Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

The clinical utility of polygenic risk scores in genomic medicine practices: a systematic review.

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

Interleukin-1 blocking agents for treating COVID-19.

BACKGROUND: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19. OBJECTIVES: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021). SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-1 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 Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 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 four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Efficacy and safety of COVID-19 vaccines.

BACKGROUND: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review. AUTHORS' CONCLUSIONS: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

High prevalence of SARS-CoV-2 detection and prolonged viral shedding in stools: A systematic review and cohort study.

OBJECTIVES: To: 1. Describe the frequency of viral RNA detection in stools in a cohort of patients infected with SARS-CoV-2, and 2. Perform a systematic review to assess the clearance time in stools of SARS-CoV-2. METHODS: We conducted a prospective cohort study in two centers between March and May 2020. We included SARS-CoV-2 infected patients of any age and severity. We collected seriated nasopharyngeal swabs and stool samples to detect SARS-CoV-2. After, we performed a systematic review of the prevalence and clearance of SARS-CoV-2 in stools (PROSPERO-ID: CRD42020192490). We estimated prevalence using a random-effects model. We assessed clearance time by using Kaplan-Meier curves. RESULTS: We included 32 patients; mean age was 43.7±17.7 years, 43.8% were female, and 40.6% reported gastrointestinal symptoms. Twenty-five percent (8/32) of patients had detectable viral RNA in stools. The median clearance time in stools of the cohort was 11[10-15] days. Systematic review included 30 studies (1392 patients) with stool samples. Six studies were performed in children and 55% were male. The pooled prevalence of viral detection in stools was 34.6% (twenty-four studies, 1393 patients; 95%CI:25.4-45.1); heterogeneity was high (I2:91.2%, Q:208.6; p≤0.001). A meta-regression demonstrates an association between female-gender and lower presence in stools (p=0.004). The median clearance time in stools was 22 days (nineteen studies, 140 patients; 95%CI:19-25). After 34 days, 19.9% (95%CI:11.3-29.7) of patients have a persistent detection in stools. CONCLUSIONS: Detection of SARS-CoV-2 in stools is a frequent finding. The clearance of SARS-CoV-2 in stools is prolonged and it takes longer than nasopharyngeal secretions.

Are Cannabis, Cannabis-Derived Products, and Synthetic Cannabinoids a Therapeutic Tool for Rheumatoid Arthritis? A Friendly Summary of the Body of Evidence.

BACKGROUND: Symptom management in rheumatoid arthritis (RA) remains a complex challenge. Widespread use of cannabis-based medicines for a myriad of symptoms has fostered rheumatology patients' interest. However, their safety and efficacy in RA remain unclear. OBJECTIVE: The aim of this study was to perform a structured summary of the body of evidence in order to determine whether cannabis, cannabis-derived products, and synthetic cannabinoids are an effective treatment for rheumatoid arthritis. METHODS: An electronic search in Epistemonikos database was performed to identify systematic reviews and their primary studies that addressed our clinical question. The body of evidence was collected in a pivot table in Epistemonikos. Information and data from the primary studies were extracted from the identified reviews. Finally, extracted data were reanalyzed, and a summary of findings table was generated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Twenty-six systematic reviews were identified which included in total only 1 randomized trial assessing our clinical question. CONCLUSIONS: Cannabis, cannabis-derived products and synthetic cannabinoids may slightly reduce disease activity in patients with RA. Its use may result in little to no difference in pain reduction and may slightly increase nervous system adverse events. The evidence is very uncertain about the effect of cannabis, cannabis-derived products, and synthetic cannabinoids on serious adverse events risk.

COVID-19 transmission during swimming-related activities: a rapid systematic review.

