccines for Candidemia

PubMed Central

Moriyama, Brad; Gordon, Lori A.; McCarthy, Matthew; Henning, Stacey A.; Walsh, Thomas J.; Penzak, Scott R.

2014-01-01

Summary Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus, and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords “Candida” or “Candidemia” or “Candidiasis” and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarized. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161, and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. PMID:25294098

Prototype Packaged Databases and Software in Health

PubMed Central

Gardenier, Turkan K.

1980-01-01

This paper describes the recent demand for packaged databases and software for health applications in light of developments in mini-and micro-computer technology. Specific features for defining prospective user groups are discussed; criticisms generated for large-scale epidemiological data use as a means of replacing clinical trials and associated controls are posed to the reader. The available collaborative efforts for access and analysis of jointly structured health data are stressed, with recommendations for new analytical techniques specifically geared to monitoring data such as the CTSS (Cumulative Transitional State Score) generated for tacking ongoing patient status over time in clinical trials. Examples of graphic display are given from the Domestic Information Display System (DIDS) which is a collaborative multi-agency effort to computerize and make accessible user-specified U.S. and local maps relating to health, environment, socio-economic and energy data.

Year in review 2005: Critical Care – nephrology

PubMed Central

Ricci, Zaccaria; Ronco, Claudio

2006-01-01

We summarize original research in the field of critical care nephrology accepted or published in 2005 in Critical Care and, when considered relevant or directly linked to this research, in other journals. The articles have been grouped into four categories to facilitate a rapid overview. First, physiopathology, epidemiology and prognosis of acute renal failure (ARF): an extensive review and some observational studies have been performed with the aim of describing aspects of ARF physiopathology, precise epidemiology and long-term outcomes. Second, several authors have performed clinical trials utilizing a potential nephro-protective drug, fenoldopam, with different results. Third, the issue of continuous renal replacement therapies dose has been addressed in a small prospective study and a large observational trial. And fourth, alternative indications to extracorporeal treatment of ARF and systemic inflammatory response syndrome have been explored by three original clinical studies. PMID:16919174

Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

PubMed

Carrera, Gemma; Garcia-Albeniz, Xabier; Ayuso, Juan Ramón; Aparicio, Jorge; Castells, Antoni; Codony-Servat, Jordi; Feliu, Jaime; Fuster, David; Gallego, Rosa; Pagés, Mario; Torres, Ferran; Maurel, Joan

2011-05-01

Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

An analysis of current pharmaceutical industry practices for making clinical trial results publicly accessible.

PubMed

Viereck, Christopher; Boudes, Pol

2009-07-01

We compared the clinical trial transparency practices of US/European pharma by analyzing the publicly-accessible clinical trial results databases of major drugs (doripenem, varenicline, lapatinib, zoledronic acid, adalimumab, insulin glargine, raltegravir, gefitinib). We evaluated their accessibility and utility from the perspective of the lay public. We included databases on company websites, http://www.clinicalstudyresults.org, http://www.clinicaltrials.gov and http://clinicaltrials.ifpma.org. Only 2 of 8 company homepages provide a direct link to the results. While the use of common terms on company search engines led to results for 5 of the 8 drugs following 2-4 clicks, no logical pathway was identified. The number of clinical trials in the databases was inconsistent: 0 for doripenem to 45 for insulin glargine. Results from all phases of clinical development were provided for 2 (insulin glargine and gefitinib) of the 8 drugs. Analyses of phase III reports revealed that most critical elements of the International Conference of Harmonization E3 Structure and Content of Synopses for Clinical Trial Reports were provided for 2 (varenicline, lapatinib) of the 8 drugs. For adalimumab and zoledronic acid, only citations were provided, which the lay public would be unable to access. None of the clinical trial reports was written in lay language. User-friendly support, when provided, was of marginal benefit. Only 1 of the databases (gefitinib) permitted the user to find the most recently updated reports. None of the glossaries included explanations for adverse events or statistical methodology. In conclusion, our study indicates that the public faces significant hurdles in finding and understanding clinical trial results databases.

Figures in clinical trial reports: current practice & scope for improvement

PubMed Central

Pocock, Stuart J; Travison, Thomas G; Wruck, Lisa M

2007-01-01

Background Most clinical trial publications include figures, but there is little guidance on what results should be displayed as figures and how. Purpose To evaluate the current use of figures in Trial reports, and to make constructive suggestions for future practice. Methods We surveyed all 77 reports of randomised controlled trials in five general medical journals during November 2006 to January 2007. The numbers and types of figures were determined, and then each Figure was assessed for its style, content, clarity and suitability. As a consequence, guidelines are developed for presenting figures, both in general and for each specific common type of Figure. Results Most trial reports contained one to three figures, mean 2.3 per article. The four main types were flow diagram, Kaplan Meier plot, Forest plot (for subgroup analyses) and repeated measures over time: these accounted for 92% of all figures published. For each type of figure there is a considerable diversity of practice in both style and content which we illustrate with selected examples of both good and bad practice. Some pointers on what to do, and what to avoid, are derived from our critical evaluation of these articles' use of figures. Conclusion There is considerable scope for authors to improve their use of figures in clinical trial reports, as regards which figures to choose, their style of presentation and labelling, and their specific content. Particular improvements are needed for the four main types of figures commonly used. PMID:18021449

Using the 'Social Marketing Mix Framework' to explore recruitment barriers and facilitators in palliative care randomised controlled trials? A narrative synthesis review.

PubMed

Dunleavy, Lesley; Walshe, Catherine; Oriani, Anna; Preston, Nancy

2018-05-01

Effective recruitment to randomised controlled trials is critically important for a robust, trustworthy evidence base in palliative care. Many trials fail to achieve recruitment targets, but the reasons for this are poorly understood. Understanding barriers and facilitators is a critical step in designing optimal recruitment strategies. To identify, explore and synthesise knowledge about recruitment barriers and facilitators in palliative care trials using the '6 Ps' of the 'Social Marketing Mix Framework'. A systematic review with narrative synthesis. Medline, CINAHL, PsycINFO and Embase databases (from January 1990 to early October 2016) were searched. Papers included the following: interventional and qualitative studies addressing recruitment, palliative care randomised controlled trial papers or reports containing narrative observations about the barriers, facilitators or strategies to increase recruitment. A total of 48 papers met the inclusion criteria. Uninterested participants (Product), burden of illness (Price) and 'identifying eligible participants' were barriers. Careful messaging and the use of scripts/role play (Promotion) were recommended. The need for intensive resources and gatekeeping by professionals were barriers while having research staff on-site and lead clinician support (Working with Partners) was advocated. Most evidence is based on researchers' own reports of experiences of recruiting to trials rather than independent evaluation. The 'Social Marketing Mix Framework' can help guide researchers when planning and implementing their recruitment strategy but suggested strategies need to be tested within embedded clinical trials. The findings of this review are applicable to all palliative care research and not just randomised controlled trials.

Combining nutrition and exercise to optimize survival and recovery from critical illness: Conceptual and methodological issues.

PubMed

Heyland, Daren K; Stapleton, Renee D; Mourtzakis, Marina; Hough, Catherine L; Morris, Peter; Deutz, Nicolaas E; Colantuoni, Elizabeth; Day, Andrew; Prado, Carla M; Needham, Dale M

2016-10-01

Survivors of critical illness commonly experience neuromuscular abnormalities, including muscle weakness known as ICU-acquired weakness (ICU-AW). ICU-AW is associated with delayed weaning from mechanical ventilation, extended ICU and hospital stays, more healthcare-related hospital costs, a higher risk of death, and impaired physical functioning and quality of life in the months after ICU admission. These observations speak to the importance of developing new strategies to aid in the physical recovery of acute respiratory failure patients. We posit that to maintain optimal muscle mass, strength and physical function, the combination of nutrition and exercise may have the greatest impact on physical recovery of survivors of critical illness. Randomized trials testing this and related hypotheses are needed. We discussed key methodological issues and proposed a common evaluation framework to stimulate work in this area and standardize our approach to outcome assessments across future studies. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Goal neglect and knowledge chunking in the construction of novel behaviour☆

PubMed Central

Bhandari, Apoorva; Duncan, John

2014-01-01

Task complexity is critical in cognitive efficiency and fluid intelligence. To examine functional limits in task complexity, we examine the phenomenon of goal neglect, where participants with low fluid intelligence fail to follow task rules that they otherwise understand. Though neglect is known to increase with task complexity, here we show that – in contrast to previous accounts – the critical factor is not the total complexity of all task rules. Instead, when the space of task requirements can be divided into separate sub-parts, neglect is controlled by the complexity of each component part. The data also show that neglect develops and stabilizes over the first few performance trials, i.e. as instructions are first used to generate behaviour. In all complex behaviour, a critical process is combination of task events with retrieved task requirements to create focused attentional episodes dealing with each decision in turn. In large part, we suggest, fluid intelligence may reflect this process of converting complex requirements into effective attentional episodes. PMID:24141034

Critical analysis of submerged membrane sequencing batch reactor operating conditions.

PubMed

McAdam, Ewan; Judd, Simon J; Gildemeister, René; Drews, Anja; Kraume, Matthias

2005-10-01

To evaluate the Submerged Membrane Sequencing Batch Reactor process, several short-term studies were conducted to define critical flux, membrane aeration and intermittent filtration operation. Critical flux trials indicated that as mixed liquor suspended solids increased in concentration so would the propensity for membrane fouling. Consequently in order to characterise the impact of biomass concentration increase (that develops during permeate withdrawal) upon submerged microfiltration operation, two longer term studies were conducted, one with a falling hydraulic head and another with a continuous hydraulic head (as in membrane bio-reactors). Trans membrane pressure data was used to predict the maximum possible operating periods at 10 and 62 days for the falling hydraulic head and continuous hydraulic head respectively. Further analysis revealed that falling hydraulic head operation would require 21% more aeration to maintain a consistent crossflow velocity than continuous operation and would rely on pumping for full permeate withdrawal 80% earlier. This study concluded that further optimisation would be required to make this technology technically and economically viable.

Hypertonic Saline for the Treatment of Bronchiolitis in Infants and Young Children: A Critical Review of the Literature

PubMed Central

Baron, Jeffrey

2016-01-01

Bronchiolitis, an infection of the lower respiratory tract, is the leading cause of infant and child hospitalization in the United States. Therapeutic options for management of bronchiolitis are limited. Hypertonic saline inhalation therapy has been studied in numerous clinical trials with mixed results. In 2014, the American Academy of Pediatrics (AAP) published updated guidelines on the diagnosis and management of bronchiolitis, which include new recommendations on the use of hypertonic saline. We reviewed all published clinical trials mentioned in the 2014 AAP guidelines, as well as additional trials published since the guidelines, and critically evaluated each trial to determine efficacy, safety, and expectations of hypertonic saline inhalation therapy. A total of 2682 infants were studied over the course of 22 clinical trials. Nine trials were carried out in the outpatient/clinic/emergency department and 13 in the inpatient setting. We agree with the AAP guidelines regarding the recommendation to use nebulized hypertonic saline for infants hospitalized with bronchiolitis, with the expectation of reducing bronchiolitis scores and length of stay when it is expected to last more than 72 hours. However, we also believe there might be an advantage for hypertonic saline in reducing admission rates from the emergency department, based on close examination of the results of recent trials. This review also highlights important gaps in the available literature that need to be addressed in order to define the role of inhaled hypertonic saline therapy. PMID:26997926

The REFLECT statement: reporting guidelines for randomized controlled trials in livestock and food safety: explanation and elaboration.

PubMed

Sargeant, J M; O'Connor, A M; Gardner, I A; Dickson, J S; Torrence, M E; Dohoo, I R; Lefebvre, S L; Morley, P S; Ramirez, A; Snedeker, K

2010-03-01

Concerns about the completeness and accuracy of reporting of randomized clinical trials (RCTs) and the impact of poor reporting on decision-making have been documented in the medical field over the past several decades. Experience from RCTs in human medicine would suggest that failure to report critical trial features can be associated with biased estimated effect measures, and there is evidence to suggest similar biases occur in RCTs conducted in livestock populations. In response to these concerns, standardized guidelines for reporting RCTs were developed and implemented in human medicine. The Consolidated Standards of Reporting Trials (CONSORT) statement was first published in 1996 with a revised edition published in 2001. The CONSORT statement consists of a 22-item checklist for reporting a RCT and a flow diagram to follow the number of participants at each stage of a trial. An explanation and elaboration document not only defines and discusses the importance of each of the items, but also provides examples of how this information could be supplied in a publication. Differences between human and livestock populations necessitate modifications to the CONSORT statement to maximize its usefulness for RCTs involving livestock. These have been addressed in an extension of the CONSORT statement titled the REFLECT statement: Methods and processes of creating reporting guidelines for randomized control trials for livestock and food safety. The modifications made for livestock trials specifically addressed the common use of group housing and group allocation to intervention in livestock studies, the use of a deliberate challenge model in some trials, and common use of non-clinical outcomes, such as contamination with a foodborne pathogen. In addition, the REFLECT statement for RCTs in livestock populations proposed specific terms or further clarified terms as they pertained to livestock studies.

The REFLECT statement: reporting guidelines for Randomized Controlled Trials in livestock and food safety: explanation and elaboration.

PubMed

Sargeant, J M; O'Connor, A M; Gardner, I A; Dickson, J S; Torrence, M E

2010-03-01

Concerns about the completeness and accuracy of reporting of randomized clinical trials (RCTs) and the impact of poor reporting on decision making have been documented in the medical field over the past several decades. Experience from RCTs in human medicine would suggest that failure to report critical trial features can be associated with biased estimated effect measures, and there is evidence to suggest that similar biases occur in RCTs conducted in livestock populations. In response to these concerns, standardized guidelines for reporting RCTs were developed and implemented in human medicine. The Consolidated Standards of Reporting Trials (CONSORT) statement was first published in 1996, with a revised edition published in 2001. The CONSORT statement consists of a 22-item checklist for reporting a RCT and a flow diagram to follow the number of participants at each stage of a trial. An explanation and elaboration document not only defines and discusses the importance of each of the items, but also provides examples of how this information could be supplied in a publication. Differences between human and livestock populations necessitate modifications to the CONSORT statement to maximize its usefulness for RCTs involving livestock. These have been addressed in an extension of the CONSORT statement titled the REFLECT statement: Methods and processes of creating reporting guidelines for randomized control trials for livestock and food safety. The modifications made for livestock trials specifically addressed the common use of group housing and group allocation to intervention in livestock studies; the use of deliberate challenge models in some trials and the common use of non-clinical outcomes, such as contamination with a foodborne pathogen. In addition, the REFLECT statement for RCTs in livestock populations proposed specific terms or further clarified terms as they pertained to livestock studies.

Recommendations for Obesity Clinical Trials in Cancer Survivors: American Society of Clinical Oncology Statement.

PubMed

Ligibel, Jennifer A; Alfano, Catherine M; Hershman, Dawn; Ballard, Rachel M; Bruinooge, Suanna S; Courneya, Kerry S; Daniels, Elvan C; Demark-Wahnefried, Wendy; Frank, Elizabeth S; Goodwin, Pamela J; Irwin, Melinda L; Levit, Laura A; McCaskill-Stevens, Worta; Minasian, Lori M; O'Rourke, Mark A; Pierce, John P; Stein, Kevin D; Thomson, Cynthia A; Hudis, Clifford A

2015-11-20

Observational evidence has established a relationship between obesity and cancer risk and outcomes. Interventional studies have demonstrated the feasibility and benefits of lifestyle change after cancer diagnosis, and guidelines recommend weight management and regular physical activity in cancer survivors; however, lifestyle interventions are not a routine part of cancer care. The ASCO Research Summit on Advancing Obesity Clinical Trials in Cancer Survivors sought to identify the knowledge gaps that clinical trials addressing energy balance factors in cancer survivors have not answered and to develop a roadmap for the design and implementation of studies with the potential to generate data that could lead to the evidence-based incorporation of weight management and physical activity programs into standard oncology practice. Recommendations highlight the need for large-scale trials evaluating the impact of energy balance interventions on cancer outcomes, as well as the concurrent conduct of studies focused on dissemination and implementation of interventions in diverse populations of cancer survivors, including answering critical questions about the degree of benefit in key subgroups of survivors. Other considerations include the importance of incorporating economic metrics into energy balance intervention trials, the need to establish intermediate biomarkers, and the importance of integrating traditional and nontraditional funding sources. Establishing lifestyle change after cancer diagnosis as a routine part of cancer care will require a multipronged effort to overcome barriers related to study development, funding, and stakeholder engagement. Given the prevalence of obesity and inactivity in cancer survivors in the United States and elsewhere, energy balance interventions hold the potential to reduce cancer morbidity and mortality in millions of patients, and it is essential that we move forward in determining their role in cancer care with the same care and precision used to test pharmacologic and other interventions.

