A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E).

BACKGROUND: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies. OBJECTIVE: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome. METHODS AND RESULTS: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias. CONCLUSION: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference.

Needs and feasibility of living systematic reviews (LSRs): Experience from LSRs on COVID-19 vaccine effectiveness.

During 2021 and 2023, a team of researchers at the Robert Koch Institute (RKI) and partnering institutions conducted two living systematic reviews (LSRs) on the effectiveness of COVID-19 vaccines in different age groups to inform recommendations of the Standing Committee on Vaccination in Germany (Ständige Impfkommission, STIKO). Based on our experience from the realization of these LSRs, we developed certain criteria to assess the needs and feasibility of conducting LSRs. Combining these with previously established criteria, we developed the following set to inform future planning of LSRs for STIKO: Needs criterion (N)1: Relevance of the research question, N2: Certainty of evidence (CoE) at baseline; N3: Expected need for Population-Intervention-Comparator-Outcome (PICO) adaptations; N4: Expected new evidence over time; N5: Expected impact of new evidence on CoE; Feasibility criterion (F)1: Availability of sufficient human resources; F2: Feasibility of timely dissemination of the results to inform decision-making. For each criterion we suggest rating options which may support the decision to conduct an LSR or other forms of evidence synthesis when following the provided flowchart. The suggested criteria were developed on the basis of the experiences from exemplary reviews in a specific research field (i.e., COVID-19 vaccination), and did not follow a formal development or validation process. However, these criteria might also be useful to assess whether questions from other research fields can and should be answered using the LSR approach, or assist in determining whether the use of an LSR is sensible and feasible for specific questions in health policy and practice.

[Development of criteria for the prospective assessment of the need for updating guideline recommendations: The AGIL criteria]. / Entwicklung von Kriterien für die prospektive Einschätzung des Aktualisierungsbedarfs von Leitlinienempfehlungen: AGIL-Kriterien.

BACKGROUND: Evidence-based guideline and vaccination recommendations should continuously be updated to appropriately support health care decisions. However, resources for updating guidelines are often limited. The aim of this project was to develop a list of criteria for the prospective assessment of the need for updating individual guideline or vaccination recommendations, which can be applied from the time a guideline or guideline update is finalised. METHODS: In this article we describe the development of the AGIL criteria (Assessment of Guidelines for Updating Recommendations). The AGIL criteria were developed by experienced scientists and experts in the field of guideline development in a multi-step process. The five steps included: 1) development of an initial list of criteria by the project team; 2) online survey of guideline experts on the initial version of the criteria list; 3) revision of the criteria list based on the results of the online survey; 4) workshop on the criteria list at the EbM Congress 2023; 5) creation of version 1.0 of the AGIL criteria based on the workshop results. RESULTS: The initial list included the following three criteria: 1) relevance of the question 2) availability of new relevant evidence, and 3) impact of potentially new evidence. The response rate of the online survey for fully completed questionnaires was 31.0% (N=195; 630 guideline experts were contacted by email). For 90.3% (n=176) of the respondents, the criteria list included all essential aspects for assessing the need for updating guideline recommendations. More than three quarters of respondents rated the importance of the three criteria as "very important" or "important" (criteria 1-3: 75.3%, 86.1%, 85.2%) and - with the exception of criterion 1 - comprehensibility as "very comprehensible" or "comprehensible" (criteria 1-3: 58.4%, 75.9%, 78.5%). The results of the online survey and the workshop generally confirmed the three criteria with their two sub-questions. The incorporation of all feedback resulted in the AGIL criteria (version 1.0), recapping: 1) relevance of the question regarding a) PICO components and b) other factors, e.g. epidemiological aspects; 2) availability of new evidence a) on health-related benefits and harms and b) on other decision factors, e.g. feasibility, acceptability; 3) impact of new evidence a) on the certainty of evidence on which the recommendation is based and b) on the present recommendation, e.g. DISCUSSION: The moderate response rate of the online survey may have limited its representativeness. Nevertheless, we consider the response rate to be satisfactory in this research context. The inclusion of many experts in the online survey and the EbM Congress workshop is a strength of the project and supports the quality of the results. CONCLUSIONS: The AGIL criteria provide a structured guidance for the prospective assessment of the need for updating individual guideline recommendations and other evidence-based recommendations. The implementation and evaluation of the AGIL criteria 1.0 in a field test is planned.