BACKGROUND: There are uncertainties about mitigating strategies for swimming-related activities in the context of the COVID-19 pandemic. There is an opportunity to learn from the experience of previous re-openings to better plan the future one. Our objectives are to systematically review the evidence on (1) the association between engaging in swimming-related activities and COVID-19 transmission; and (2) the effects of strategies for preventing COVID-19 transmission during swimming-related activities. METHODS: We conducted a rapid systematic review. We searched in the L·OVE (Living OVerview of Evidence) platform for COVID-19. The searches covered the period from the inception date of each database until April 19, 2021. We included non-randomized studies for the review on association of COVID-19 transmission and swimming-related activities. We included guidance documents reporting on the strategies for prevention of COVID-19 transmission during swimming-related activities. We also included studies on the efficacy and safety of the strategies. Teams of two reviewers independently assessed article eligibility. For the guidance documents, a single reviewer assessed the eligibility and a second reviewer verified the judgement. Teams of two reviewers extracted data independently. We summarized the findings of included studies narratively. We synthesized information from guidance documents according to the identified topics and subtopics, and presented them in tabular and narrative formats. RESULTS: We identified three studies providing very low certainty evidence for the association between engaging in swimming-related activities and COVID-19 transmission. The analysis of 50 eligible guidance documents identified 11 topics: ensuring social distancing, ensuring personal hygiene, using personal protective equipment, eating and drinking, maintaining the pool, managing frequently touched surfaces, ventilation of indoor spaces, screening and management of sickness, delivering first aid, raising awareness, and vaccination. One study assessing the efficacy of strategies to prevent COVID-19 transmission did not find an association between compliance with precautionary restrictions and COVID-19 transmission. CONCLUSIONS: There are major gaps in the research evidence of relevance to swimming-related activities in the context of the COVID-19 pandemic. However, the synthesis of the identified strategies from guidance documents can inform public health management strategies for swimming-related activities, particularly in future re-opening plans.

Stem cell therapy for dilated cardiomyopathy.

BACKGROUND: Stem cell therapy (SCT) has been proposed as an alternative treatment for dilated cardiomyopathy (DCM), nonetheless its effectiveness remains debatable. OBJECTIVES: To assess the effectiveness and safety of SCT in adults with non-ischaemic DCM. SEARCH METHODS: We searched CENTRAL in the Cochrane Library, MEDLINE, and Embase for relevant trials in November 2020. We also searched two clinical trials registers in May 2020. SELECTION CRITERIA: Eligible studies were randomized controlled trials (RCT) comparing stem/progenitor cells with no cells in adults with non-ischaemic DCM. We included co-interventions such as the administration of stem cell mobilizing agents. Studies were classified and analysed into three categories according to the comparison intervention, which consisted of no intervention/placebo, cell mobilization with cytokines, or a different mode of SCT. The first two comparisons (no cells in the control group) served to assess the efficacy of SCT while the third (different mode of SCT) served to complement the review with information about safety and other information of potential utility for a better understanding of the effects of SCT. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references for eligibility, assessed trial quality, and extracted data. We undertook a quantitative evaluation of data using random-effects meta-analyses. We evaluated heterogeneity using the I² statistic. We could not explore potential effect modifiers through subgroup analyses as they were deemed uninformative due to the scarce number of trials available. We assessed the certainty of the evidence using the GRADE approach. We created summary of findings tables using GRADEpro GDT. We focused our summary of findings on all-cause mortality, safety, health-related quality of life (HRQoL), performance status, and major adverse cardiovascular events. MAIN RESULTS: We included 13 RCTs involving 762 participants (452 cell therapy and 310 controls). Only one study was at low risk of bias in all domains. There were many shortcomings in the publications that did not allow a precise assessment of the risk of bias in many domains. Due to the nature of the intervention, the main source of potential bias was lack of blinding of participants (performance bias). Frequently, the format of the continuous data available was not ideal for use in the meta-analysis and forced us to seek strategies for transforming data in a usable format. We are uncertain whether SCT reduces all-cause mortality in people with DCM compared to no intervention/placebo (mean follow-up 12 months) (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.54 to 1.31; I² = 0%; studies = 7, participants = 361; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection in people with DCM (data could not be pooled; studies = 7; participants = 361; very low-certainty evidence). We are uncertain whether SCT improves HRQoL (standardized mean difference (SMD) 0.62, 95% CI 0.01 to 1.23; I² = 72%; studies = 5, participants = 272; very low-certainty evidence) and functional capacity (6-minute walk test) (mean difference (MD) 70.12 m, 95% CI -5.28 to 145.51; I² = 87%; studies = 5, participants = 230; very low-certainty evidence). SCT may result in a slight functional class (New York Heart Association) improvement (data could not be pooled; studies = 6, participants = 398; low-certainty evidence). None of the included studies reported major adverse cardiovascular events as defined in our protocol. SCT may not increase the risk of ventricular arrhythmia (data could not be pooled; studies = 8, participants = 504; low-certainty evidence). When comparing SCT to cell mobilization with granulocyte-colony stimulating factor (G-CSF), we are uncertain whether SCT reduces all-cause mortality (RR 0.46, 95% CI 0.16 to 1.31; I² = 39%; studies = 3, participants = 195; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection (studies = 1, participants = 60; very low-certainty evidence). SCT may not improve HRQoL (MD 4.61 points, 95% CI -5.62 to 14.83; studies = 1, participants = 22; low-certainty evidence). SCT may improve functional capacity (6-minute walk test) (MD 140.14 m, 95% CI 119.51 to 160.77; I² = 0%; studies = 2, participants = 155; low-certainty evidence). None of the included studies reported MACE as defined in our protocol or ventricular arrhythmia. The most commonly reported outcomes across studies were based on physiological measures of cardiac function where there were some beneficial effects suggesting potential benefits of SCT in people with non-ischaemic DCM. However, it is unclear if this intermediate effects translates into clinical benefits for these patients. With regard to specific aspects related to the modality of cell therapy and its delivery, uncertainties remain as subgroup analyses could not be performed as planned, making it necessary to wait for the publication of several studies that are currently in progress before any firm conclusion can be reached. AUTHORS' CONCLUSIONS: We are uncertain whether SCT in people with DCM reduces the risk of all-cause mortality and procedural complications, improves HRQoL, and performance status (exercise capacity). SCT may improve functional class (NYHA), compared to usual care (no cells). Similarly, when compared to G-CSF, we are also uncertain whether SCT in people with DCM reduces the risk of all-cause mortality although some studies within this comparison observed a favourable effect that should be interpreted with caution. SCT may not improve HRQoL but may improve to some extent performance status (exercise capacity). Very low-quality evidence reflects uncertainty regarding procedural complications. These suggested beneficial effects of SCT, although uncertain due to the very low certainty of the evidence, are accompanied by favourable effects on some physiological measures of cardiac function. Presently, the most effective mode of administration of SCT and the population that could benefit the most is unclear. Therefore, it seems reasonable that use of SCT in people with DCM is limited to clinical research settings. Results of ongoing studies are likely to modify these conclusions.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