Feasibility, design and conduct of a pragmatic randomized controlled trial to reduce overweight and obesity in children: The electronic games to aid motivation to exercise (eGAME) study

PubMed Central

Maddison, Ralph; Foley, Louise; Ni Mhurchu, Cliona; Jull, Andrew; Jiang, Yannan; Prapavessis, Harry; Rodgers, Anthony; Vander Hoorn, Stephen; Hohepa, Maea; Schaaf, David

2009-01-01

Background Childhood obesity has reached epidemic proportions in developed countries. Sedentary screen-based activities such as video gaming are thought to displace active behaviors and are independently associated with obesity. Active video games, where players physically interact with images onscreen, may have utility as a novel intervention to increase physical activity and improve body composition in children. The aim of the Electronic Games to Aid Motivation to Exercise (eGAME) study is to determine the effects of an active video game intervention over 6 months on: body mass index (BMI), percent body fat, waist circumference, cardio-respiratory fitness, and physical activity levels in overweight children. Methods/Design Three hundred and thirty participants aged 10–14 years will be randomized to receive either an active video game upgrade package or to a control group (no intervention). Discussion An overview of the eGAME study is presented, providing an example of a large, pragmatic randomized controlled trial in a community setting. Reflection is offered on key issues encountered during the course of the study. In particular, investigation into the feasibility of the proposed intervention, as well as robust testing of proposed study procedures is a critical step prior to implementation of a large-scale trial. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12607000632493 PMID:19450288

Learning spinal manipulation: A best-evidence synthesis of teaching methods.

PubMed

Stainsby, Brynne E; Clarke, Michelle C S; Egonia, Jade R

2016-10-01

The purpose of this study was to evaluate the effectiveness of different reported methods used to teach spinal manipulative therapy to chiropractic students. For this best-evidence literature synthesis, 5 electronic databases were searched from 1900 to 2015. Eligible studies were critically appraised using the criteria of the Scottish Intercollegiate Guidelines Network. Scientifically admissible studies were synthesized following best-evidence synthesis principles. Twenty articles were critically appraised, including 9 randomized clinical trials, 9 cohort studies, and 2 systematic reviews/meta-analyses. Eleven articles were accepted as scientifically admissible. The type of teaching method aids included a Thrust in Motion cervical manikin, instrumented cardiopulmonary reanimation manikin, padded contact with a load cell, instrumented treatment table with force sensor/transducer, and Dynadjust instrument. Several different methods exist in the literature for teaching spinal manipulative therapy techniques; however, future research in this developing area of chiropractic education is proposed. It is suggested that various teaching methods be included in the regular curricula of chiropractic colleges to aid in developing manipulation skills, efficiency, and knowledge of performance.

Brain structural connectivity increases concurrent with functional improvement: evidence from diffusion tensor MRI in children with cerebral palsy during therapy.

PubMed

Englander, Zoë A; Sun, Jessica; Laura Case; Mikati, Mohamad A; Kurtzberg, Joanne; Song, Allen W

2015-01-01

Cerebral Palsy (CP) refers to a heterogeneous group of permanent but non-progressive movement disorders caused by injury to the developing fetal or infant brain (Bax et al., 2005). Because of its serious long-term consequences, effective interventions that can help improve motor function, independence, and quality of life are critically needed. Our ongoing longitudinal clinical trial to treat children with CP is specifically designed to meet this challenge. To maximize the potential for functional improvement, all children in this trial received autologous cord blood transfusions (with order randomized with a placebo administration over 2 years) in conjunction with more standard physical and occupational therapies. As a part of this trial, magnetic resonance imaging (MRI) is used to improve our understanding of how these interventions affect brain development, and to develop biomarkers of treatment efficacy. In this report, diffusion tensor imaging (DTI) and subsequent brain connectome analyses were performed in a subset of children enrolled in the clinical trial (n = 17), who all exhibited positive but varying degrees of functional improvement over the first 2-year period of the study. Strong correlations between increases in white matter (WM) connectivity and functional improvement were demonstrated; however no significant relationships between either of these factors with the age of the child at time of enrollment were identified. Thus, our data indicate that increases in brain connectivity reflect improved functional abilities in children with CP. In future work, this potential biomarker can be used to help differentiate the underlying mechanisms of functional improvement, as well as to identify treatments that can best facilitate functional improvement upon un-blinding of the timing of autologous cord blood transfusions at the completion of this study.

Novel ways to explore surgical interventions in randomised controlled trials: applying case study methodology in the operating theatre.

PubMed

Blencowe, Natalie S; Blazeby, Jane M; Donovan, Jenny L; Mills, Nicola

2015-12-28

Multi-centre randomised controlled trials (RCTs) in surgery are challenging. It is particularly difficult to establish standards of surgery and ensure that interventions are delivered as intended. This study developed and tested methods for identifying the key components of surgical interventions and standardising interventions within RCTs. Qualitative case studies of surgical interventions were undertaken within the internal pilot phase of a surgical RCT for obesity (the By-Band study). Each case study involved video data capture and non-participant observation of gastric bypass surgery in the operating theatre and interviews with surgeons. Methods were developed to transcribe and synchronise data from video recordings with observational data to identify key intervention components, which were then explored in the interviews with surgeons. Eight qualitative case studies were undertaken. A novel combination of video data capture, observation and interview data identified variations in intervention delivery between surgeons and centres. Although surgeons agreed that the most critical intervention component was the size and shape of the gastric pouch, there was no consensus regarding other aspects of the procedure. They conceded that evidence about the 'best way' to perform bypass was lacking and, combined with the pragmatic nature of the By-Band study, agreed that strict standardisation of bypass might not be required. This study has developed and tested methods for understanding how surgical interventions are designed and delivered delivered in RCTs. Applying these methods more widely may help identify key components of interventions to be delivered by surgeons in trials, enabling monitoring of key components and adherence to the protocol. These methods are now being tested in the context of other surgical RCTs. Current Controlled Trials ISRCTN00786323 , 05/09/2011.

Assessing Impact and Bridging Methodological Divides: Randomized Trials in Countries Affected by Conflict

ERIC Educational Resources Information Center

Burde, Dana

2012-01-01

Randomized trials have experienced a marked surge in endorsement and popularity in education research in the past decade. This surge reignited paradigm debates and spurred qualitative critics to accuse these experimental designs of eclipsing qualitative research. This article reviews a current iteration of this debate and examines two randomized…

Some New Facets of the Psychology-Law Interface.

ERIC Educational Resources Information Center

Freeman, James T.

While the field of forensic psychology has emerged as a recognized discipline, psychologists who work within institutional settings frequently feel frustration in dealing with inmates for whom they have had no responsibility or input during the critical pre-trial, trial and sentencing decision-making process. The roles and ways in which psychology…

Putting Rhetoric on Trial: Using a Simulated Courtroom in the Rhetoric Classroom

ERIC Educational Resources Information Center

Hess, Aaron

2013-01-01

This article describes an activity in which students will be able to apply rhetorical theory effectively and critically from specific theorists throughout history to modern-day issues. Through a simulated trial of a current figure, this activity makes connections between rhetorical theories to current affairs, thereby inviting students to consider…

Community Oncology and Prevention Trials Clinical Trials | Division of Cancer Prevention

Cancer.gov

The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

Ketamine for Analgosedation in the Intensive Care Unit: A Systematic Review.

PubMed

Patanwala, Asad E; Martin, Jennifer R; Erstad, Brian L

2017-07-01

To evaluate the evidence for the use of intravenous ketamine for analgosedation in the intensive care unit. MEDLINE and EMBASE were queried from inception until July 2015. Search terms used included ketamine, intensive care, and critical care. The search retrieved 584 articles to be screened for inclusion. The intent was to include randomized controlled studies using sustained intravenous infusions (>24 hours) of ketamine in the critically ill patients. One trial evaluated opioid consumption as an outcome in postoperative critically ill patients who were randomized to ketamine or saline infusions. The mean cumulative morphine consumption at 48 hours was significantly lower in the ketamine group (58 ± 35 mg) compared to the morphine-only group (80 ± 37 mg; P < .05). Other trials showed the potential safety of ketamine in terms of cerebral hemodynamics in patients with traumatic brain injury, improved gastrointestinal motility, and decreased vasopressor requirements. The observational study and case reports suggest that ketamine is safe and effective and may have a role in patients who are refractory to other therapies. Ketamine use may decrease analgesic consumption in the intensive care unit. Additional trials are needed to further delineate the role of ketamine for analgosedation.

A feasible strategy for preventing blood clots in critically ill patients with acute kidney injury (FBI): study protocol for a randomized controlled trial.

PubMed

Robinson, Sian; Zincuk, Aleksander; Larsen, Ulla Lei; Ekstrøm, Claus; Toft, Palle

2014-06-13

Previous pharmacokinetic trials suggested that 40 mg subcutaneous enoxaparin once daily provided inadequate thromboprophylaxis for intensive care unit patients. Critically ill patients with acute kidney injury are at increased risk of venous thromboembolism and yet are often excluded from these trials. We hypothesized that for critically ill patients with acute kidney injury receiving continuous renal replacement therapy, a dose of 1 mg/kg enoxaparin subcutaneously once daily would improve thromboprophylaxis without increasing the risk of bleeding. In addition, we seek to utilize urine output prior to discontinuing dialysis, and low neutrophil gelatinase-associated lipocalin in dialysis-free intervals, as markers of renal recovery. In a multicenter, double-blind randomized controlled trial in progress at three intensive care units across Denmark, we randomly assign eligible critically ill adults with acute kidney injury into a treatment (1 mg/kg enoxaparin subcutaneously once daily) or control arm (40 mg enoxaparin subcutaneously once daily) upon commencement of continuous renal replacement therapy.We calculated that with 133 patients in each group, the study would have 80% power to show a 40% reduction in the relative risk of venous thromboembolism with 1 mg/kg enoxaparin, at a two-sided alpha level of 0.05. An interim analysis will be conducted after the first 67 patients have been included in each group.Enrolment began in March 2013, and will continue for two years. The primary outcome is the occurrence of venous thromboembolism. Secondary outcomes include anti-factor Xa activity, bleeding, heparin-induced thrombocytopenia, filter lifespan, length of stay, ventilator free days, and mortality. We will also monitor neutrophil gelatinase-associated lipocalin and urine volume to determine whether they can be used as prognostic factors for renal recovery. Critically ill unit patients with acute kidney injury present a particular challenge in the provision of thromboprophylaxis. This study hopes to add to the growing evidence that the existing recommendation of 40 mg enoxaparin is inadequate and that 1 mg/kg is both safe and effective for thromboprophylaxis.In addition, the study seeks to identify predictors of renal recovery allowing for the proper utilization of resources. EU Clinical Trials Register: EudraCT number: 2012-004368-23, 25 September 2012.

Stakeholders' engagement with Ebola therapy research in resource limited settings.

PubMed

Folayan, Morenike Oluwatoyin; Brown, Brandon; Haire, Bridget; Yakubu, Aminu; Peterson, Kristin; Tegli, Jemee

2015-06-26

The current Ebola Virus Disease (EVD) outbreak in West Africa is the largest in history. As of February 18(th) 2015, 23,258 cases of EVD have been cumulatively reported from Nigeria, Senegal, Guinea, Liberia, Mali, Sierra Leone, Spain, the United Kingdom and the United States of America resulting in more than 9,000 deaths. It is therefore exigent to develop prevention and treatment therapies for EVD. Several new EVD treatments are in clinical development at this time. Based on lessons learned, four critical processes need to be implemented before clinical trials begin. First, all global EVD research need to be coordinated to promote data sharing and synergistic overlap, while reducing unnecessary duplication of efforts. The World Health Organization is well-placed to undertake such an endeavor. Second, governments of affected nations where trials are being proposed need to lead discussions regarding immediate access to any proven medications for epidemics. Also, governments need to leverage international resources to support and expand existing national expertise to jointly conduct high-caliber clinical research; and resources must be used to enhance local technical skills and expand existing personnel. Third, ethics committees must review protocols, monitor the research process, and work closely with research scientists to insure the ethical integrity of research throughout the trials. Fourth, community advisory boards (CAB) need to be formed, linked with existing community leadership structures and organized in conjunction with trial implementation. These community structures should work together with ethics committees to facilitate the study design, informed consent process, and study implementation. We must facilitate communication and mutual understanding between trial communities and research teams, and promote positive collaborations between all stakeholders engaged in EVD research. The community engagement process for EVD research is crucial to address myths and misconceptions, and to promote study volunteers' understanding of the research details. The collaboration between all stakeholders is crucial for continued long term partnership to address EVD outbreak and none of the stakeholders should be left behind in ongoing efforts to develop EVD therapies.

Evidence-based guides in tracheostomy use in critical patients.

PubMed

Raimondi, N; Vial, M R; Calleja, J; Quintero, A; Cortés Alban, A; Celis, E; Pacheco, C; Ugarte, S; Añón, J M; Hernández, G; Vidal, E; Chiappero, G; Ríos, F; Castilleja, F; Matos, A; Rodriguez, E; Antoniazzi, P; Teles, J M; Dueñas, C; Sinclair, J; Martínez, L; Von der Osten, I; Vergara, J; Jiménez, E; Arroyo, M; Rodriguez, C; Torres, J; Fernandez-Bussy, S; Nates, J L

2017-03-01

Provide evidence based guidelines for tracheostomy in critically ill adult patients and identify areas needing further research. A task force composed of representatives of 10 member countries of the Pan-American and Iberic Federation of Societies of Critical and Intensive Therapy Medicine and of the Latin American Critical Care Trial Investigators Network developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation system. The group identified 23 relevant questions among 87 issues that were initially identified. In the initial search, 333 relevant publications were identified of which 226 publications were chosen. The task force generated a total of 19 recommendations: 10 positive (1B=3, 2C=3, 2D=4) and 9 negative (1B=8, 2C=1). A recommendation was not possible in six questions. Percutaneous techniques are associated with a lower risk of infections compared to surgical tracheostomy. Early tracheostomy only seems to reduce the duration of ventilator use but not the incidence of pneumonia, the length of stay, or the long-term mortality rate. The evidence does not support the use of routine bronchoscopy guidance or laryngeal masks during the procedure. Finally, proper prior training is as important or even a more significant factor in reducing complications than the technique used. Copyright © 2017 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

A noncontact RF-based respiratory sensor: results of a clinical trial.

PubMed

Madsen, Spence; Baczuk, Jordan; Thorup, Kurt; Barton, Richard; Patwari, Neal; Langell, John T

2016-06-01

Respiratory rate (RR) is a critical vital signs monitored in health care setting. Current monitors suffer from sensor-contact failure, inaccurate data, and limited patient mobility. There is a critical need for an accurate and reliable and noncontact system to monitor RR. We developed a contact-free radio frequency (RF)-based system that measures movement using WiFi signal diffraction, which is converted into interpretable data using a Fourier transform. Here, we investigate the system's ability to measure fine movements associated with human respiration. Testing was conducted on subjects using visual cue, fixed-tempo instruction to breath at standard RRs. Blinded instruction-based RRs were compared to RF-acquired data to determine measurement accuracy. The RF-based technology was studied on postoperative ventilator-dependent patients. Blinded ventilator capnographic RR data were collected for each patient and compared to RF-acquired data to determine measurement accuracy. Respiratory rate data collected from 10 subjects breathing at a fixed RR (14, 16, 18, or 20) demonstrated 95.5% measurement accuracy between the patient's actual rate and that measured by our RF technology. Ten patients were enrolled into the clinical trial. Blinded ventilator capnographic RR data were compared to RF-based acquired data. The RF-based data showed 88.8% measurement accuracy with ventilator capnography. Initial clinical pilot trials with our contact-free RF-based monitoring system demonstrate a high degree of RR measurement accuracy when compared to capnographic data. Based on these results, we believe RF-based systems present a promising noninvasive, inexpensive, and accurate tool for continuous RR monitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

What can we learn from trial decliners about improving recruitment? Qualitative study.

PubMed

Hughes-Morley, Adwoa; Young, Bridget; Hempel, Roelie J; Russell, Ian T; Waheed, Waquas; Bower, Peter

2016-10-12

Trials increasingly experience problems in recruiting participants. Understanding the causes of poor recruitment is critical to developing solutions. We interviewed people who had declined a trial of an innovative psychological therapy for depression (REFRAMED) about their response to the trial invitation, in order to understand their decision and identify ways to improve recruitment. Of 214 people who declined the trial, 35 (16 %) gave permission to be contacted about a qualitative study to explore their decision. Analysis of transcripts of semi-structured interviews was informed by grounded theory. We interviewed 20 informants: 14 women and six men, aged 18 to 77 years. Many interviewees had prior experience of research participation and positive views of the trial. Interviewees' decision making resembled a four-stage sequential process; in each stage they either decided not to participate in the trial or progressed to the next stage. In stage 1, interviewees assessed the invitation in the context of their experiences and attitudes; we term those who opted out at this stage 'prior decliners' as they had an established position of declining trials. In stage 2, interviewees assessed their own eligibility; those who judged themselves ineligible and opted out at this stage are termed 'self-excluders'. In stage 3, interviewees assessed their need for the trial therapy and potential to benefit; we term those who decided they did not need the trial therapy and opted out at this stage 'treatment decliners'. In stage 4, interviewees deliberated the benefits and costs of trial participation; those who opted out after judging that disadvantages outweighed advantages are termed 'trial decliners'. Across all stages, most individuals declined because they judged themselves ineligible or not in need of the trial therapy. While 'prior decliners' are unlikely to respond to any trial recruitment initiative, the factors leading others to decline are amenable to amelioration as they do not arise from a rejection of trials or a personal stance. To improve recruitment in similar trials, the most successful interventions are likely to address patients' assessments of their eligibility and their potential to benefit from the trial treatment, rather than reducing trial burden. International Standard Randomised Controlled Trial Number: ISRCTN85784627 . Registration date 10 August 2011.

The basics of preclinical drug development for neurodegenerative disease indications.

PubMed

Steinmetz, Karen L; Spack, Edward G

2009-06-12

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial.

