Clinical Research Methodology Research Articles

Evaluación del primer "Entrenamiento en Metodología de Investigación Clínica en Chile"

This paper describes the evaluation of the first training on clinical research methodology in Chile (EMIC-Chile) 12 months after its completion. An online survey was conducted for students and the Delphi method was used for the teaching team. Among the students, the majority reported that the program had contributed to their professional development and that they had shared some of the knowledge acquired with colleagues in their workplace. Forty-one percent submitted a project to obtain research funding through a competitive grants process once they had completed the course. Among the teachers, the areas of greatest interest were the communication strategy, teaching methods, the characteristics of the teaching team, and potential strategies for making the EMIC-Chile permanent in the future. This experience could contribute to future research training initiatives for health professionals. Recognized challenges are the involvement of nonmedical professions in clinical research, the complexities associated with the distance learning methodology, and the continued presence of initiatives of this importance at the national and regional level.

The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: Half a century of anxiolytic drugs

The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of this drug, which was filled with chance events, and numerous chemical and clinical errors of approach. Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium ®. The benzodiazepines became the most widely prescribed drugs worldwide, provided truly effective treatment for “minor forms” (neuroses) of mental disorders for the first time, increased the quality of scientific methodology in clinical research, and enabled the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in 1977 of their high-affinity receptor complex.

Instability and impending instability of the thoracolumbar spine in patients with spinal metastases: a systematic review

Metastatic disease commonly occurs in the spine and incidence is likely to increase secondary to improved survival rates in many cancer patients. Despite published research on instability in patients with metastatic disease of the thoracolumbar spine, controversy exists regarding risk factors for instability and indications for surgical stabilization. The objective of this systematic review was to determine what defines instability and impending instability in patients with metastatic disease of the thoracic and lumbar spine. We systematically reviewed the medical literature in order to identify all the relevant studies concerning patients with metastatic involvement of T1-L5, in the domains of biomechanics, epidemiology, clinical issues, and radiographic parameters. Two independent observers performed study selection, methodological quality assessment, and data extraction in a blinded and objective manner for all the identified studies. We were then able to define the criteria to identify instability of the spine with metastases. A literature search and review identified 14 relevant, good quality studies for inclusion. The predictors of instability included increased tumor size, a larger cross-sectional area of bone defect, increased force of spinal loading, decreased bone density, posterior location of the tumor within the vertebrae, destruction of the costovertebral joint, pedicle destruction in the thoracolumbar spine, increased axial rigidity, and sagittal spinal deformity. Definitive conclusions cannot be reached due to lack of evidence. However, variables such as tumor size, magnitude of spinal loading, bone density, tumor location within the vertebrae and spine, and tumor type are risk factors for instability in spinal metastases. Improved clinical research methodology for this patient population is required.

Advances in clinical research methodology for pain clinical trials

Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies.