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; I2 = 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; I2 = 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; I2 = 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; I2 = 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; I2 = 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; I2 = 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).

Users' experiences with an interactive Evidence to Decision (iEtD) framework: a qualitative analysis.

BACKGROUND: Evidence to Decision (EtD) frameworks bring clarity, structure and transparency to health care decision making. The interactive Evidence to Decision (iEtD) tool, developed in the context of the DECIDE project and published by Epistemonikos, is a stand-alone online solution for producing and using EtD frameworks. Since its development, little is known about how organizations have been using the iEtD tool and what characterizes users' experiences with it. This missing information is necessary for any teams planning future developments of the iEtD tool. METHODS: This study aimed to describe users' experiences with the iEtD and identify main barriers and facilitators related to use. We contacted all users registered in the iEtD via email and invited people who identified themselves as having used the solution to a semi-structured interview. Audio recordings were transcribed, and one researcher conducted a directed content analysis of the interviews guided by a user experience framework. Two researchers checked the content independently for accuracy. RESULTS: Out of 860 people contacted, 81 people replied to our introductory email (response rate 9.4%). Twenty of these had used the tool in a real scenario and were invited to an interview. We interviewed all eight users that accepted this invitation (from six countries, four continents). 'Guideline development' was the iEtD use scenario they most commonly identified. Most participants reported an overall positive experience, without major difficulties navigating or using the different sections. They reported having used most of the EtD framework criteria. Participants reported tailoring their frameworks, for instance by adding or deleting criteria, translating to another language, or rewording headings. Several people preferred to produce a Word version rather than working online, due to the burden of completing the framework, or lack of experience with the tool. Some reported difficulties working with the exportable formats, as they needed considerable editing. CONCLUSION: A very limited number of guideline developers have used the iEtD tool published by Epistemonikos since its development. Although users' general experiences are positive, our work has identified some aspects of the tool that need improvement. Our findings could be also applied to development or improvement of other solutions for producing or using EtD frameworks.

Epistemonikos: a comprehensive database of systematic reviews for health decision-making.

