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Objective To provide practical principles and examples to help GRADE users make optimal choices regarding their ratings of certainty of evidence using a minimally or partially contextualized approach. Study Design and Setting Based on the GRADE clarification of certainty of evidence in 2017, a project group within the GRADE Working Group conducted iterative discussions and presentations at GRADE Working Group meetings to refine this construct and produce practical guidance. Results Systematic review and health technology assessment authors need to clarify what it is in which they are rating their certainty of evidence (i.e., the target of their certainty rating). The decision depends on the degree of contextualization (partially or minimally contextualized), thresholds (null, small, moderate or large effect threshold), and where the point estimate lies in relation to the chosen threshold(s). When the 95% confidence interval crosses multiple possible thresholds (i.e., including both large benefit and large harm), it is not worthwhile for authors to determine the target of certainty rating. Conclusion GRADE provides practical principles to help systematic review and health technology assessment authors specify the target of their certainty of evidence rating.

Objectives The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. Study Design and Setting We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989–October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. Results We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). Conclusion A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.

ObjectiveClinical trialists, meta-analysts and clinical guideline developers are increasingly using minimal important differences (MIDs) to enhance the interpretability of patient-reported outcome measures (PROMs). Here, we elucidate three critical issues of which MID users should be aware. Improved understanding of MID concepts and awareness of common pitfalls in methodology and reporting will better inform the application of MIDs in clinical research and decision-making.MethodsWe conducted a systematic review to inform the development of an inventory of anchor-based MID estimates for PROMs. We searched four electronic databases to identify primary studies empirically calculating an anchor-based MID estimate for any PROM in adolescent or adult populations across all clinical areas. Our findings are based on information from 338 studies reporting 3389 MIDs for 358 PROMs published between 1989 and 2015.ResultsWe identified three key issues in the MID literature that demand attention. (1) The profusion of terms representing the MID concept adds unnecessary complexity to users’ task in identifying relevant MIDs, requiring meticulous inspection of methodology to ensure estimates offered truly reflect the MID. (2) A multitude of diverse methods for MID estimation that will yield different estimates exist, and whether there are superior options remains unresolved. (3) There are serious issues of incomplete presentation and reporting of key aspects of the design, methodology and results of studies providing anchor-based MIDs, which threatens the optimal use of these estimates for interpretation of intervention effects on PROMs.ConclusionsAlthough the MID represents a powerful tool for enhancing the interpretability of PROMs, realising its full value will require improved understanding and reporting of its measurement fundamentals.

Background Hip fractures are a leading cause of disability worldwide, with displaced femoral neck fractures being of particular concern. A recent meta-analysis reported that total hip arthroplasty (THA) was superior to hemiarthroplasty (HA) in terms of reoperations, but inferior in terms of dislocations. However, publication of 4 additional randomized controlled trials that enrolled nearly 1,780 additional patients merits an updated meta-analysis. Methods We conducted a literature search of 4 databases to identify randomized controlled trials comparing THA and HA in patients with displaced femoral neck fractures. For patient-reported outcomes, the minimally important difference informed calculation of risk differences. We performed a subgroup analysis to address the possible impact of risk of bias and performed meta-regression to assess the possible impact of duration of follow-up. Results Sixteen studies that enrolled 3,084 patients randomized to undergo THA (n = 1,521) or HA (n = 1,563) proved eligible. There were no significant differences between the 2 groups in terms of the revision rate at up to 5 years of follow-up or functional outcome at up to 3 years. Health-related quality of life was superior in the THA group (mean difference [MD] = 0.05, 95% confidence interval [CI] = 0.02 to 0.07, minimally important difference, 0.145). There was no significant difference between the groups in terms of dislocation or periprosthetic fracture incidence. Operative time was significantly shorter in the HA group (MD = 22 minutes, 95% CI = 9 to 35 minutes). Analyses addressing risk of bias and length of follow-up did not reveal subgroup differences. Certainty of evidence for all outcomes was rated as moderate. Conclusions The best evidence showed, with moderate certainty, that HA and THA likely result in similar revision rate, function, mortality, periprosthetic fracture, and dislocation at up to 5 years, with a small, possibly unimportant benefit in health-related quality of life with THA. More specifically, the improvements are well below established cutoffs for clinical importance. Almost half of all patients were from a single large randomized controlled trial, although the results were consistent across the studies. In addition, HA likely results in a clinically unimportant reduction in operative time. Level of evidence Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

COVID-19 is a global pandemic that has currently infected >300,000 globally. Fever and cough are the most common symptoms of the disease, and it is important to remember that the virus can even be transmitted by individuals who test positive for the disease but do not have any symptoms. Currently reported mortality rates vary because of the rapid spread of the disease and different approaches to calculating this estimate, but it is clear that the risk of death is associated with age and the presence of underlying conditions. Risk mitigation techniques (i.e., hand washing, social distancing, and self-isolation) have already been emphasized across major news outlets. It is essential that we continue these practices, as the outbreak is currently expected to last for many more months and we must be mindful of the lessons learned from past pandemics to prevent a second wave from occurring.

