B-vitamins for neuroprotection: narrowing the evidence gap

A compelling and extensive epidemiological literature documents the strong association of inadequate status of folate, vitamin B??, and to a lesser degree vitamin B6, with increased risk of neurodegenerative and cerebrovascular disease. Mildly elevated plasma total homocysteine, which is biochemically related to low status of these B-vitamins, is similarly associated with increased risk for these conditions. This, together with experimental data showing that experimental B-vitamin deficiency and/or hyperhomocysteinemia can cause a variety of neurological and vascular deficits in animals, has provided the evidence base and motivation for a growing number of large randomized, double-blind clinical trials aimed at determining the efficacy and safety of B-vitamin supplementation for preserving cognitive function in older adults. Despite some encouraging trials showing benefit of B-vitamins for slowing brain atrophy and cognitive decline, the majority of these studies have not demonstrated that B-vitamin supplementation has protective or therapeutic cognitive benefit. There are many possible explanations for the inconsistency between the clinical trials and for the discrepancy between their findings and the predictions of the epidemiological evidence. Among these are the possibility of inadequate hypotheses guiding the trials, design limitations of the individual trials, and inherent limitations of nutritional randomized clinical trials. Resolving these issues will be crucial for designing definitive trials and ultimately for guiding nutritional interventions for cognitive protection.     

A novel approach to reducing disparities in health outcomes by enhancing interpretation of cancer clinical trials for underrepresented patient groups

There has been a growing realization, based on emerging evidence from the point of care, that real-world outcomes of patients with cancer are often inferior to those reported in conventional clinical trials. This phenomenon can be attributed in part to deficits in external validity that are present in many studies. Several factors contribute to external validity deficits, including: narrow eligibility criteria; differences between protocol-specified procedures and routine care; and inadequate access to clinical trial participation among underrepresented and socioeconomically disadvantaged groups. As a result, the current body of clinical evidence derived from conventional clinical trials can be inadequate to inform patient-specific treatment decisions at the point of care. Furthermore, lack of practical guidance on how to evaluate the impact of external validity deficits can impede both the design of more generalizable clinical trials and efforts to personalize treatment decisions for individual patients. In this methodological review, we suggest an approach to aid clinicians in such evaluations, providing visual and quantitative methods for assessing the magnitude of, and adjusting for, the impact of external validity deficits in conventional clinical trials. Our methods and visualizations have broad applicability across important areas of real-world medical decision-making and research, providing opportunities to design clinical studies that are more reflective of the diverse needs of patients with cancer, including those excluded from traditional clinical trials due to narrow eligibility criteria, socioeconomic disadvantages, and other systemic barriers to equitable access to healthcare resources.     

The roles of ASK family proteins in stress responses and diseases

The aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. Although we are still continuing to explore the optimum use of traditional chemotherapy agents, the introduction of targeted therapies has significantly broadened the therapeutic options. Interestingly, the results from current trials put the underlying biological concept often into a new, less favorable perspective. Recent data suggested that altered pathways underlie cancer, and not just altered genes. Thus, an effective therapeutic agent will sometimes have to target downstream parts of a signaling pathway or physiological effects rather than individual genes. In addition, over the past few years increasing evidence has suggested that solid tumors represent a very heterogeneous group of cells with different susceptibility to cancer therapy. Thus, since therapeutic concepts and pathophysiological understanding are continuously evolving a combination of current concepts in tumor therapy and tumor biology is needed. This review aims to present current problems of cancer therapy by highlighting exemplary results from recent clinical trials with colorectal and pancreatic cancer patients and to discuss the current understanding of the underlying reasons.     

Evidence-based medicine,opinion-based medicine,and real-world medicine

The freedom of a doctor to treat an individual patient in the way he believes best has been markedly limited by the concept of evidence-based medicine. Clearly all would wish to practice according to the best available evidence, but it has become accepted that "evidence-based" means that which is derived from randomized, and preferably double-blind, clinical trials. The history of clinical trial development, which can be traced to the use of oranges and lemons for the treatment of scurvy in 1747, has reflected a progressive need to establish whether smaller and smaller effects of treatment are real. It has led to difficult concepts such as "equivalence" and aberrations such as "meta-analysis." An examination of evidence-based practice shows that it has usually been filtered through the opinions of experts and journal editors, and "opinion-based medicine" would be a more appropriate term. In the real world of individual patients with multiple diseases who are receiving a number of different drugs, the practice of evidence-based (or even opinion-based) medicine is extremely difficult. For each patient a judgment has to be made by the clinician of the likely balance of risks and benefits of any therapy. Good practice still requires clinical freedom for doctors.     