The basics of preclinical drug development for neurodegenerative disease indications

PubMed Central

Steinmetz, Karen L; Spack, Edward G

2009-01-01

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial. PMID:19534731

The evolving landscape of therapeutic drug development for hepatocellular carcinoma.

PubMed

Chong, Dawn Qingqing; Tan, Iain Beehuat; Choo, Su-Pin; Toh, Han Chong

2013-11-01

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. Copyright © 2013 Elsevier Inc. All rights reserved.

"I need to hear from women who have 'been there'": Developing a woman-focused intervention for drug use and partner violence in the emergency department.

PubMed

Choo, Esther; Guthrie, K Morrow; Mello, Michael; Wetle, Terrie F; Ranney, Megan; Tapé, Chantal; Zlotnick, Caron

2016-04-01

Addressing violence and linking women to community services in parallel with drug change goals is critical for women with coexisting intimate partner violence (IPV) and substance use disorders (SUD). Our objective was to develop a Web-based intervention to address violence and drug use among women patients in the ED. The intervention was developed in a five-step process: 1) Initial intervention development based on selected theoretical frameworks; 2) In-depth interviews with the target population; 3) Intervention adaptation, with iterative feedback from further interviews; 4) Beta testing and review by an advisory committee of domestic violence advocates; 5) Acceptability and feasibility testing in a small open trial. Themes supported the selection of MI and empowerment models but also guided major adaptations to the intervention, including the introduction of videos and a more robust booster phone call. Participants in the open trial reported high scores for satisfaction, usability, and consistency with essential elements of motivational interviewing. This qualitative work with our target population of women in the ED with SUD experiencing IPV underscored the importance of connection to peers and empathetic human contact. We developed an acceptable and feasible intervention distinct from prior ED-based brief interventions for substance-using populations.

Session 6: Infant nutrition: future research developments in Europe EARNEST, the early nutrition programming project: EARly Nutrition programming - long-term Efficacy and Safety Trials and integrated epidemiological, genetic, animal, consumer and economic research.

PubMed

Fewtrell, M S

2007-08-01

Increasing evidence from lifetime experimental studies in animals and observational and experimental studies in human subjects suggests that pre- and postnatal nutrition programme long-term health. However, key unanswered questions remain on the extent of early-life programming in contemporary European populations, relevant nutritional exposures, critical time periods, mechanisms and the effectiveness of interventions to prevent or reverse programming effects. The EARly Nutrition programming - long-term Efficacy and Safety Trials and integrated epidemiological, genetic, animal, consumer and economic research (EARNEST) consortium brings together a multi-disciplinary team of scientists from European research institutions in an integrated programme of work that includes experimental studies in human subjects, modern prospective observational studies and mechanistic animal work including physiological studies, cell-culture models and molecular techniques. Theme 1 tests early nutritional programming of disease in human subjects, measuring disease markers in childhood and early adulthood in nineteen randomised controlled trials of nutritional interventions in pregnancy and infancy. Theme 2 examines associations between early nutrition and later outcomes in large modern European population-based prospective studies, with detailed measures of diet in pregnancy and early life. Theme 3 uses animal, cellular and molecular techniques to study lifetime effects of early nutrition. Biomedical studies are complemented by studies of the social and economic importance of programming (themes 4 and 5), and themes encouraging integration, communication, training and wealth creation. The project aims to: help formulate policies on the composition and testing of infant foods; improve the nutritional value of infant formulas; identify interventions to prevent and reverse adverse early nutritional programming. In addition, it has the potential to develop new products through industrial partnerships, generate information on the social and economic cost of programming in Europe and help maintain Europe's lead in this critical area of research.

Controlled Trials in Children: Quantity, Methodological Quality and Descriptive Characteristics of Pediatric Controlled Trials Published 1948-2006

PubMed Central

Thomson, Denise; Hartling, Lisa; Cohen, Eyal; Vandermeer, Ben; Tjosvold, Lisa; Klassen, Terry P.

2010-01-01

Background The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. Methodology/Principal Findings We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). Conclusions/Significance The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials. PMID:20927344

Considerations for the Development of Mobile Phone Apps to Support Diabetes Self-Management: Systematic Review.

PubMed

Adu, Mary D; Malabu, Usman H; Callander, Emily J; Malau-Aduli, Aduli Eo; Malau-Aduli, Bunmi S

2018-06-21

There is increased research interest in the use of mobile phone apps to support diabetes management. However, there are divergent views on what constitute the minimum standards for inclusion in the development of mobile phone apps. Mobile phone apps require an evidence-based approach to development which will consequently impact on their effectiveness. Therefore, comprehensive information on developmental considerations could help designers and researchers to develop innovative and effective patient-centered self-management mobile phone apps for diabetes patients. This systematic review examined the developmental considerations adopted in trials that engaged mobile phone applications for diabetes self-management. A comprehensive search strategy was implemented across 5 electronic databases; Medline, Scopus, Social Science Citation Index, the Cochrane Central Register of Controlled Trials and Cumulative Index of Nursing and Allied Health Literature (CINALHL) and supplemented by reference list from identified studies. Study quality was evaluated using the Joanna Briggs Critical appraisal checklist for trials. Information on developmental factors (health behavioral theory, functionality, pilot testing, user and clinical expert involvements, data privacy and app security) were assessed across experimental studies using a template developed for the review. A total of 11 studies (10 randomized controlled trials and 1 quasi-experimental trial) that fitted the inclusion criteria were identified. All the included studies had the functionality of self-monitoring of blood glucose. However, only some of them included functions for data analytics (7/11, 63.6%), education (6/11, 54.5%) and reminder (6/11, 54.5%). There were 5/11(45.5%) studies with significantly improved glycosylated hemoglobin in the intervention groups where educational functionality was present in the apps used in the 5 trials. Only 1 (1/11, 9.1%) study considered health behavioral theory and user involvement, while 2 (2/11, 18.1%) other studies reported the involvement of clinical experts in the development of their apps. There were 4 (4/11, 36.4%) studies which referred to data security and privacy considerations during their app development while 7 (7/12, 63.6%) studies provided information on pilot testing of apps before use in the full trial. Overall, none of the studies provided information on all developmental factors assessed in the review. There is a lack of elaborate and detailed information in the literature regarding the factors considered in the development of apps used as interventions for diabetes self-management. Documentation and inclusion of such vital information will foster a transparent and shared decision-making process that will ultimately lead to the development of practical and user-friendly self-management apps that can enhance the quality of life for diabetes patients. ©Mary D Adu, Usman H Malabu, Emily J Callander, Aduli E O Malau-Aduli, Bunmi S Malau-Aduli. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 21.06.2018.

Is the Generally Held View That Intravenous Dihydroergotamine Is Effective in Migraine Based on Wrong "General Consensus" of One Trial? A Critical Review of the Trial and Subsequent Quotations.

PubMed

Bekan, Goran; Tfelt-Hansen, Peer

2016-10-01

The claim that parenteral dihydroergotamine (DHE) is effective in migraine is based on one randomized, placebo-controlled, crossover trial from 1986. The aim of this review was to critically evaluate the original article. It was also found to be of interest to review quotes concerning the results in the more than 100 articles subsequently referring to the article. The correctness of the stated effect of intravenous DHE in the randomized clinical trial (RCT) was first critically evaluated. Then, Google Scholar was searched for references to the article and these references were classified as to whether they judged the reported RCT as positive or negative. The design of the RCT, with a crossover within one migraine attack, only allows evaluation of the results for the first period and the effect of DHE and placebo were quite comparable. About 151 references were found for the article in Google scholar. Among the 95 articles with a judgment on the efficacy of intravenous DHE in the RCT, 90 stated that DHE was effective or likely effective whereas only 5 articles stated that DHE was ineffective. Despite a "negative" RCT, authors of subsequent articles on the efficacy of parenteral DHE overwhelmingly reported this RCT as "positive." This is probably due to the fact that the authors concluded in the abstract that DHE is effective, and to a kind of "wrong general consensus." © 2016 American Headache Society.

A Roadmap for Academic Health Centers to Establish Good Laboratory Practice-Compliant Infrastructure

PubMed Central

Adamo, Joan E.; Bauer, Gerhard; Berro, Marlene; Burnett, Bruce K.; Hartman, Karen A.; Masiello, Lisa M.; Moorman-White, Diane; Rubinstein, Eric P.; Schuff, Kathryn G.

2012-01-01

Prior to human clinical trials, nonclinical safety and toxicology studies are required to demonstrate that a new product appears safe for human testing; these nonclinical studies are governed by good laboratory practice (GLP) regulations. As academic health centers (AHCs) embrace the charge to increase the translation of basic science research into clinical discoveries, researchers at these institutions increasingly will be conducting GLP-regulated nonclinical studies. Because the consequences for noncompliance are severe and many AHC researchers are unfamiliar with Food and Drug Administration (FDA) regulations, the authors describe the regulatory requirements for conducting GLP research, including the strict documentation requirements, the necessary personnel training, the importance of study monitoring, and the critical role that compliance oversight plays in the process. They then explain the process that AHCs interested in conducting GLP studies should take prior to the start of their research program, including conducting a needs assessment and a gap analysis and selecting a model for GLP compliance. Finally, the authors identify and analyze several critical barriers to developing and implementing a GLP-compliant infrastructure at an AHC. Despite these challenges, the capacity to perform such research will help AHCs to build and maintain competitive research programs and to facilitate the successful translation of faculty-initiated research from nonclinical studies to first-in-human clinical trials. PMID:22373618

The Tricky Tear Trough

PubMed Central

Belden, Sarah; Miller, Richard A.

2015-01-01

There is a growing demand for noninvasive anti-aging products for which the periorbital region serves as a critical aspect of facial rejuvenation. This article reviews a multitude of cosmeceutical ingredients that have good scientific data, specifically for the periorbital region. Topical treatment options have exponentially grown from extensively studied retinoids, to recently developed technology, such as growth factors and peptides. With a focus on the periorbital anatomy, the authors review the mechanisms of action of topical cosmeceutical ingredients, effectiveness of ingredient penetration through the stratum corneum, and validity of clinical trials. PMID:26430490

Expression of HLA Class II Molecules in Humanized NOD.Rag1KO.IL2RgcKO Mice is Critical for Development and Function of Human T and B Cells

DTIC Science & Technology

2011-05-17

HSC-infused DRAG and control mice were immunized with 1 flocculation unit of TT vaccine ( Sanofi Pasteur) by the intramuscular route, and the titers... Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America, 2 Department...human vaccines prior to clinical trials. However, current humanized mouse models show sub-optimal human T cell reconstitution and limited ability to

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use

PubMed Central

Nayak, Satyaprakash; Sander, Oliver; Al‐Huniti, Nidal; de Alwis, Dinesh; Chain, Anne; Chenel, Marylore; Sunkaraneni, Soujanya; Agrawal, Shruti; Gupta, Neeraj

2018-01-01

Quantitative pharmacology (QP) applications in translational medicine, drug‐development, and therapeutic use were crowd‐sourced by the ASCPT Impact and Influence initiative. Highlighted QP case studies demonstrated faster access to innovative therapies for patients through 1) rational dose selection for pivotal trials; 2) reduced trial‐burden for vulnerable populations; or 3) simplified posology. Critical success factors were proactive stakeholder engagement, alignment on the value of model‐informed approaches, and utilizing foundational clinical pharmacology understanding of the therapy. PMID:29330855

American Society of Clinical Oncology policy statement: oversight of clinical research.

PubMed

2003-06-15

Well-publicized lapses in the review or implementation of clinical research studies have raised public questions about the integrity of the clinical research process. Public trust in the integrity of research is critical not only for funding and participation in clinical trials but also for confidence in the treatments that result from the trials. The questions raised by these unfortunate cases pose an important opportunity to reassess the clinical trials oversight system to ensure the integrity of clinical research and the safety of those who enroll in clinical trials. Since its inception, the American Society of Clinical Oncology (ASCO) has worked for the advancement of cancer treatments through clinical research and to help patients gain prompt access to scientifically excellent and ethically unimpeachable clinical trials. As an extension of its mission, ASCO is affirming with this policy statement the critical importance of a robust review and oversight system to ensure that clinical trials participants give fully informed consent and that their safety is a top priority. Ensuring the integrity of research cannot be stressed enough because of its seminal connection to the advancement of clinical cancer treatment. The overall goal of this policy is to enhance public trust in the cancer clinical trials process. To achieve this, the following elements are essential: 1. Ensure safety precautions for clinical trial participants and their fully informed consent. 2. Ensure the validity and integrity of scientific research. 3. Enhance the educational training of clinical scientists and research staff to ensure the highest standards of research conduct. 4. Promote accountability and responsibility among all those involved in clinical research (not just those serving on institutional review boards [IRBs], but also institutional officials, researchers, sponsors, and participants) and ensure support for an effective oversight process. 5. Enhance the professional and public understanding of clinical research oversight. 6. Enhance the efficiency and cost-effectiveness of the clinical research oversight system. This policy statement makes recommendations in several areas that serve as principles to support an improved system of oversight for clinical research. ASCO will work with all parties involved in the clinical research system to develop the steps necessary to implement these recommendations. Centralized Trial Review: A large percentage of oncology clinical trials are coordinated through the National Cancer Institute's (NCI) system of cooperative groups, which already incorporates centralized scientific review. As such, there is a tremendous opportunity to employ a centralized mechanism to provide ethical review by highly trained IRB members, allowing local IRBs to take advantage of the financial and time efficiencies that central review provides. Centralized review boards (CRBs) would also contribute consistency and efficiency to the process. Once successfully completed, the review would represent an approval to open the protocol at all of the institutions that have subscribed to the centralized review system. Local IRBs would be able to devote time usually spent on initial review to ongoing monitoring of the trial taking place at their institution. Considering the enormous size and complexity of the clinical research enterprise, ASCO envisions multiple CRBs, which could be distributed as regional review boards. Central review will use a single protocol and consent form, and monitor and evaluate adverse events (AEs) on a global basis, eliminating many of the time-consuming steps for the local IRB. Global monitoring and assessment of AEs has real potential to enhance trial participants' safety by giving local institutions more information on the overall trial and enabling them to devote more time to ongoing review of the trial onsite. Use of a CRB also has real potential to reduce the costs of clinical trial oversight by allowing local IRBs to eliminate the costs of initial review. These efficiencies will likely lead to institutions redirecting funds toward monitoring ongoing trials. Although a CRB has potential to improve the efficiency of the process, a CRB could also have tremendous ability to delay valuable trials. Checks and balances must be included in the newly devised system to ensure timely review and appeals of CRB actions. ASCO proposes the advent of a new pilot program for centralizing review of clinical trials. It requires clear engagement of all stakeholders in planning the experiment, clear articulation of the goals, and assurance of federal regulatory protection for institutions choosing to participate. If successful, this CRB pilot project could be expanded to include multi-institutional industry-sponsored research. Education and Training:Education and training are critical to the ultimate success of an improved oversight system. All members of the research team should receive comprehensive education on conducting scientifically and ethically valid clinical research. The curriculum should also include information on the prevailing local and federal regulations that pertain to the clinical trials process. IRB members should also receive ongoing education and training in the review of clinical research protocols. IRB training should pay particular attention to nonscientific members to give them the tools necessary to speak on behalf of research participants. ASCO should develop a curriculum that focuses on the proper conduct of human research and emphasize ethically sound clinical research in the context of its Annual Meeting. Informed Consent: Investigators and review boards have specific roles to play in ensuring the education of trial participants through the informed consent process, both when they are considering trial enrollment and as they participate in the trial. Review boards and investigators should focus primarily on the informed consent process, rather than the informed consent documents. Federal Oversight: The federal government has an important role to play in the oversight of clinical research. This role should be expanded to cover all research, not just that which is funded by the federal government or conducted with the oversight of the Food and Drug Administration (FDA). The Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and the FDA should provide clear regulatory support and guidance for local institutions that choose to employ a CRB. In the case of the pilot CRB discussed in this policy statement, it should serve as the preferred option for the cancer cooperative group clinical trials. Ideally, the federal government should unify and streamline its regulations for the oversight of clinical research. Resources Supporting Clinical Research Infrastructure:An effective oversight process demands the highest quality scientific and ethical review and onsite monitoring of the safety of trial participants. This can only be accomplished by the involvement of an experienced IRB that receives funding, resources, and institutional support enabling it to fulfill its mandate. Critical to the integrity of research is the absence of bias in the process. ASCO strongly recommends the adoption of standards for the identification, management, and, where appropriate, elimination of conflicts of interests, whether they are actual, potential, or apparent.

Balanced crystalloids versus saline in the intensive care unit: study protocol for a cluster-randomized, multiple-crossover trial.