BACKGROUND: Systematic reviews allow health decisions to be informed by the best available research evidence. However, their number is proliferating quickly, and many skills are required to identify all the relevant reviews for a specific question. METHODS AND FINDINGS: We screen 10 bibliographic databases on a daily or weekly basis, to identify systematic reviews relevant for health decision-making. Using a machine-based approach developed for this project we select reviews, which are then validated by a network of more than 1000 collaborators. After screening over 1,400,000 records we have identified more than 300,000 systematic reviews, which are now stored in a single place and accessible through an easy-to-use search engine. This makes Epistemonikos the largest database of its kind. CONCLUSIONS: Using a systematic approach, recruiting a broad network of collaborators and implementing automated methods, we developed a one-stop shop for systematic reviews relevant for health decision making.

A comparative evaluation of PDQ-Evidence.

BACKGROUND: A strategy for minimising the time and obstacles to accessing systematic reviews of health system evidence is to collect them in a freely available database and make them easy to find through a simple 'Google-style' search interface. PDQ-Evidence was developed in this way. The objective of this study was to compare PDQ-Evidence to six other databases, namely Cochrane Library, EVIPNet VHL, Google Scholar, Health Systems Evidence, PubMed and Trip. METHODS: We recruited healthcare policy-makers, managers and health researchers in low-, middle- and high-income countries. Participants selected one of six pre-determined questions. They searched for a systematic review that addressed the chosen question and one question of their own in PDQ-Evidence and in two of the other six databases which they would normally have searched. We randomly allocated participants to search PDQ-Evidence first or to search the two other databases first. The primary outcomes were whether a systematic review was found and the time taken to find it. Secondary outcomes were perceived ease of use and perceived time spent searching. We asked open-ended questions about PDQ-Evidence, including likes, dislikes, challenges and suggestions for improvements. RESULTS: A total of 89 people from 21 countries completed the study; 83 were included in the primary analyses and 6 were excluded because of data errors that could not be corrected. Most participants chose PubMed and Cochrane Library as the other two databases. Participants were more likely to find a systematic review using PDQ-Evidence than using Cochrane Library or PubMed for the pre-defined questions. For their own questions, this difference was not found. Overall, it took slightly less time to find a systematic review using PDQ-Evidence. Participants perceived that it took less time, and most participants perceived PDQ-Evidence to be slightly easier to use than the two other databases. However, there were conflicting views about the design of PDQ-Evidence. CONCLUSIONS: PDQ-Evidence is at least as efficient as other databases for finding health system evidence. However, using PDQ-Evidence is not intuitive for some people. TRIAL REGISTRATION: The trial was prospectively registered in the ISRCTN registry 17 April 2015. Registration number: ISRCTN12742235 .

The GRADE Evidence to Decision (EtD) framework for health system and public health decisions.

OBJECTIVE: To describe a framework for people making and using evidence-informed health system and public health recommendations and decisions. BACKGROUND: We developed the GRADE Evidence to Decision (EtD) framework for health system and public health decisions as part of the DECIDE project, in which we simultaneously developed frameworks for these and other types of healthcare decisions, including clinical recommendations, coverage decisions and decisions about diagnostic tests. DEVELOPING THE FRAMEWORK: Building on GRADE EtD tables, we used an iterative approach, including brainstorming, consultation of the literature and with stakeholders, and an international survey of policy-makers. We applied the framework to diverse examples, conducted workshops and user testing with health system and public health guideline developers and policy-makers, and observed and tested its use in real-life guideline panels. FINDINGS: All the GRADE EtD frameworks share the same basic structure, including sections for formulating the question, making an assessment and drawing conclusions. Criteria listed in the assessment section of the health system and public health framework cover the important factors for making these types of decisions; in addition to the effects and economic impact of an option, the priority of the problem, the impact of the option on equity, and its acceptability and feasibility are important considerations that can inform both whether and how to implement an option. Because health system and public health interventions are often complex, detailed implementation considerations should be made when making a decision. The certainty of the evidence is often low or very low, but decision-makers must still act. Monitoring and evaluation are therefore often important considerations for these types of decisions. We illustrate the different components of the EtD framework for health system and public health decisions by presenting their application in a framework adapted from a real-life guideline. DISCUSSION: This framework provides a structured and transparent approach to support policy-making informed by the best available research evidence, while making the basis for decisions accessible to those whom they will affect. The health system and public health EtD framework can also be used to facilitate dissemination of recommendations and enable decision-makers to adopt, and adapt, recommendations or decisions.