Evidence-Based Medicine,Clinical Practice Guidelines,and Common Sense in the Management of Osteoporosis

ObjectiveTo evaluate the benefits and limitations of randomized controlled trials (RCTs), clinical practice guidelines (CPGs), and clinical judgment in the management of osteoporosis.MethodsA review was conducted of the English-language literature on the origins and applications of RCTs, CPGs, evidence-based medicine, and clinical judgment in the management of osteoporosis.ResultsEvidence-based medicine is use of the currently available best evidence in making clinical decisions for individual patients. CPGs are recommendations for making clinical decisions based on research evidence, sometimes with consideration of expert opinion, health care policy, and costs of care. The highest levels of medical evidence are usually thought to be RCTs and meta-analyses of high-quality RCTs. Although it is desirable and appropriate for clinicians to consider research evidence from RCTs and recommendations presented in CPGs in making clinical decisions, other factors—such as patient preference, comorbidities, affordability, and availability of care—are important for the actual implementation of evidence-based medicine.ConclusionDecisions about who to treat, which drug to use, how best to monitor, and how long to treat require clinical skills in addition to knowledge of medical research. The necessity of integrating common sense and clinical judgment is highlighted by the fact that many patients treated for osteoporosis in clinical practice would not qualify for participation in the pivotal clinical trials that demonstrated efficacy and safety of the drugs used to treat them. (Endocr Pract. 2009;15:573-579)     

Pharmacogenetics of cardiovascular drugs.

Pharmacogenetics is a field aimed at understanding the genetic contribution to inter-patient variability in drug efficacy and toxicity. Treatment of cardiovascular disease is, in most cases, guided by evidence from well-controlled clinical trials. Given the solid scientific basis for the treatment of most cardiovascular diseases, it is common for patients with a given disease to be treated in essentially the same manner. Thus, the clinical trials have been very informative about treating large groups of patients with a given disease, but are slightly less informative about the treatment of individual patients. Pharmacogenetics and pharmacogenomics have the potential of taking the information derived from large clinical trials and further refining it to select the drugs with the greatest likelihood for benefit, and least likelihood for harm, in individual patients, based on their genetic make-up. In this paper, the current literature on cardiovascular pharmacogenetics is emphasised, and how the use of pharmacogenetic/pharmacogenomic information may be particularly useful in the future in the treatment of cardiovascular diseases is also highlighted.     

Clinical trials of fatty acid treatment in ADHD, dyslexia, dyspraxia and the autistic spectrum

Considerable clinical and experimental evidence now supports the idea that deficiencies or imbalances in certain highly unsaturated fatty acids may contribute to a range of common developmental disorders including ADHD, dyslexia, dyspraxia and autistic spectrum disorders (ASD). Definitive evidence of a causal contribution, however, can only come from intervention studies in the form of randomised, double-blind, placebo-controlled trials. Published studies of this kind are still fairly few in number, and mainly involve the diagnostic categories of ADHD and dyslexia, although other trials involving individuals with dyspraxia or ASD are in progress. The main findings to date from such studies are reviewed and evaluated here with the primary aim of guiding future research, although given that fatty acid supplementation for these conditions is already being adopted in many quarters, it is hoped that some of the information provided may also help to inform clinical practice.     

Meta-analysis of clinical trials with competing time-to-event endpoints

Recommendations for the analysis of competing risks in the context of randomized clinical trials are well established. Meta-analysis of individual patient data (IPD) is the gold standard for synthesizing evidence for clinical interpretation based on multiple studies. Surprisingly, no formal guidelines have been yet proposed to conduct an IPD meta-analysis with competing risk endpoints. To fill this gap, this work details (i) how to handle the heterogeneity between trials via a stratified regression model for competing risks and (ii) that the usual metrics of inconsistency to assess heterogeneity can readily be employed. Our proposal is illustrated by the re-analysis of a recently published meta-analysis in nasopharyngeal carcinoma, aiming at quantifying the benefit of the addition of chemotherapy to radiotherapy on each competing endpoint.     