PubMed

Semler, Matthew W; Self, Wesley H; Wang, Li; Byrne, Daniel W; Wanderer, Jonathan P; Ehrenfeld, Jesse M; Stollings, Joanna L; Kumar, Avinash B; Hernandez, Antonio; Guillamondegui, Oscar D; May, Addison K; Siew, Edward D; Shaw, Andrew D; Bernard, Gordon R; Rice, Todd W

2017-03-16

Saline, the intravenous fluid most commonly administered to critically ill adults, contains a high chloride content, which may be associated with acute kidney injury and death. Whether using balanced crystalloids rather than saline decreases the risk of acute kidney injury and death among critically ill adults remains unknown. The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) is a pragmatic, cluster-level allocation, cluster-level crossover trial being conducted between 1 June 2015 and 30 April 2017 in five intensive care units at Vanderbilt University Medical Center in Nashville, TN, USA. SMART compares saline (0.9% sodium chloride) with balanced crystalloids (clinician's choice of lactated Ringer's solution or Plasma-Lyte A®). Each intensive care unit is assigned to provide either saline or balanced crystalloids each month, with the assigned crystalloid alternating monthly over the course of the trial. All adults admitted to participating intensive care units during the study period are enrolled and followed until hospital discharge or 30 days after enrollment. The anticipated enrollment is approximately 14,000 patients. The primary outcome is Major Adverse Kidney Events within 30 days-the composite of in-hospital death, receipt of new renal replacement therapy, or persistent renal dysfunction (discharge creatinine ≥200% of baseline creatinine). Secondary clinical outcomes include in-hospital mortality, intensive care unit-free days, ventilator-free days, vasopressor-free days, and renal replacement therapy-free days. Secondary renal outcomes include new renal replacement therapy receipt, persistent renal dysfunction, and incidence of stage 2 or higher acute kidney injury. This ongoing pragmatic trial will provide the largest and most comprehensive comparison to date of clinical outcomes with saline versus balanced crystalloids among critically ill adults. For logistical reasons, SMART was prospectively registered separately for the medical ICU (SMART-MED; ClinicalTrials.gov identifier: NCT02444988 ; registered on 11 May 2015; date of first patient enrollment: 1 June 2015) and the nonmedical ICUs (SMART-SURG; ClinicalTrials.gov identifier: NCT02547779 ; registered on 9 September 2015; date of first patient enrollment: 1 October 2015).

Patient Endorsement of the Outcome Measures in Rheumatology (OMERACT) Total Joint Replacement (TJR) clinical trial draft core domain set.

PubMed

Singh, Jasvinder A; Dowsey, Michelle; Choong, Peter F

2017-03-15

A patient- and surgeon-Delphi-derived Outcome Measures in Rheumatology (OMERACT) draft core domain set for total joint arthroplasty (TJR) trials was recently developed. Our objective was to obtain further patient stakeholder endorsement of draft core domain set for TJR clinical trials. We surveyed two patient groups: (1) OMERACT patient partners; and (2) patients who had undergone hip or knee TJR. Patients received an introductory email with explanations about the core domain set and instructions to rate the core domains, i.e., important aspects, of OMERACT TJR clinical trial draft core domain set. Rating was on a nominal scale, where 1-3 indicated a domain of limited importance, 4-6 an important, but not critical domain, and 7-9 a critical domain. We used Mann-Whitney test (a non-parametric test) to compare the distribution of ratings between the two groups. Thirty one survey participants from the OMERACT patient partner group and 118 knee/hip TJR patients responded with response rates of 66 and 80%, respectively. Majority of the survey respondents were female, 87 vs. 53%, and were 55 years or older, 57 vs. 94%. Median (interquartile range [IQR]) scores for six core domains by OMERACT and knee/hip TJR patient groups were, respectively: pain, 8 [8, 9] and 9 [8, 9]; function, 9 [8, 9] and 9 [8, 9]; patient satisfaction, 8 [8, 9] and 8 [7, 9]; revision surgery, 7 [7, 8] and 7 [5, 9]; adverse events, 8 [7, 9] and 8 [6, 9]; and death, 9 [6, 9] and 9 [4, 9]. No statistically significant differences in rating were noted for any of the six core domains between the two groups (p ≥ 0.31). Among the additional domains, ratings for patient participation did not differ by group (p = 0.98), but ratings for cost were significantly different (p = 0.005). Patients provided qualitative feedback regarding core domains, and did not propose any modifications to the draft core domain set. Two separate patient stakeholder groups endorsed the OMERACT TJR draft core domain set for TJR trials.

Vaccine platform recombinant measles virus.

PubMed

Mühlebach, Michael D

2017-10-01

The classic development of vaccines is lengthy, tedious, and may not necessarily be successful as demonstrated by the case of HIV. This is especially a problem for emerging pathogens that are newly introduced into the human population and carry the inherent risk of pandemic spread in a naïve population. For such situations, a considerable number of different platform technologies are under development. These are also under development for pathogens, where directly derived vaccines are regarded as too complicated or even dangerous due to the induction of inefficient or unwanted immune responses causing considerable side-effects as for dengue virus. Among platform technologies are plasmid-based DNA vaccines, RNA replicons, single-round infectious vector particles, or replicating vaccine-based vectors encoding (a) critical antigen(s) of the target pathogens. Among the latter, recombinant measles viruses derived from vaccine strains have been tested. Measles vaccines are among the most effective and safest life-attenuated vaccines known. Therefore, the development of Schwarz-, Moraten-, or AIK-C-strain derived recombinant vaccines against a wide range of mostly viral, but also bacterial pathogens was quite straightforward. These vaccines generally induce powerful humoral and cellular immune responses in appropriate animal models, i.e., transgenic mice or non-human primates. Also in the recent first clinical phase I trial, the results have been quite encouraging. The trial indicated the expected safety and efficacy also in human patients, interestingly independent from the level of prevalent anti-measles immunity before the trial. Thereby, recombinant measles vaccines expressing additional antigens are a promising platform for future vaccines.

Development and clinical application of an evidence-based pharmaceutical care service algorithm in acute coronary syndrome.

PubMed

Kang, J E; Yu, J M; Choi, J H; Chung, I-M; Pyun, W B; Kim, S A; Lee, E K; Han, N Y; Yoon, J-H; Oh, J M; Rhie, S J

2018-06-01

Drug therapies are critical for preventing secondary complications in acute coronary syndrome (ACS). The purpose of this study was to develop and apply a pharmaceutical care service (PCS) algorithm for ACS and confirm that it is applicable through a prospective clinical trial. The ACS-PCS algorithm was developed according to extant evidence-based treatment and pharmaceutical care guidelines. Quality assurance was conducted through two methods: literature comparison and expert panel evaluation. The literature comparison was used to compare the content of the algorithm with the referenced guidelines. Expert evaluations were conducted by nine experts for 75 questionnaire items. A trial was conducted to confirm its effectiveness. Seventy-nine patients were assigned to either the pharmacist-included multidisciplinary team care (MTC) group or the usual care (UC) group. The endpoints of the trial were the prescription rate of two important drugs, readmission, emergency room (ER) visit and mortality. The main frame of the algorithm was structured with three tasks: medication reconciliation, medication optimization and transition of care. The contents and context of the algorithm were compliant with class I recommendations and the main service items from the evidence-based guidelines. Opinions from the expert panel were mostly positive. There were significant differences in beta-blocker prescription rates in the overall period (P = .013) and ER visits (four cases, 9.76%, P = .016) in the MTC group compared to the UC group, respectively. We developed a PCS algorithm for ACS based on the contents of evidence-based drug therapy and the core concept of pharmacist services. © 2018 John Wiley & Sons Ltd.

The potential of alkaline phosphatase as a treatment for sepsis-associated acute kidney injury.

PubMed

Peters, Esther; Masereeuw, Rosalinde; Pickkers, Peter

2014-01-01

Sepsis-associated acute kidney injury (AKI) is associated with a high attributable mortality and an increased risk of developing chronic kidney failure in survivors. As a successful therapy is, as yet, unavailable, a pharmacological treatment option is clearly warranted. Recently, two small phase II clinical trials demonstrated beneficial renal effects of bovine-derived alkaline phosphatase administration in critically ill patients with sepsis-associated AKI. The rationale behind the renal protective effects remains to be fully elucidated, but is likely to be related to dephosphorylation and thereby detoxification of detrimental molecules involved in the pathogenesis of sepsis-associated AKI. A potent candidate target molecule might be endotoxin (lipopolysaccharide) from the cell wall of Gram-negative bacteria, which is associated with the development of sepsis and becomes nontoxic after being dephosphorylated by alkaline phosphatase. Another target of alkaline phosphatase could be adenosine triphosphate, a proinflammatory mediator released during cellular stress, which can be converted by alkaline phosphatase into the tissue-protective and anti-inflammatory molecule adenosine. Human recombinant alkaline phosphatase, a recently developed replacement for bovine-derived alkaline phosphatase, has shown promising results in the preclinical phase. As its safety and tolerability were recently confirmed in a phase I clinical trial, the renal protective effect of human recombinant alkaline phosphatase in sepsis-associated AKI shall be investigated in a multicenter phase II clinical trial starting at the end of this year. 2014 S. Karger AG, Basel.

Effect of periodontal treatment on preterm birth rate: a systematic review of meta-analyses.

PubMed

López, Néstor J; Uribe, Sergio; Martinez, Benjamín

2015-02-01

Preterm birth is a major cause of neonatal morbidity and mortality in both developed and developing countries. Preterm birth is a highly complex syndrome that includes distinct clinical subtypes in which many different causes may be involved. The results of epidemiological, molecular, microbiological and animal-model studies support a positive association between maternal periodontal disease and preterm birth. However, the results of intervention studies carried out to determine the effect of periodontal treatment on reducing the risk of preterm birth are controversial. This systematic review critically analyzes the methodological issues of meta-analyses of the studies to determine the effect of periodontal treatment to reduce preterm birth. The quality of the individual randomized clinical trials selected is of highest relevance for a systematic review. This article describes the methodological features that should be identified a priori and assessed individually to determine the quality of a randomized controlled trial performed to evaluate the effect of periodontal treatment on pregnancy outcomes. The AMSTAR and the PRISMA checklist tools were used to assess the quality of the six meta-analyses selected, and the bias domain of the Cochrane Collaboration's Tool was applied to evaluate each of the trials included in the meta-analyses. In addition, the methodological characteristics of each clinical trial were assessed. The majority of the trials included in the meta-analyses have significant methodological flaws that threaten their internal validity. The lack of effect of periodontal treatment on preterm birth rate concluded by four meta-analyses, and the positive effect of treatment for reducing preterm birth risk concluded by the remaining two meta-analyses are not based on consistent scientific evidence. Well-conducted randomized controlled trials using rigorous methodology, including appropriate definition of the exposure, adequate control of confounders for preterm birth and application of effective periodontal interventions to eliminate periodontal infection, are needed to confirm the positive association between periodontal disease and preterm birth. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Increasing Efficiency of Recruitment in Early Parkinson's Disease Trials: A Case Study Examination of the STEADY-PD III Trial.

PubMed

Berk, Sarah; Greco, Brittany L; Biglan, Kevin; Kopil, Catherine M; Holloway, Robert G; Meunier, Claire; Simuni, Tanya

2017-01-01

Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson's disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. A total of 336 individuals, including 34 minorities, were enrolled within 12 months - 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research.

Increasing Efficiency of Recruitment in Early Parkinson’s Disease Trials: A Case Study Examination of the STEADY-PD III Trial

PubMed Central

Berk, Sarah; Greco, Brittany L.; Biglan, Kevin; Kopil, Catherine M.; Holloway, Robert G.; Meunier, Claire; Simuni, Tanya

2017-01-01

Background: Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson’s disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. Objective: This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. Methods: STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. Results: A total of 336 individuals, including 34 minorities, were enrolled within 12 months – 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). Conclusions: STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research. PMID:29103052

Methods to Prove 20+ Year Life of CPV Products (in less than 20 Years)

NASA Astrophysics Data System (ADS)

Bowman, John; Spencer, Mark

2011-12-01

Due to the long term life expectations of photovoltaic products and the short duration of most introduced CPV technologies, it is critical for CPV companies to carefully construct field trials to prove product life. Because of the complicated geometric, thermal, and spectral characteristics of CPV systems, conducting very precise power output measurements reproducibly over many months is very difficult. Robust normalization methods specific to the exact optical system and PV cell type must be developed. Once the performance over a specific duration, e.g. one year, is established, then some justification is required to extrapolate to future performance. Comparisons to accelerated test results provide this justification. SolFocus has been conducting field trials of the SF-1100S CPV system for over two years. These field trials consist of controlled populations of SF-1100P modules, operating in grid-tied systems, which have been repeatedly measured at the individual module level over the duration of the trials. In this paper, field data will be presented along with normalization methodology and statistical methods for determining power degradation slope distributions for populations of individual modules. These results will be correlated with accelerated field tests which have been ongoing for 1.5 years and are estimated to be equivalent to 10 to 15 years of non-accelerated operation.

Barriers and Facilitators to Initiating and Completing Time-Limited Trials in Critical Care.

PubMed

Bruce, Courtenay R; Liang, Cecilia; Blumenthal-Barby, Jennifer S; Zimmerman, Janice; Downey, Andrea; Pham, Linda; Theriot, Lisette; Delgado, Estevan D; White, Douglas

2015-12-01

A time-limited trial is an agreement between clinicians and patients or surrogate decision makers to use medical therapies over a defined period of time to see if the patient improves or deteriorates according to agreed-upon clinical milestones. Although time-limited trials are broadly advocated, there is little empirical evidence of the benefits and risks of time-limited trials, when they are initiated, when and why they succeed or fail, and what facilitates completion of them. Our study objectives were to 1) identify the purposes for which clinicians use time-limited trials and 2) identify barriers and facilitators to initiating and completing time-limited trials. Semistructured interviews: We analyzed interviews using qualitative description with constant comparative techniques. Nine hundred-bed, academic, tertiary hospital in Houston, Texas. Interviewees were from open medical, surgical, neurosurgical, and cardiovascular ICUs. Thirty healthcare professionals were interviewed (nine surgeons, 16 intensivists, three nurse practitioners, and two "other" clinicians). None. Interviewees reported initiating time-limited trials for three different purposes: to prepare surrogates and clinicians for discussion and possible shifts toward comfort-care only therapies, build consensus, and refine prognostic information. The main barriers to initiating time-limited trials involve clinicians' or surrogate decision makers' disagreement on setting a time limit. Barriers to completing time-limited trials include 1) requesting more time; 2) communication breakdowns because of rotating call schedules; and 3) changes in clinical course. Finally, facilitators to completing time-limited trials include 1) having defined goals about what could be achieved during an ICU stay, either framed in narrow, numeric terms or broad goals focusing on achievable activities of daily living; 2) applying time-limited trials in certain types of cases; and 3) taking ownership to ensure completion of the trial. An understanding of barriers and facilitators to initiating and completing time-limited trials is an essential first step toward appropriate utilization of time-limited trials in the ICUs, as well as developing educational or communication interventions with clinicians to facilitate time-limited trial use. We provide practical suggestions on patient populations in whom time-limited trials may be successful, the setting, and clinicians likely to benefit from educational interventions, allowing clinicians to have a fuller sense of when and how to use time-limited trials.

Extended infusion of beta-lactam antibiotics: optimizing therapy in critically-ill patients in the era of antimicrobial resistance.

PubMed

Rizk, Nesrine A; Kanafani, Zeina A; Tabaja, Hussam Z; Kanj, Souha S

2017-07-01

Beta-lactams are at the cornerstone of therapy in critical care settings, but their clinical efficacy is challenged by the rise in bacterial resistance. Infections with multi-drug resistant organisms are frequent in intensive care units, posing significant therapeutic challenges. The problem is compounded by a dearth in the development of new antibiotics. In addition, critically-ill patients have unique physiologic characteristics that alter the drugs pharmacokinetics and pharmacodynamics. Areas covered: The prolonged infusion of antibiotics (extended infusion [EI] and continuous infusion [CI]) has been the focus of research in the last decade. As beta-lactams have time-dependent killing characteristics that are altered in critically-ill patients, prolonged infusion is an attractive approach to maximize their drug delivery and efficacy. Several studies have compared traditional dosing to EI/CI of beta-lactams with regard to clinical efficacy. Clinical data are primarily composed of retrospective studies and some randomized controlled trials. Several reports show promising results. Expert commentary: Reviewing the currently available evidence, we conclude that EI/CI is probably beneficial in the treatment of critically-ill patients in whom an organism has been identified, particularly those with respiratory infections. Further studies are needed to evaluate the efficacy of EI/CI in the management of infections with resistant organisms.

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

PubMed

Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients.

PubMed

Roberts, Jason A; Choi, Gordon Y S; Joynt, Gavin M; Paul, Sanjoy K; Deans, Renae; Peake, Sandra; Cole, Louise; Stephens, Dianne; Bellomo, Rinaldo; Turnidge, John; Wallis, Steven C; Roberts, Michael S; Roberts, Darren M; Lassig-Smith, Melissa; Starr, Therese; Lipman, Jeffrey

2016-03-01

Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality. We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics. Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT. Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013.

Alcohol Prevention and School Students: Findings from an Australian 2-Year Trial of Integrated Harm Minimization School Drug Education

ERIC Educational Resources Information Center

Midford, Richard; Ramsden, Robyn; Lester, Leanne; Cahill, Helen; Mitchell, Johanna; Foxcroft, David R.; Venning, Lynne

2014-01-01

The Drug Education in Victorian Schools program provided integrated education about licit and illicit drugs, employed a harm minimization approach that incorporated participatory, critical thinking and skill-based teaching methods, and engaged parental influence through home activities. A cluster-randomized, controlled trial of the program was…

Phase 0/I/II Cancer Prevention Clinical Trials Program Clinical Trials | Division of Cancer Prevention

Cancer.gov

The Division of Cancer Prevention (DCP) conducts and supports research to determine a person's risk of cancer and to find ways to reduce the risk. This knowledge is critical to making progress against cancer because risk varies over the lifespan as genetic and epigenetic changes can transform healthy tissue into invasive cancer.

A randomized trial examining the effects of parent engagement on early language and literacy: the Getting Ready intervention.