Musical and vocal interventions to improve neurodevelopmental outcomes for preterm infants.

BACKGROUND: Preterm birth interferes with brain maturation, and subsequent clinical events and interventions may have additional deleterious effects. Music as therapy is offered increasingly in neonatal intensive care units aiming to improve health outcomes and quality of life for both preterm infants and the well-being of their parents. Systematic reviews of mixed methodological quality have demonstrated ambiguous results for the efficacy of various types of auditory stimulation of preterm infants. A more comprehensive and rigorous systematic review is needed to address controversies arising from apparently conflicting studies and reviews. OBJECTIVES: We assessed the overall efficacy of music and vocal interventions for physiological and neurodevelopmental outcomes in preterm infants (< 37 weeks' gestation) compared to standard care. In addition, we aimed to determine specific effects of various interventions for physiological, anthropometric, social-emotional, neurodevelopmental short- and long-term outcomes in the infants, parental well-being, and bonding. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, RILM Abstracts, and ERIC in November 2021; and Proquest Dissertations in February 2019. We searched the reference lists of related systematic reviews, and of studies selected for inclusion and clinical trial registries. SELECTION CRITERIA: We included parallel, and cluster-randomised controlled trials with preterm infants < 37 weeks` gestation during hospitalisation, and parents when they were involved in the intervention. Interventions were any music or vocal stimulation provided live or via a recording by a music therapist, a parent, or a healthcare professional compared to standard care. The intervention duration was greater than five minutes and needed to occur more than three times. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. We analysed the treatment effects of the individual trials using RevMan Web using a fixed-effects model to combine the data. Where possible, we presented results in meta-analyses using mean differences with 95% CI. We performed heterogeneity tests. When the I2 statistic was higher than 50%, we assessed the source of the heterogeneity by sensitivity and subgroup analyses. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 25 trials recruiting 1532 infants and 691 parents (21 parallel-group RCTs, four cross-over RCTs). The infants gestational age at birth varied from 23 to 36 weeks, taking place in NICUs (level 1 to 3) around the world. Within the trials, the intervention varied widely in type, delivery, frequency, and duration. Music and voice were mainly characterised by calm, soft, musical parameters in lullaby style, often integrating the sung mother's voice live or recorded, defined as music therapy or music medicine. The general risk of bias in the included studies varied from low to high risk of bias. Music and vocal interventions compared to standard care Music/vocal interventions do not increase oxygen saturation in the infants during the intervention (mean difference (MD) 0.13, 95% CI -0.33 to 0.59; P = 0.59; 958 infants, 10 studies; high-certainty evidence). Music and voice probably do not increase oxygen saturation post-intervention either (MD 0.63, 95% CI -0.01 to 1.26; P = 0.05; 800 infants, 7 studies; moderate-certainty evidence). The intervention may not increase infant development (Bayley Scales of Infant and Toddler Development (BSID)) with the cognitive composition score (MD 0.35, 95% CI -4.85 to 5.55; P = 0.90; 69 infants, 2 studies; low-certainty evidence); the motor composition score (MD -0.17, 95% CI -5.45 to 5.11; P = 0.95; 69 infants, 2 studies; low-certainty evidence); and the language composition score (MD 0.38, 95% CI -5.45 to 6.21; P = 0.90; 69 infants, 2 studies; low-certainty evidence). Music therapy may not reduce parental state-trait anxiety (MD -1.12, 95% CI -3.20 to 0.96; P = 0.29; 97 parents, 4 studies; low-certainty evidence). The intervention probably does not reduce respiratory rate during the intervention (MD 0.42, 95% CI -1.05 to 1.90; P = 0.57; 750 infants; 7 studies; moderate-certainty evidence) and post-intervention (MD 0.51, 95% CI -1.57 to 2.58; P = 0.63; 636 infants, 5 studies; moderate-certainty evidence). However, music/vocal interventions probably reduce heart rates in preterm infants during the intervention (MD -1.38, 95% CI -2.63 to -0.12; P = 0.03; 1014 infants; 11 studies; moderate-certainty evidence). This beneficial effect was even stronger after the intervention. Music/vocal interventions reduce heart rate post-intervention (MD -3.80, 95% CI -5.05 to -2.55; P < 0.00001; 903 infants, 9 studies; high-certainty evidence) with wide CIs ranging from medium to large beneficial effects. Music therapy may not reduce postnatal depression (MD 0.50, 95% CI -1.80 to 2.81; P = 0.67; 67 participants; 2 studies; low-certainty evidence). The evidence is very uncertain about the effect of music therapy on parental state anxiety (MD -0.15, 95% CI -2.72 to 2.41; P = 0.91; 87 parents, 3 studies; very low-certainty evidence). We are uncertain about any further effects regarding all other secondary short- and long-term outcomes on the infants, parental well-being, and bonding/attachment. Two studies evaluated adverse effects as an explicit outcome of interest and reported no adverse effects from music and voice. AUTHORS' CONCLUSIONS: Music/vocal interventions do not increase oxygen saturation during and probably not after the intervention compared to standard care. The evidence suggests that music and voice do not increase infant development (BSID) or reduce parental state-trait anxiety. The intervention probably does not reduce respiratory rate in preterm infants. However, music/vocal interventions probably reduce heart rates in preterm infants during the intervention, and this beneficial effect is even stronger after the intervention, demonstrating that music/vocal interventions reduce heart rates in preterm infants post-intervention. We found no reports of adverse effects from music and voice. Due to low-certainty evidence for all other outcomes, we could not draw any further conclusions regarding overall efficacy nor the possible impact of different intervention types, frequencies, or durations. Further research with more power, fewer risks of bias, and more sensitive and clinically relevant outcomes are needed.