Geriatric oncology field comes into its own

Geriatric oncology field comes into its own

Borderline Personality Disorder, PTSD, and Suicide

Borderline Personality Disorder, PTSD, and Suicide

Mount Sinai School of Medicine

Mount Sinai School of Medicine

Response to Selvaraj and Nair

HomeCirculation ResearchVol. 107, No. 3Response to Selvaraj and Nair Free AccessReplyPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Selvaraj and Nair Alexey V. Glukhov, Vadim V. Fedorov and Igor R. Efimov Alexey V. GlukhovAlexey V. Glukhov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail (Glukhov, Fedorov, Efimov) Search for more papers by this author , Vadim V. FedorovVadim V. Fedorov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail (Glukhov, Fedorov, Efimov) Search for more papers by this author and Igor R. EfimovIgor R. Efimov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail (Glukhov, Fedorov, Efimov) Search for more papers by this author Originally published6 Aug 2010https://doi.org/10.1161/CIRCRESAHA.110.224733Circulation Research. 2010;107:e10We thank Drs Selvaraj and Nair for the opportunity to discuss the clinical relevance of our recent findings in explanted human hearts and to bridge the gap between clinical and basic electrophysiology research methodologies. Using the basic science methodology of optical mapping, which is not yet available in clinical electrophysiological laboratories, we have recently found that end-stage heart failure results in anatomically heterogeneous repolarization remodeling in humans.1 In this human study, we have used a measure of intrinsic repolarization properties that is commonly accepted in basic studies, action potential duration (APD),2–4 which is the basis for activation–recovery interval (ARI) and a close approximation of the functional refractory period (RP) used in clinical studies.5 Mapping APD dispersion is methodologically challenging in clinical settings, unlike basic research laboratories.A repolarization map is simply an algebraic sum of the activation map and the map of APD. APD map has become an important characteristic because it represents intrinsic repolarization properties, which are less dependent on activation sequence and more dependent on local functional state, cell–cell coupling, and gene expression responsible for repolarizing currents. Thus, APD dispersion is a frequently used measure for estimation of repolarization remodeling. We are surprised that the authors of the letter found this approach “an artificial measurement with no physiological significance,” given that it was introduced to cardiac electrophysiology by Thomas Lewis6 in 1925 and, since that time, has been used by numerous groups.2–5In our early studies,7,8 we have demonstrated that APD base-to-apex gradient governs repolarization and RP pattern in the guinea pig heart, because activation is relatively fast, and therefore the conduction delay is significantly shorter compared to global APD gradient. But, if activation were relatively slow, it may indeed influence the repolarization sequence and dispersion. In our present study,1 activation sequence during endocardial pacing, which represents normal excitation, was similar in all hearts, with activation time ranging from 45 to 70 ms. Our findings are in agreement with the observation of Taggart et al,5 who demonstrated the absence of the ARI dispersion in patients measured during routine coronary artery surgery using plunge needle electrodes. To address the question of Drs Selvaraj and Nair, we constructed maps of repolarization (data are not shown because of editorial limitations for Letters). Contrary to their hypothesis, repolarization pattern to a significant degree is determined by APD maps in these hearts during endocardial pacing. In a nonfailing heart with 150-ms intrinsic transmural APD gradient (range from 380 to 530 ms), 50-ms transmural activation slightly delayed epicardial repolarization and thus produced 122-ms transmural repolarization gradient, which was governed by APD distribution pattern. In a failing heart with 35-ms transmural APD gradient (range from 435 to 470 ms), 69-ms heterogeneous transmural activation significantly delayed both midmyocardial and subepicardial repolarization and resulted in 40-ms repolarization gradient (range from 485 to 525 ms), which was still governed by APD pattern.However, in general, we agree that dispersion of repolarization depends on the activation sequence, which indeed could be distorted in failing hearts by scars, regions of ischemia, remodeling, and fibrosis. In our Limitations section, we have discussed the fact that we selected regions of the left ventricles without these structural abnormalities to focus on intrinsic repolarization remodeling. Moreover, this study provided assessment of repolarization in relatively small samples of tissue, which cannot predict global dispersion of repolarization of the whole heart. Unfortunately, we still do not have a methodology to map repolarization in the entire heart in 3D. But optical mapping is a promising first step in this direction. Our follow-up study focuses on this issue.9Alexey V. GlukhovVadim V. FedorovIgor R. Efimov Department of Biomedical Engineering Washington University St Louis, Missouri E-mail [email protected]Sources of FundingSupported by NIH grant R01 HL085369.DisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.

CANadian Network and Centre for Trials INternationally (CANNeCTIN): A national network for Canadian-led trials in cardiovascular diseases and diabetes mellitus

The Canadian Network and Centre for Trials INternationally (CANNeCTIN) was jointly funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation in April 2008 to provide infrastructure for clinical studies of cardiovascular diseases and diabetes mellitus. Its functional components include a national coordinating centre at the Population Health Research Institute (PHRI) in Hamilton (Ontario), a collaborative Canadian network and an affiliated international network of hospitals and clinics. The rationales for CANNeCTIN include the global health burden of cardiovascular diseases and diabetes, the strengths of randomized controlled trials - particularly large, multicentre and international - and the track record of success of the PHRI. CANNeCTIN will provide investigators from across Canada with opportunities to become the principal investigators of national and international trials coordinated by the PHRI. CANNeCTIN will support priority pilot studies, and successful investigators will be encouraged and assisted to apply for peer review and industrial funding for full studies to be conducted within the network and coordinated by the PHRI. An extensive education program offers hands-on experience in organizing and leading large national⁄international clinical trials led by accomplished researchers, distance learning courses in clinical research methodology, biostatistics and study coordination, and 'cutting-edge' workshops. A knowledge translation program seeks opportunities arising from clinical trials and encourages research into this paradigm for understanding how best to close the gaps between knowledge and effective practice. The five-year goals are to enhance the capacity of Canadian investigators to lead major clinical studies, facilitate knowledge translation and exchange, and augment Canada's capacity to train the next generation of leaders in cardiovascular and diabetes clinical research.

