Search

ObjectiveTo evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis.DesignSystematic review and meta-analysis of randomised trials.Data sourcesSearches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries.Eligibility criteria for study selectionRandomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment.Main outcome measuresThe prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was −0.37 SMD. Serious adverse events were analysed as relative risks.MethodsTwo reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed.Results169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger’s tests with PConclusionStrong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis.Systematic review registrationPROSPERO CRD42021236894.

The objective of this study was to determine the association between biases related to attrition, missing data, and the use of intention to treat and changes in effect size estimates in physical therapy randomized trials. A meta-epidemiological study was conducted. A random sample of randomized controlled trials included in meta-analyses in the physical therapy discipline were identified. Data extraction including assessments of the use of intention to treat principle, attrition-related bias, and missing data was conducted independently by two reviewers. To determine the association between these methodological issues and effect sizes, a two-level analysis was conducted using a meta-meta-analytic approach. Three hundred ninety-three trials included in 43 meta-analyses, analyzing 44,622 patients contributed to this study. Trials that did not use the intention-to-treat principle (effect size = -0.13, 95% confidence interval = -0.26 to 0.01) or that were assessed as having inappropriate control of incomplete outcome data tended to underestimate the treatment effect when compared with trials with adequate use of intention to treat and control of incomplete outcome data (effect size = -0.18, 95% confidence interval = -0.29 to -0.08).Researchers and clinicians should pay attention to these methodological issues because they could provide inaccurate effect estimates. Authors and editors should make sure that intention-to-treat and missing data are properly reported in trial reports.

Interval training has become an essential component of endurance training programs because it can facilitate a substantial improvement in endurance sport performance. Two forms of interval training that are commonly used to improve endurance sport performance are high-intensity interval training (HIIT) and sprint interval training (SIT). Despite extensive research, there is no consensus concerning the optimal method to manipulate the interval training programming variables to maximize endurance performance for differing individuals. The objective of this manuscript was to perform a systematic review and meta-analysis of interval training studies to determine the influence that individual characteristics and training variables have on time-trial (TT) performance. SPORTDiscus and Medline with Full Text were explored to conduct a systematic literature search. The following criteria were used to select studies appropriate for the review: 1. the studies were prospective in nature; 2. included individuals between the ages of 18 and 65 years; 3. included an interval training (HIIT or SIT) program at least 2 weeks in duration; 4. included a TT test that required participants to complete a set distance; 5. and programmed HIIT by power or velocity. Twenty-nine studies met the inclusion criteria for the quantitative analysis with a total of 67 separate groups. The participants included males (n = 400) and females (n = 91) with a mean group age of 25 (range 19–45) years and mean $$V{\text{O}}_{{2{\text{max}}}}$$ of 52 (range 32–70) mL·kg−1·min−1. The training status of the participants comprised of inactive (n = 75), active (n = 146) and trained (n = 258) individuals. Training status played a significant role in improvements in TT performance with trained individuals only seeing improvements of approximately 2% whereas individuals of lower training status demonstrated improvements as high as 6%. The change in TT performance with HIIT depended on the duration but not the intensity of the interval work-bout. There was a dose–response relationship with the number of HIIT sessions, training weeks and total work with changes in TT performance. However, the dose–response was not present with SIT. Optimization of interval training programs to produce TT performance improvements should be done according to training status. Our analysis suggests that increasing interval training dose beyond minimal requirements may not augment the training response. In addition, optimal dosing differs between high intensity and sprint interval programs.

Objectives The aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents. Background The role of abbreviated DAPT followed by an oral P2Y12 inhibitor after PCI remains uncertain. Methods Two randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO ( CRD42019143120 ). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale. Results Bleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p Conclusions Ticagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events.

RESUME CONTEXTE: On ignore si les variations climatiques saisonnieres, la fermeture des etablissements scolaires ou d’autres interventions de sante publique entraineront un ralentissement de la pandemie actuelle de maladie a coronavirus 2019 (COVID-19). Nous avons voulu determiner si de facon globale la progression de l’epidemie est associee au climat ou aux interventions de sante publique visant a reduire la transmission du coronavirus du syndrome respiratoire aigu severe 2 (SRAS-CoV-2). METHODES: Nous avons procede a une etude de cohorte prospective des 144 regions geopolitiques de la planete (375 609 cas) presentant au moins 10 cas de COVID-19, avec transmission locale, en date du 20 mars 2020, a l’exclusion de la Chine, de la Coree du Sud, de l’Iran et de l’Italie. Par analyse de regression a effets aleatoires ponderee, nous avons evalue le lien entre la progression de l’epidemie (exprimee sous forme de rapports de taux d’incidence [RTI] comparant les nombres cumulatifs de cas de COVID-19 du 27 mars 2020 a ceux du 20 mars 2020) avec les facteurs de latitude, temperature, humidite, fermeture des etablissements scolaires, interdiction des grands rassemblements et mesures d’eloignement social qui etaient en place les 7 et 13 mars 2020 (periode de 14 jours anterieure a l’evaluation). RESULTATS: Les analyses univariees ont revele aucuns lien entre la progression de l’epidemie et les facteurs de latitude et de temperature, mais des liens negatifs faibles avec l’humidite relative (RTI par 10 %, 0,91, intervalle de confiance [IC] de 95 % 0,85–0,96) et l’humidite absolue (RTI par 5 g/m3 0,92, IC a 95 % 0,85–0,99). Des liens etroits ont ete observes avec l’interdiction des grands rassemblements (RTI 0,65, IC a 95 % 0,53–0,79), la fermeture des etablissements scolaires (RTI 0,63, IC a 95 % 0,52–0,78) et les mesures d’eloignement social (RTI 0,62, IC a 95 % 0,45–0,85). Dans un modele multivarie, on a note un lien etroit avec le nombre de mesures deployees par la sante publique (p pour tendance = 0,001), tandis que le lien avec l’humidite absolue s’attenuait. INTERPRETATION: La progression de l’epidemie de COVID-19 ne s’est pas revelee en lien avec la latitude ni avec la temperature, mais faiblement en lien avec l’humidite relative ou absolue. A l’inverse, les interventions de sante publique ont ete etroitement associees a un ralentissement de la progression de l’epidemie.