PubMed

Sheridan, Susan M; Knoche, Lisa L; Kupzyk, Kevin A; Edwards, Carolyn Pope; Marvin, Christine A

2011-06-01

Language and literacy skills established during early childhood are critical for later school success. Parental engagement with children has been linked to a number of adaptive characteristics in preschoolers including language and literacy development, and family-school collaboration is an important contributor to school readiness. This study reports the results of a randomized trial of a parent engagement intervention designed to facilitate school readiness among disadvantaged preschool children, with a particular focus on language and literacy development. Participants included 217 children, 211 parents, and 29 Head Start teachers in 21 schools. Statistically significant differences in favor of the treatment group were observed between treatment and control participants in the rate of change over 2 academic years on teacher reports of children's language use (d=1.11), reading (d=1.25), and writing skills (d=0.93). Significant intervention effects on children's direct measures of expressive language were identified for a subgroup of cases where there were concerns about a child's development upon entry into preschool. Additionally, other child and family moderators revealed specific variables that influenced the treatment's effects. Copyright © 2011 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

A Randomized Trial Examining the Effects of Parent Engagement on Early Language and Literacy: The Getting Ready Intervention

PubMed Central

Knoche, Lisa L.; Kupzyk, Kevin A.; Edwards, Carolyn Pope; Marvin, Christine A.

2011-01-01

Language and literacy skills established during early childhood are critical for later school success. Parental engagement with children has been linked to a number of adaptive characteristics in preschoolers including language and literacy development, and family-school collaboration is an important contributor to school readiness. This study reports the results of a randomized trial of a parent engagement intervention designed to facilitate school readiness among disadvantaged preschool children, with a particular focus on language and literacy development. Participants included 217 children, 211 parents, and 29 Head Start teachers in 21 schools. Statistically significant differences in favor of the treatment group were observed between treatment and control participants in the rate of change over 2 academic years on teacher reports of children’s language use (d = 1.11), reading (d = 1.25), and writing skills (d = .93). Significant intervention effects on children’s direct measures of expressive language were identified for a subgroup of cases where there were concerns about a child’s development upon entry into preschool. Additionally, other child and family moderators revealed specific variables that influenced the treatment’s effects. PMID:21640249

Vitamin D and the Development of Atopic Eczema

PubMed Central

Palmer, Debra J.

2015-01-01

A “vitamin D hypothesis” has been proposed to explain the increased prevalence of eczema in regions with higher latitude. This review focuses on the current available evidence with regard to the possible effect of vitamin D on the development of atopic eczema. Observational studies have indicated a link between vitamin D status and eczema outcomes, including lower serum vitamin D levels associated with increased incidence and severity of eczema symptoms. Vitamin D is known to have a regulatory influence on both the immune system and skin barrier function, both critical in the pathogenesis of eczema. However heterogeneous results have been found in studies to date investigating the effect of vitamin D status during pregnancy and infancy on the prevention of eczema outcomes. Well-designed, adequately powered, randomised controlled trials are needed. The study design of any new intervention trials should measure vitamin D levels at multiple time points during the intervention, ultraviolet (UV) radiation exposure via the use of individual UV dosimeters, and investigate the role of individual genetic polymorphisms. In conclusion, the current available evidence does not allow firm conclusions to be made on whether vitamin D status affects the development of atopic eczema. PMID:26239464

Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series.

PubMed

Martínez-Lavín, Manuel; Amezcua-Guerra, Luis

2017-10-01

This article critically reviews HPV vaccine serious adverse events described in pre-licensure randomized trials and in post-marketing case series. HPV vaccine randomized trials were identified in PubMed. Safety data were extracted. Post-marketing case series describing HPV immunization adverse events were reviewed. Most HPV vaccine randomized trials did not use inert placebo in the control group. Two of the largest randomized trials found significantly more severe adverse events in the tested HPV vaccine arm of the study. Compared to 2871 women receiving aluminum placebo, the group of 2881 women injected with the bivalent HPV vaccine had more deaths on follow-up (14 vs. 3, p = 0.012). Compared to 7078 girls injected with the 4-valent HPV vaccine, 7071 girls receiving the 9-valent dose had more serious systemic adverse events (3.3 vs. 2.6%, p = 0.01). For the 9-valent dose, our calculated number needed to seriously harm is 140 (95% CI, 79–653) [DOSAGE ERROR CORRECTED] . The number needed to vaccinate is 1757 (95% CI, 131 to infinity). Practically, none of the serious adverse events occurring in any arm of both studies were judged to be vaccine-related. Pre-clinical trials, post-marketing case series, and the global drug adverse reaction database (VigiBase) describe similar post-HPV immunization symptom clusters. Two of the largest randomized HPV vaccine trials unveiled more severe adverse events in the tested HPV vaccine arm of the study. Nine-valent HPV vaccine has a worrisome number needed to vaccinate/number needed to harm quotient. Pre-clinical trials and post-marketing case series describe similar post-HPV immunization symptoms.

The optimal blood glucose level for critically ill adult patients.

PubMed

Lv, Shaoning; Ross, Paul; Tori, Kathleen

2017-09-01

Glycaemic control is recognized as one of the important aspects in managing critically ill patients. Both hyperglycaemia and hypoglycaemia independently increase the risk of patient mortality. Hence, the identification of optimal glycaemic control is of paramount importance in the management of critically ill patients. The aim of this literature review is to examine the current status of glycaemic control in critically ill adult patients. This literature review will focus on randomized controlled trials comparing intensive insulin therapy to conventional insulin therapy, with an objective to identify optimal blood glucose level targets for critically ill adult patients. A literature review was conducted to identify large randomized controlled trials for the optimal targeted blood glucose level for critically ill adult patients published since 2000. A total of eight studies fulfilled the selection criteria of this review. With current human and technology resources, the results of the studies support commencing glycaemic control once the blood glucose level of critically ill patients reaches 10 mmol/L and maintaining this level between 8 mmol/L and 10 mmol/L. This literature review provides a recommendation for targeting the optimal blood glucose level for critically ill patients within moderate blood glucose level target range (8-10 mmol/L). The need for uniformed glucometrics for unbiased reporting and further research for optimal blood glucose target is required, especially in light of new technological advancements in closed-loop insulin delivery and monitoring devices. This literature review has revealed a need to call for consensus in the measurement and reporting of glycaemic control using standardized glucometrics. © 2017 British Association of Critical Care Nurses.

Adjudicating outcomes: fundamentals.

PubMed

Vannabouathong, Christopher; Saccone, Michel; Sprague, Sheila; Schemitsch, Emil H; Bhandari, Mohit

2012-07-18

The adjudication of outcomes has rarely been reported in the orthopaedic literature, although this process is commonly used and reported in clinical trials of other medical disciplines. Adjudication of outcomes provides more reliable and valid outcome assessment, especially when the outcome is subjective as in the case of fracture-healing. The successful implementation of adjudication in a clinical trial is an important and complex process. The process requires a substantial infrastructure of research personnel to oversee data collection at the clinical sites. The development of an adjudication charter specific to the study is a critical aspect of adjudication as it outlines the adjudication committee membership as well as their roles and responsibilities and defines the adjudication process and the decision rules. Web-based adjudication has facilitated the process as it allows rapid, efficient, and timely adjudication. This article provides an overview of the adjudication process, along with details on the common pearls and pitfalls associated with this method of outcomes assessment.

The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal.

PubMed

Brissos, Sofia; Veguilla, Miguel Ruiz; Taylor, David; Balanzá-Martinez, Vicent

2014-10-01

Despite their widespread use, long-acting injectable (LAI) antipsychotics (APs) are often regarded with some negativity because of the assumption of punishment, control and insufficient evolution towards psychosocial development of patients. However, LAI APs have proved effective in schizophrenia and other severe psychotic disorders because they assure stable blood levels, leading to a reduction of the risk of relapse. Therapeutic opportunities have also arisen after introduction of newer, second-generation LAI APs in recent years. Newer LAI APs are more readily dosed optimally, may be better tolerated and are better suited to integrated rehabilitation programmes. This review outlines the older and newer LAI APs available for the treatment of schizophrenia, with considerations of past and present pharmacological and therapeutic issues. Traditional, evidence-based approaches to systematic reviews and randomized clinical trials are of limited utility in this area so this paper's blending of experimental trials with observational research is particularly appropriate and effective.

Drug discovery for hearing loss: Phenotypic screening of chemical compounds on primary cultures of the spiral ganglion.

PubMed

Whitlon, Donna S

2017-06-01

In the United States there are, at present, no drugs that are specifically FDA approved to treat hearing loss. Although several clinical trials are ongoing, including one testing D-methionine that is supported by the US Army, none of these trials directly address the effect of noise exposure on cochlear spiral ganglion neurons. We recently published the first report of a systematic chemical compound screen using primary, mammalian spiral ganglion cultures in which we were able to detect a compound and others in its class that increased neurite elongation, a critical step in restoring cochlear synapses after noise induced hearing loss. Here we discuss the issues, both pro and con, that influenced the development of our approach. These considerations may be useful for future compound screens that target the same or other attributes of cochlear spiral ganglion neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

Implications of the ethical-legal framework for adolescent HIV vaccine trials--report of a consultative forum.

PubMed

Slack, Catherine; Strode, Ann; Grant, Catherine; Milford, Cecilia

2005-09-01

The ethical-legal framework in South Africa is in a period of transition, with a number of new developments changing the substantive principles and procedures for health research in the country. Some of the changing dynamics include both law reform and the review of ethical guidelines. This changing environment poses many complexities for researchers, research ethics committees and participating communities involved in planning, implementing and reviewing research with child participants, including HIV vaccine trials. This paper presents the major themes and outcomes of a consultative meeting convened by the HIV AIDS Vaccines Ethics Group in July 2004 for key stakeholder groups. At this forum participants discussed the complexities posed by a transitional and sometimes contradictory ethical-legal framework and how the framework could be improved to simultaneously promote critical research and the welfare of child participants.

New treatments for mitochondrial disease—no time to drop our standards

PubMed Central

Pfeffer, Gerald; Horvath, Rita; Klopstock, Thomas; Mootha, Vamsi K.; Suomalainen, Anu; Koene, Saskia; Hirano, Michio; Zeviani, Massimo; Bindoff, Laurence A.; Yu-Wai-Man, Patrick; Hanna, Michael; Carelli, Valerio; McFarland, Robert; Majamaa, Kari; Turnbull, Douglas M.; Smeitink, Jan; Chinnery, Patrick F.

2016-01-01

Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new biomarkers of mitochondrial disease. In this Perspectives article, we make recommendations for the design of future treatment trials in mitochondrial diseases. Patients and physicians should no longer rely on potentially biased data, with the associated costs and risks. PMID:23817350

Role of Psychotropic Medications in the Management of Anorexia Nervosa: Rationale, Evidence and Future Prospects

PubMed Central

Frank, Guido K.W.; Shott, Megan E.

2016-01-01

Anorexia nervosa is a severe psychiatric disorder without approved medication intervention. Every class of psychoactive medication has been tried to improve treatment outcome; however, randomized controlled trials have been ambiguous at best and across studies have not shown robust improvements in weight gain and recovery. Here we review the available literature on pharmacological interventions since anorexia nervosa came to greater public recognition in the 1960s. This will include a critical review of why those trials may not have been successful. We further provide a neurobiological background for the disorder and discuss how cognition, learning and emotion-regulating circuits could become treatment targets in the future. Making every effort to develop effective pharmacological treatment options for anorexia nervosa is imperative, as it continues to be a complex psychiatric disorder with high disease burden and mortality. PMID:27106297

Vemurafenib: a new treatment for BRAF-V600 mutated advanced melanoma

PubMed Central

Fisher, Rosalie; Larkin, James

2012-01-01

The BRAF inhibitor, vemurafenib, has demonstrated improved progression-free and overall survival compared with chemotherapy in a randomized trial, and represents a new standard of care in patients with advanced melanoma harboring a BRAF-V600 mutation. A BRAF-V600 mutation is identified in approximately half of patients with cutaneous melanoma, and is unequivocally a biomarker predictive of profound clinical benefit for these patients. However, acquired vemurafenib resistance is a major clinical challenge and therapy is not yet curative. A substantial body of translational research has been performed alongside clinical trials of vemurafenib, providing key insights into the molecular basis of response and resistance. This review summarizes the development of vemurafenib for the treatment of BRAF-V600 mutant melanoma and discusses how knowledge of critical signaling pathways will be applied for its optimal clinical use in future. PMID:22904646

Patients' Perceptions of an Exercise Program Delivered Following Discharge From Hospital After Critical Illness (the Revive Trial).

PubMed

Ferguson, Kathryn; Bradley, Judy M; McAuley, Daniel F; Blackwood, Bronagh; O'Neill, Brenda

2017-01-01

The REVIVE randomized controlled trial (RCT) investigated the effectiveness of an individually tailored (personalized) exercise program for patients discharged from hospital after critical illness. By including qualitative methods, we aimed to explore patients' perceptions of engaging in the exercise program. Patients were recruited from general intensive care units in 6 hospitals in Northern Ireland. Patients allocated to the exercise intervention group were invited to participate in this qualitative study. Independent semistructured interviews were conducted at 6 months after randomization. Interviews were audio-recorded, transcribed, and content analysis used to explore themes arising from the data. Of 30 patients allocated to the exercise group, 21 completed the interviews. Patients provided insight into the physical and mental sequelae they experienced following critical illness. There was a strong sense of patients' need for the exercise program and its importance for their recovery following discharge home. Key facilitators of the intervention included supervision, tailoring of the exercises to personal needs, and the exercise manual. Barriers included poor mental health, existing physical limitations, and lack of motivation. Patients' views of outcome measures in the REVIVE RCT varied. Many patients were unsure about what would be the best way of measuring how the program affected their health. This qualitative study adds an important perspective on patients' attitude to an exercise intervention following recovery from critical illness, and provides insight into the potential facilitators and barriers to delivery of the program and how programs should be evolved for future trials.

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).

Designing and conducting a randomized trial for pandemic critical illness: the 2009 H1N1 influenza pandemic.

PubMed

Annane, Djillali; Antona, Marion; Lehmann, Blandine; Kedzia, Cecile; Chevret, Sylvie

2012-01-01

To analyze the hurdles in implementing a randomized trial of corticosteroids for severe 2009 H1N1 influenza infections. This was an investigator-led, multicenter, randomized, placebo-controlled, double-blind trial of corticosteroids in ICU patients with 2009 H1N1 influenza pneumonia requiring mechanical ventilation. The feasibility of and hurdles in designing and initiating a phase III trial in a short-lived pandemic crisis were analyzed. The regulatory agency and ethics committee approved the study's scientific, financial, and ethical aspects within 4 weeks. Hydrocortisone and placebo were prepared centrally and shipped to participating hospitals within 6 weeks. The inclusion period started on November 9, 2009. From August 1, 2009 to March 8, 2010, only 205/224 ICU patients with H1N1 infections required mechanical ventilation. The peak of the wave was missed by 2-3 weeks and only 26 patients were randomized. The two main reasons for non-inclusion were patients' admission before the beginning of the trial and ICU personnel overwhelmed by clinical duties. Parallel rather than sequential regulatory and ethics approval, and preparation and masking of study drugs by local pharmacists would have allowed the study to start 1 month earlier and before the peak of the "flu" wave. A dedicated research team in each participating center would have increased the ratio of screened to randomized patients. This report highlights the main hurdles in implementing a randomized trial for a pandemic critical illness and proposes solutions for future trials.

The effectiveness of interventions to meet family needs of critically ill patients in an adult intensive care unit: a systematic review.

PubMed

Kynoch, Kate; Chang, Anne M; Coyer, Fiona

Background Attending to the needs of family members of critically ill patients is an important and necessary step in providing appropriate care for both the patient and the family. An initial search of the Cochrane and Joanna Briggs Institute Libraries did not reveal any published systematic reviews recommending effective interventions for addressing family needs of critically ill patients in an acute intensive care unit.Objectives This systematic review aims to establish best practice in addressing the needs of family members with a relative admitted to an adult critical care unit.Search strategy An extensive search of the major databases was conducted. Databases searched included: MEDLINE, CINAHL, psycINFO, Health source, Web of science, EMBASE, the Cochrane library and Database of abstracts of reviews of effects (DARE) as well as Pubmed. The search included published and unpublished studies and papers in English from 1980-2010.Selection criteria This review considered any randomised controlled trials that evaluated the effectiveness of interventions in addressing family needs of critically ill patients in an adult intensive care unit. In the absence of randomised controlled trials, other research designs such as quasi-experimental as well as before and after studies were considered for inclusion in the narrative summary to enable the identification of current approaches and possible future strategies for addressing family needs of critically ill patients.Assessment of quality Each included study was assessed by two independent reviewers using the appropriate appraisal checklist developed by the Joanna Briggs Institute.Data collection and analysis Data was extracted from the papers included in this review using standardised data extraction tools from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument package. The studies included in this review were not suitable for meta-analysis and therefore the results are presented in narrative form.Results Fourteen studies and one dissertation met the inclusion criteria and were included in the review. There were 12 quasi-experimental studies identified including 8 two or three group, pre-test/post-test studies; 1 one-way between subjects design; 1 interrupted time series and 1 two-group comparative design study. The dissertation was a quasi-experimental three group pre-test/post-test design. There were 3 prospective randomised trials included. The evidence identified includes: the use of support groups for family members of patients admitted to an intensive care unit, structured communication and/or education programs for family members, the use of leaflets or brochures to meet family information needs and open or more flexible visiting hours.Conclusion/Recommendations This review makes several recommendations for clinical practice to address family needs of patients admitted to a critical care unit, however this review highlights the need for significant further research in this area. Future intervention studies focusing on family needs could include: the use of technology such as DVD's and SMS for informing families and interventions specifically designed to improve family comfort.