Evidence mapping based on systematic reviews of therapeutic interventions for gastrointestinal stromal tumors (GIST).

BACKGROUND: Gastrointestinal Stromal Tumours (GISTs) are the most common mesenchymal tumours. Currently, different pharmacological and surgical options are used to treat localised and metastatic GISTs, although this research field is broad and the body of evidence is scattered and expanding. Our objectives are to identify, describe and organise the current available evidence for GIST through an evidence mapping approach. METHODS: We followed the methodology of Global Evidence Mapping (GEM). We searched Pubmed, EMBASE, The Cochrane Library and Epistemonikos in order to identify systematic reviews (SRs) with or without meta-analyses published between 1990 and March 2016. Two authors assessed eligibility and extracted data. Methodological quality of the included systematic reviews was assessed using AMSTAR. We organised the results according to identified PICO questions and presented the evidence map in tables and a bubble plot. RESULTS: A total of 17 SRs met eligibility criteria. These reviews included 66 individual studies, of which three quarters were either observational or uncontrolled clinical trials. Overall, the quality of the included SRs was moderate or high. In total, we extracted 14 PICO questions from them and the corresponding results mostly favoured the intervention arm. CONCLUSIONS: The most common type of study used to evaluate therapeutic interventions in GIST sarcomas has been non-experimental studies. However, the majority of the interventions are reported as beneficial or probably beneficial by the respective authors of SRs. The evidence mapping is a useful and reliable methodology to identify and present the existing evidence about therapeutic interventions.

Financial arrangements for health systems in low-income countries: an overview of systematic reviews.

BACKGROUND: One target of the Sustainable Development Goals is to achieve "universal health coverage, including financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all". A fundamental concern of governments in striving for this goal is how to finance such a health system. This concern is very relevant for low-income countries. OBJECTIVES: To provide an overview of the evidence from up-to-date systematic reviews about the effects of financial arrangements for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on financial arrangements, and informing refinements in the framework for financial arrangements presented in the overview. METHODS: We searched Health Systems Evidence in November 2010 and PDQ-Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language, or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of financial arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use, healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty, employment, or financial burden of patients, e.g. out-of-pocket payment, catastrophic disease expenditure) and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the findings. Two overview authors independently screened reviews, extracted data, and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence), and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 reviews and included 15 in this overview, on: collection of funds (2 reviews), insurance schemes (1 review), purchasing of services (1 review), recipient incentives (6 reviews), and provider incentives (5 reviews). The reviews were published between 2008 and 2015; focused on 13 subcategories; and reported results from 276 studies: 115 (42%) randomised trials, 11 (4%) non-randomised trials, 23 (8%) controlled before-after studies, 51 (19%) interrupted time series, 9 (3%) repeated measures, and 67 (24%) other non-randomised studies. Forty-three per cent (119/276) of the studies included in the reviews took place in low- and middle-income countries. Collection of funds: the effects of changes in user fees on utilisation and equity are uncertain (very low-certainty evidence). It is also uncertain whether aid delivered under the Paris Principles (ownership, alignment, harmonisation, managing for results, and mutual accountability) improves health outcomes compared to aid delivered without conforming to those principles (very low-certainty evidence). Insurance schemes: community-based health insurance may increase service utilisation (low-certainty evidence), but the effects on health outcomes are uncertain (very low-certainty evidence). It is uncertain whether social health insurance improves utilisation of health services or health outcomes (very low-certainty evidence). Purchasing of services: it is uncertain whether increasing salaries of public sector healthcare workers improves the quantity or quality of their work (very low-certainty evidence). Recipient incentives: recipient incentives may improve adherence to long-term treatments (low-certainty evidence), but it is uncertain whether they improve patient outcomes. One-time recipient incentives probably improve patient return for start or continuation of treatment (moderate-certainty evidence) and may improve return for tuberculosis test readings (low-certainty evidence). However, incentives may not improve completion of tuberculosis prophylaxis, and it is uncertain whether they improve completion of treatment for active tuberculosis. Conditional cash transfer programmes probably lead to an increase in service utilisation (moderate-certainty evidence), but their effects on health outcomes are uncertain. Vouchers may improve health service utilisation (low-certainty evidence), but the effects on health outcomes are uncertain (very low-certainty evidence). Introducing a restrictive cap may decrease use of medicines for symptomatic conditions and overall use of medicines, may decrease insurers' expenditures on medicines (low-certainty evidence), and has uncertain effects on emergency department use, hospitalisations, and use of outpatient care (very low-certainty evidence). Reference pricing, maximum pricing, and index pricing for drugs have mixed effects on drug expenditures by patients and insurers as well as the use of brand and generic drugs. Provider incentives: the effects of provider incentives are uncertain (very low-certainty evidence), including: the effects of provider incentives on the quality of care provided by primary care physicians or outpatient referrals from primary to secondary care, incentives for recruiting and retaining health professionals to serve in remote areas, and the effects of pay-for-performance on provider performance, the utilisation of services, patient outcomes, or resource use in low-income countries. AUTHORS' CONCLUSIONS: Research based on sound systematic review methods has evaluated numerous financial arrangements relevant to low-income countries, targeting different levels of the health systems and assessing diverse outcomes. However, included reviews rarely reported social outcomes, resource use, equity impacts, or undesirable effects. We also identified gaps in primary research because of uncertainty about applicability of the evidence to low-income countries. Financial arrangements for which the effects are uncertain include external funding (aid), caps and co-payments, pay-for-performance, and provider incentives. Further studies evaluating the effects of these arrangements are needed in low-income countries. Systematic reviews should include all outcomes that are relevant to decision-makers and to people affected by changes in financial arrangements.