To evaluate the prognostic association between preoperative features seen on optical coherence tomography (OCT) imaging and postoperative visual acuity (VA) outcomes in rhegmatogenous retinal detachments (RRD).Currently, there is limited literature on the prognostic value of preoperative RRD OCT features.A literature search was conducted on Ovid MEDLINE, EMBASE and Cochrane CENTRAL from inception through September 15, 2022. A meta-analysis was performed using a random-effects model. Quality of studies and evidence was assessed using the JBI tools and GRADE framework, respectively.A total of 1,671 eyes of 1,670 patients from 29 observational studies were included. Eighty-nine percent of eyes had a macula-off RRD at presentation. The mean average duration of detachment was 15±10 days. The majority of eyes (62%) underwent pars plana vitrectomy. Six preoperative OCT features were analyzed: height of retinal detachment (HRD) at the fovea, central macular thickness (CMT), disruption of the ellipsoid zone (EZ) and/or external limiting membrane (ELM), intraretinal cystic cavities (ICCs), outer retinal corrugations (ORCs) and macular detachment. A greater HRD was weakly associated with postoperative VA (Pearson's correlation r=0.35, 95% CI=[0.20─0.48], p0.01), and there was no change in this association throughout the postoperative follow-up period. The CMT was not associated with postoperative VA. Eyes with disruption of the EZ and/or ELM had a postoperative VA worse by 0.35 logMAR (95% CI=[0.15─0.54], p0.01) or three Snellen lines. Eyes with ICCs had a postoperative VA worse by 0.14 logMAR (95% CI=[0.01─0.26], p0.01) or two Snellen lines. Eyes with ORCs did not have a significantly different postoperative VA than eyes without. Eyes with macular detachment had a postoperative VA worse by 0.15 logMAR (95% CI=[-0.31─0.00], p=0.02) or two Snellen lines. Overall, the quality of studies ranged from moderate to good (73─100%). All associations had a low quality of evidence, with CMT being very low quality.Despite the low quality of evidence, a greater HRD, disruption of the EZ and/or ELM, presence of ICCs and macular detachment were associated with a poor postoperative VA. We propose a standardized nomenclature for consistency and accuracy in reporting preoperative RRD OCT features for future studies.

ObjectivesTo assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients admitted to hospital with covid-19.DesignMulticentre pragmatic randomised clinical trial.Setting15 hospitals in Canada and the United States from May 2020 until May 2021.ParticipantsEligible patients had a laboratory confirmed or a clinically highly suspected diagnosis of covid-19, needed supplemental oxygen (up to 50% fraction of inspired oxygen), and were able to independently lie prone with verbal instruction. Of the 570 patients who were assessed for eligibility, 257 were randomised and 248 were included in the analysis.InterventionPatients were randomised 1:1 to prone positioning (that is, instructing a patient to lie on their stomach while they are in bed) or standard of care (that is, no instruction to adopt prone position).Main outcome measuresThe primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as needing at least 60% fraction of inspired oxygen for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to fraction of inspired oxygen.ResultsThe trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomisation was 1 day, the median age of patients was 56 (interquartile range 45-65) years, 89 (36%) patients were female, and 222 (90%) were receiving oxygen via nasal prongs at the time of randomisation. The median time spent prone in the first 72 hours was 6 (1.5-12.8) hours in total for the prone arm compared with 0 (0-2) hours in the control arm. The risk of the primary outcome was similar between the prone group (18 (14%) events) and the standard care group (17 (14%) events) (odds ratio 0.92, 95% confidence interval 0.44 to 1.92). The change in the ratio of oxygen saturation to fraction of inspired oxygen after 72 hours was similar for patients randomised to prone positioning and standard of care.ConclusionAmong non-critically ill patients with hypoxaemia who were admitted to hospital with covid-19, a multifaceted intervention to increase prone positioning did not improve outcomes. However, wide confidence intervals preclude definitively ruling out benefit or harm. Adherence to prone positioning was poor, despite multiple efforts to increase it. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.Study registrationClinicalTrials.govNCT04383613.

