Bruno R. da Costa

Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis

BACKGROUND Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis. PURPOSE To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis. DATA SOURCES MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources. STUDY SELECTION Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis. DATA EXTRACTION Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression. DATA SYNTHESIS Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, -0.37 [95% CI, -0.46 to -0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of -0.03 (CI, -0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of -0.11 (CI, -0.18 to -0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]). LIMITATIONS Trial quality was generally low. Safety data were often not reported. CONCLUSION In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events. PRIMARY FUNDING SOURCE Arco Foundation.

Uses and misuses of the STROBE statement: bibliographic study

Objectives Appropriate reporting is central to the application of findings from research to clinical practice. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations consist of a checklist of 22 items that provide guidance on the reporting of cohort, case–control and cross-sectional studies, in order to facilitate critical appraisal and interpretation of results. STROBE was published in October 2007 in several journals including The Lancet, BMJ, Annals of Internal Medicine and PLoS Medicine. Within the framework of the revision of the STROBE recommendations, the authors examined the context and circumstances in which the STROBE statement was used in the past. Design The authors searched the Web of Science database in August 2010 for articles which cited STROBE and examined a random sample of 100 articles using a standardised, piloted data extraction form. The use of STROBE in observational studies and systematic reviews (including meta-analyses) was classified as appropriate or inappropriate. The use of STROBE to guide the reporting of observational studies was considered appropriate. Inappropriate uses included the use of STROBE as a tool to assess the methodological quality of studies or as a guideline on how to design and conduct studies. Results The authors identified 640 articles that cited STROBE. In the random sample of 100 articles, about half were observational studies (32%) or systematic reviews (19%). Comments, editorials and letters accounted for 15%, methodological articles for 8%, and recommendations and narrative reviews for 26% of articles. Of the 32 observational studies, 26 (81%) made appropriate use of STROBE, and three uses (10%) were considered inappropriate. Among 19 systematic reviews, 10 (53%) used STROBE inappropriately as a tool to assess study quality. Conclusions The STROBE reporting recommendations are frequently used inappropriately in systematic reviews and meta-analyses as an instrument to assess the methodological quality of observational studies.

Comparison of drug-eluting stents with bare metal stents in patients with ST-segment elevation myocardial infarction

AIMS To evaluate safety and effectiveness of early generation drug-eluting stents (DES) compared with bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), and to determine whether benefits and risks vary over time. METHODS AND RESULTS We performed a meta-analysis of 15 randomized controlled trials enrolling a total of 7867 patients comparing first-generation FDA-approved DES with BMS in patients with STEMI. Random effect models were used to assess differences in outcomes between DES and BMS among different time periods with regard to the pre-specified primary outcomes stent thrombosis (ST) and target vessel revascularization (TVR). The overall risk of definite ST was similar for DES and BMS [risk ratio (RR) = 1.08, 95% CI 0.82-1.43]. However, there were time-dependent effects, with a RR of 0.80 during the first year (95% CI 0.58-1.12) and 2.10 during subsequent years (95% CI 1.20-3.69), with a positive test for interaction between RR of ST and time (P for interaction = 0.009). Results were similar for definite or probable ST (P for interaction = 0.015). In the overall analysis, TVR was performed less frequently in patients with DES when compared with BMS (RR 0.51, 95% CI 0.43-0.61), with a greater benefit in the first year (RR 0.46, 95% CI 0.38-0.55) when compared with subsequent years (RR 0.75, 95% CI 0.59-0.94; P for interaction = 0.007). CONCLUSION An early benefit of early generation DES in primary PCI for STEMI with a reduction in TVR and a trend towards less definite ST is offset in subsequent years by an increased risk of very late ST.

Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. METHODS For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. FINDINGS We identified 8973 manuscripts from our search, of which 74 randomised trials with a total of 58,556 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0·37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0·57, 95% credibility interval [CrI] -0·69 to -0·46) and etoricoxib 60 mg/day (ES -0·58, -0·73 to -0·43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for celecoxib (p=0·030), diclofenac (p=0·031), and naproxen (p=0·026). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. INTERPRETATION On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. FUNDING Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Influenza A Virus Protein PB1-F2 Exacerbates IFN-β Expression of Human Respiratory Epithelial Cells

The PB1-F2 protein of the influenza A virus (IAV) contributes to viral pathogenesis by a mechanism that is not well understood. PB1-F2 was shown to modulate apoptosis and to be targeted by the CD8+ T cell response. In this study, we examined the downstream effects of PB1-F2 protein during IAV infection by measuring expression of the cellular genes in response to infection with wild-type WSN/33 and PB1-F2 knockout viruses in human lung epithelial cells. Wild-type virus infection resulted in a significant induction of genes involved in innate immunity. Knocking out the PB1-F2 gene strongly decreased the magnitude of expression of cellular genes implicated in antiviral response and MHC class I Ag presentation, suggesting that PB1-F2 exacerbates innate immune response. Biological network analysis revealed the IFN pathway as a link between PB1-F2 and deregulated genes. Using quantitative RT-PCR and IFN-β gene reporter assay, we determined that PB1-F2 mediates an upregulation of IFN-β expression that is dependent on NF-κB but not on AP-1 and IFN regulatory factor-3 transcription factors. Recombinant viruses knocked out for the PB1-F2 and/or the nonstructural viral protein 1 (the viral antagonist of the IFN response) genes provide further evidence that PB1-F2 increases IFN-β expression and that nonstructural viral protein 1 strongly antagonizes the effect of PB1-F2 on the innate response. Finally, we compared the effect of PB1-F2 variants taken from several IAV strains on IFN-β expression and found that PB1-F2–mediated IFN-β induction is significantly influenced by its amino acid sequence, demonstrating its importance in the host cell response triggered by IAV infection.

Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis

BACKGROUND Up to 40% of ischaemic strokes are cryptogenic. A strong association between cryptogenic stroke and the prevalence of patent foramen ovale (PFO) suggests paradoxical embolism via PFO as a potential cause. Randomized trials failed to demonstrate superiority of PFO closure over medical therapy. METHODS AND RESULTS Randomized trials comparing percutaneous PFO closure against medical therapy or devices head-to-head published or presented by March 2013 were identified through a systematic search. We performed a network meta-analysis to determine the effectiveness and safety of PFO closure with different devices when compared with medical therapy. We included four randomized trials (2963 patients with 9309 patient-years). Investigated devices were Amplatzer (AMP), STARFlex (STF), and HELEX (HLX). Patients allocated to PFO closure with AMP were less likely to experience a stroke than patients allocated to medical therapy [rate ratio (RR) 0.39; 95% CI: 0.17-0.84]. No significant differences were found for STF (RR 1.01; 95% CI: 0.44-2.41), and HLX (RR, 0.71; 95% CI: 0.17-2.78) when compared with medical therapy. The probability to be best in preventing strokes was 77.1% for AMP, 20.9% for HLX, 1.7% for STF, and 0.4% for medical therapy. No significant differences were found for transient ischaemic attack and death. The risk of new-onset atrial fibrillation was more pronounced for STF (RR 7.67; 95% CI: 3.25-19.63), than AMP (RR 2.14; 95% CI: 1.00-4.62) and HLX (RR 1.33; 95%-CI 0.33-4.50), when compared with medical therapy. CONCLUSIONS The effectiveness of PFO closure depends on the device used. PFO closure with AMP appears superior to medical therapy in preventing strokes in patients with cryptogenic embolism.

Stretching to reduce work-related musculoskeletal disorders: a systematic review.

OBJECTIVE This article reviewed the literature to clarify the physiological effects and benefits of, and misconceptions about, stretches used to reduce musculoskeletal disorders. METHODS Nine databases were reviewed to identify studies exploring the effectiveness of stretching to prevent work-related musculoskeletal disorders. Included studies were reviewed and their methodological quality was assessed using the PEDro scale. RESULTS The physiological effects of stretches may contribute to reducing discomfort and pain. However, if other measures are not in place to remediate their causes, stretches may suppress awareness of risks, resulting in more debilitating injuries. If inadequately performed, stretches may also cause or aggravate injuries. Careful analysis and stretching program design are required before implementing stretches. Seven studies evaluating the effectiveness of stretching to prevent musculoskeletal disorders in different occupations were identified and reviewed. CONCLUSION The studies provided mixed findings, but demonstrated some beneficial effect of stretching in preventing work-related musculoskeletal disorders. However, due to the relatively low methodological quality of the studies available in the literature, future studies are necessary for a definite response. Future studies should minimize threats to internal and external validity, have control groups, use appropriate follow-up periods, and present a more detailed description of the interventions and worker population.

Measurement Issues in Trials of Pediatric Acute Diarrheal Diseases: A Systematic Review

BACKGROUND: Worldwide, diarrheal diseases rank second among conditions that afflict children. Despite the disease burden, there is limited consensus on how to define and measure pediatric acute diarrhea in trials. OBJECTIVES: In RCTs of children involving acute diarrhea as the primary outcome, we documented (1) how acute diarrhea and its resolution were defined, (2) all primary outcomes, (3) the psychometric properties of instruments used to measure acute diarrhea and (4) the methodologic quality of included trials, as reported. METHODS: We searched CENTRAL, Embase, Global Health, and Medline from inception to February 2009. English-language RCTs of children younger than 19 years that measured acute diarrhea as a primary outcome were chosen. RESULTS: We identified 138 RCTs reporting on 1 or more primary outcomes related to pediatric acute diarrhea/diseases. Included trials used 64 unique definitions of diarrhea, 69 unique definitions of diarrhea resolution, and 46 unique primary outcomes. The majority of included trials evaluated short-term clinical disease activity (incidence and duration of diarrhea), laboratory outcomes, or a composite of these end points. Thirty-two trials used instruments (eg, single and multidomain scoring systems) to support assessment of disease activity. Of these, 3 trials stated that their instrument was valid; however, none of the trials (or their citations) reported evidence of this validity. The overall methodologic quality of included trials was good. CONCLUSIONS: Even in what would be considered methodologically sound clinical trials, definitions of diarrhea, primary outcomes, and instruments employed in RCTs of pediatric acute diarrhea are heterogeneous, lack evidence of validity, and focus on indices that may not be important to participants.

Guideline for opioid therapy and chronic noncancer pain

Chronic noncancer pain includes any painful condition that persists for at least three months and is not associated with malignant disease.[1][1] According to seven national surveys conducted between 1994 and 2008, 15%–19% of Canadian adults live with chronic noncancer pain.[2][2] Chronic