Beta-carotene supplementation: a good thing, a bad thing, or nothing?

Available data from several completed large-scale randomized trials indicate that beta-carotene supplementation for durations up to 12 years has no overall benefit in well-nourished populations on the incidence of cardiovascular disease or the middle-to-late stages of carcinogenesis. Several important questions, however, remain unanswered. The post-trial follow-up of completed trials, together with the results of several ongoing trials of beta-carotene supplementation, will contribute reliable information to the totality of evidence from basic research, animal studies, observational epidemiologic studies, and completed trials, thus allowing more rational clinical decisions for individual patients and policy decisions for the health of the general public.     

Embryonic stem cells: are useful in clinic treatments?

It is not uncommon to find statements in the social media and even in some scientific journals declaring that embryonic stem cells can be used in human medicine for therapeutic purposes. In our opinion, this statement does not fit the medical reality. To go into this subject in depth, and if possible to clarify it, we reviewed the most recent literature on clinical trials conducted with embryonic stem cells, concluding that up to the present time, there is only one ongoing clinical trial being carried out with these types of cells to treat a small group of patients with spinal cord injury. The results of this trial have still not been published. In conclusion, at present, there is only evidence of one phase I clinical trial conducted with embryonic stem cells, in comparison to the numerous trials conducted with adult stem cells.     

Scientific Section: Coronary Artery Surgery,Task Force Appointed by the Conference of Deputy Ministers of Health: 2. Results,indications and recommendations

The large majority of reported studies of patients treated by aortocoronary bypass have not been randomized clinical trials, and hence must be interpreted with great caution.Review of the seven randomized clinical trials in the literature leads to only one firm, positive conclusion: aortocoronary bypass results in a reduction in the morbidity of coronary artery disease, due to the alleviation of cardiac pain, for at least 3 years. In addition, there is some evidence that mortality for symptomatic patients with significant left main-stem coronary artery stenosis may be reduced by coronary artery bypass surgery. A significant effect on mortaliy form other forms of coronary artery disease has not yet been conclusively demonstrated but also has not been excluded. Most of the reports are preliminary and involve small numbers of patients followed for relatively short periods. The operation is still being improved. It is to be hoped that the randomized trials, involving large numbers of patients, now in progress will supply some of these answers.Aortocoronary bypass surgery is the treatment of choice for patients with stable cardiac pain that is disabling despite adequate treatment, or when adequate treatment is impractial; for patients with unstable cardiac pain, uncontrolled despite adequate treatment; and for symptomatic patients with critical stenosis of the left main-stem coronary artery.     

Ten Years after the International Committee of Medical Journal Editors’ Clinical Trial Registration Initiative,One Quarter of Phase 3 Pediatric Epilepsy Clinical Trials Still Remain Unpublished: A Cross Sectional Analysis

Introduction

Although selective reporting of clinical trial results introduces bias into evidence based clinical decision making, publication bias in pediatric epilepsy is unknown today. Since there is a considerable ambiguity in the treatment of an important and common clinical problem, pediatric seizures, we assessed the public availability of results of phase 3 clinical trials that evaluated treatments of seizures in children and adolescents as a surrogate for the extent of publication bias in pediatric epilepsy.

Methods

We determined the proportion of published and unpublished study results of phase 3 clinical trials that were registered as completed on ClinicalTrials.gov. We searched ClinicalTrials.gov, PubMed, and Google Scholar for publications and contacted principal investigators or sponsors. The analysis was performed according to STROBE criteria.

Results

Considering studies that were completed before 2014 (N = 99), 75 (76%) pediatric phase 3 clinical trials were published but 24 (24%) remained unpublished. The unpublished studies concealed evidence from 4,437 patients. Mean time-to-publication was 25 SD ± 15.6 months, more than twice as long as mandated.