Decreasing orthodontic treatment duration is at the forefront of innovation for clinical orthodontics. This network meta-analysis aimed to determine the relative efficacy and safety of treatments for accelerated orthodontic tooth movement (OTM) in patients undergoing extraction of maxillary first premolars followed by canine retraction in any orthodontic setting. MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL and SCOPUS were searched (from inception to 20 April 2020). Study selection and data extraction were performed in duplicate. Eligible randomized controlled trials (RCTs) were meta-analysed to estimate the rate of tooth movement, 95% credible interval and surface under the cumulative ranking curve (SUCRA) in the first 3 months following the application of the adjunctive accelerative method. Eligible RCTs were assessed by Cochrane risk of bias tool, and quality of evidence was assessed by GRADE approach, obtained from CINeMA web application. Interventions were ranked for efficacy and reviewed for safety. Nineteen studies pertaining to eight interventions, with data from 415 patients were included. Quality of evidence was very low to moderate. Very low-to low-quality evidence suggests that corticotomy is an efficacious and safe adjunctive treatment to accelerate OTM in comparison with conventional treatment in the first 2 months of treatment. Low-quality evidence suggests that piezocision and micro-osteoperforations (MOP) are efficacious and safe adjunctive treatments only in the first month of treatment. Frequent MOP in conjunction with low-level laser therapy appeared to be an efficacious and safe adjunctive treatment only in the first month following its initial application but not thereafter.

Background Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain. Methods We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days. Results Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P=0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P

Background Sponsorship bias could affect research results to inform decision makers when using the results of these trials. The extent to which sponsorship bias affect results in the field of physical therapy has been unexplored in the literature. Therefore, the main aim of this study was to evaluate the influence of sponsorship bias on the treatment effects of randomized controlled trials in physical therapy area. Methods This was a meta-epidemiological study. A random sample of randomized controlled trials included in meta-analyses of physical therapy area were identified. Data extraction including assessments of appropriate influence of funders was conducted independently by two reviewers. To determine the association between biases related to sponsorship biases and effect sizes, a two-level analysis was conducted using a meta-meta-analytic approach. Results We analyzed 393 trials included in 43 meta-analyses. The most common sources of sponsorship for this sample of physical therapy trials were government (n = 205, 52%), followed by academic (n = 44, 11%) and industry (n = 39, 10%). The funding was not declared in a high percentage of the trials (n = 85, 22%). The influence of the trial sponsor was assessed as being appropriate in 246 trials (63%) and considered inappropriate/unclear in 147 (37%) of them. We have moderate evidence to say that trials with inappropriate/unclear influence of funders tended to have on average a larger effect size than those with appropriate influence of funding (effect size = 0.15; 95% confidence interval = -0.03 to 0.33). Conclusions Based on our sample of physical therapy trials, it seems that most of the trials are funded by either government and academia and a small percentage are funded by the industry. Treatment effect size estimates were on average 0.15 larger in trials with lack of appropriate influence of funders as compared with trials with appropriate influence of funding. Contrarily to other fields, industry funding was relatively small and their influence perhaps less marked. All these results could be explained by the relative youth of the field and/or the absence of clear industry interests. In front of the call for action by the World Health Organization to strengthen rehabilitation in health systems, these results raise the issue of the need of public funding in the field.

BACKGROUND The majority of children in North America consume cow-milk daily. Children aged >2 y are recommended to consume reduced-fat (0.1-2%) cow-milk to lower the risk of obesity. OBJECTIVES To evaluate the relation between cow-milk fat consumption and adiposity in children aged 1-18 y. METHODS Embase (Excerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), MEDLINE, Scopus, and Cochrane Library databases from inception to August 2019 were used. The search included observational and interventional studies of healthy children aged 1-18 y that described the association between cow-milk fat consumption and adiposity. Two reviewers extracted data, using the Newcastle-Ottawa Scale to assess risk of bias. Meta-analysis was conducted using random effects to evaluate the relation between cow-milk fat and risk of overweight or obesity. Adiposity was assessed using BMI z-score (zBMI). RESULTS Of 5862 reports identified by the search, 28 met the inclusion criteria: 20 were cross-sectional and 8 were prospective cohort. No clinical trials were identified. In 18 studies, higher cow-milk fat consumption was associated with lower child adiposity, and 10 studies did not identify an association. Meta-analysis included 14 of the 28 studies (n = 20,897) that measured the proportion of children who consumed whole milk compared with reduced-fat milk and direct measures of overweight or obesity. Among children who consumed whole (3.25% fat) compared with reduced-fat (0.1-2%) milk, the OR of overweight or obesity was 0.61 (95% CI: 0.52, 0.72; P