Models of integrated care for multi-morbidity assessed in systematic reviews: a scoping review.

BACKGROUND: The prevalence of multi-morbidity is increasing globally. Integrated models of care present a potential intervention to improve patient and health system outcomes. However, the intervention components and concepts within different models of care vary widely and their effectiveness remains unclear. We aimed to describe and map the definitions, characteristics, components, and reported effects of integrated models of care in systematic reviews (SRs). METHODS: We conducted a scoping review of SRs according to pre-specified methods (PROSPERO 2019 CRD42019119265). Eligible SRs assessed integrated models of care at primary health care level for adults and children with multi-morbidity. We searched in PubMed (MEDLINE), Embase, Cochrane Database of Systematic Reviews, Epistemonikos, and Health Systems Evidence up to 3 May 2022. Two authors independently assessed eligibility of SRs and extracted data. We identified and described common components of integrated care across SRs. We extracted findings of the SRs as presented in the conclusions and reported on these verbatim. RESULTS: We included 22 SRs, examining data from randomised controlled trials and observational studies conducted across the world. Definitions and descriptions of models of integrated care varied considerably. However, across SRs, we identified and described six common components of integrated care: (1) chronic conditions addressed, (2) where services were provided, (3) the type of services provided, (4) healthcare professionals involved in care, (5) coordination and organisation of care and (6) patient involvement in care. We observed differences in the components of integrated care according to the income setting of the included studies. Some SRs reported that integrated care was beneficial for health and process outcomes, while others found no difference in effect when comparing integrated care to other models of care. CONCLUSIONS: Integrated models of care were heterogeneous within and across SRs. Information that allows the identification of effective components of integrated care was lacking. Detailed, standardised and transparent reporting of the intervention components and their effectiveness on health and process outcomes is needed.

Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables. MAIN RESULTS: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine). AUTHORS CONCLUSIONS: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

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.