PurposeThere are a number of developments in intra-articular therapies that have been determined to be differentiating factors within the classes of treatments. This study evaluated the efficacy and safety of intra-articular treatments of primary knee osteoarthritis in the short term (3 months follow-up), using a network meta-analysis design, while taking within-class differentiating factors into consideration.MethodsA literature search of MEDLINE (through OVID), EMBASE (through OVID), Cochrane Central Register of Controlled Trials for all trials comparing intra-articular therapies was conducted on November 12, 2018. The treatments assessed were high molecular weight and low molecular weight hyaluronic acid injections, extended-release corticosteroids, standard-release corticosteroids, platelet-rich plasma, and saline. A frequentist network meta-analysis was conducted for each outcome.ResultsSixty-four articles (9710 patients) met the inclusion criteria. High molecular weight hyaluronic acid (− 0.53, 95% CI − 0.81 to − 0.25) and PRP (− 0.79, 95% CI − 1.32 to − 0.26) were the only treatments with a confidence interval that lay completely above the MID threshold; however, PRP results varied within sensitivity analyses. For the function analysis, high molecular weight hyaluronic acid (SMD − 0.76, 95% CI − 1.30 to − 0.22) was the only treatment with a confidence interval entirely above the MID. Extended-release corticosteroid demonstrated a possible benefit in functional improvement (SMD − 0.98, 95% CI − 1.79 to − 0.17) compared to that of standard-release corticosteroid (SMD − 0.14, 95% CI − 0.72 to 0.44).ConclusionHigh molecular weight HA was the only treatment to surpass the MID for both pain and function outcomes. Extended-release corticosteroids may provide additional clinical benefit over standard-release corticosteroids. Platelet-rich plasma demonstrated possibly beneficial results; however, wide confidence intervals and sensitivity analyses made the conclusions of efficacy uncertain.Level of evidenceLevel 1. Systematic review of level 1 evidence.

We produced, through a systematic review of quantitative and qualitative evidence, a synthesis of the issues of importance (values and preferences) to adult patients with type 1 diabetes regarding treatment with automated insulin delivery systems.We searched MEDLINE, CINAHL, EMBASE, and PsycINFO from the inception of each database through September 2018. We included studies examining patient values and preferences for outcomes related to continuous subcutaneous insulin infusion or artificial pancreas treatment. We compiled structured summaries of the results and assessed the relative importance of each outcome. GRADE (Grading of Recommendations, Assessment Development, and Evaluation) and CERQual (Confidence in Evidence from Reviews of Qualitative research) approaches provided the structure for the evaluation of the quality of evidence and confidence in the findings. A mixed-methods result-based convergent design provided the structure for integration and presentation of results.We reviewed 1665 unique citations; 19 studies (8 quantitative and 11 qualitative) proved eligible. Glycemic control is the key attribute that drives patients' preference. Reduction of glycemic variability and decreased incidence of hypoglycemia and chronic complications proved of intermediate importance and were ranked similarly to components of treatment burden, including the size and appearance of devices, cost, ease of use, and the embarrassment of public use.Clinician guidance may play a crucial role in determining patient values and preferences (for instance, patients' priority in glucose control rather than avoiding diabetic complications). Our results provide guidance for clinicians in discussing preferred insulin delivery systems with patients with type 1 diabetes.

BackgroundCough severity represents an important subjective endpoint in assessing the effectiveness of therapies for patients with chronic cough. Although cough-specific quality of life questionnaires exist, a widely available cough severity instrument with established measurement properties remains unavailable.AimsTo identify and summarise the results of studies reporting on the experience of patients with chronic cough and, in the process, develop a conceptual framework to inform development of a patient-reported outcome measurement (PROM) addressing cough severity.ResultsWe identified 61 eligible studies reporting on patient experience with chronic cough. Studies provided 82 potential items, of which 43 proved unique and relevant to cough severity. The urge-to-cough sensation and the cough symptom itself represented broad domains of cough severity. Two subdomains under urge-to-cough included frequency (1 item) and intensity (1 item). Five subdomains under cough symptoms included control (2 items), frequency (6 items), bout duration (1 item), intensity (8 items), and associated features/sequelae (24 items).ConclusionsOur systematic survey and conceptual framework identified items and domains of cough severity in patients with refractory or unexplained chronic cough. The results support item generation and content validity for a PROM assessing cough severity.

