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Background: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance., Objectives: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly., Search Methods: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021., Selection Criteria: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity., Data Collection and Analysis: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events., Main Results: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I 2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I 2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I 2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I 2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I 2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I 2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes., Authors' Conclusions: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com)., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is widely used and reliable and accurate for assessing the certainty in the body of health evidence. The GRADE working group has provided detailed guidance for assessing the certainty in the body of evidence in systematic reviews and health technology assessments (HTAs) and how to grade the strength of health recommendations. However, there is limited advice regarding how to maximize transparency of these judgments, in particular through explanatory footnotes or explanations in Summary of Findings tables and Evidence Profiles (GRADE evidence tables)., Methods: We conducted this study to define the essential attributes of useful explanations and to develop specific guidance for explanations associated with GRADE evidence tables. We used a sample of explanations according to their complexity, type of judgment involved, and appropriateness from a database of published GRADE evidence tables in Cochrane reviews and World Health Organization guidelines. We used an iterative process and group consensus to determine the attributes and develop guidance., Results: Explanations in GRADE evidence tables should be concise, informative, relevant, easy to understand, and accurate. We provide general and domain-specific guidance to assist authors with achieving these desirable attributes in their explanations associated with GRADE evidence tables., Conclusions: Adhering to the general and GRADE domain-specific guidance should improve the quality of explanations associated with GRADE evidence tables, assist authors of systematic reviews, HTA reports, or guidelines with information that they can use in other parts of their evidence synthesis. This guidance will also support editorial evaluation of evidence syntheses using GRADE and provide a minimum quality standard of judgments across tables., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Systematic reviews are an integral component of evidence-based health care. However, little is known on how well they report the potential harms of interventions. We assessed the reporting of harms in recently published systematic reviews of interventions relevant to clinical gastroenterology., Study Design: We identified all systematic reviews of randomized trials of gastroenterology interventions published from 2008 to 2012 in highly cited gastroenterology and general medical journals. We adapted the Consolidated Standards of Reporting Trials guidelines for harms and assessed qualitative and quantitative parameters of harms reporting. Regression analyses determined predictors of more comprehensive harms reporting., Results: In total, 78 systematic reviews were identified, with 72 published in gastroenterology journals and six in general medical journals. Overall, one in three systematic reviews (26/78, 33%) did not refer to harms of the intervention anywhere in the article. Less than half of the studies included adverse events as an outcome measure, and data on absolute rates of adverse events were only provided in 28%. Most (65%) did not include any figures or tables on adverse event; however, all included these on efficacy outcomes (mean, 3 and range, 1-7). Regression analyses indicated that the use of reporting guidelines was significantly associated with better harms reporting (P = 0.04)., Conclusion: The reporting of harms in gastroenterology systematic reviews is largely inadequate and highly asymmetrical compared with the reporting of benefits. We suggest that review authors routinely assess both efficacy and harms outcomes of an intervention and that reporting guidelines specifically targeting harms reporting be developed., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

This article describes the background and contribution of The Cochrane Collaboration to the WHO Nutrition Guidelines program. Systematic reviews, augmented by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for assessing the quality of a body of evidence, form the evidence basis for WHO guidelines. Our shared experience of working together has highlighted a number of issues that are challenging, such as decisions made about selecting appropriate questions for evidence synthesis and the nature of study types that are included, in particular the decision on whether or not to extend a search beyond randomized studies. Although the skills and experience required for evidence synthesis are different from those needed to determine recommendations for policy and practice, our experience suggests that some engagement between the two groups is mutually beneficial. Finally, our experience highlights the recognition that evidence of effectiveness is essential but by no means sufficient to guide decisions on recommendations. Programmatic and implementation considerations are important to guide decision making and the evidence basis for this may be limited; therefore, it is essential that groups involved in delivering interventions to populations are also engaged in the guidelines process.

The WHO evidence-informed guidelines provide recommendations to Member States and their partners on interventions with vitamins and minerals. Evidence gathered and synthesized through systematic reviews contributes to the development of these guidelines, a process that is dependent on the availability and quality of evidence. Although the guideline development process is stringently governed and supervised to maintain clarity and transparency, the lack of adequacy and specificity of available evidence poses limitations to the formulation of recommendations that can be easily applied for policy and program decision making in diverse contexts. The symposium created a space for dialogue among scientists and public health practitioners to improve the understanding of how evidence fulfills the needs and reflect on mechanisms by which policy and program guidance and priorities for research could be better informed by policy and program needs. Ultimately, programmatic success depends not only on identifying efficacious agents but ensuring effective delivery to those with the potential to respond. To do this, we must understand the rationale for recommending interventions, the biological pathways by which interventions work, delivery systems required to make efficacious interventions work, and other contextual factors that might limit or facilitate successful implementation.