Governance arrangements for health systems in low-income countries: an overview of systematic reviews.

BACKGROUND: Governance arrangements include changes in rules or processes that determine authority and accountability for health policies, organisations, commercial products and health professionals, as well as the involvement of stakeholders in decision-making. Changes in governance arrangements can affect health and related goals in numerous ways, generally through changes in authority, accountability, openness, participation and coherence. A broad overview of the findings of systematic reviews can help policymakers, their technical support staff and other stakeholders to identify strategies for addressing problems and improving the governance of their health systems. OBJECTIVES: To provide an overview of the available evidence from up-to-date systematic reviews about the effects of governance arrangements for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on governance arrangements and informing refinements of the framework for governance arrangements outlined in the overview. METHODS: We searched Health Systems Evidence in November 2010 and PDQ Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of governance arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use (health expenditures, healthcare provider costs, out-of-pocket payments, cost-effectiveness), healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty, employment) and that were published after April 2005. We excluded reviews with limitations that were important enough to compromise the reliability of the findings of the review. Two overview authors independently screened reviews, extracted data and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence) and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 systematic reviews and included 21 of them in this overview (19 primary reviews and 2 supplementary reviews). We focus here on the results of the 19 primary reviews, one of which had important methodological limitations. The other 18 were reliable (with only minor limitations).We grouped the governance arrangements addressed in the reviews into five categories: authority and accountability for health policies (three reviews); authority and accountability for organisations (two reviews); authority and accountability for commercial products (three reviews); authority and accountability for health professionals (seven reviews); and stakeholder involvement (four reviews).Overall, we found desirable effects for the following interventions on at least one outcome, with moderate- or high-certainty evidence and no moderate- or high-certainty evidence of undesirable effects. Decision-making about what is covered by health insurance- Placing restrictions on the medicines reimbursed by health insurance systems probably decreases the use of and spending on these medicines (moderate-certainty evidence). Stakeholder participation in policy and organisational decisions- Participatory learning and action groups for women probably improve newborn survival (moderate-certainty evidence).- Consumer involvement in preparing patient information probably improves the quality of the information and patient knowledge (moderate-certainty evidence). Disclosing performance information to patients and the public- Disclosing performance data on hospital quality to the public probably encourages hospitals to implement quality improvement activities (moderate-certainty evidence).- Disclosing performance data on individual healthcare providers to the public probably leads people to select providers that have better quality ratings (moderate-certainty evidence). AUTHORS' CONCLUSIONS: Investigators have evaluated a wide range of governance arrangements that are relevant for low-income countries using sound systematic review methods. These strategies have been targeted at different levels in health systems, and studies have assessed a range of outcomes. Moderate-certainty evidence shows desirable effects (with no undesirable effects) for some interventions. However, there are important gaps in the availability of systematic reviews and primary studies for the all of the main categories of governance arrangements.