Background: For patients with chronic, non-cancer pain, traditional pain-relieving medications include opioids, which have shown benefits but are associated with increased risks of addiction and adverse effects. Medical cannabis has emerged as a treatment alternative for managing these patients and there has been a rise in the number of randomized clinical trials in recent years; therefore, a systematic review of the evidence was warranted. Objective: To analyze the evidence surrounding the benefits and harms of medical cannabinoids in the treatment of chronic, non-cancer-related pain. Design: Systematic review with meta-analysis. Data sources: Medline, Embase, CINAHL, SCOPUS, Google Scholar, and Cochrane Databases. Eligibility criteria: English language randomized clinical trials of cannabinoids for the treatment of chronic, non-cancer-related pain. Data extraction and synthesis: Study quality was assessed using the Cochrane risk of bias tool. All stages were conducted independently by a team of 6 reviewers. Data were pooled through meta-analysis with different durations of treatment (2 weeks, 2 months, 6 months) and stratified by route of administration (smoked, oromucosal, oral), conditions, and type of cannabinoids. Main outcomes and measures: Patient-reported pain and adverse events (AEs). Results: Thirty-six trials (4006 participants) were included, examining smoked cannabis (4 trials), oromucosal cannabis sprays (14 trials), and oral cannabinoids (18 trials). Compared with placebo, cannabinoids showed a significant reduction in pain which was greatest with treatment duration of 2 to 8 weeks (weighted mean difference on a 0-10 pain visual analogue scale −0.68, 95% confidence interval [CI], −0.96 to −0.40, I2 = 8%, P .05 in all the 3 durations of treatment); cannabinoids had a smaller reduction in pain due to multiple sclerosis compared with placebo relative to other neuropathic pain ( P[interaction] = .05) within 2 weeks and the difference was not significant relative to pain due to rheumatic arthritis; nabilone had a greater reduction in pain compared with placebo relative to other types of cannabinoids longer than 2 weeks of treatment but the difference was not significant ( P[interaction] > .05). Serious AEs were rare, and similar across the cannabinoid (74 out of 2176, 3.4%) and placebo groups (53 out of 1640, 3.2%). There was an increased risk of non-serious AEs with cannabinoids compared with placebo. Conclusions: There was moderate evidence to support cannabinoids in treating chronic, non-cancer pain at 2 weeks. Similar results were observed at later time points, but the confidence in effect is low. There is little evidence that cannabinoids increase the risk of experiencing serious AEs, although non-serious AEs may be common in the short-term period following use.

Objective To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19. Design Living systematic review and network meta-analysis. Data sources World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021. Study selection Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. Methods Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. Results The first iteration of this living network meta-analysis includes nine randomised trials—six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain. Conclusions Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. Systematic review registration This review was not registered. The protocol established a priori is included as a supplement. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Immune checkpoint inhibitors have revolutionized treatment of advanced cutaneous melanoma. This group of novel therapeutic agents differs from other systemic treatments and has necessitated a new approach for several fundamental aspects of clinical practice in oncology. Marked differences in outcomes associated with immune checkpoint inhibitors compared with other systemic therapies has required a new paradigm for prognostication in the setting of advanced melanoma. Distinct patterns of tumor response have required new norms for disease monitoring. A unique spectrum of toxicity is associated with use of immune checkpoint inhibitors which can be severe and refractory. Patients and clinicians must be informed regarding immune-related adverse events, yet in the published literature, there is substantial variability in reporting. As immune checkpoint inhibitors gain a prominent role in cancer treatment, standardization of adverse event reporting will be vital to ensure validity of evidence and to promote safe clinical practice.

Objective To develop an instrument to evaluate the credibility of anchor based minimal important differences (MIDs) for outcome measures reported by patients, and to assess the reliability of the instrument. Design Instrument development and reliability study. Data sources Initial criteria were developed for evaluating the credibility of anchor based MIDs based on a literature review (Medline, Embase, CINAHL, and PsycInfo databases) and the experience of the authors in the methodology for estimation of MIDs. Iterative discussions by the team and pilot testing with experts and potential users facilitated the development of the final instrument. Participants With the newly developed instrument, pairs of masters, doctoral, or postdoctoral students with a background in health research methodology independently evaluated the credibility of a sample of MID estimates. Main outcome measures Core credibility criteria applicable to all anchor types, additional criteria for transition rating anchors, and inter-rater reliability coefficients were determined. Results The credibility instrument has five core criteria: the anchor is rated by the patient; the anchor is interpretable and relevant to the patient; the MID estimate is precise; the correlation between the anchor and the outcome measure reported by the patient is satisfactory; and the authors select a threshold on the anchor that reflects a small but important difference. The additional criteria for transition rating anchors are: the time elapsed between baseline and follow-up measurement for estimation of the MID is optimal; and the correlations of the transition rating with the baseline, follow-up, and change score in the patient reported outcome measures are satisfactory. Inter-rater reliability coefficients (ĸ) for the core criteria and for one item from the additional criteria ranged from 0.70 to 0.94. Reporting issues prevented the evaluation of the reliability of the three other additional criteria for the transition rating anchors. Conclusions Researchers, clinicians, and healthcare policy decision makers can consider using this instrument to evaluate the design, conduct, and analysis of studies estimating anchor based minimal important differences.