Clinical research training of Peruvian neurologists: a baseline assessment

In Peru, despite a strong clinical research infrastructure in Lima, and Masters degree programs in epidemiology at three universities, few neurologists participate in clinical research. It was our objective to identify perceived needs and opportunities for increasing clinical research capacity and training opportunities for Peruvian neurologists. We conducted a descriptive, cross-sectional survey of Peruvian neurologists in Lima and Arequipa, Peru. Forty-eight neurologists completed written surveys and oral interviews. All neurologists reported interest in clinical research, but noted that lack of time and financial resources limited their ability to participate. Although most neurologists had received some training in epidemiology and research design as medical students or residents, the majority felt these topics were not adequately covered. Neurologists in Arequipa noted international funding for clinical research was uncommon outside the capital city of Lima. We concluded that clinical research is important to Peruvian neurologists. The three main barriers to increased participation in clinical research identified by neurologists were insufficient training in clinical research methodology, meager funding opportunities, and lack of dedicated time to participate in clinical research. Distance learning holds promise as a method for providing additional training in clinical research methodology, especially for neurologists who may have difficulty traveling to larger cities for additional training.

Health Related Quality of Life for Men Treated for Localized Prostate Cancer With Long-Term Followup

Men who undergo primary treatment for prostate cancer can expect changes in health related quality of life. Long-term changes after treatment are not yet fully understood. We characterized health related quality of life evolution from baseline to 4 years after treatment. We identified 1,269 men in CaPSURE who underwent primary treatment for clinically localized prostate cancer and completed followup health related quality of life questionnaires for at least 4 years. The men underwent radical prostatectomy, external beam radiotherapy, brachytherapy, combined external beam radiotherapy/brachytherapy or androgen deprivation therapy. Health related quality of life was measured using patient reported questionnaires. Effects of select covariates on quality of life were measured with a multivariate mixed model. Age at diagnosis, time from treatment and primary treatment were significant predictors of health related quality of life in all domains (p <0.05) except primary treatment on sexual bother. Men who underwent radical prostatectomy experienced the most pronounced worsening urinary function but also had the greatest recovery. All treatments worsened urinary bother, and sexual function and bother. All forms of radiotherapy moderately worsened bowel function and bother after treatment but eventual recovery to baseline was noted. Age at diagnosis, time from treatment and primary treatment type affect health related quality of life. Treatment has a greater impact on disease specific than general health related quality of life. All treatments adversely affect urinary and sexual function. Most adverse changes develop immediately after treatment. Recovery occurs mostly within 2 years after treatment with little change beyond 3 years.

XVIII WFN World Congress on Parkinson’s Disease and Related Disorders Synopsis

Several interesting concepts regarding Parkinson’s disease were recently presented at the XVIII World Congress on Parkinson’s disease. The theory of α-synuclein acting as a prion, resulting in the spread of Parkinson’s disease, was presented and related to the Braak hypothesis of neuropathology of Parkinson’s disease. Nonmotor symptomatology of Parkinson’s disease was presented and also related to the above. Research was emphasized at the meeting, and novel compounds thought to slow the progression of the disease were mentioned. Clinical research methodology designed to best prove an agent as disease modifying, and the merits of clinical research, were debated. Finally, treatment strategies for early Parkinson’s disease, as well as continuous dopamine stimulation, were presented. This article briefly discusses these concepts presented at this important meeting of the World Congress on Parkinson’s disease.

Critical appraisal of case–control studies of risk factors or etiology of Hyperemesis gravidarum

Critical appraisal of published case-control studies examining the etiology or risk factors of Hyperemesis gravidarum (HG). We searched the Medline/PubMed database from 1966 to February 12, 2009. A total of 48 case-control studies were retrieved and each article was evaluated using a structured assessment devised for the purpose. The case-control studies were published between 1978 and 2008. The majority investigated hormonal, gastrointestinal, and metabolic risk factors associated with hyperemesis gravidarum (37 studies). Selection bias and non-response received insufficient attention in many articles. Sample size varied widely with a median number of 40 cases and 42 controls. Association uncommonly was expressed by odds ratios and confidence intervals (9 studies), confounding rarely controlled for (10 studies) and few examined effect modification (2 studies). We are concerned as far the inadequacies in the design, analysis, and reporting of case-control studies examining the etiology of HG. It is mandatory to follow adequate clinical research methodology in executing and reporting such studies.