Safety and effectiveness of vaccines against COVID-19 in children aged 5-11 years: a systematic review and meta-analysis.

BACKGROUND: To date, more than 761 million confirmed SARS-CoV-2 infections have been recorded globally, and more than half of all children are estimated to be seropositive. Despite high SARS-CoV-2 infection incidences, the rate of severe COVID-19 in children is low. We aimed to assess the safety and efficacy or effectiveness of COVID-19 vaccines approved in the EU for children aged 5-11 years. METHODS: In this systematic review and meta-analysis, we included studies of any design identified through searching the COVID-19 L·OVE (living overview of evidence) platform up to Jan 23, 2023. We included studies with participants aged 5-11 years, with any COVID-19 vaccine approved by the European Medicines Agency-ie, mRNA vaccines BNT162b2 (Pfizer-BioNTech), BNT162b2 Bivalent (against original strain and omicron [BA.4 or BA.5]), mRNA-1273 (Moderna), or mRNA-1273.214 (against original strain and omicron BA.1). Efficacy and effectiveness outcomes were SARS-CoV-2 infection (PCR-confirmed or antigen-test confirmed), symptomatic COVID-19, hospital admission due to COVID-19, COVID-19-related mortality, multisystem inflammatory syndrome in children (MIS-C), and long-term effects of COVID-19 (long COVID or post-COVID-19 condition as defined by study investigators or per WHO definition). Safety outcomes of interest were serious adverse events, adverse events of special interest (eg, myocarditis), solicited local and systemic events, and unsolicited adverse events. We assessed risk of bias and rated the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluation approach. This study was prospectively registered with PROSPERO, CRD42022306822. FINDINGS: Of 5272 screened records, we included 51 (1·0%) studies (n=17 [33%] in quantitative synthesis). Vaccine effectiveness after two doses against omicron infections was 41·6% (95% CI 28·1-52·6; eight non-randomised studies of interventions [NRSIs]; CoE low), 36·2% (21·5-48·2; six NRSIs; CoE low) against symptomatic COVID-19, 75·3% (68·0-81·0; six NRSIs; CoE moderate) against COVID-19-related hospitalisations, and 78% (48-90, one NRSI; CoE very low) against MIS-C. Vaccine effectiveness against COVID-19-related mortality was not estimable. Crude event rates for deaths in unvaccinated children were less than one case per 100 000 children, and no events were reported for vaccinated children (four NRSIs; CoE low). No study on vaccine effectiveness against long-term effects was identified. Vaccine effectiveness after three doses was 55% (50-60; one NRSI; CoE moderate) against omicron infections, and 61% (55-67; one NRSI; CoE moderate) against symptomatic COVID-19. No study reported vaccine efficacy or effectiveness against hospitalisation following a third dose. Safety data suggested no increased risk of serious adverse events (risk ratio [RR] 0·83 [95% CI 0·21-3·33]; two randomised controlled trials; CoE low), with approximately 0·23-1·2 events per 100 000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4·6 [0·1-156·1]; one NRSI; CoE low), with 0·13-1·04 observed events per 100 000 administered vaccines. The risk of solicited local reactions was 2·07 (1·80-2·39; two RCTs; CoE moderate) after one dose and 2·06 (1·70-2·49; two RCTs; CoE moderate) after two doses. The risk of solicited systemic reactions was 1·09 (1·04-1·16; two RCTs; CoE moderate) after one dose and 1·49 (1·34-1·65; two RCTs; CoE moderate) after two doses. The risk of unsolicited adverse events after two doses (RR 1·21 [1·07-1·38]; CoE moderate) was higher among mRNA-vaccinated compared with unvaccinated children. INTERPRETATION: In children aged 5-11 years, mRNA vaccines are moderately effective against infections with the omicron variant, but probably protect well against COVID-19 hospitalisations. Vaccines were reactogenic but probably safe. Findings of this systematic review can serve as a basis for public health policy and individual decision making on COVID-19 vaccination in children aged 5-11 years. FUNDING: German Federal Joint Committee.