Conclusion

Ten years after the ICMJE’s clinical trials registration initiative there is still a considerable amount of selective reporting and delay of publication that potentially distorts the body of evidence in the treatment of pediatric seizures.     

Evidence based general practice: a retrospective study of interventions in one training practice.

OBJECTIVES--To estimate the proportion of interventions in general practice that are based on evidence from clinical trials and to assess the appropriateness of such an evaluation. DESIGN--Retrospective review of case notes. SETTING--One suburban training general practice. SUBJECTS--122 consecutive doctor-patient consultations over two days. MAIN OUTCOME MEASURES--Proportions of interventions based on randomised controlled trials (from literature search with Medline, pharmaceutical databases, and standard textbooks), on convincing non-experimental evidence, and without substantial evidence. RESULTS--21 of the 122 consultations recorded were excluded due to insufficient data; 31 of the interventions were based on randomised controlled trial evidence and 51 based on convincing non-experimental evidence. Hence 82/101 (81%) of interventions were based on evidence meeting our criteria. CONCLUSIONS--Most interventions within general practice are based on evidence from clinical trials, but the methods used in such trials may not be the most appropriate to apply to this setting.     

Metabolic deterioration of the sedentary control group in clinical trials

Randomized clinical trials of exercise training regimens in sedentary individuals have provided a mechanistic understanding of the long-term health benefits and consequences of physical activity and inactivity. The sedentary control periods from these trials have provided evidence of the progressive metabolic deterioration that results from as little as 4-6 mo of continuing a physically inactive lifestyle. These clinical trials have also demonstrated that only a modest amount of physical activity is required to prevent this metabolic deterioration, and this amount of physical activity is consistent with current physical activity recommendations (150 min/wk of moderate intensity physical activity). These recommendations have been issued to the general population for a vast array of health benefits. While greater adherence to these recommendations should result in substantial improvements in the health of the population, these recommendations still remain inadequate for many individuals. An individual's physical activity requirements are influenced by such factors as an individual's diet, nonexercise physical activity patterns, genetic profile, and medications. Improving the understanding of how these factors influence an individual's physical activity requirements will help advance the field and help move the field toward the development of more personalized physical activity recommendations.     

From hierarchy to network: a richer view of evidence for evidence-based medicine

Evidence-based medicine (EBM) advocates the improvement of patient care through the use of current best research evidence in medical decision making. In practice, "best evidence" generally refers to where a study fits on a hierarchy of evidence, which places randomized controlled trials (RCTs) and other population-level research above laboratory research. Because population research is concerned primarily with average results obtained from large groups of people, ranking evidence on the basis of its place in the hierarchy is shortsighted and ultimately limits the ability of research results to inform the care of individual patients. The history and methodology of epidemiology reveals a close relationship between population-level and laboratory research; both types of research are necessary if we are to understand the causes of a disease. What EBM does not take into account in its hierarchy of evidence is that the same thing is true for research on the safety and efficacy of medical interventions. To maximize the information that clinical research can provide for clinical care, RCTs should be designed to elucidate within-group variability. This can only be done if the hierarchy of evidence is replaced by a network that takes into account the relationship between epidemiological and laboratory research.     

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing. Preliminary exploration into the pathophysiology of ischemia-reperfusion injury, together with the accumulation of clinical evidence, led to the discovery of ischemic preconditioning, which has been the main hypothesis for over three decades for how ischemia-reperfusion injury can be attenuated. The subcellular pathophysiological mechanism of ischemia-reperfusion injury and preconditioning-induced cardioprotection is not well understood, but extensive research into components, including autacoids, ion channels, receptors, subcellular signaling cascades, and mitochondrial modulators, as well as strategies for modulating these components, has made evolutional progress. Owing to the accumulation of both basic and clinical evidence, the idea of ischemic postconditioning with a cardioprotective potential has been discovered and established, making it possible to apply this knowledge in the clinical setting after ischemia-reperfusion insult. Another a great outcome has been the launch of translational studies that apply basic findings for manipulating ischemia-reperfusion injury into practical clinical treatments against ischemic heart diseases. In this review, we discuss the current findings regarding the fundamental pathophysiological mechanisms of ischemia-reperfusion injury, the associated protective mechanisms of ischemic pre- and postconditioning, and the potential seeds for molecular, pharmacological, or mechanical treatments against ischemia-reperfusion injury, as well as subsequent adverse outcomes by modulation of subcellular signaling mechanisms (especially mitochondrial function). We also review emerging translational clinical trials and the subsistent clinical comorbidities that need to be overcome to make these trials applicable in clinical medicine.     

