Protocol for a systematic review on the extent of non-publication of research studies and associated study characteristics.

BACKGROUND: Methodological research has found that non-published studies often have different results than those that are published, a phenomenon known as publication bias. When results are not published, or are published selectively based on the direction or the strength of the findings, healthcare professionals and consumers of healthcare cannot base their decision-making on the full body of current evidence. METHODS: As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:1. To determine the proportion and/or rate of non-publication of studies by systematically reviewing methodological research projects that followed up a cohort of studies that a. received research ethics committee (REC) approval,b. were registered in trial registries, orc. were presented as abstracts at conferences.2. To assess the association of study characteristics (for example, direction and/or strength of findings) with likelihood of full publication.To identify reports of relevant methodological research projects we will conduct electronic database searches, check reference lists, and contact experts. Published and unpublished projects will be included. The inclusion criteria are as follows:a. RECs: methodological research projects that examined the subsequent proportion and/or rate of publication of studies that received approval from RECs;b. Trial registries: methodological research projects that examine the subsequent proportion and/or rate of publication of studies registered in trial registries;c. Conference abstracts: methodological research projects that examine the subsequent proportion and/or rate of full publication of studies which were initially presented at conferences as abstracts.Primary outcomes: Proportion/rate of published studies; time to full publication (mean/median; cumulative publication rate by time).Secondary outcomes: Association of study characteristics with full publication.The different questions (a, b, and c) will be investigated separately. Data synthesis will involve a combination of descriptive and statistical summaries of the included methodological research projects. DISCUSSION: Results are expected to be publicly available in mid 2013.

Place de l'aspirine en prévention primaire des maladies cardiovasculaires [The role of aspirin in the primary prevention of cardiovascular disease]

For persons without cardiovascular disease, the benefit of aspirin in primary prevention has been controversial until the recent publication of several major randomized controlled trials. Since then, several medical societies recommend that clinicians discuss aspirin prevention with adults at high cardiovascular risk. Patients with low cardiovascular risk are unlikely to benefit from aspirin, as potential harms (hemorrhagic strokes, gastrointestinal bleedings) may outweigh benefits. Aspirin should be recommended in primary prevention only in patients with a 10-year cardiovascular risk > or = 10% or in diabetic patients aged > or = 40 years with a concomitant cardiovascular risk factor, after assessing contraindications for aspirin and individual's preferences for the risks and benefits associated with aspirin.

Sepsis: time to reconsider the concept.

OBJECTIVE: To discuss the difficulty in using the concept of sepsis for clinical trials and propose new ways for designing future trials for severe infections. DESIGN: Short position statement. METHODS AND MAIN RESEARCH: Using a thorough evaluation of the recent literature in the field of severe sepsis and septic shock, the authors challenge the concept of sepsis as used in the past two decades and propose new ideas for designing future trials in this setting. The two main proposals are first to use a systematic assessment of the targeted inflammatory mediators when the study intends to counteract or replace those mediators (e.g., anti-tumor necrosis factor-alpha, activated protein C) and, second, to select more homogeneous populations, coming back to "precise infectious diseases," such as severe community-acquired pneumonia, severe peritonitis, or meningitis. CONCLUSIONS: The concept of sepsis has been useful to help clinicians to suspect and detect severe infections. Due to a considerable heterogeneity in the patients and type of infections included in the trials performed in the last two decades, it has not been useful in demonstrating the efficacy of new compounds. The authors propose a dramatic change in the design of future trials dealing with severe infections.

Mechanism of urinary calcium regulation by urinary magnesium and pH.

Urinary magnesium and pH are known to modulate urinary calcium excretion, but the mechanisms underlying these relationships are unknown. In this study, the data from 17 clinical trials in which urinary magnesium and pH were pharmacologically manipulated were analyzed, and it was found that the change in urinary calcium excretion is directly proportional to the change in magnesium excretion and inversely proportional to the change in urine pH; a regression equation was generated to relate these variables (R(2) = 0.58). For further exploration of these relationships, intravenous calcium chloride, magnesium chloride, or vehicle was administered to rats. Magnesium infusion significantly increased urinary calcium excretion (normalized to urinary creatinine), but calcium infusion did not affect magnesium excretion. Parathyroidectomy did not prevent this magnesium-induced hypercalciuria. The effect of magnesium loading on calciuria was still observed after treatment with furosemide, which disrupts calcium and magnesium absorption in the thick ascending limb, suggesting that the effect may be mediated by the distal nephron. The calcium channel TRPV5, normally present in the distal tubule, was expressed in Xenopus oocytes. Calcium uptake by TRPV5 was directly inhibited by magnesium and low pH. In summary, these data are compatible with the hypothesis that urinary magnesium directly inhibits renal calcium absorption, which can be negated by high luminal pH, and that this regulation likely takes place in the distal tubule.

Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?

Since 2004, four antiangiogenic drugs have been approved for clinical use in patients with advanced solid cancers, on the basis of their capacity to improve survival in phase III clinical studies. These achievements validated the concept introduced by Judah Folkman that the inhibition of tumor angiogenesis could control tumor growth. It has been suggested that biomarkers of angiogenesis would greatly facilitate the clinical development of antiangiogenic therapies. For these four drugs, the pharmacodynamic effects observed in early clinical studies were important to corroborate activities, but were not essential for the continuation of clinical development and approval. Furthermore, no validated biomarkers of angiogenesis or antiangiogenesis are available for routine clinical use. Thus, the quest for biomarkers of angiogenesis and their successful use in the development of antiangiogenic therapies are challenges in clinical oncology and translational cancer research. We review critical points resulting from the successful clinical trials, review current biomarkers, and discuss their potential impact on improving the clinical use of available antiangiogenic drugs and the development of new ones.

Le nébivolol: un bêta-bloquant pourvu de propriétés vasodilatatrices [Nebivolol: a beta blocker with vasodilator properties]

Nebivolol is a new cardioselective beta-blocking agent possessing vasodilatory properties involving the endothelium. This compound is a dl-racemic mixture. The d-enantiomer is responsible for the beta-blocking properties whereas the l-enantiomer induces a vasodilation via a nitric oxide (NO) mechanism. Nebivolol is an unique agent that appears promising for the management of patients with hypertension, coronary heart disease or congestive heart failure.

HIV-1 vaccines and adaptive trial designs.

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

Atherosclerosis screening by noninvasive imaging for cardiovascular prevention: a systematic review.

BACKGROUND: Noninvasive imaging of atherosclerosis is being increasingly used in clinical practice, with some experts recommending to screen all healthy adults for atherosclerosis and some jurisdictions mandating insurance coverage for atherosclerosis screening. Data on the impact of such screening have not been systematically synthesized. OBJECTIVES: We aimed to assess whether atherosclerosis screening improves cardiovascular risk factors (CVRF) and clinical outcomes. DESIGN: This study is a systematic review. DATA SOURCES: We searched MEDLINE and the Cochrane Clinical Trial Register without language restrictions. STUDY ELIGIBILITY CRITERIA: We included studies examining the impact of atherosclerosis screening with noninvasive imaging (e.g., carotid ultrasound, coronary calcification) on CVRF, cardiovascular events, or mortality in adults without cardiovascular disease. RESULTS: We identified four randomized controlled trials (RCT, n=709) and eight non-randomized studies comparing participants with evidence of atherosclerosis on screening to those without (n=2,994). In RCTs, atherosclerosis screening did not improve CVRF, but smoking cessation rates increased (18% vs. 6%, p=0.03) in one RCT. Non-randomized studies found improvements in several intermediate outcomes, such as increased motivation to change lifestyle and increased perception of cardiovascular risk. However, such data were conflicting and limited by the lack of a randomized control group. No studies examined the impact of screening on cardiovascular events or mortality. Heterogeneity in screening methods and studied outcomes did not permit pooling of results. CONCLUSION: Available evidence about atherosclerosis screening is limited, with mixed results on CVRF control, increased smoking cessation in one RCT, and no data on cardiovascular events. Such screening should be validated by large clinical trials before widespread use.

Fistulizing Crohn's disease.

Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%). Medical therapy is the main option for perianal fistula once abscesses, if present, have been drained, and should include antibiotics (both ciprofloxacin and metronidazole) and immunomodulators. Infliximab should be reserved for refractory patients. Surgery is often necessary for internal fistulas.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window.

Dix ans de revue de la littérature en médecine interne générale--un premier bilan [Ten years of literature review in general internal medicine--a first assessment].

A group of family physicians in an outpatient clinic in Switzerland prospectively followed scientific literature for ten years. What to remember among the numerous articles retrieved and which paper really changed our practice? If many readings are quickly forgotten, some of them marked our minds and changed our habits. This article is a summary of our efforts to keep the essential tools in clinical practice.

Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs.

Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

Committees for ethics in research involving human subjects

In Brazil since October 1996 there have been guidelines for research involving human subjects. Now human subjects know when their treatment is part of research. Deceit is no longer tolerated. But is not enough to say we offer an explanation to the potential subject and we offer a choice before he or she is confronted with an informed consent form. As in all professional activity, scientific investigation needs social controls. In Brazil, the ultimate responsibility of an investigation lies on the investigator, but in every institution where research is carried out there is a Committee for Ethics in Research. All Committees are subordinated to the National Commission of Ethics in Research, which is submitted to the Brazilian Institute of Health. During 2005 around 17,000 protocols involving 700,000 human subjects were revised by 475 Committees distributed all over the country. Approximately 7,000 people are now working in these Committees.