ObjectivesTo identify credible anchor-based minimal important differences (MIDs) for patient-reported outcome measures (PROMs) relevant to aBMJRapid Recommendations addressing subacromial decompression surgery for shoulder pain.DesignSystematic review.Outcome measuresEstimates of anchor-based MIDs, and their credibility, for PROMs judged by the parallelBMJRapid Recommendations panel as important for informing their recommendation (pain, function and health-related quality of life (HRQoL)).Data sourcesMEDLINE, EMBASE and PsycINFO up to August 2018.Study selection and review methodsWe included original studies of any intervention for shoulder conditions reporting estimates of anchor-based MIDs for relevant PROMs. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria. Six reviewers, working in pairs, independently extracted data from eligible studies using a predesigned, standardised, pilot-tested extraction form and independently assessed the credibility of included studies using an MID credibility tool.ResultsWe identified 22 studies involving 5562 patients that reported 74 empirically estimated anchor-based MIDs for 10 candidate instruments to assess shoulder pain, function and HRQoL. We identified MIDs of high credibility for pain and function outcomes and of low credibility for HRQoL. We offered median estimates for the systematic review team who applied these MIDs in Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence summaries and in their interpretations of results in the linked systematic review addressing the effectiveness of surgery for shoulder pain.ConclusionsOur review provides anchor-based MID estimates, as well as a rating of their credibility, for PROMs for patients with shoulder conditions. The MID estimates inform the interpretation for a linked systematic review and guideline addressing subacromial decompression surgery for shoulder pain, and could also prove useful for authors addressing other interventions for shoulder problems.PROSPERO registration numberCRD42018106531.

Objective The objective of the study was to systematically survey the methodological literature and collect suggested criteria for assessing the credibility of effect modification and associated rationales. Study Design and Setting We searched MEDLINE, Embase, and WorldCat up to March 2018 for publications providing guidance for assessing the credibility of effect modification identified in randomized trials or meta-analyses. Teams of two investigators independently identified eligible publications and extracted credibility criteria and authors’ rationale, reaching consensus through discussion. We created a taxonomy of criteria that we iteratively refined during data abstraction. Results We identified 150 eligible publications that provided 36 criteria and associated rationales. Frequent criteria included significant test for interaction (n = 54), a priori hypothesis (n = 49), providing a causal explanation (n = 47), accounting for multiplicity (n = 45), testing a small number of effect modifiers (n = 38), and prespecification of analytic details (n = 39). For some criteria, we found more than one rationale; some criteria were connected through a common rationale. For some criteria, experts disagreed regarding their suitability (e.g., added value of stratified randomization; trustworthiness of biologic rationales). Conclusion Methodologists have expended substantial intellectual energy providing criteria for critical appraisal of apparent effect modification. Our survey highlights popular criteria, expert agreement and disagreement, and where more work is needed, including testing criteria in practice.

Objectives We conducted a survey to explore practice patterns regarding the assessment of hypovitaminosis D and the prescription of vitamin D in acute fracture patients. Our secondary objective was to determine whether practice patterns differed between fragility and nonfragility fracture patients. Design Cross-sectional survey. Setting All surveys were completed using SurveyMonkey. Patients/participants We surveyed surgeon members of the Canadian Orthopaedic Association and the Orthopaedic Trauma Association. Intervention Survey. Main outcome measurements The proportion of surgeons who routinely prescribe vitamin D to fracture patients. Results A total of 397 surveys were completed. Of total, 65.8% of surgeons indicated that they routinely prescribe vitamin D to fragility fracture patients and 25.7% routinely prescribe vitamin D to nonfragility fracture patients. We identified considerable variability in dosing regimens, as 45 different dosing regimens were prescribed in fragility fracture patients and 29 in nonfragility fracture patients. They ranged from daily doses of 400 IU to loading doses of 600,000 IU. The most frequently prescribed doses were 1000 IU daily (14.6%), 2000 IU daily (13.4%), and 50,000 IU weekly (8.7%). Respondents indicated that they heavily relied on clinical experience to guide their decisions to prescribe vitamin D to fracture patients. Conclusions The results of this survey demonstrate multiple areas of uncertainty and a lack of consensus in the prescription of vitamin D to fracture patients. Fragility patients frequently receive vitamin D supplementation, whereas most surgeons do not prescribe vitamin D to young fracture patients. High-quality clinical research is needed to determine whether vitamin D supplementation is beneficial to fracture patients. Level of evidence Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.