Permission to Speak: Therapists’ Understandings of Psychogenic Nonepileptic Seizures and Their Treatment

Psychogenic nonepileptic seizures (PNES), somatoform symptoms that diminish quality of life, can be difficult to treat. A previously proposed conceptualization of PNES is further developed using grounded theory methodology to explore the understandings of therapists who successfully treated clients with PNES. Participants conceptualized PNES as nonverbal communication behaviors that usually evolved in traumatic, interpersonal systems in which verbal expression of affect was proscribed and nonverbal communication of affect was prescribed. Clients without significant trauma and psychiatric comorbidity were successfully treated by means of sensitive delivery of the diagnosis and brief cognitive interventions. Traumatized clients with compromised orientation to the present required a process of cultural transformation in a safe therapeutic relationship. Implications for clinical practice, research methodology, professional training, and service funding are discussed.

Entre o ensino, a pesquisa e a assistência médica: um estudo de caso

The article explores the relations between teaching, research, and health care through an analysis of documents and reports by a group of professors with the Department of Clinical Medicine at the Universidade Federal do Rio de Janeiro's School of Medicine. Findings suggest that the two-hundred year old medical school has a strong tradition in teaching and health care and that although research predated inauguration of the thirty-year-old Clementino Fraga Filho University Hospital, this academic activity has only gradually occupied a larger space within the institution following creation of the hospital, which brought a radical change in clinical research methodology, concomitant with the development of a graduate program and the emergence of clinical epidemiology.

A survey of attitudes toward clinical research among physicians at Kyoto University Hospital.

BackgroundIn Japan, only clinical research related to investigational new drug trials must be notified to regulatory bodies, and this lack of a uniform standard for clinical research has caused a number of difficulties. The objective of this study was to assess the willingness of physicians to participate in clinical research and to identify effective methods to promote and enhance clinical research.MethodsWe conducted a cross-sectional survey by administrating questionnaires to physicians in 31 departments in Kyoto University Hospital from October through November 2007.ResultsA total of 51.5% (310 of 602) of physicians completed the questionnaire. More than two-thirds of them reported currently participating in clinical research, and nearly all believed that clinical research is necessary for physicians. Less than 20% of respondents had specific training regarding clinical research, and most reported a need to acquire concepts and skills regarding clinical research, especially those related to statistics. "Paperwork was complicated and onerous" was the most frequently cited obstacle in conducting clinical research, followed by "few eligible patients" and "lack of time". Previous participation in and prospective participation in clinical research, previous writing a research protocol were positively associated with current participation in clinical research.ConclusionsPhysicians in university hospitals need more training regarding clinical research, particularly in biostatistics. They also require administrative assistance. Our findings indicate that the quality of clinical research could be improved if training in clinical research methodology and biostatistics were provided, and if greater assistance in the preparation of study documents requested by the institutional Independent Ethics Committee were available.

Characterization of Whole Blood Gene Expression Profiles as a Sequel to Globin mRNA Reduction in Patients with Sickle Cell Disease

Global transcriptome analysis of whole blood RNA using microarrays has been proven to be challenging due to the high abundance of globin transcripts that constitute 70% of whole blood mRNA. This is a particular problem in patients with sickle cell disease, secondary to the high abundance of globin-expressing nucleated red blood cells and reticulocytes in the circulation. In order to accurately measure the steady state blood transcriptome in sickle cell patients we evaluated the efficacy of reducing globin transcripts in PAXgene stabilized RNA for genome-wide transcriptome analyses using microarrays. We demonstrate here by both microarrays and Q-PCR that the globin mRNA depletion method resulted in 55–65 fold reduction in globin transcripts in whole blood collected from healthy volunteers and sickle cell disease patients. This led to an improvement in microarray data quality by reducing data variability, with increased detection rate of expressed genes and improved overlap with the expression signatures of isolated peripheral blood mononuclear (PBMC) preparations. Analysis of differences between the whole blood transcriptome and PBMC transcriptome revealed important erythrocyte genes that participate in sickle cell pathogenesis and compensation. The combination of globin mRNA reduction after whole-blood RNA stabilization represents a robust clinical research methodology for the discovery of biomarkers for hematologic diseases.