ObjectiveTo evaluate the effect of a one-time cash transfer of $C1000 in people who are unable to physically distance due to insufficient income.DesignOpen-label, multi-centre, randomised superiority trial.SettingSeven primary care sites in Ontario, Canada; six urban sites associated with St. Michael’s Hospital in Toronto and one in Manitoulin Island.Participants392 individuals who reported trouble affording basic necessities due to disruptions related to COVID-19.InterventionAfter random allocation, participants either received the cash transfer of $C1000 (n=196) or physical distancing guidelines alone (n=196).Main outcome measuresThe primary outcome was the maximum number of symptoms consistent with COVID-19 over 14 days. Secondary outcomes were meeting clinical criteria for COVID-19, SARS-CoV-2 presence, number of close contacts, general health and ability to afford basic necessities.ResultsThe primary outcome of number of symptoms reported by participants did not differ between groups after 2 weeks (cash transfer, mean 1.6 vs 1.9, ratio of means 0.83; 95% CI 0.56 to 1.24). There were no statistically significant effects on secondary outcomes of the meeting COVID-19 clinical criteria (7.9% vs 12.8%; risk difference −0.05; 95% CI −0.11 to 0.01), SARS-CoV-2 presence (0.5% vs 0.6%; risk difference 0.00 95% CI −0.02 to 0.02), mean number of close contacts (3.5 vs 3.7; rate ratio 1.10; 95% CI 0.83 to 1.46), general health very good or excellent (60% vs 63%; risk difference −0.03 95% CI −0.14 to 0.08) and ability to make ends meet (52% vs 51%; risk difference 0.01 95% CI −0.10 to 0.12).ConclusionsA single cash transfer did not reduce the COVID-19 symptoms or improve the ability to afford necessities. Further studies are needed to determine whether some groups may benefit from financial supports and to determine if a higher level of support is beneficial.Trial registration numberNCT04359264.

Objectives To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. Trial design Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial Participants The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; Admitted to hospital for COVID-19; One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: D-Dimer ≥2 times ULN OR D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; > 18 years of age; Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin platelet count 9/L in the last 72 hours; known fibrinogen known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; Imminent death according to the judgement of the most responsible physician; enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. Intervention and comparator Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. Main outcomes The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): All-cause death Composite of ICU admission or all-cause death Composite of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; Red blood cell transfusion (>1 unit); Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; Renal replacement therapy; Hospital-free days alive; ICU-free days alive; Ventilator-free days alive; Organ support-free days alive; Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Heparin induced thrombocytopenia; Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. Randomisation Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. Blinding (masking) No blinding involved. This is an open-label trial. Numbers to be randomised (sample size) 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. Trial Status Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. Trial registration ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

ObjectivesTo assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients hospitalized with COVID-19DesignPragmatic randomized clinical trial of prone positioning of patients hospitalized with COVID-19 across 15 hospitals in Canada and the United States from May 2020 until May 2021.SettingsPatients were eligible is they had a laboratory-confirmed or a clinically highly suspected diagnosis of COVID-19, required supplemental oxygen (up to 50% fraction of inspired oxygen [FiO2]), and were able to independently prone with verbal instruction. (NCT04383613).Main Outcome MeasuresThe primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as requiring at least 60% FiO2 for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to FiO2 (S/F ratio).ResultsA total of 248 patients were included. The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomization was 1 day, the median age of patients was 56 years (interquartile range [IQR] 45,65), 36% were female, and 90% of patients were receiving oxygen via nasal prongs at the time of randomization. The median time spent prone in the first 72 hours was 6 hours total (IQR 1.5,12.8) for the prone arm compared to 0 hours (0,2) in the control arm. The risk of the primary outcome was similar between the prone group (18 [14.3%] events) and the standard care group (17 [13.9%] events), odds ratio 0.92 (95% CI 0.44 to 1.92). The change in the S/F ratio after 72 hours was similar for patients randomized to prone compared to standard of care.ConclusionAmong hypoxic but not critically patients with COVID-19 in hospital, a multifaceted intervention to increase prone positioning did not improve outcomes. Adherence to prone positioning was poor, despite multiple efforts. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.What is already known on this topicProne positioning is considered standard of care for mechanically ventilated patients who have severe acute respiratory distress syndrome. Recent data suggest prone positioning is beneficial for patients with COVID-19 who are requiring high flow oxygen. It is unknown of prone positioning is beneficial for patients not on high flow oxygen.What this study addsProne positioning is generally not well tolerated and innovative approaches are needed to improve adherence. Clinical and physiologic outcomes were not improved with prone positioning among hypoxic but not critically ill patients hospitalized with COVID-19.