A combination of intradermal jet-injection and electroporation overcomes in vivodose restriction of DNA vaccines

Development of various vaccines for prostate cancer (PCa) is becoming an active research area. PCa vaccines are perceived to have less toxicity compared with the available cytotoxic agents. While various immune-based strategies can elicit anti-tumour responses, DNA vaccines present increased efficacy, inducing both humoural and cellular immunity. This immune activation has been proven effective in animal models and initial clinical trials are encouraging. However, to validate the role of DNA vaccination in currently available PCa management paradigms, strong clinical evidence is still lacking. This article provides an overview of the basic principles of DNA vaccines and aims to provide a summary of preclinical and clinical trials outlining the benefits of this immunotherapy in the management of PCa.     

Designing theoretically-informed implementation interventions

Background

A better theoretical base for understanding professional behaviour change is needed to support evidence-based changes in medical practice. Traditionally strategies to encourage changes in clinical practices have been guided empirically, without explicit consideration of underlying theoretical rationales for such strategies. This paper considers a theoretical framework for reasoning from within psychology for identifying individual differences in cognitive processing between doctors that could moderate the decision to incorporate new evidence into their clinical decision-making.

Discussion

Parallel dual processing models of reasoning posit two cognitive modes of information processing that are in constant operation as humans reason. One mode has been described as experiential, fast and heuristic; the other as rational, conscious and rule based. Within such models, the uptake of new research evidence can be represented by the latter mode; it is reflective, explicit and intentional. On the other hand, well practiced clinical judgments can be positioned in the experiential mode, being automatic, reflexive and swift. Research suggests that individual differences between people in both cognitive capacity (e.g., intelligence) and cognitive processing (e.g., thinking styles) influence how both reasoning modes interact. This being so, it is proposed that these same differences between doctors may moderate the uptake of new research evidence. Such dispositional characteristics have largely been ignored in research investigating effective strategies in implementing research evidence. Whilst medical decision-making occurs in a complex social environment with multiple influences and decision makers, it remains true that an individual doctor's judgment still retains a key position in terms of diagnostic and treatment decisions for individual patients. This paper argues therefore, that individual differences between doctors in terms of reasoning are important considerations in any discussion relating to changing clinical practice.

Summary

It is imperative that change strategies in healthcare consider relevant theoretical frameworks from other disciplines such as psychology. Generic dual processing models of reasoning are proposed as potentially useful in identifying factors within doctors that may moderate their individual uptake of evidence into clinical decision-making. Such factors can then inform strategies to change practice.     

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials

PURPOSE OF REVIEW: Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. RECENT FINDINGS: Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. SUMMARY: Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.     

Measuring quality of life in clinical trials: a taxonomy and review.

Measurement of quality of life is becoming increasingly relevant to controlled clinical trials. Two basic types of instrument are available: generic instruments, which include health profiles and utility measurements based on the patient''s preferences in regard to treatment and outcome; and specific instruments, which focus on problems associated with individual diseases, patient groups or areas of function. The two approaches are not mutually exclusive; each has its strengths and weaknesses and may be suitable under different circumstances. We surveyed 75 randomized trials published in three medical journals in 1986 and categorized them according to the importance of quality of life as a measure of outcome and the extent to which quality of life was actually measured. Although a number of the investigators used quality-of-life instruments in a sophisticated manner, in only 10 of 55 trials in which the measurement had been judged to be crucial or important were instruments with established validity and responsiveness used. We conclude that although accurate measurement of quality of life in randomized trials is now feasible it is still not widely done. Using the framework we have outlined, investigators can choose generic or specific instruments according to the purpose and the focus of their trial.