E-cigarettes are increasingly popular as smoking cessation aids. This review assessed the efficacy of e-cigarettes for smoking cessation as well as desire to smoke, withdrawal symptoms, and adverse events in adult smokers. A systematic review was conducted. Studies comparing e-cigarettes to other nicotine replacement therapies or placebo were included. Data were pooled using meta-analysis. Of 569 articles, 5 were eligible. Study participants were more likely to stop smoking when using nicotine e-cigarettes (43/489, 9 %) versus placebo e-cigarettes (8/173, 5 %); however, this difference was not statistically significant (RR 2.02; 95 % CI 0.97, 4.22). The pooled effect estimates for the desire to smoke (RR −0.22; 95 % CI −0.80, 0.36), irritability (RR −0.03; 95% CI −0.38, 0.31), restlessness (RR −0.03; 95 % CI −0.42, 0.35), poor concentration (RR −0.01; 95 % CI −0.35, 0.32), depression (RR −0.01; 95 % CI −0.22, 0.20), hunger (RR −0.01; 95 % CI −0.32, 0.30), and average number of non-serious adverse events (RR −0.09; 95 % CI −0.28, 0.46) were not statistically significantly different. Only one study reported serious adverse events with no apparent association with e-cigarette use. Limited low-quality evidence of a non-statistically significant trend toward smoking cessation in adults using nicotine e-cigarettes exists compared with other therapies or placebo. Larger, high-quality studies are needed to inform policy decisions.

Background The spectrum of treatment options for patients with metastatic BRAF-mutated melanoma is broad, spanning multiple treatment classes. However, there is a lack of head-to-head evidence comparing targeted and immunotherapies. The purpose of this study is to conduct a network meta-analysis (NMA) in previously untreated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this patient population at the treatment level. Methods The literature review included searches of MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) to November 2018. Randomized controlled trials of previously untreated patients with advanced melanoma were eligible if at least one intervention was either a targeted or immune therapy. Relative treatment effects were estimated by fixed effect Bayesian NMAs on progression-free survival (PFS) and overall survival (OS), based on the hazard ratio. Results Combination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combination vemurafenib with cobimetinib (HR 0.22 [95% CrI 0.17, 0.29] vs dacarbazine) were likely to rank as the most favorable treatment options for PFS, while combination nivolumab with ipilimumab was likely to be the most efficacious in terms of OS (HR 0.33 [0.24, 0.47] vs dacarbazine). Conclusions and relevance The findings highlight the efficacy of combination PD-1 with CTLA-4 inhibitors and combination BRAF with MEK inhibitors in the treatment of advanced melanoma. However, as few trials informed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape.

IntroductionMeta-analyses of clinical trials often provide sufficient information for decision-makers to evaluate whether chance can explain apparent differences between interventions. Interpretation of the magnitude and importance of treatment effects beyond statistical significance can, however, be challenging, particularly for patient-reported outcomes (PROs) measured using questionnaires with which clinicians have limited familiarity. The objectives of our study are to systematically evaluate Cochrane systematic review authors’ approaches to calculation, reporting and interpretation of pooled estimates of patient-reported outcome measures (PROMs) in meta-analyses.Methods and analysisWe will conduct a methodological survey of a random sample of Cochrane systematic reviews published from 1 January 2015 to 1 April 2017 that report at least one statistically significant pooled result for at least one PRO in the abstract. Author pairs will independently review all titles, abstracts and full texts identified by the literature search, and they will extract data using a standardised data extraction form. We will extract the following: year of publication, number of included trials, number of included participants, clinical area, type of intervention(s) and control(s), type of meta-analysis and use of the Grading of Recommendations, Assessment, Development and Evaluation approach to rate the quality of evidence, as well as information regarding the characteristics of PROMs, calculation and presentation of PROM effect estimates and interpretation of PROM effect estimates. We will document and summarise the methods used for the analysis, reporting and interpretation of each summary effect measure. We will summarise categorical variables with frequencies and percentages and continuous outcomes as means and/or medians and associated measures of dispersion.Ethics and disseminationEthics approval for this study is not required. We will disseminate the results of this review in peer-reviewed publications and conference presentations.

© 2017, © The Author(s), 2017. Osteoarthritis (OA) is a chronic condition characterized by a loss of joint cartilage and is a major cause of disability in Canada, with an estimated CN$195 billion annual cost. Knee OA leads to persistent pain and loss of function, and treatment goals primarily focus on symptom relief and retention of function. Intra-articular hyaluronic acid (IAHA) has therapeutic benefits, and numerous recently published meta-analyses (MAs) and commentaries have highlighted new evidence on the role of IAHA therapy for knee OA. A diverse, multidisciplinary group of specialists met independently in closed sessions to review findings from eight MAs with literature search end dates no earlier than 2012 to address controversies surrounding IAHA therapy for mild-to-moderate knee OA within the Canadian treatment context. Outcomes from a total of eight MAs were reviewed, and consistent and statistically significant improvements in pain, function and stiffness up to 26 weeks were found with IAHA therapy compared with IA placebo or controls, regardless of MA size or trial quality. These findings are in line with those of a Cochrane review, another recent systematic review and patient satisfaction survey. Overall, three MAs reported outcomes based on molecular weight (MW), with the two reporting effect sizes showing significantly improved pain outcomes for higher compared with lower MW HAs. Recent evidence suggests that HA therapy is well tolerated with no increased risk of serious adverse events compared with placebo and the full therapeutic effect of IAHA therapy appears to have considerable clinical importance, consisting of the combined IA placebo and HA therapeutic effects. IAHA therapy is a well-tolerated and effective option for patients with mild-to-moderate knee OA failing first-line pharmacological therapy.