Identifying febrile children at risk of sepsis in low-resource settings can improve survival, but recognition triage tools are lacking. Here we test the hypothesis that measuring circulating markers of immune and endothelial activation may identify children with sepsis at risk of all-cause mortality. In a prospective cohort study of 2,502 children in Uganda, we show that Soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) measured at first clinical presentation, had high predictive accuracy for subsequent in-hospital mortality. sTREM-1 had the best performance, versus 10 other markers, with an AUROC for discriminating children at risk of death of 0.893 in derivation (95% CI 0.843–0.944) and 0.901 in validation (95% CI 0.856–0.947) cohort. sTREM-1 cutoffs corresponding to a negative likelihood ratio (LR) of 0.10 and a positive LR of 10 classified children into low (1,306 children, 53.1%), intermediate (942, 38.3%) and high (212, 8.6%) risk zones. The estimated incidence of death was 0.5%, 3.9%, and 31.8%, respectively, suggesting sTREM-1 could be used to risk-stratify febrile children. These findings do not attempt to derive a risk prediction model, but rather define sTREM-1 cutoffs as the basis for rapid triage test for all cause fever syndromes in children in low-resource settings., Identification of febrile children at risk of death in low-resource settings can improve survival, but tools for their prompt recognition are lacking. Here, the authors show that sTREM-1 measured at clinical presentation predicts in-hospital mortality in febrile children in Uganda.

Aims: To assess the feasibility and efficacy of interatrial shunt devices (IASD) for the treatment of chronic heart failure (CHF). Methods and results: MEDLINE and the Cochrane Central Register of Controlled Trials from inception until April 2021 were searched for prospective studies investigating dedicated transcatheter IASD for the treatment of CHF. Standardised mean differences were calculated for the within‐group changes before and after implantation of the IASD. The pre‐defined primary outcome was change in 6‐min walking distance (6MWD) from baseline to 12 months. Other outcomes were change in New York Heart Association class, health‐related quality of life (HRQoL), echocardiographic and haemodynamic data, device performance and safety. Subgroup analyses were crude univariable meta‐regression analyses. Six studies (five single‐arm open‐label studies, one sham‐controlled trial) were included. In these, 226 patients underwent IASD implantation using four different devices. From baseline to 12 months, 6MWD increased by 28.1 m [95% confidence interval (CI) 10.9–45.3] with no evidence for a difference between devices (P for interaction = 0.66) and patients with left ventricular ejection fraction (LVEF) >40% or ≤40% (P for interaction = 0.21). At 12 months, HRQoL improved by 17.7 points (95% CI 10.8–24.6) and pulmonary capillary wedge pressure (PCWP) decreased by 2.0 mmHg (95% CI −3.6 to −0.4). There were no changes in LVEF or N‐terminal pro brain natriuretic peptide during follow‐up. Shunt patency ranged from 50% for the first‐generation v‐Wave to 100% for the Corvia IASD II and the second‐generation v‐Wave system, respectively. The summary risk of serious adverse device‐related effects was 8% (95% CI 1–20) at 12 months. Conclusions: Interatrial shunt device implantation in CHF is feasible and associates with improved submaximal exercise capacity (measured by 6MWD) and HRQoL, and reductions in PCWP.

Background This study aimed to assess the effectiveness of sodium‐glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta‐analysis of randomized controlled trials comparing sodium‐glucose cotransporter 2 inhibitors with placebo. We used meta‐regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty‐three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63–0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69–1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72–1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61–1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63–1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71–1.08), with a 90.1% to 98.7% probability for the true RR to be Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause and cardiovascular mortality versus placebo. Treatment effects of sodium‐glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

BackgroundHeparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.MethodsWe randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.ResultsAt 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).ConclusionsIn moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days.Trial registration numbers: NCT04362085; NCT04444700

Background Due to clinical and methodological diversity, clinical studies included in meta-analyses often differ in ways that lead to differences in treatment effects across studies. Meta-regression analysis is generally recommended to explore associations between study-level characteristics and treatment effect, however, three key pitfalls of meta-regression may lead to invalid conclusions. Our aims were to determine the frequency of these three pitfalls of meta-regression analyses, examine characteristics associated with the occurrence of these pitfalls, and explore changes between 2002 and 2012. Methods A meta-epidemiological study of studies including aggregate data meta-regression analysis in the years 2002 and 2012. We assessed the prevalence of meta-regression analyses with at least 1 of 3 pitfalls: ecological fallacy, overfitting, and inappropriate methods to regress treatment effects against the risk of the analysed outcome. We used logistic regression to investigate study characteristics associated with pitfalls and examined differences between 2002 and 2012. Results Our search yielded 580 studies with meta-analyses, of which 81 included meta-regression analyses with aggregated data. 57 meta-regression analyses were found to contain at least one pitfall (70%): 53 were susceptible to ecological fallacy (65%), 14 had a risk of overfitting (17%), and 5 inappropriately regressed treatment effects against the risk of the analysed outcome (6%). We found no difference in the prevalence of meta-regression analyses with methodological pitfalls between 2002 and 2012, nor any study-level characteristic that was clearly associated with the occurrence of any of the pitfalls. Conclusion The majority of meta-regression analyses based on aggregate data contain methodological pitfalls that may result in misleading findings.