Implementation strategies for health systems in low-income countries: an overview of systematic reviews.

BACKGROUND: A key function of health systems is implementing interventions to improve health, but coverage of essential health interventions remains low in low-income countries. Implementing interventions can be challenging, particularly if it entails complex changes in clinical routines; in collaborative patterns among different healthcare providers and disciplines; in the behaviour of providers, patients or other stakeholders; or in the organisation of care. Decision-makers may use a range of strategies to implement health interventions, and these choices should be based on evidence of the strategies' effectiveness. OBJECTIVES: To provide an overview of the available evidence from up-to-date systematic reviews about the effects of implementation strategies for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on alternative implementation strategies and informing refinements of the framework for implementation strategies presented in the overview. METHODS: We searched Health Systems Evidence in November 2010 and PDQ-Evidence up to December 2016 for systematic reviews. We did not apply any date, language or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of implementation strategies on professional practice and patient outcomes and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the review findings. Two overview authors independently screened reviews, extracted data and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence) and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 systematic reviews and included 39 of them in this overview. An additional four reviews provided supplementary information. Of the 39 reviews, 32 had only minor limitations and 7 had important methodological limitations. Most studies in the reviews were from high-income countries. There were no studies from low-income countries in eight reviews.Implementation strategies addressed in the reviews were grouped into four categories - strategies targeting:1. healthcare organisations (e.g. strategies to change organisational culture; 1 review);2. healthcare workers by type of intervention (e.g. printed educational materials; 14 reviews);3. healthcare workers to address a specific problem (e.g. unnecessary antibiotic prescription; 9 reviews);4. healthcare recipients (e.g. medication adherence; 15 reviews).Overall, we found the following interventions to have desirable effects on at least one outcome with moderate- or high-certainty evidence and no moderate- or high-certainty evidence of undesirable effects.1.Strategies targeted at healthcare workers: educational meetings, nutrition training of health workers, educational outreach, practice facilitation, local opinion leaders, audit and feedback, and tailored interventions.2.Strategies targeted at healthcare workers for specific types of problems: training healthcare workers to be more patient-centred in clinical consultations, use of birth kits, strategies such as clinician education and patient education to reduce antibiotic prescribing in ambulatory care settings, and in-service neonatal emergency care training.3. Strategies targeted at healthcare recipients: mass media interventions to increase uptake of HIV testing; intensive self-management and adherence, intensive disease management programmes to improve health literacy; behavioural interventions and mobile phone text messages for adherence to antiretroviral therapy; a one time incentive to start or continue tuberculosis prophylaxis; default reminders for patients being treated for active tuberculosis; use of sectioned polythene bags for adherence to malaria medication; community-based health education, and reminders and recall strategies to increase vaccination uptake; interventions to increase uptake of cervical screening (invitations, education, counselling, access to health promotion nurse and intensive recruitment); health insurance information and application support. AUTHORS' CONCLUSIONS: Reliable systematic reviews have evaluated a wide range of strategies for implementing evidence-based interventions in low-income countries. Most of the available evidence is focused on strategies targeted at healthcare workers and healthcare recipients and relates to process-based outcomes. Evidence of the effects of strategies targeting healthcare organisations is scarce.

Delivery arrangements for health systems in low-income countries: an overview of systematic reviews.