Objective To determine the frequency of survival, stroke, atrial fibrillation, structural valve deterioration, and length of hospital stay after surgical replacement of an aortic valve (SAVR) with a bioprosthetic valve in patients with severe symptomatic aortic stenosis. Design Systematic review and meta-analysis of observational studies. Data sources Medline, Embase, PubMed (non-Medline records only), Cochrane Database of Systematic Reviews, and Cochrane CENTRAL from 2002 to June 2016. Study selection Eligible observational studies followed patients after SAVR with a bioprosthetic valve for at least two years. Methods Reviewers, independently and in duplicate, evaluated study eligibility, extracted data, and assessed risk of bias for patient important outcomes. We used the GRADE system to quantify absolute effects and quality of evidence. Published survival curves provided data for survival and freedom from structural valve deterioration, and random effect models provided the framework for estimates of pooled incidence rates of stroke, atrial fibrillation, and length of hospital stay. Results In patients undergoing SAVR with a bioprosthetic valve, median survival was 16 years in those aged 65 or less, 12 years in those aged 65 to 75, seven years in those aged 75 to 85, and six years in those aged more than 85. The incidence rate of stroke was 0.25 per 100 patient years (95% confidence interval 0.06 to 0.54) and atrial fibrillation 2.90 per 100 patient years (1.78 to 4.79). Post-SAVR, freedom from structural valve deterioration was 94.0% at 10 years, 81.7% at 15 years, and 52% at 20 years, and mean length of hospital stay was 12 days (95% confidence interval 9 to 15). Conclusion Patients with severe symptomatic aortic stenosis undergoing SAVR with a bioprosthetic valve can expect only slightly lower survival than those without aortic stenosis, and a low incidence of stroke and, up to 10 years, of structural valve deterioration. The rate of deterioration increases rapidly after 10 years, and particularly after 15 years.

COPYRIGHT © 2016 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED. The body of evidence surrounding the use of viscosupplementation in knee osteoarthritis is extensive and fraught with heterogeneous trials with conflicting conclusions.Attempts to aggregate the evidence through systematic reviews, meta-analyses, and guidelines have also resulted in unclear, discordant recommendations. Closer examination reveals that the evidence around viscosupplementation favors clinically important reductions in pain among higher-molecular-weight and cross-linked formulations and is a safe option in patients with knee osteoarthritis.Further large trials assessing the use of viscosupplementation across various formulations in knee osteoarthritis may confirm subgroup findings from meta-analyses; however, immediate focus on improved knowledge translation is required to ensure evidence-based approaches to the treatment of knee osteoarthritis.

INTRODUCTION:Providing optimal critical care in developing countries is limited by lack of recognition of critical illness and lack of essential resources. The Modified Early Warning Score (MEWS), based on physiological parameters, is validated in adult medical and surgical patients as a predictor of mortality. The objective of this study performed in Uganda was to determine the prevalence of critical illness on the wards as defined by the MEWS, to evaluate the MEWS as a predictor of death, and to describe additional risk factors for mortality. METHODS:We conducted a prospective observational study at Mulago National Referral Teaching Hospital in Uganda. We included medical and surgical ward patients over 18 years old, excluding patients discharged the day of enrolment, obstetrical patients, and patients who self-discharged prior to study completion. Over a 72-hour study period, we collected demographic and vital signs, and calculated MEWS; at 7-days we measured outcomes. Patients discharged prior to 7 days were assumed to be alive at study completion. Descriptive and inferential statistical analyses were performed. RESULTS:Of 452 patients, the median age was 40.5 (IQR 29-54) years, 53.3% were male, 24.3% were HIV positive, and 45.1% had medical diagnoses. MEWS ranged from 0 to 9, with higher scores representing hemodynamic instability. The median MEWS was 2 [IQR 1-3] and the median length of hospital stay was 9 days [IQR 4-24]. In-hospital mortality at 7-days was 5.5%; 41.4% of patients were discharged and 53.1% remained on the ward. Mortality was independently associated with medical admission (OR: 7.17; 95% CI: 2.064-24.930; p = 0.002) and the MEWS ≥ 5 (OR: 5.82; 95% CI: 2.420-13.987; p