The Development and Implementation of Cognitive Aids for Critical Events in Pediatric Anesthesia: The Society for Pediatric Anesthesia Critical Events Checklists.

PubMed

Clebone, Anna; Burian, Barbara K; Watkins, Scott C; Gálvez, Jorge A; Lockman, Justin L; Heitmiller, Eugenie S

2017-03-01

Cognitive aids such as checklists are commonly used in modern operating rooms for routine processes, and the use of such aids may be even more important during critical events. The Quality and Safety Committee of the Society for Pediatric Anesthesia (SPA) has developed a set of critical-event checklists and cognitive aids designed for 3 purposes: (1) as a repository of the latest evidence-based and expert opinion-based information to guide response and management of critical events, (2) as a source of just-in-time information during critical events, and (3) as a method to facilitate a shared understanding of required actions among team members during a critical event. Committee members, who represented children's hospitals from across the nation, used the recent literature and established guidelines (where available) and incorporated the expertise of colleagues at their institutions to develop these checklists, which included relevant factors to consider and steps to take in response to critical events. Human factors principles were incorporated to enhance checklist usability, facilitate error-free accomplishment, and ensure a common approach to checklist layout, formatting, structure, and design.The checklists were made available in multiple formats: a PDF version for easy printing, a mobile application, and at some institutions, a Web-based application using the anesthesia information management system. After the checklists were created, training commenced, and plans for validation were begun. User training is essential for successful implementation and should ideally include explanation of the organization of the checklists; familiarization of users with the layout, structure, and formatting of the checklists; coaching in how to use the checklists in a team environment; reviewing of the items; and simulation of checklist use. Because of the rare and unpredictable nature of critical events, clinical trials that use crisis checklists are difficult to conduct; however, recent and future simulation studies with adult checklists provide a promising avenue for future validation of the SPA checklists. This article will review the developmental steps in producing the SPA crisis checklists, including creation of content, incorporation of human factors elements, and validation in simulation. Critical-events checklists have the potential to improve patient care during emergency events, and it is hoped that incorporating the elements presented in this article will aid in successful implementation of these essential cognitive aids.

Hypocaloric vs Normocaloric Nutrition in Critically Ill Patients: A Prospective Randomized Pilot Trial.

PubMed

Petros, Sirak; Horbach, Monika; Seidel, Frank; Weidhase, Lorenz

2016-02-01

Optimal nutrition of critically ill patients is still a matter of debate. This pilot trial aimed to compare the impact of normocaloric vs hypocaloric feeding in critically ill patients in the first 7 days in the intensive care unit (ICU). The primary end point was the rate of nosocomial infections during the ICU stay. Critically ill patients requiring artificial nutrition for at least 72 hours were included within 24 hours of ICU admission and randomized into a normocaloric group (receiving 100% of their daily energy expenditure) and a hypocaloric group (receiving 50% of their daily energy expenditure). One hundred patients were included (54 in the normocaloric group and 46 in the hypocaloric group). There were 66 male and 34 female patients with a mean age of 65.8 ± 11.6 years. The mean daily caloric supply was 19.7 ± 5.7 kcal/kg for the normocaloric group and 11.3 ± 3.1 kcal/kg for the hypocaloric group (P = .0001). Insulin demand was significantly higher and gastrointestinal intolerance more frequent in the normocaloric group than in the hypocaloric group. Nosocomial infections were detected more frequently in the hypocaloric group than in the normocaloric group (26.1% vs 11.1%, respectively). The ICU mortality rate was 22.2% in the normocaloric group and 21.7% in the hypocaloric group (not significant). The hospital mortality rate was 31.5% in the normocaloric group and 37.0% in the hypocaloric group (P = .67). Hypocaloric feeding in the first 7 days in critically ill patients was associated with more nosocomial infections but less insulin demand and less gastrointestinal intolerance compared with normocaloric feeding. DRKS00000104 (German Clinical Trials Register). © 2014 American Society for Parenteral and Enteral Nutrition.

Identifying research priorities for effective retention strategies in clinical trials.

PubMed

Kearney, Anna; Daykin, Anne; Shaw, Alison R G; Lane, Athene J; Blazeby, Jane M; Clarke, Mike; Williamson, Paula; Gamble, Carrol

2017-08-31

The failure to retain patients or collect primary-outcome data is a common challenge for trials and reduces the statistical power and potentially introduces bias into the analysis. Identifying strategies to minimise missing data was the second highest methodological research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs) and is important to minimise waste in research. Our aim was to assess the current retention practices within the UK and priorities for future research to evaluate the effectiveness of strategies to reduce attrition. Seventy-five chief investigators of NIHR Health Technology Assessment (HTA)-funded trials starting between 2009 and 2012 were surveyed to elicit their awareness about causes of missing data within their trial and recommended practices for improving retention. Forty-seven CTUs registered within the UKCRC network were surveyed separately to identify approaches and strategies being used to mitigate missing data across trials. Responses from the current practice surveys were used to inform a subsequent two-round Delphi survey with registered CTUs. A consensus list of retention research strategies was produced and ranked by priority. Fifty out of seventy-five (67%) chief investigators and 33/47 (70%) registered CTUs completed the current practice surveys. Seventy-eight percent of trialists were aware of retention challenges and implemented strategies at trial design. Patient-initiated withdrawal was the most common cause of missing data. Registered CTUs routinely used newsletters, timeline of participant visits, and telephone reminders to mitigate missing data. Whilst 36 out of 59 strategies presented had been formally or informally evaluated, some frequently used strategies, such as site initiation training, have had no research to inform practice. Thirty-five registered CTUs (74%) participated in the Delphi survey. Research into the effectiveness of site initiation training, frequency of patient contact during a trial, the use of routinely collected data, the frequency and timing of reminders, triggered site training and the time needed to complete questionnaires was deemed critical. Research into the effectiveness of Christmas cards for site staff was not of critical importance. The surveys of current practices demonstrates that a variety of strategies are being used to mitigate missing data but with little evidence to support their use. Six retention strategies were deemed critically important within the Delphi survey and should be a primary focus of future retention research.

The Development of a Social Networking–Based Relatedness Intervention Among Young, First-Time Blood Donors: Pilot Study

PubMed Central

Frye, Victoria; Duffy, Louisa; France, Janis L; Kessler, Debra A; Rebosa, Mark; Shaz, Beth H; Carlson, Bruce W

2018-01-01

Background Increasing repeat blood donation behavior is a critical public health goal. According to self-determination theory, the process of developing internal motivation to give blood and an associated self-identity as a blood donor may be promoted by feelings of “relatedness” or a connection to other donors, which may be enhanced through social relations and interactions. Objective The purpose of this report it to describe the development and pilot testing of a social networking-based (Facebook) intervention condition designed to increase feelings of relatedness via virtual social interaction and support. Methods To develop the intervention condition content, images, text, polls, and video content were assembled. Ohio University college students (N=127) rated the content (82 images/text) presented by computer in random order using a scale of one to five on various dimensions of relatedness. Mean ratings were calculated and analyses of variance were conducted to assess associations among the dimensions. Based on these results, the relatedness intervention was adapted and evaluated for feasibility, acceptability, and preliminary efficacy among 24 first-time donors, aged 18 to 24 years, in a 30-day pilot trial. Paired t-tests were conducted to examine change over time in relatedness and connectedness. Results The intervention condition that was developed was acceptable and feasible. Results of the uncontrolled, preintervention, and postintervention evaluation revealed that feelings of individual-level relatedness increased significantly after the intervention. Conclusions By promoting first-time blood donor relatedness, our goal is to enhance internal motivation for donating and the integration of the blood donor identity, thus increasing the likelihood of future repeat donation. Trial Registration ClinicalTrials.gov NCT02717338; https://clinicaltrials.gov/ct2/show/NCT02717338 (Archived by WebCite at http://www.webcitation.org/6ymHRBCwu) PMID:29699961

Attention to local health burden and the global disparity of health research.

PubMed

Evans, James A; Shim, Jae-Mahn; Ioannidis, John P A

2014-01-01

Most studies on global health inequality consider unequal health care and socio-economic conditions but neglect inequality in the production of health knowledge relevant to addressing disease burden. We demonstrate this inequality and identify likely causes. Using disability-adjusted life years (DALYs) for 111 prominent medical conditions, assessed globally and nationally by the World Health Organization, we linked DALYs with MEDLINE articles for each condition to assess the influence of DALY-based global disease burden, compared to the global market for treatment, on the production of relevant MEDLINE articles, systematic reviews, clinical trials and research using animal models vs. humans. We then explored how DALYs, wealth, and the production of research within countries correlate with this global pattern. We show that global DALYs for each condition had a small, significant negative relationship with the production of each type of MEDLINE articles for that condition. Local processes of health research appear to be behind this. Clinical trials and animal studies but not systematic reviews produced within countries were strongly guided by local DALYs. More and less developed countries had very different disease profiles and rich countries publish much more than poor countries. Accordingly, conditions common to developed countries garnered more clinical research than those common to less developed countries. Many of the health needs in less developed countries do not attract attention among developed country researchers who produce the vast majority of global health knowledge--including clinical trials--in response to their own local needs. This raises concern about the amount of knowledge relevant to poor populations deficient in their own research infrastructure. We recommend measures to address this critical dimension of global health inequality.

"CriticalThinkRx" May Reduce Psychiatric Prescribing to Foster Youth: Results from an Intervention Trial

ERIC Educational Resources Information Center

Cohen, David; Lacasse, Jeffrey R.; Duan, Rui; Sengelmann, Inge

2013-01-01

Objectives: To test the potential impact of a critical curriculum on psychiatric medications designed for child welfare workers. Method: In a quasiexperimental, longitudinal study, the monthly proportion of medicated foster children and the average number of prescriptions per medicated child at Agency 1 (669 clients) exposed to the…

The validation of science virtual test to assess 7th grade students’ critical thinking on matter and heat topic (SVT-MH)

NASA Astrophysics Data System (ADS)

Sya’bandari, Y.; Firman, H.; Rusyati, L.

2018-05-01

The method used in this research was descriptive research for profiling the validation of SVT-MH to measure students’ critical thinking on matter and heat topic in junior high school. The subject is junior high school students of 7th grade (13 years old) while science teacher and expert as the validators. The instruments that used as a tool to obtain the data are rubric expert judgment (content, media, education) and rubric of readability test. There are four steps to validate SVT-MH in 7th grade Junior High School. These steps are analysis of core competence and basic competence based on Curriculum 2013, expert judgment (content, media, education), readability test and trial test (limited and larger trial test). The instrument validation resulted 30 items that represent 8 elements and 21 sub-elements to measure students’ critical thinking based on Inch in matter and heat topic. The alpha Cronbach (α) is 0.642 which means that the instrument is sufficient to measure students’ critical thinking matter and heat topic.

[Fish oil containing lipid emulsions in critically ill patients: Critical analysis and future perspectives].

PubMed

Manzanares, W; Langlois, P L

2016-01-01

Third-generation lipid emulsions (LE) are soybean oil sparing strategies with immunomodulatory and antiinflammatory effects. Current evidence supporting the use of intravenous (i.v) fish oil (FO) LE in critically ill patients requiring parenteral nutrition or receiving enteral nutrition (pharmaconutrient strategy) mainly derives from small phase ii clinical trials in heterogenous intensive care unit patient's population. Over the last three years, there have been published different systematic reviews and meta-analyses evaluating the effects of FO containing LE in the critically ill. Recently, it has been demonstrated that i.v FO based LE may be able to significantly reduce the incidence of infections as well as mechanical ventilation days and hospital length of stay. Nonetheless, more robust evidence is required before giving a definitive recommendation. Finally, we strongly believe that a dosing study is required before new phase iii clinical trials comparing i.v FO containing emulsions versus other soybean oil strategies can be conducted. Copyright © 2015 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

Cardiorespiratory performance during prolonged swimming tests with salmonids: a perspective on temperature effects and potential analytical pitfalls.

PubMed

Farrell, A P

2007-11-29

A prolonged swimming trial is the most common approach in studying steady-state changes in oxygen uptake, cardiac output and tissue oxygen extraction as a function of swimming speed in salmonids. The data generated by these sorts of studies are used here to support the idea that a maximum oxygen uptake is reached during a critical swimming speed test. Maximum oxygen uptake has a temperature optimum. Potential explanations are advanced to explain why maximum aerobic performance falls off at high temperature. The valuable information provided by critical swimming tests can be confounded by non-steady-state swimming behaviours, which typically occur with increasing frequency as salmonids approach fatigue. Two major concerns are noted. Foremost, measurements of oxygen uptake during swimming can considerably underestimate the true cost of transport near critical swimming speed, apparently in a temperature-dependent manner. Second, based on a comparison with voluntary swimming ascents in a raceway, forced swimming trials in a swim tunnel respirometer may underestimate critical swimming speed, possibly because fish in a swim tunnel respirometer are unable to sustain a ground speed.

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.

Treatment benefit and the risk of suicidality in multicenter, randomized, controlled trials of sertraline in children and adolescents.

PubMed

March, John S; Klee, Brian J; Kremer, Charlotte M E

2006-01-01

The aim of this study was to examine the balance between the benefits of treatment and the risk of suicidality in children and adolescents in multicenter, randomized, controlled trials of sertraline versus placebo. The published literature was searched for multicenter, randomized, placebo-controlled trials of sertraline for pediatric mental disorders. Four trials were identified: Two (pooled) in pediatric major depressive disorder (MDD; Wagner 2003) and two in obsessive-compulsive disorder (OCD; March et al. 1998; POTS Team 2004). Using intent-to-treat (ITT) analysis populations, the authors calculated the number needed to treat (NNT) for response and remission and the number needed to harm (NNH) for suicidality, and their ratio, for each clinical trial. NNTs ranged from 2 to 10, indicating clinically meaningful benefits. Benefit was greater for OCD than for MDD, and for adolescents as compared with children in MDD. No age effect was apparent for OCD. Suicidality was reported in 8 patients (5 assigned to sertraline and 3 assigned to placebo). All but 1 (a placebo-treated patient in the Pfizer OCD trial) were enrolled in the sertraline MDD trial. The NNH for suicidality in MDD was 64. Treatment emergent suicidality was more common in children (NNH 28.7) than in adolescents (NNH 706.3). Because no patient developed suicidality in sertraline-treated OCD patients, the NNH for sertraline in OCD approaches infinity. With the stipulation that doctor and patient preferences necessarily play a critical role in the choice of treatment, NNT to NNH ratios indicate a positive benefit-to-risk ratio for sertraline in adolescents with MDD and in patients of all ages with OCD.

The uses and abuses of Vitamin D compounds in chronic kidney disease-mineral bone disease (CKD-MBD).

PubMed

Goldsmith, D J A; Massy, Z A; Brandenburg, V

2014-11-01

Vitamin D is of paramount importance to skeletal development, integrity and health. Vitamin D homeostatis is typically deranged in a number of chronic conditions, of which chronic kidney disease is one of the most important. The use of vitamin D based therapy to target secondary hyperparathyroidism is now several decades old, and there is a large body of clinical practice, experience, guidelines and research to underpin this. However, there are many unknowns, of significant clinical relevance. Amongst which is what "species" of vitamin D we should be using, in what patient, and, under what conditions. Sadly, there has been a real dearth of randomised controlled trials, and trials with outputs of clinical relevance, which means our clinical practice has not developed and refined adequately ove the last 4 decades. This article will discuss the vexed but critical questions of which vitamin D therapies might suit which kidney patients, and will high-light the many important clinical questions which urgently require answering. Copyright © 2014. Published by Elsevier Inc.

Cardiac surgery-associated acute kidney injury.

PubMed

Vives, Marc; Wijeysundera, Duminda; Marczin, Nandor; Monedero, Pablo; Rao, Vivek

2014-05-01

Acute kidney injury develops in up to 30% of patients who undergo cardiac surgery, with up to 3% of patients requiring dialysis. The requirement for dialysis after cardiac surgery is associated with an increased risk of infection, prolonged stay in critical care units and long-term need for dialysis. The development of acute kidney injury is independently associated with substantial short- and long-term morbidity and mortality. Its pathogenesis involves multiple pathways. Haemodynamic, inflammatory, metabolic and nephrotoxic factors are involved and overlap each other leading to kidney injury. Clinical studies have identified predictors for cardiac surgery-associated acute kidney injury that can be used effectively to determine the risk for acute kidney injury in patients undergoing cardiac surgery. High-risk patients can be targeted for renal protective strategies. Nonetheless, there is little compelling evidence from randomized trials supporting specific interventions to protect or prevent acute kidney injury in cardiac surgery patients. Several strategies have shown some promise, including less invasive procedures in those at greatest risk, natriuretic peptide, fenoldopam, preoperative hydration, preoperative optimization of anaemia and postoperative early use of renal replacement therapy. The efficacy of larger-scale trials remains to be confirmed.