Background: Registry-based randomized controlled trials allow for outcome ascertainment using routine health data (RHD). While this method provides a potential solution to the rising cost and complexity of clinical trials, comparative analyses of outcome ascertainment by clinical end point committee (CEC) adjudication compared with RHD sources are sparse. Among cardiovascular trials, we set out to systematically compare the incidence of cardiovascular events and estimated randomized treatment effects ascertained from RHD versus traditional clinical evaluation and adjudication. Methods: We searched MEDLINE (1976 to August 2020) for studies where outcome ascertainment was performed by both RHD and CEC adjudication to compare the incidence of cardiovascular events and treatment effects. We derived ratios of hazard ratios to compare treatment effects from RHD and CEC adjudication. We pooled ratios of hazard ratios using an inverse variance random-effects meta-analysis. Results: Nine studies (1988–2020; 32 156 patients) involving 10 randomized control trials compared outcome ascertainment with RHD and CEC in patients with or at risk of cardiovascular disease. There was a high degree of agreement and interrater reliability between CEC and RHD outcome determination for all-cause mortality (agreement percentage: 98.4%–100% and κ: 0.95–1.0) and cardiovascular mortality (agreement percentage: 97.8%–99.9% and κ: 0.66–0.99). For myocardial infarction, the κ values ranged from 0.67–0.98, and for stroke the values ranged from 0.52–0.89. In contrast, the κ value for peripheral artery disease was low (κ: 0.27). There was little difference in the randomized treatment effect derived from CEC and RHD ascertainment of events based on the ratios of hazard ratio, with pooled ratios of hazard ratios ranging from 0.93 (95% CI, 0.63–1.39) for cardiovascular mortality to 1.27 (95% CI, 0.67–2.41) for stroke. Conclusions: Clinical outcome ascertainment using retrospectively acquired RHD displayed high levels of agreement with CEC adjudication for identifying all-cause mortality and cardiovascular outcomes. Importantly, cardiovascular treatment effects in randomized control trials determined from RHD and CEC resulted in similar point estimates. Overall, our review supports the use of RHD as a potential alternative source for clinical outcome ascertainment in cardiovascular trials. Validation studies with prospectively planned linkage are warranted.

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; PCONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).

Item does not contain fulltext BACKGROUND: The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results. METHODS: The SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries. Patients with de-novo three-vessel and left main coronary artery disease were randomly assigned (1:1) to the PCI group or CABG group. Patients with a history of PCI or CABG, acute myocardial infarction, or an indication for concomitant cardiac surgery were excluded. The primary endpoint of the SYNTAXES study was 10-year all-cause death, which was assessed according to the intention-to-treat principle. Prespecified subgroup analyses were performed according to the presence or absence of left main coronary artery disease and diabetes, and according to coronary complexity defined by core laboratory SYNTAX score tertiles. This study is registered with ClinicalTrials.gov, NCT03417050. FINDINGS: From March, 2005, to April, 2007, 1800 patients were randomly assigned to the PCI (n=903) or CABG (n=897) group. Vital status information at 10 years was complete for 841 (93%) patients in the PCI group and 848 (95%) patients in the CABG group. At 10 years, 244 (27%) patients had died after PCI and 211 (24%) after CABG (hazard ratio 1.17 [95% CI 0.97-1.41], p=0.092). Among patients with three-vessel disease, 151 (28%) of 546 had died after PCI versus 113 (21%) of 549 after CABG (hazard ratio 1.41 [95% CI 1.10-1.80]), and among patients with left main coronary artery disease, 93 (26%) of 357 had died after PCI versus 98 (28%) of 348 after CABG (0.90 [0.68-1.20], pinteraction=0.019). There was no treatment-by-subgroup interaction with diabetes (pinteraction=0.66) and no linear trend across SYNTAX score tertiles (ptrend=0.30). INTERPRETATION: At 10 years, no significant difference existed in all-cause death between PCI using first-generation paclitaxel-eluting stents and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with left main coronary artery disease. FUNDING: German Foundation of Heart Research (SYNTAXES study, 5-10-year follow-up) and Boston Scientific Corporation (SYNTAX study, 0-5-year follow-up).

Administering Pfizer-BioNTech’s COVID-19 vaccine during the early stage of the vaccine rollout (January/February 2021) to as many individuals as possible would prevent more COVID-19 cases in Ontario as compared to reserving half of the initial allotments as second booster doses (Figure 1). On-label use of the vaccine with the administration of two doses is important, as the second dose significantly boosts the immune response and results in a substantial increase in neutralizing antibodies. However, using 100% of the initial allotments immediately to vaccinate as many individuals as possible does not preclude on-label use with two doses, even though the interval between first and second booster dose may become longer than 21 days.