Objective To examine the effect of transcatheter aortic valve implantation (TAVI) versus surgical replacement of an aortic valve (SAVR) in patients with severe aortic stenosis at low and intermediate risk of perioperative death. Design Systematic review and meta-analysis Data sources Medline, Embase, and Cochrane CENTRAL. Study selection Randomized trials of TAVI compared with SAVR in patients with a mean perioperative risk of death Review methods Two reviewers independently extracted data and assessed risk of bias for outcomes important to patients that were selected a priori by a parallel guideline committee, including patient advisors. We used the GRADE system was used to quantify absolute effects and quality of evidence. Results 4 trials with 3179 patients and a median follow-up of two years were included. Compared with SAVR, transfemoral TAVI was associated with reduced mortality (risk difference per 1000 patients: −30, 95% confidence interval −49 to −8, moderate certainty), stroke (−20, −37 to 1, moderate certainty), life threatening bleeding (−252, −293 to −190, high certainty), atrial fibrillation (−178, −150 to −203, moderate certainty), and acute kidney injury (−53, −39 to −62, high certainty) but increased short term aortic valve reintervention (7, 1 to 21, moderate certainty), permanent pacemaker insertion (134, 16 to 382, moderate certainty), and moderate or severe symptoms of heart failure (18, 5 to 34, moderate certainty). Compared with SAVR, transapical TAVI was associated higher mortality (57, −16 to 153, moderate certainty, P=0.015 for interaction between transfemoral versus transapical TAVI) and stroke (45, −2 to 125, moderate certainty, interaction P=0.012). No study reported long term follow-up, which is particularly important for structural valve deterioration. Conclusions Many patients, particularly those who have a shorter life expectancy or place a lower value on the risk of long term valve degeneration, are likely to perceive net benefit with transfemoral TAVI versus SAVR. SAVR, however, performs better than transapical TAVI, which is of interest to patients who are not candidates for transfemoral TAVI. Systematic review registration PROSPERO CRD42016042879

Made available in DSpace on 2018-11-26T15:45:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-08-01 Objective: To assess analytic approaches randomized controlled trial (RCT) authors use to address missing participant data (MPD) for patient-important continuous outcomes. Study Design and Setting: We conducted a systematic survey of RCTs published in 2014 in the core clinical journals that reported at least one patient-important outcome analyzed as a continuous variable. Results: Among 200 studies, 187 (93.5%) trials explicitly reported whether MPD occurred. In the 163 (81.5%) trials that reported the occurrence of MPD, the median and interquartile ranges of the percentage of participants with MPD were 11.4% (2.5%-22.6%).Among the 147 trials in which authors made clear their analytical approach to MPD, the approaches chosen included available data only (109, 67%); mixed-effect models (10, 6.1%); multiple imputation (9, 4.5%); and last observation carried forward (9, 4.5). Of the 163 studies reporting MPD, 16 (9.8%) conducted sensitivity analyses examining the impact of the MPD and (18, 11.1%) discussed the risk of bias associated with MPD. Conclusion: RCTs reporting continuous outcomes typically have over 10% of participant data missing. Most RCTs failed to use optimal analytic methods, and very few conducted sensitivity analyses addressing the possible impact of MPD or commented on how MPD might influence risk of bias. (C) 2017 Elsevier Inc. All rights reserved. McMaster Univ, Dept Hlth Res Methods Evidence & Impact, Hamilton, ON, Canada China Acad Chinese Med Sci, Guanganmen Hosp, Beijing, Peoples R China Univ Antioquia, Dept Pediat, Medellin, Colombia Hosp Angeles del Carmen, Dept Crit Care, Guadalajara, Jalisco, Mexico Singapore Gen Hosp, Nursing Div, Singapore, Singapore Univ Toronto, Dept Diagnost Radiol, Toronto, ON, Canada Michael G DeGroote Natl Pain Ctr, Dept Anesthesiol, Hamilton, ON, Canada GSK, Med Affairs, Hlth Econ & Outcomes Res, Mississauga, ON, Canada Univ Toronto, Fac Med, Toronto, ON, Canada Univ Sorocaba, Dept Pharmaceut Sci, Sao Paulo, Brazil Univ Estadual Paulista, Dept Pharmaceut Sci, Sao Paulo, Brazil McMaster Univ, Dept Family Med, Hamilton, ON, Canada Beijing Univ Chinese Med, Ctr Evidence Based Chinese Med, Chaoyang Qu, Peoples R China Univ Chile, Evidence Based Dent Unit, Santiago, Region Metropol, Chile Univ Chile, Dept Oral & Maxillofacial Surg, Santiago, Region Metropol, Chile Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon Dept Med, Hamilton, ON, Canada Dept Hlth Res Methods Evidence & Impact, Hamilton, ON, Canada Univ Estadual Paulista, Dept Pharmaceut Sci, Sao Paulo, Brazil