Teaching transfusion medicine research methods in the developing world

Teaching transfusion medicine research methods in the developing world

Challenges in Clinical Aging Research: Building the Evidence Base for Care of the Older Adult

With the article in this issue of JAGS by Mody et al.,1 we initiate an important new series on clinical aging research methods. Older adults are more likely to suffer from multiple diseases, take more medications, undergo more procedures, and use more health care than any other age group,2,3 yet the evidence base for care of the older adult is frequently derived from studies of younger, less complex populations.4–8 This discrepancy between the evidence and the population to which it is applied can be attributed to numerous conceptual and pragmatic challenges in clinical research methodology. Clinical investigators within and beyond the field of geriatrics have developed new approaches and creative strategies to overcome such challenges, but these solutions are often not explicitly presented in research manuscripts and are not widely known. One of the core missions of the American Geriatrics Society (AGS) and the Journal of the American Geriatrics Society (JAGS) is to promote evidence based care for older adults that results in better quality of life and functional independence.9 Thus, it is incumbent on us to disseminate knowledge that will help to generate that evidence. The goal of this new research series is to examine the ways that clinical research methodologies create barriers to increasing the evidence base for care of the older adult and to describe solutions based on thoughtful application of new and emerging research concepts and practices. Traditionally, the standards for rigorous research and evidence were designed to elucidate the causes and treatment of isolated diseases. These traditional design assumptions do not work well in aging, and alternative approaches are needed.10 The focus of the research question changes as chronic illnesses accumulate and interact with aging; healthcare research must incorporate new paradigms to understand the underlying contributors to disease,11 multisystem problems such as geriatric syndromes,12 and the importance of outcomes such as function and quality of life.13–15 The new concepts and approaches developed by clinical investigators in the field of aging permit study of this broader and more-relevant range of research questions and increase the repertoire of methods to manage the complexity of including older adults in research. We hope that the articles in this series will be useful to healthcare providers, investigators, health professions trainees, proposal reviewers, grant sponsors, and policy makers, all of whom depend on the creation and use of evidence to provide the best care to older adults. Each article in this series will focus on a type of challenge or barrier in clinical aging research. Using examples from the literature, the article will explain how the problem affects the creation of evidence and will present a repertoire of established and novel strategies to prevent or manage it. Several of the articles will be based on the Research Issues and Methods symposia presented at the annual meeting of the AGS and sponsored by the AGS Research Committee. In addition, JAGS invites authors to submit original articles that are responsive to the goals of the series. As the demand for care of older adults continues to increase, so will the demand for evidence to guide that care.16 We hope that this new series on challenges in clinical aging research will contribute to the continued growth of that evidence.

Clinical research for rare disease: Opportunities, challenges, and solutions

Over 7000 rare diseases, each <200,000 US residents, affect nearly 30 million people in the United States. Furthermore, for the 10% of people with a rare disease and for their families, these disorders no longer seem rare. Molecular genetics have characterized the cause of many rare diseases and provide unprecedented opportunities for identifying patients, determining phenotypes, and devising treatments to prevent, stabilize, or improve each disease. Rare disease research poses challenges to investigators requiring specific approaches to: (1) the design of clinical studies; (2) the funding of research programs; (3) the discovery, testing, and approval of new treatments, and (4) the training of clinical scientists. Rigorous, statistically-valid, natural history-controlled, cross-over, and n-of-1 trials can establish efficacy and support regulatory approval of new treatments for rare diseases. The U.S. Orphan Drug Act of the U.S. FDA has stimulated industry investment in clinical trials to develop treatments for rare diseases. For trainees interested in finding a treatment for a rare disease, a commitment to longitudinal care of patients provides a base for the characterization of phenotype and natural history, a stimulus for innovation, a target population for research and helps fund training and research. The scientific methodology, financial resources, and logistics of clinical research for rare diseases have changed dramatically in the past two decades resulting in increased understanding of the pathophysiology of these disorders and direct benefit to patients.