Summary Objective To determine the effectiveness of TENS at relieving pain and improving physical function as compared to placebo TENS, and to determine its safety, in patients with knee osteoarthritis. Methods Multi-centre, parallel, 1:1 randomized, double-blind, placebo-controlled clinical trial conducted in 6 outpatient clinics in Switzerland. We included 220 participants with knee osteoarthritis recruited between October 15, 2012, and October 15, 2014. Patients were randomized to 3 weeks of treatment with TENS (n=108) or placebo TENS (n=112). Our pre-specified primary endpoint was knee pain at the end of 3-weeks treatment assessed with the WOMAC pain subscale. Secondary outcome measures included WOMAC physical function subscale and safety outcomes. Results There was no difference between TENS and placebo TENS in WOMAC pain at the end of treatment (mean difference -0.06; 95%CI -0.41 to 0.29; p=0.74), nor throughout the trial duration (p=0.98). Subgroup analyses did not indicate an interaction between patient/treatment characteristics and treatment effect on WOMAC pain at the end of treatment (p-interaction ≥0.22). The occurrence of adverse events was similar across groups, with 10.4% and 10.6% of patients reporting events in the TENS and placebo TENS groups, respectively (p=0.95). No relevant differences were observed in secondary outcomes. Conclusions TENS does not improve knee osteoarthritis pain when compared to placebo TENS. Therapists should consider other potentially more effective treatment modalities to decrease knee osteoarthritis pain and facilitate strengthening and aerobic exercise. Our findings are conclusive and further trials comparing TENS and placebo TENS in this patient population are not necessary.

ObjectiveTo assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.DesignSystematic review and network meta-analysis of randomised trials.Data sourcesCochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.Eligibility criteria for selecting studiesRandomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.Outcomes and measuresThe prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.Review methodsTwo reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.Results192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).ConclusionsEtoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.Systematic review registrationPROSPERO number CRD42020213656

Importance Whether intervention should be performed in patients with asymptomatic severe aortic stenosis (AS) remains debated. Objective To meta-analyze the natural history of asymptomatic severe AS and examine the association of early intervention with survival. Data Sources PubMed, Embase, and Cochrane databases were searched from inception to February 1, 2020. Study Selection Observational studies of adult patients with asymptomatic severe AS. Data Extraction and Synthesis Two investigators independently extracted study and patient characteristics, follow-up time, events, and prognostic indicators of events. Random-effects models were used to derive pooled estimates. Main Outcomes and Measures The meta-analysis on natural history was performed on the primary end point of all-cause death occurring during a conservative treatment period, with secondary end points consisting of cardiac death, death due to heart failure, sudden death, development of symptoms, development of an indication for aortic valve intervention, and aortic valve intervention. The primary end point for the meta-analysis of early intervention vs a conservative strategy was all-cause death during long-term follow-up. Finally, meta-analysis was performed on the association of prognostic indicators with the composite of death or aortic valve intervention found in multivariable models. Results A total of 29 studies with 4075 patients with 11 901 years of follow-up were included. Pooled rates per 100 patients per year were 4.8 (95% CI, 3.6-6.4) for all-cause death, 3.0 (95% CI, 2.2-4.1) for cardiac death, 2.0 (95% CI, 1.3-3.1) for death due to heart failure, 1.1 (95% CI, 0.6-2.1) for sudden death, 18.1 (95% CI, 12.8-25.4) for an indication for aortic valve intervention, 18.5 (95% CI, 13.4-25.5) for development of symptoms, and 19.2 (95% CI, 15.5-23.8) for aortic valve intervention. Early intervention was associated with a significant reduction in long-term mortality (hazard ratio, 0.38; 95% CI, 0.25-0.58). Factors associated with worse prognosis were severity of AS, low-flow AS, left ventricular damage, and atherosclerotic risk factors. Conclusions and Relevance Data from observational studies and a recent randomized clinical trial suggest that many patients with asymptomatic severe AS develop an indication for aortic valve intervention, and their deaths are mostly cardiac but not only sudden. Other end points besides sudden death should be considered during the decision to perform early intervention that are associated with improved survival.

The aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents.The role of abbreviated DAPT followed by an oral P2YTwo randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO (CRD42019143120). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale.Bleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p 0.001). The composite of all-cause death, myocardial infarction, or stroke occurred in 231 patients (3.2%) with ticagrelor and in 254 patients (3.5%) with DAPT (HR: 0.92; 95% CI: 0.76 to 1.10; p 0.001 for noninferiority). Ticagrelor was associated with lower risk for all-cause (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.027) and cardiovascular (HR: 0.68; 95% CI: 0.47 to 0.99; p = 0.044) mortality. Rates of myocardial infarction (2.01% vs. 2.05%; p = 0.88), stent thrombosis (0.29% vs. 0.38%; p = 0.32), and stroke (0.47% vs. 0.36%; p = 0.30) were similar.Ticagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events.

Background In this meta-epidemiological study, we aimed to examine associations between treatment effect size estimates and sponsorship bias in oral health randomized clinical trials. Methods We selected oral health related meta-analyses that included a minimum of five randomized controlled trials. We extracted data, in duplicate, related to influence of sponsorship bias. We quantified the extent of bias associated with influence of sponsorship on the magnitude of effect size estimates of continuous variables using a two-level meta-meta-analytic approach with random-effects models to allow for intra- and inter-meta-analysis heterogeneity. Results We initially identified 540 randomized trials included in 64 meta-analyses. Risk of sponsorship bias was judged as being “unclear” in 72.8% (n = 393) of the trials, while it was assessed as “low” in 16.7% (n = 90) and as “high” in 10.6% (n = 57) of the trials. Using a meta-epidemiological analysis (37 meta-analyses, including 328 trials that analyzed 85,934 patients), we identified statistically significant larger treatment effect size estimates in trials that had ”high or unclear” risk of sponsorship bias (difference in treatment effect size estimates=0.10; 95% confidence intervals: 0.02 to 0.19) than in trials that had “low” risk of sponsorship bias. Conclusions We identified significant differences in treatment effect size estimates between dental trials based on sponsorship bias. Treatment effect size estimates were 0.10 larger in trials with “high or unclear” risk of sponsorship bias. Practical Implications Clinicians should have an adequate knowledge of sponsorship bias in a clinical trial and be able to estimate the degree to which the conclusions of a systematic review are synthesized and interpreted, based on trials with low risk of sponsorship bias.