Genotoxicity of retroviral hematopoietic stem cell gene therapy

PubMed Central

Trobridge, Grant D

2012-01-01

Introduction Retroviral vectors have been developed for hematopoietic stem cell (HSC) gene therapy and have successfully cured X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy, and Wiskott-Aldrich syndrome. However, in HSC gene therapy clinical trials, genotoxicity mediated by integrated vector proviruses has led to clonal expansion, and in some cases frank leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity with the aim of developing safer vectors and safer gene therapy protocols. These genotoxicity studies are critical to advancing HSC gene therapy. Areas covered This review provides an introduction to the mechanisms of retroviral vector genotoxicity. It also covers advances over the last 20 years in designing safer gene therapy vectors, and in integration site analysis in clinical trials and large animal models. Mechanisms of retroviral-mediated genotoxicity, and the risk factors that contribute to clonal expansion and leukemia in HSC gene therapy are introduced. Expert opinion Continued research on virus–host interactions and next-generation vectors should further improve the safety of future HSC gene therapy vectors and protocols. PMID:21375467

Improving the design of maintenance studies for bipolar disorder.

PubMed

Gitlin, Michael J; Abulseoud, Osama; Frye, Mark A

2010-08-01

In contrast to the trial design of acute mania studies, there is no standard design for bipolar maintenance studies. Over the past 15 years, the design of monotherapy maintenance studies in bipolar disorder has evolved significantly, but recent study designs continue to differ in important ways. We reviewed the design of recent controlled bipolar maintenance studies, using PubMed, from August 2006 to August 2009, examining the strengths and weaknesses of different study design features. Design differences are sufficiently important that the disparate results across maintenance studies may reflect either true differences in medication efficacy or the effects of these design differences on outcome. Design elements such as recent episode polarity, stabilization criteria, using enriched versus nonenriched samples, length of stabilization before randomization, length of experimental phase, and recurrence outcome criteria are critical factors that differ widely across studies and likely play a role in study outcome. As consensus for trial designs for bipolar maintenance therapy is developed, it will be easier to develop algorithms for maintenance treatment based on results from studies as opposed to clinical opinions.

Development of quality control and instrumentation performance metrics for diffuse optical spectroscopic imaging instruments in the multi-center clinical environment

NASA Astrophysics Data System (ADS)

Keene, Samuel T.; Cerussi, Albert E.; Warren, Robert V.; Hill, Brian; Roblyer, Darren; Leproux, AnaÑ--s.; Durkin, Amanda F.; O'Sullivan, Thomas D.; Haghany, Hosain; Mantulin, William W.; Tromberg, Bruce J.

2013-03-01

Instrument equivalence and quality control are critical elements of multi-center clinical trials. We currently have five identical Diffuse Optical Spectroscopic Imaging (DOSI) instruments enrolled in the American College of Radiology Imaging Network (ACRIN, #6691) trial located at five academic clinical research sites in the US. The goal of the study is to predict the response of breast tumors to neoadjuvant chemotherapy in 60 patients. In order to reliably compare DOSI measurements across different instruments, operators and sites, we must be confident that the data quality is comparable. We require objective and reliable methods for identifying, correcting, and rejecting low quality data. To achieve this goal, we developed and tested an automated quality control algorithm that rejects data points below the instrument noise floor, improves tissue optical property recovery, and outputs a detailed data quality report. Using a new protocol for obtaining dark-noise data, we applied the algorithm to ACRIN patient data and successfully improved the quality of recovered physiological data in some cases.

Emerging lipid-lowering drugs: squalene synthase inhibitors.

PubMed

Elsayed, Raghda K; Evans, Jeffery D

2008-06-01

Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism. The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors. A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms "squalene synthase inhibitors" or "lapaquistat". All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis. Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug-drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.

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

PubMed Central

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

2014-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2013-12-01

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

Guidelines for the Design and Conduct of Clinical Studies in Knee Articular Cartilage Repair

PubMed Central

Mithoefer, Kai; Saris, Daniel B.F.; Farr, Jack; Kon, Elizaveta; Zaslav, Kenneth; Cole, Brian J.; Ranstam, Jonas; Yao, Jian; Shive, Matthew; Levine, David; Dalemans, Wilfried; Brittberg, Mats

2011-01-01

Objective: To summarize current clinical research practice and develop methodological standards for objective scientific evaluation of knee cartilage repair procedures and products. Design: A comprehensive literature review was performed of high-level original studies providing information relevant for the design of clinical studies on articular cartilage repair in the knee. Analysis of cartilage repair publications and synopses of ongoing trials were used to identify important criteria for the design, reporting, and interpretation of studies in this field. Results: Current literature reflects the methodological limitations of the scientific evidence available for articular cartilage repair. However, clinical trial databases of ongoing trials document a trend suggesting improved study designs and clinical evaluation methodology. Based on the current scientific information and standards of clinical care, detailed methodological recommendations were developed for the statistical study design, patient recruitment, control group considerations, study endpoint definition, documentation of results, use of validated patient-reported outcome instruments, and inclusion and exclusion criteria for the design and conduct of scientifically sound cartilage repair study protocols. A consensus statement among the International Cartilage Repair Society (ICRS) and contributing authors experienced in clinical trial design and implementation was achieved. Conclusions: High-quality clinical research methodology is critical for the optimal evaluation of current and new cartilage repair technologies. In addition to generally applicable principles for orthopedic study design, specific criteria and considerations apply to cartilage repair studies. Systematic application of these criteria and considerations can facilitate study designs that are scientifically rigorous, ethical, practical, and appropriate for the question(s) being addressed in any given cartilage repair research project. PMID:26069574

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

PubMed

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

2013-12-01

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

RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group.

PubMed

Schwartz, Lawrence H; Seymour, Lesley; Litière, Saskia; Ford, Robert; Gwyther, Stephen; Mandrekar, Sumithra; Shankar, Lalitha; Bogaerts, Jan; Chen, Alice; Dancey, Janet; Hayes, Wendy; Hodi, F Stephen; Hoekstra, Otto S; Huang, Erich P; Lin, Nancy; Liu, Yan; Therasse, Patrick; Wolchok, Jedd D; de Vries, Elisabeth

2016-07-01

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation. Copyright © 2016. Published by Elsevier Ltd.

Biomarkers and surrogate endpoints in glaucoma clinical trials.

PubMed

Medeiros, Felipe A

2015-05-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. 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.

SPIRIT trial: A phase III pragmatic trial of an advance care planning intervention in ESRD.

PubMed

Song, Mi-Kyung; Unruh, Mark L; Manatunga, Amita; Plantinga, Laura C; Lea, Janice; Jhamb, Manisha; Kshirsagar, Abhijit V; Ward, Sandra E

2018-01-01

Advance care planning (ACP) is a central tenet of dialysis care, but the vast majority of dialysis patients report never engaging in ACP discussions with their care providers. Over the last decade, we have developed and iteratively tested SPIRIT (Sharing Patient's Illness Representation to Increase Trust), a theory-based, patient- and family-centered advance care planning intervention. SPIRIT is a six-step, two-session, face-to-face intervention to promote cognitive and emotional preparation for end-of-life decision making for patients with ESRD and their surrogates. In these explanatory trials, SPIRIT was delivered by trained research nurses. Findings consistently revealed that patients and surrogates in SPIRIT showed significant improvement in preparedness for end-of-life decision making, and surrogates in SPIRIT reported significantly improved post-bereavement psychological outcomes after the patient's death compared to a no treatment comparison condition. As a critical next step, we are conducting an effectiveness-implementation study. This study is a multicenter, clinic-level cluster randomized pragmatic trial to evaluate the effectiveness of SPIRIT delivered by dialysis care providers as part of routine care in free-standing outpatient dialysis clinics, compared to usual care plus delayed SPIRIT implementation. Simultaneously, we will evaluate the implementation of SPIRIT, including sustainability. We will recruit 400 dyads of patients at high risk of death in the next year and their surrogates from 30 dialysis clinics in four states. This trial of SPIRIT will generate novel, meaningful insights about improving ACP in dialysis care. ClinicalTrials.govNCT03138564, registered 05/01/2017. Copyright © 2017 Elsevier Inc. All rights reserved.

Plasma-Generating Glucose Monitor Accuracy Demonstrated in an Animal Model

PubMed Central

Magarian, Peggy; Sterling, Bernhard

2009-01-01

Introduction Four randomized controlled trials have compared mortality and morbidity of tight glycemic control versus conventional glucose for intensive care unit (ICU) patients. Two trials showed a positive outcome. However, one single-center trial and a large multicenter trial had negative results. The positive trials used accurate portable lab analyzers. The negative trial allowed the use of meters. The portable analyzer measures in filtered plasma, minimizing the interference effects. OptiScan Biomedical Corporation is developing a continuous glucose monitor using centrifuged plasma and mid-infrared spectroscopy for use in ICU medicine. The OptiScanner draws approximately 0.1 ml of blood every 15 min and creates a centrifuged plasma sample. Internal quality control minimizes sample preparation error. Interference adjustment using this technique has been presented at the Society of Critical Care Medicine in separate studies since 2006. Method A good laboratory practice study was conducted on three Yorkshire pigs using a central venous catheter over 6 h while performing a glucose challenge. Matching Yellow Springs Instrument glucose readings were obtained. Results Some 95.7% of the predicted values were in the Clarke Error Grid A zone and 4.3% in the B zone. Of those in the B zone, all were within 3.3% of the A zone boundaries. The coefficient of determination (R2) was 0.993. The coefficient of variance was 5.02%. Animal necropsy and blood panels demonstrated safety. Conclusion The OptiScanner investigational device performed safely and accurately in an animal model. Human studies using the device will begin soon. PMID:20144396

Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients

PubMed Central

Loftus, Tyler J; Mira, Juan C; Ozrazgat-Baslanti, Tezcan; Ghita, Gabriella L; Wang, Zhongkai; Stortz, Julie A; Brumback, Babette A; Bihorac, Azra; Segal, Mark S; Anton, Stephen D; Leeuwenburgh, Christiaan; Mohr, Alicia M; Efron, Philip A; Moldawer, Lyle L; Moore, Frederick A; Brakenridge, Scott C

2017-01-01

Introduction Sepsis is a common, costly and morbid cause of critical illness in trauma and surgical patients. Ongoing advances in sepsis resuscitation and critical care support strategies have led to improved in-hospital mortality. However, these patients now survive to enter state of chronic critical illness (CCI), persistent low-grade organ dysfunction and poor long-term outcomes driven by the persistent inflammation, immunosuppression and catabolism syndrome (PICS). The Sepsis and Critical Illness Research Center (SCIRC) was created to provide a platform by which the prevalence and pathogenesis of CCI and PICS may be understood at a mechanistic level across multiple medical disciplines, leading to the development of novel management strategies and targeted therapies. Methods Here, we describe the design, study cohort and standard operating procedures used in the prospective study of human sepsis at a level 1 trauma centre and tertiary care hospital providing care for over 2600 critically ill patients annually. These procedures include implementation of an automated sepsis surveillance initiative, augmentation of clinical decisions with a computerised sepsis protocol, strategies for direct exportation of quality-filtered data from the electronic medical record to a research database and robust long-term follow-up. Ethics and dissemination This study has been registered at ClinicalTrials.gov, approved by the University of Florida Institutional Review Board and is actively enrolling subjects. Dissemination of results is forthcoming. PMID:28765125

Efficient design of clinical trials and epidemiological research: is it possible?

PubMed

Lauer, Michael S; Gordon, David; Wei, Gina; Pearson, Gail

2017-08-01

Randomized clinical trials and large-scale, cohort studies continue to have a critical role in generating evidence in cardiovascular medicine; however, the increasing concern is that ballooning costs threaten the clinical trial enterprise. In this Perspectives article, we discuss the changing landscape of clinical research, and clinical trials in particular, focusing on reasons for the increasing costs and inefficiencies. These reasons include excessively complex design, overly restrictive inclusion and exclusion criteria, burdensome regulations, excessive source-data verification, and concerns about the effect of clinical research conduct on workflow. Thought leaders have called on the clinical research community to consider alternative, transformative business models, including those models that focus on simplicity and leveraging of digital resources. We present some examples of innovative approaches by which some investigators have successfully conducted large-scale, clinical trials at relatively low cost. These examples include randomized registry trials, cluster-randomized trials, adaptive trials, and trials that are fully embedded within digital clinical care or administrative platforms.

Liquid biopsy and its role in an advanced clinical trial for lung cancer.

PubMed

Johann, Donald J; Steliga, Mathew; Shin, Ik J; Yoon, Donghoon; Arnaoutakis, Konstantinos; Hutchins, Laura; Liu, Meeiyueh; Liem, Jason; Walker, Karl; Pereira, Andy; Yang, Mary; Jeffus, Susanne K; Peterson, Erich; Xu, Joshua

2018-02-01

Liquid biopsy methodologies, for the purpose of plasma genotyping of cell-free DNA (cfDNA) of solid tumors, are a new class of novel molecular assays. Such assays are rapidly entering the clinical sphere of research-based monitoring in translational oncology, especially for thoracic malignancies. Potential applications for these blood-based cfDNA assays include: (i) initial diagnosis, (ii) response to therapy and follow-up, (iii) tumor evolution, and (iv) minimal residual disease evaluation. Precision medicine will benefit from cutting-edge molecular diagnostics, especially regarding treatment decisions in the adjuvant setting, where avoiding over-treatment and unnecessary toxicity are paramount. The use of innovative genetic analysis techniques on individual patient tumor samples is being pursued in several advanced clinical trials. Rather than using a categorical treatment plan, the next critical step of therapeutic decision making is providing the "right" cancer therapy for an individual patient, including correct dose and timeframe based on the molecular analysis of the tumor in question. Per the 21st Century Cures Act, innovative clinical trials are integral for biomarker and drug development. This will include advanced clinical trials utilizing: (i) innovative assays, (ii) molecular profiling with cutting-edge bioinformatics, and (iii) clinically relevant animal or tissue models. In this paper, a mini-review addresses state-of-the-art liquid biopsy approaches. Additionally, an on-going advanced clinical trial for lung cancer with novelty through synergizing liquid biopsies, co-clinical trials, and advanced bioinformatics is also presented. Impact statement Liquid biopsy technology is providing a new source for cancer biomarkers, and adds new dimensions in advanced clinical trials. Utilizing a non-invasive routine blood draw, the liquid biopsy provides abilities to address perplexing issues of tumor tissue heterogeneity by identifying mutations in both primary and metastatic lesions. Regarding the assessment of response to cancer therapy, the liquid biopsy is not ready to replace medical imaging, but adds critical new information; for instance, through a temporal assessment of quantitative circulating tumor DNA (ctDNA) assay results, and importantly, the ability to monitor for signs of resistance, via emerging clones. Adjuvant therapy may soon be considered based on a quantitative cfDNA assay. As sensitivity and specificity of the technology continue to progress, cancer screening and prevention will improve and save countless lives by finding the cancer early, so that a routine surgery may be all that is required for a definitive cure.

Gestational diabetes from A to Z

PubMed Central

Mirghani Dirar, AbdelHameed; Doupis, John

2017-01-01

Gestational diabetes mellitus (GDM) is defined as any degree of hyperglycaemia that is recognized for the first time during pregnancy. This definition includes cases of undiagnosed type 2 diabetes mellitus (T2DM) identified early in pregnancy and true GDM which develops later. GDM constitutes a greater impact on diabetes epidemic as it carries a major risk of developing T2DM to the mother and foetus later in life. In addition, GDM has also been linked with cardiometabolic risk factors such as lipid abnormalities, hypertensive disorders and hyperinsulinemia. These might result in later development of cardiovascular disease and metabolic syndrome. The understanding of the different risk factors, the pathophysiological mechanisms and the genetic factors of GDM, will help us to identify the women at risk, to develop effective preventive measures and to provide adequate management of the disease. Clinical trials have shown that T2DM can be prevented in women with prior GDM, by intensive lifestyle modification and by using pioglitazone and metformin. However, a matter of controversy surrounding both screening and management of GDM continues to emerge, despite several recent well-designed clinical trials tackling these issues. The aim of this manuscript is to critically review GDM in a detailed and comprehensive manner, in order to provide a scientific analysis and updated write-up of different related aspects. PMID:29290922

What are the roles and valued attributes of a Trial Steering Committee? Ethnographic study of eight clinical trials facing challenges.

PubMed

Daykin, Anne; Selman, Lucy E; Cramer, Helen; McCann, Sharon; Shorter, Gillian W; Sydes, Matthew R; Gamble, Carrol; Macefield, Rhiannon; Lane, J Athene; Shaw, Alison

2016-07-01

Clinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference. An ethnographic study was conducted during 2013-2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC. Eight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a 'critical friend' or a provider of 'tough love'. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise. We found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs' quality assurance role. Concerns were raised regarding whose interests are served by funders' criteria of independence; in particular, funders' selection of TSC members was thought to potentially inhibit TSCs' ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.

Are randomised controlled trials positivist? Reviewing the social science and philosophy literature to assess positivist tendencies of trials of social interventions in public health and health services.

PubMed

Bonell, Chris; Moore, Graham; Warren, Emily; Moore, Laurence

2018-04-19

We have previously proposed that trials of social interventions can be done within a "realist" research paradigm. Critics have countered that such trials are irredeemably positivist and asked us to explain our philosophical position. We set out to explore what is meant by positivism and whether trials adhere to its tenets (of necessity or in practice) via a narrative literature review of social science and philosophical discussions of positivism, and of the trials literature and three case studies of trials. The philosophical literature described positivism as asserting: (1) the epistemic primacy of sensory information; (2) the requirement that theoretical terms equate with empirical terms; (3) the aim of developing universal laws; and (4) the unity of method between natural and social sciences. Regarding (1), it seems that rather than embodying the epistemic primacy of sensory data, randomised controlled trials (RCTs) of social interventions in health embrace an anti-positivist approach aiming to test hypotheses derived deductively from prior theory. Considering (2), while some RCTs of social interventions appear to limit theorisation to concepts with empirical analogues, others examine interventions underpinned by theories engaging with mechanisms and contextual contingencies not all of which can be measured. Regarding (3), while some trialists and reviewers in the health field do limit their role to estimating statistical trends as a mechanistic form of generalisation, this is not an inevitable feature of RCT-based research. Trials of social interventions can instead aim to generalise at the level of theory which specifies how mechanisms are contingent on context. In terms of (4), while RCTs are used to examine biomedical as well as social interventions in health, RCTs of social interventions are often distinctive in using qualitative analyses of data on participant accounts to examine questions of meaning and agency not pursued in the natural sciences. We conclude that the most appropriate paradigm for RCTs of social interventions is realism not positivism.