The objectives of this systematic review and meta-analyses are (1) to estimate the prevalence of hypovitaminosis D in fracture patients and (2) to summarize the available evidence on the efficacy of vitamin D supplementation in fracture patients.A comprehensive search of the MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials databases was conducted. Conference abstracts from relevant meetings were also searched.We included studies that investigate vitamin D insufficiency or examine the effect of vitamin D supplementation on 25-hydroxy-vitamin D (25(OH)D) serum levels in fracture patients.Two authors independently extracted data using a predesigned form.We performed a pooled analysis to determine the prevalence of postfracture hypovitaminosis D and mean postfracture 25(OH)D levels. We present detailed summaries of each of the studies evaluating the impact of vitamin D supplementation.The weighted pooled prevalence of hypovitaminosis D was 70.0% (95% confidence interval: 63.7%-76.0%, I = 97.7). The mean postfracture serum 25(OH)D was 19.5 ng/mL. The studies that evaluated the efficacy of vitamin D supplementation suggest that vitamin D supplementation safely increases serum 25(OH)D levels. Only 1 meeting abstract showed a trend toward reduced risk of nonunion after a single large loading dose of vitamin D.This review found a high prevalence of hypovitaminosis D in fracture patients and that vitamin D supplementation at a range of doses safely increases 25(OH)D serum levels. To date, only 1 pilot study published as a meeting abstract has demonstrated a trend toward improved fracture healing with vitamin D supplementation.Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Importance Multiple effective first-line systemic treatment options are available for patients with advancedBRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment. Objective To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive,BRAF-mutated melanoma. Data Sources We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016. Study Selection We included RCTs in which at least 1 intervention was a targeted (BRAForMEK) or an immune checkpoint (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] or programmed cell death 1 [PD-1]) inhibitor. Data Extraction and Synthesis Two reviewers performed study selection, data abstraction, and risk of bias assessment. We performed a Bayesian network meta-analysis using a fixed-effect model to combine direct comparisons with indirect evidence. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (OR) for objective response rate (ORR) and serious adverse events. Results Sixteen eligible articles reporting 15 RCTs involving 6662 patients assigned to 1 of 10 treatment strategies were included. BothBRAF/MEKand PD-1 were associated with improved OS benefit compared with all other treatments except CTLA-4/granulocyte macrophage colony-stimulating factor. There was no significant difference in OS betweenBRAF/MEKand PD-1 (HR, 1.02; 95% credible interval [CrI], 0.72-1.45). The network meta-analysis showed a significant advantage ofBRAF/MEKcompared with all other treatment strategies for PFS.BRAF/MEKwas associated with higher ORR (OR, 2.00; 95% CrI, 1.64-2.45) compared withBRAFalone, with both being superior in achieving ORR compared with other treatments. Chemotherapy and PD-1 were associated with lowest risk of serious adverse events. There was no significant difference in the risk of serious adverse events between chemotherapy and PD-1 (OR, 1.00; 95% CrI, 0.74-1.34). Conclusions and Relevance Compared with other treatments,BRAF/MEKand PD-1 inhibition significantly improved OS. The favorable safety profile of PD-1 inhibitors supports using this option as first-line therapy in circumstances where rapid response is not a priority.

Sarcolipin (SLN) and phospholamban (PLN) inhibit the activity of sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs) by reducing their apparent affinity for Ca(2+). A ternary complex between SLN, PLN, and SERCAs results in super-inhibition of SERCA activity. Analysis of skeletal muscle homogenate has limited our current understanding of whether SLN and PLN regulate SERCA1a, SERCA2a, or both in skeletal muscle and whether SLN and PLN are co-expressed in skeletal muscle fibers. Biopsies from human vastus lateralis were analyzed through single fiber Western blotting and immunohisto/fluorescence staining to circumvent this limitation. With a newly generated SLN antibody, we report for the first time that SLN protein is present in human skeletal muscle. Addition of the SLN antibody (50 µg) to vastus lateralis homogenates increased the apparent Ca(2+) affinity of SERCA (K Ca, pCa units) (-Ab, 5.85 ± 0.02 vs. +Ab, 5.95 ± 0.02) and maximal SERCA activity (μmol/g protein/min) (-Ab, 122 ± 6.4 vs. +Ab, 159 ± 11) demonstrating a functional interaction between SLN and SERCAs in human vastus lateralis. Specifically, our results suggest that although SLN and PLN may preferentially regulate SERCA1a, and SERCA2a, respectively, physiologically they both may regulate either SERCA isoform. Furthermore, we show that SLN and PLN co-immunoprecipitate in human vastus lateralis homogenate and are simultaneously expressed in 81% of the fibers analyzed with Western blotting which implies that super-inhibition of SERCA may exist in human skeletal muscle. Finally, we demonstrate unequivocally that mouse soleus contains PLN protein suggesting that super-inhibition of SERCA may also be important physiologically in rodent skeletal muscle.

ObjectivesHyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA.MethodsMEDLINE and Embase databases were searched for articles published up to and including August 14th, 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (≤3 months) and long-term (6–12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null effect in a comparator group) that were combined and weighted using a random effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics.ResultsFrom 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1705 patients (SMD = −0.68; 95% CI: −0.78 to −0.57; P < 0.001; I2 = 50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD = −0.61; 95% CI: −0.76 to −0.45; P < 0.001) with a substantial degree of inconsistency (I2 = 74%). Overall, 29 of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline.ConclusionsPain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a “placebo.”