Background: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.Methods: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 µg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.Results: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05).Conclusion: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.

Importance Treatment with noninvasive oxygenation strategies such as noninvasive ventilation and high-flow nasal oxygen may be more effective than standard oxygen therapy alone in patients with acute hypoxemic respiratory failure. Objective To compare the association of noninvasive oxygenation strategies with mortality and endotracheal intubation in adults with acute hypoxemic respiratory failure. Data Sources The following bibliographic databases were searched from inception until April 2020: MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and LILACS. No limits were applied to language, publication year, sex, or race. Study Selection Randomized clinical trials enrolling adult participants with acute hypoxemic respiratory failure comparing high-flow nasal oxygen, face mask noninvasive ventilation, helmet noninvasive ventilation, or standard oxygen therapy. Data Extraction and Synthesis Two reviewers independently extracted individual study data and evaluated studies for risk of bias using the Cochrane Risk of Bias tool. Network meta-analyses using a bayesian framework to derive risk ratios (RRs) and risk differences along with 95% credible intervals (CrIs) were conducted. GRADE methodology was used to rate the certainty in findings. Main Outcomes and Measures The primary outcome was all-cause mortality up to 90 days. A secondary outcome was endotracheal intubation up to 30 days. Results Twenty-five randomized clinical trials (3804 participants) were included. Compared with standard oxygen, treatment with helmet noninvasive ventilation (RR, 0.40 [95% CrI, 0.24-0.63]; absolute risk difference, -0.19 [95% CrI, -0.37 to -0.09]; low certainty) and face mask noninvasive ventilation (RR, 0.83 [95% CrI, 0.68-0.99]; absolute risk difference, -0.06 [95% CrI, -0.15 to -0.01]; moderate certainty) were associated with a lower risk of mortality (21 studies [3370 patients]). Helmet noninvasive ventilation (RR, 0.26 [95% CrI, 0.14-0.46]; absolute risk difference, -0.32 [95% CrI, -0.60 to -0.16]; low certainty), face mask noninvasive ventilation (RR, 0.76 [95% CrI, 0.62-0.90]; absolute risk difference, -0.12 [95% CrI, -0.25 to -0.05]; moderate certainty) and high-flow nasal oxygen (RR, 0.76 [95% CrI, 0.55-0.99]; absolute risk difference, -0.11 [95% CrI, -0.27 to -0.01]; moderate certainty) were associated with lower risk of endotracheal intubation (25 studies [3804 patients]). The risk of bias due to lack of blinding for intubation was deemed high. Conclusions and Relevance In this network meta-analysis of trials of adult patients with acute hypoxemic respiratory failure, treatment with noninvasive oxygenation strategies compared with standard oxygen therapy was associated with lower risk of death. Further research is needed to better understand the relative benefits of each strategy.

Background A cointervention in a randomized clinical trial ( RCT ) is medical care given in addition to the tested intervention. If cointerventions are unbalanced between trial arms, the results may be biased. We hypothesized that cointerventions would be more adequately reported in RCT s without full blinding or at risk of bias. Methods and Results To describe the reporting of cointerventions and to evaluate the factors associated with their reporting, we did a systematic search of all RCT s evaluating pharmacological interventions on cardiovascular outcomes published in 5 high‐impact journals. The reporting of cointerventions, blinding, and risk of bias were extracted and evaluated independently by 2 reviewers (E.M., L.A.). Cointerventions were inadequately reported in 87 of 123 RCT s (70.7%), with 56 (45.5%) providing no information on cointerventions and 31 (25.2%) providing only partial information. Of the RCT s, 52 (42.3%) had inadequate blinding of participants and/or personnel and 63 (51.2%) of the RCT s were judged at risk of bias. In univariable analysis, the reporting of cointerventions was not associated with blinding of participants and/or personnel (odds ratio [OR], 1.04; 95% CI, 0.47–2.27 for adequately versus inadequately blinded trials) or with risk of bias ( OR, 1.47; 95% CI, 0.67–3.21 for at low risk of bias versus trials at risk of bias). In multivariable analysis, only a follow‐up of OR, 3.63; 95% CI, 1.21–10.91). Conclusions More than two‐thirds of recent major cardiovascular trials did not adequately report cointerventions. The quality of reporting was not better among trials that were not fully blinded or at risk for bias. Registration URL : https://www.crd.york.ac.uk/PROSP​ERO/ . Unique identifier: CRD 42018106771.