The PACE trial: It's time to broaden perceptions and move on.

PubMed

Petrie, Keith J; Weinman, John

2017-08-01

The continued critiques of the PACE trial highlight how differing beliefs about the causes of chronic fatigue syndrome still influence how scientific studies in this area are accepted and evaluated. Causal beliefs about chronic fatigue syndrome and a modern version of Cartesian dualism are important in understanding the reaction to the PACE trial. The continued debate on the PACE trial seems to miss the fact that science is incremental. An unfortunate outcome of the PACE controversy and intimidation of researchers may be less research in the area. It is time to move on from criticism and collect more data on effective treatments.

Rosuvastatin and the JUPITER trial: critical appraisal of a lifeless planet in the galaxy of primary prevention.

PubMed

López, Antonio; Wright, James M

2012-01-01

In November 2008, the JUPITER trial was published in the New England Journal of Medicine. JUPITER is an acronym for Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. It was an AstraZeneca sponsored randomized double-blind trial comparing rosuvastatin 20 mg with placebo in 17,802 apparently healthy men and women with LDL cholesterol <3.4 mmol/L and elevated C-reactive protein (CRP). The results of the JUPITER trial have been widely publicized, and based on the trial, the main regulatory agencies have approved rosuvastatin for the indication of primary prevention of vascular events. However, the interpretation and clinical implications of the JUPITER trial have been questioned and remain controversial. The objective of this commentary is to evaluate the relevance, design, results, and conclusions of the JUPITER study.

A performance improvement case study in aircraft maintenance and its implications for hazard identification.

PubMed

Ward, Marie; McDonald, Nick; Morrison, Rabea; Gaynor, Des; Nugent, Tony

2010-02-01

Aircraft maintenance is a highly regulated, safety critical, complex and competitive industry. There is a need to develop innovative solutions to address process efficiency without compromising safety and quality. This paper presents the case that in order to improve a highly complex system such as aircraft maintenance, it is necessary to develop a comprehensive and ecologically valid model of the operational system, which represents not just what is meant to happen, but what normally happens. This model then provides the backdrop against which to change or improve the system. A performance report, the Blocker Report, specific to aircraft maintenance and related to the model was developed gathering data on anything that 'blocks' task or check performance. A Blocker Resolution Process was designed to resolve blockers and improve the current check system. Significant results were obtained for the company in the first trial and implications for safety management systems and hazard identification are discussed. Statement of Relevance: Aircraft maintenance is a safety critical, complex, competitive industry with a need to develop innovative solutions to address process and safety efficiency. This research addresses this through the development of a comprehensive and ecologically valid model of the system linked with a performance reporting and resolution system.

The International College of Neuropsychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 1: Background and Methods of the Development of Guidelines

PubMed Central

Young, Allan; Yatham, Lakshmi; Grunze, Heinz; Vieta, Eduard; Blier, Pierre; Moeller, Hans Jurgen; Kasper, Siegfried

2017-01-01

Abstract Background: This paper includes a short description of the important clinical aspects of Bipolar Disorder with emphasis on issues that are important for the therapeutic considerations, including mixed and psychotic features, predominant polarity, and rapid cycling as well as comorbidity. Methods: The workgroup performed a review and critical analysis of the literature concerning grading methods and methods for the development of guidelines. Results: The workgroup arrived at a consensus to base the development of the guideline on randomized controlled trials and related meta-analyses alone in order to follow a strict evidence-based approach. A critical analysis of the existing methods for the grading of treatment options was followed by the development of a new grading method to arrive at efficacy and recommendation levels after the analysis of 32 distinct scenarios of available data for a given treatment option. Conclusion: The current paper reports details on the design, method, and process for the development of CINP guidelines for the treatment of Bipolar Disorder. The rationale and the method with which all data and opinions are combined in order to produce an evidence-based operationalized but also user-friendly guideline and a specific algorithm are described in detail in this paper. PMID:27815414

The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design

PubMed Central

Cozza, Giorgio

2017-01-01

Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by “trial and error testing”. In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising. PMID:28230762

Motor planning in children with cerebral palsy: A longitudinal perspective.

PubMed

Lust, Jessica Mireille; Spruijt, Steffie; Wilson, Peter H; Steenbergen, Bert

2018-08-01

Motor planning is important for daily functioning. Deficits in motor planning can result in slow, inefficient, and clumsy motor behavior and are linked to disruptions in performance of activities of daily living in children with cerebral palsy (CP). However, the evidence in CP is primarily based on cross-sectional data. Data are presented on the development of motor planning in children with CP using a longitudinal design with three measurement occasions, each separated by 1 year. Twenty-two children with CP (9 boys, 13 girls; age in years;months, M = 7;1, SD = 1;2) and 22 age-matched controls (10 boys, 12 girls, M  = 7;1, SD = 1;3) participated. Children performed a bar transport task in which some conditions ("critical angles") required participants to sacrifice initial posture comfort in order to achieve end-state comfort. Performance on critical trials was analyzed using linear growth curve modeling. In general, children with CP showed poor end-state planning for critical angles. Importantly, unlike in controls, motor planning ability did not improve across the three measurement occasions in children with CP. These longitudinal results show that motor planning issues in CP do not resolve with development over childhood. Strategies to enhance motor planning are suggested for intervention.

Exploring the experiences of substitute decision-makers with an exception to consent in a paediatric resuscitation randomised controlled trial: study protocol for a qualitative research study.

PubMed

Parker, Melissa J; de Laat, Sonya; Schwartz, Lisa

2016-09-13

Prospective informed consent is required for most research involving human participants; however, this is impracticable under some circumstances. The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS) outlines the requirements for research involving human participants in Canada. The need for an exception to consent (deferred consent) is recognised and endorsed in the TCPS for research in individual medical emergencies; however, little is known about substitute decision-maker (SDM) experiences. A paediatric resuscitation trial (SQUEEZE) (NCT01973907) using an exception to consent process began enrolling at McMaster Children's Hospital in January 2014. This qualitative research study aims to generate new knowledge on SDM experiences with the exception to consent process as implemented in a randomised controlled trial. The SDMs of children enrolled into the SQUEEZE pilot trial will be the sampling frame from which ethics study participants will be derived. Qualitative research study involving individual interviews and grounded theory methodology. SDMs for children enrolled into the SQUEEZE pilot trial. Up to 25 SDMs. Qualitative methodology: SDMs will be invited to participate in the qualitative ethics study. Interviews with consenting SDMs will be conducted in person or by telephone, taped and professionally transcribed. Participants will be encouraged to elaborate on their experience of being asked to consent after the fact and how this process occurred. Data gathering and analysis will be undertaken simultaneously. The investigators will collaborate in developing the coding scheme, and data will be coded using NVivo. Emerging themes will be identified. This research represents a rare opportunity to interview parents/guardians of critically ill children enrolled into a resuscitation trial without their knowledge or prior consent. Findings will inform implementation of the exception to consent process in the planned definitive SQUEEZE trial and support development of evidence-based ethics guidelines. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The Efficacy of Phonics-Based Instruction of English as a Second Language in an Italian High School: A Randomised Controlled Trial

ERIC Educational Resources Information Center

Coates, Robert Alexander Graham; Gorham, Judith; Nicholas, Richard

2017-01-01

Recent neurological breakthroughs in our understanding of the Critical Period Hypothesis and prosody may suggest strategies on how phonics instruction could improve L2 language learning and in particular phoneme/grapheme decoding. We therefore conducted a randomised controlled-trial on the application of prosody and phonics techniques, to improve…

Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma

PubMed Central

Bassiri, Hamid; Benavides, Adriana; Haber, Michelle; Gilmour, Susan K.; Norris, Murray D.

2015-01-01

Neuroblastoma is a childhood tumor in which MYC oncogenes are commonly activated to drive tumor progression. Survival for children with high-risk neuroblastoma remains poor despite treatment that incorporates high-dose chemotherapy, stem cell support, surgery, radiation therapy and immunotherapy. More effective and less toxic treatments are sought and one approach under clinical development involves re-purposing the anti-protozoan drug difluoromethylornithine (DFMO; Eflornithine) as a neuroblastoma therapeutic. DFMO is an irreversible inhibitor of ornithine decarboxylase (Odc), a MYC target gene, bona fide oncogene, and the rate-limiting enzyme in polyamine synthesis. DFMO is approved for the treatment of Trypanosoma brucei gambiense encephalitis (“African sleeping sickness”) since polyamines are essential for the proliferation of these protozoa. However, polyamines are also critical for mammalian cell proliferation and the finding that MYC coordinately regulates all aspects of polyamine metabolism suggests polyamines may be required to support cancer promotion by MYC. Pre-emptive blockade of polyamine synthesis is sufficient to block tumor initiation in an otherwise fully penetrant transgenic mouse model of neuroblastoma driven by MYCN, underscoring the necessity of polyamines in this process. Moreover, polyamine depletion regimens exert potent anti-tumor activity in pre-clinical models of established neuroblastoma as well, in combination with numerous chemotherapeutic agents and even in tumors with unfavorable genetic features such as MYCN, ALK or TP53 mutation. This has led to the testing of DFMO in clinical trials for children with neuroblastoma. Current trial designs include testing lower dose DFMO alone (2,000 mg/m2/day) starting at the completion of standard therapy, or higher doses combined with chemotherapy (up to 9,000 mg/m2/day) for patients with relapsed disease that has progressed. In this review we will discuss important considerations for the future design of DFMO-based clinical trials for neuroblastoma, focusing on the need to better define the principal mechanisms of anti-tumor activity for polyamine depletion regimens. Putative DFMO activities that are both cancer cell intrinsic (targeting the principal oncogenic driver, MYC) and cancer cell extrinsic (altering the tumor microenvironment to support anti-tumor immunity) will be discussed. Understanding the mechanisms of DFMO activity are critical in determining how it might be best leveraged in upcoming clinical trials. This mechanistic approach also provides a platform by which iterative pre-clinical testing using translational tumor models may complement our clinical approaches. PMID:26835380

Understanding how pain education causes changes in pain and disability: protocol for a causal mediation analysis of the PREVENT trial.

PubMed

Lee, Hopin; Moseley, G Lorimer; Hübscher, Markus; Kamper, Steven J; Traeger, Adrian C; Skinner, Ian W; McAuley, James H

2015-07-01

Pain education is a complex intervention developed to help clinicians manage low back pain. Although complex interventions are usually evaluated by their effects on outcomes, such as pain or disability, most do not directly target these outcomes; instead, they target intermediate factors that are presumed to be associated with the outcomes. The mechanisms underlying treatment effects, or the effect of an intervention on an intermediate factor and its subsequent effect on outcome, are rarely investigated in clinical trials. This leaves a gap in the evidence for understanding how treatments exert their effects on outcomes. Mediation analysis provides a method for identifying and quantifying the mechanisms that underlie interventions. To determine whether the effect of pain education on pain and disability is mediated by changes in self-efficacy, catastrophisation and back pain beliefs. Causal mediation analysis of the PREVENT randomised controlled trial. Two hundred and two participants with acute low back pain from primary care clinics in the Sydney metropolitan area. Participants will be randomised to receive either 'pain education' (intervention group) or 'sham education' (control group). All outcome measures (including patient characteristics), primary outcome measures (pain and disability), and putative mediating variables (self-efficacy, catastrophisation and back pain beliefs) will be measured prior to randomisation. Putative mediators and primary outcome measures will be measured 1 week after the intervention, and primary outcome measures will be measured 3 months after the onset of low back pain. Causal mediation analysis under the potential outcomes framework will be used to test single and multiple mediator models. A sensitivity analysis will be conducted to evaluate the robustness of the estimated mediation effects on the influence of violating sequential ignorability--a critical assumption for causal inference. Mediation analysis of clinical trials can estimate how much the total effect of the treatment on the outcome is carried through an indirect path. Using mediation analysis to understand these mechanisms can generate evidence that can be used to tailor treatments and optimise treatment effects. In this study, the causal mediation effects of a pain education intervention for acute non-specific low back pain will be estimated. This knowledge is critical for further development and refinement of interventions for conditions such as low back pain. Copyright © 2015 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.

Intravenous immunoglobulin and Alzheimer's disease: what now?

PubMed

Loeffler, David A

2013-06-05

Intravenous immunoglobulin (IVIG) products are prepared from purified plasma immunoglobulins from large numbers of healthy donors. Pilot studies with the IVIG preparations Octagam and Gammagard in individuals with mild-to-moderate Alzheimer's disease (AD) suggested stabilization of cognitive functioning in these patients, and a phase II trial with Gammagard reported similar findings. However, subsequent reports from Octagam's phase II trial and Gammagard's phase III trial found no evidence for slowing of AD progression. Although these recent disappointing results have reduced enthusiasm for IVIG as a possible treatment for AD, it is premature to draw final conclusions; a phase III AD trial with the IVIG product Flebogamma is still in progress. IVIG was the first attempt to use multiple antibodies to treat AD. This approach should be preferable to administration of single monoclonal antibodies in view of the multiple processes that are thought to contribute to AD neuropathology. Development of "AD-specific" preparations with higher concentrations of selected human antibodies and perhaps modified in other ways (such as increasing their anti-inflammatory effects and/or ability to cross the blood-brain barrier) should be considered. Such preparations, if generated with recombinant technology, could overcome the problems of high cost and limited supplies, which have been major concerns relating to the possible widespread use of IVIG in AD patients. This review summarizes the recent AD IVIG trials and discusses the major issues relating to possible use of IVIG for treating AD, as well as the critical questions which remain.

Randomized Controlled Trial of Nuevo Amanecer: A Peer-delivered Stress Management Intervention for Spanish-speaking Latinas with Breast Cancer

PubMed Central

Nápoles, Anna María; Santoyo-Olsson, Jasmine; Ortiz, Carmen; Gregorich, Steven; Lee, Howard E.; Duron, Ysabel; Graves, Kristi; Luce, Judith A.; McGuire, Peggy; Díaz-Méndez, Marynieves; Stewart, Anita L.

2014-01-01

Background Latinas with breast cancer suffer symptom and psychosocial health disparities. Effective interventions have not been developed for or tested in this population. Purpose We describe community-based participatory research methods used to develop and implement the Nuevo Amanecer program, a culturally tailored, peer-delivered cognitive-behavioral stress management intervention for low-income Spanish-speaking Latinas with breast cancer, and unique considerations in implementing a randomized controlled trial to test the program in community settings. Methods We applied an implementation science framework to delineate the methodological phases used to develop and implement the Nuevo Amanecer program and trial, emphasizing community engagement processes. Results In phase 1, we established project infrastructure: academic and community Co-Principal Investigators, community partners, community advisory board, steering committee, and funding. In phase 2, we identified three program inputs: formative research, a community best practices model, and an evidence-based intervention tested in non-Latinas. In phase 3, we created the new program by integrating and adapting intervention components from the three sources, making adaptations to accommodate low-literacy, Spanish language, cultural factors, community context, and population needs. In phase 4, we built community capacity for the program and trial by training field staff (recruiters and interventionists embedded in community sites), compensating field staff, and creating a system for identifying potential participants. In phase 5, we implemented and monitored the program and trial. Engaging community partners in all phases has resulted in a new, culturally tailored program that is suitable for newly diagnosed Latinas with breast cancer and a trial that is acceptable and supported by community and clinical partners. Lessons Learned Engagement of community-based organizations and cancer survivors as research partners and hiring recruiters and interventionists from the community were critical to successful implementation in community settings. Having culturally and linguistically competent research staff with excellent interpersonal skills facilitated implementation. Facilitating and maintaining excellent communication among community partners was imperative to troubleshoot implementation issues. Randomization was challenging due to community concerns about assigning women to a control group. Patient privacy regulations and the need for extensive outreach to establish relationships between community partners and clinical sites hampered initial recruitment. Limitations These were resource-intensive processes to develop and implement the program that need to be compared to less intensive alternatives. Conclusions Engaging community members in design and implementation of community-based programs and trials enhances cultural appropriateness and congruence with the community context. If the randomized trial demonstrates that the intervention is effective, it will fill a gap in evidence-based programs to address ethnic disparities in quality of life among Spanish-speaking Latinas with breast cancer. PMID:24577971

Neutrophils in critical illness.

PubMed

McDonald, Braedon

2018-03-01

During critical illness, dramatic alterations in neutrophil biology are observed including abnormalities of granulopoeisis and lifespan, cell trafficking and antimicrobial effector functions. As a result, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. In this article, the role of neutrophils in the pathogenesis of critical illness (sepsis, trauma, burns and others) will be explored, including pathological changes to neutrophil function during critical illness and the utility of monitoring aspects of the neutrophil phenotype as biomarkers for diagnosis and prognostication. Lastly, we review findings from clinical trials of therapies that target the harmful effects of neutrophils, providing a bench-to-bedside perspective on neutrophils in critical illness.