Automated Monitoring of Adherence to Evidenced-Based Clinical Guideline Recommendations: Design and Implementation Study.

BACKGROUND: Clinical practice guidelines are systematically developed statements intended to optimize patient care. However, a gapless implementation of guideline recommendations requires health care personnel not only to be aware of the recommendations and to support their content but also to recognize every situation in which they are applicable. To not miss situations in which recommendations should be applied, computerized clinical decision support can be provided through a system that allows an automated monitoring of adherence to clinical guideline recommendations in individual patients. OBJECTIVE: This study aims to collect and analyze the requirements for a system that allows the monitoring of adherence to evidence-based clinical guideline recommendations in individual patients and, based on these requirements, to design and implement a software prototype that integrates guideline recommendations with individual patient data, and to demonstrate the prototype's utility in treatment recommendations. METHODS: We performed a work process analysis with experienced intensive care clinicians to develop a conceptual model of how to support guideline adherence monitoring in clinical routine and identified which steps in the model could be supported electronically. We then identified the core requirements of a software system to support recommendation adherence monitoring in a consensus-based requirements analysis within the loosely structured focus group work of key stakeholders (clinicians, guideline developers, health data engineers, and software developers). On the basis of these requirements, we designed and implemented a modular system architecture. To demonstrate its utility, we applied the prototype to monitor adherence to a COVID-19 treatment recommendation using clinical data from a large European university hospital. RESULTS: We designed a system that integrates guideline recommendations with real-time clinical data to evaluate individual guideline recommendation adherence and developed a functional prototype. The needs analysis with clinical staff resulted in a flowchart describing the work process of how adherence to recommendations should be monitored. Four core requirements were identified: the ability to decide whether a recommendation is applicable and implemented for a specific patient, the ability to integrate clinical data from different data formats and data structures, the ability to display raw patient data, and the use of a Fast Healthcare Interoperability Resources-based format for the representation of clinical practice guidelines to provide an interoperable, standards-based guideline recommendation exchange format. CONCLUSIONS: Our system has advantages in terms of individual patient treatment and quality management in hospitals. However, further studies are needed to measure its impact on patient outcomes and evaluate its resource effectiveness in different clinical settings. We specified a modular software architecture that allows experts from different fields to work independently and focus on their area of expertise. We have released the source code of our system under an open-source license and invite for collaborative further development of the system.

In Cochrane nutrition reviews assessment of dietary adherence varied considerably.

OBJECTIVES: Our aim was to investigate if and how Cochrane nutrition reviews assess dietary adherence to a specific dietary regimen. STUDY DESIGN AND SETTING: Cochrane nutrition reviews fulfilling the following criteria were included: systematic review of randomized controlled trials including adults and investigating the effect of caloric restriction, dietary pattern, foods, nutrients, supplements, or other nutrition-related-interventions. Extensive data extraction and descriptive statistics were conducted. RESULTS: Overall, 226 Cochrane reviews were included. Most reviews mentioned dietary adherence in the main text (n = 174), predominantly in the Methods and Results. Dietary adherence was assessed in 76 reviews and defined in 19. It was included in the risk of bias (RoB) assessment in 20 reviews with nine using a newly created RoB domain for dietary adherence, and considered as outcome in 37 reviews. Seventy-five reviews addressed degree of adherence and five treatment effects considering the degree of adherence. CONCLUSION: Dietary adherence was reported in a heterogeneous manner in Cochrane nutrition reviews. Due to its high importance, we suggest that systematic reviews report the assessment and degree of dietary adherence measured in primary studies. Dietary adherence can further be examined as outcome, evaluated within the RoB (deviations from intended interventions) and included in sensitivity analyses.

Representation of evidence-based clinical practice guideline recommendations on FHIR.