BACKGROUND: Delivery arrangements include changes in who receives care and when, who provides care, the working conditions of those who provide care, coordination of care amongst different providers, where care is provided, the use of information and communication technology to deliver care, and quality and safety systems. How services are delivered can have impacts on the effectiveness, efficiency and equity of health systems. This broad overview of the findings of systematic reviews can help policymakers and other stakeholders identify strategies for addressing problems and improve the delivery of services. OBJECTIVES: To provide an overview of the available evidence from up-to-date systematic reviews about the effects of delivery arrangements for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on delivery arrangements and informing refinements of the framework for delivery arrangements outlined in the review. METHODS: We searched Health Systems Evidence in November 2010 and PDQ-Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of delivery arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use, healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty or employment) and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the findings. Two overview authors independently screened reviews, extracted data, and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence), and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 systematic reviews and included 51 of them in this overview. We judged 6 of the 51 reviews to have important methodological limitations and the other 45 to have only minor limitations. We grouped delivery arrangements into eight categories. Some reviews provided more than one comparison and were in more than one category. Across these categories, the following intervention were effective; that is, they have desirable effects on at least one outcome with moderate- or high-certainty evidence and no moderate- or high-certainty evidence of undesirable effects. Who receives care and when: queuing strategies and antenatal care to groups of mothers. Who provides care: lay health workers for caring for people with hypertension, lay health workers to deliver care for mothers and children or infectious diseases, lay health workers to deliver community-based neonatal care packages, midlevel health professionals for abortion care, social support to pregnant women at risk, midwife-led care for childbearing women, non-specialist providers in mental health and neurology, and physician-nurse substitution. Coordination of care: hospital clinical pathways, case management for people living with HIV and AIDS, interactive communication between primary care doctors and specialists, hospital discharge planning, adding a service to an existing service and integrating delivery models, referral from primary to secondary care, physician-led versus nurse-led triage in emergency departments, and team midwifery. Where care is provided: high-volume institutions, home-based care (with or without multidisciplinary team) for people living with HIV and AIDS, home-based management of malaria, home care for children with acute physical conditions, community-based interventions for childhood diarrhoea and pneumonia, out-of-facility HIV and reproductive health services for youth, and decentralised HIV care. Information and communication technology: mobile phone messaging for patients with long-term illnesses, mobile phone messaging reminders for attendance at healthcare appointments, mobile phone messaging to promote adherence to antiretroviral therapy, women carrying their own case notes in pregnancy, interventions to improve childhood vaccination. Quality and safety systems: decision support with clinical information systems for people living with HIV/AIDS. Complex interventions (cutting across delivery categories and other health system arrangements): emergency obstetric referral interventions. AUTHORS' CONCLUSIONS: A wide range of strategies have been evaluated for improving delivery arrangements in low-income countries, using sound systematic review methods in both Cochrane and non-Cochrane reviews. These reviews have assessed a range of outcomes. Most of the available evidence focuses on who provides care, where care is provided and coordination of care. For all the main categories of delivery arrangements, we identified gaps in primary research related to uncertainty about the applicability of the evidence to low-income countries, low- or very low-certainty evidence or a lack of studies.

The comprehensive 'Communicate to Vaccinate' taxonomy of communication interventions for childhood vaccination in routine and campaign contexts.

BACKGROUND: Communication can be used to generate demand for vaccination or address vaccine hesitancy, and is crucial to successful childhood vaccination programmes. Research efforts have primarily focused on communication for routine vaccination. However, vaccination campaigns, particularly in low- or middle-income countries (LMICs), also use communication in diverse ways. Without a comprehensive framework integrating communication interventions from routine and campaign contexts, it is not possible to conceptualise the full range of possible vaccination communication interventions. Therefore, vaccine programme managers may be unaware of potential communication options and researchers may not focus on building evidence for interventions used in practice. In this paper, we broaden the scope of our existing taxonomy of communication interventions for routine vaccination to include communication used in campaigns, and integrate these into a comprehensive taxonomy of vaccination communication interventions. METHODS: Building on our taxonomy of communication for routine vaccination, we identified communication interventions used in vaccination campaigns through a targeted literature search; observation of vaccination activities in Cameroon, Mozambique and Nigeria; and stakeholder consultations. We added these interventions to descriptions of routine vaccination communication and categorised the interventions according to their intended purposes, building from an earlier taxonomy of communication related to routine vaccination. RESULTS: The comprehensive taxonomy groups communication used in campaigns and routine childhood vaccination into seven purpose categories: 'Inform or Educate'; 'Remind or Recall'; 'Enhance Community Ownership'; 'Teach Skills'; 'Provide Support'; 'Facilitate Decision Making' and 'Enable Communication'. Consultations with LMIC stakeholders and experts informed the taxonomy's definitions and structure and established its potential uses. CONCLUSIONS: This taxonomy provides a standardised way to think and speak about vaccination communication. It is categorised by purpose to help conceptualise communication interventions as potential solutions to address needs or problems. It can be utilised by programme planners, implementers, researchers and funders to see the range of communication interventions used in practice, facilitate evidence synthesis and identify evidence gaps.