BACKGROUND: Various formalisms have been developed to represent clinical practice guideline recommendations in a computer-interpretable way. However, none of the existing formalisms leverage the structured and computable information that emerge from the evidence-based guideline development process. Thus, we here propose a FHIR-based format that uses computer-interpretable representations of the knowledge artifacts that emerge during the process of evidence-based guideline development to directly serve as the basis of evidence-based recommendations. METHODS: We identified the information required to represent evidence-based clinical practice guideline recommendations and reviewed the knowledge artifacts emerging during the evidence-based guideline development process. We then conducted a consensus-based design process with domain experts to develop an information model for guideline recommendation representation that is structurally aligned to the evidence-based guideline recommendation development process and a corresponding representation based on FHIR resources developed for evidence-based medicine (EBMonFHIR). The resulting recommendations were modelled and represented in conformance with the FHIR Clinical Guidelines (CPG-on-FHIR) implementation guide. RESULTS: The information model of evidence-based clinical guideline recommendations and its EBMonFHIR-/CPG-on-FHIR-based representation contain the clinical contents of individual guideline recommendations, a set of metadata for the recommendations, the ratings for the recommendations (e.g., strength of recommendation, certainty of overall evidence), the ratings of certainty of evidence for individual outcomes (e.g., risk of bias) and links to the underlying evidence (systematic reviews based on primary studies). We created profiles and an implementation guide for all FHIR resources required to represent the knowledge artifacts generated during evidence-based guideline development and their re-use as the basis for recommendations and used the profiles to implement an exemplary clinical guideline recommendation. CONCLUSIONS: The FHIR implementation guide presented here can be used to directly link the evidence assessment process of evidence-based guideline recommendation development, i.e. systematic reviews and evidence grading, and the underlying evidence from primary studies to the resulting guideline recommendations. This not only allows the evidence on which recommendations are based on to be evaluated transparently and critically, but also enables guideline developers to leverage computable evidence in a more direct way to facilitate the generation of computer-interpretable guideline recommendations.

Public information needs and preferences on COVID-19: a cross-sectional study.

BACKGROUND: Right from the beginning of the SARS-CoV-2 pandemic the general public faced the challenge to find reliable and understandable information in the overwhelming flood of information. To enhance informed decision-making, evidence-based information should be provided. Aim was to explore the general public's information needs and preferences on COVID-19 as well as the barriers to accessing evidence-based information. METHODS: We performed a cross-sectional study. Nine hundred twenty-seven panel members were invited to an online survey (12/2020-02/2021). The HeReCa-online-panel is installed at the Martin Luther University Halle-Wittenberg to assess regularly the general public's view on health issues in five regions in Germany. The survey was set up in LimeSurvey, with nine items, multiple-choice and open-ended questions that allowed to gather qualitative data. Quantitative data were analysed descriptively and a content analysis was carried out to categorise the qualitative data. RESULTS: Six hundred thirty-six panel members provided data; mean age 52 years, 56.2% female, and 64.9% with higher education qualifications. Asked about relevant topics related to COVID-19, most participants selected vaccination (63.8%), infection control (52%), and long-term effects (47.8%). The following 11 categories were derived from the qualitative analysis representing the topics of interest: vaccination, infection control, long-term effects, therapies, test methods, mental health, symptoms, structures for pandemic control, infrastructure in health care, research. Participants preferred traditional media (TV 70.6%; radio 58.5%; newspaper 32.7%) to social media, but also used the internet as sources of information, becoming aware of new information on websites (28.5%) or via email/newsletter (20.1%). The knowledge question (Which European country is most affected by the SARS-CoV-2 pandemic?) was correctly answered by 7.5% of participants. The Robert Koch Institute (93.7%) and the World Health Organization (78%) were well known, while other organisations providing health information were rarely known (< 10%). Barriers to accessing trustworthy information were lack of time (30.7%), little experience (23.1%), uncertainty about how to get access (22.2%), complexity and difficulties in understanding (23.9%), and a lack of target group orientation (15,3%). CONCLUSIONS: There are extensive information needs regarding various aspects on COVID-19 among the general population. In addition, target-specific dissemination strategies are still needed to reach different groups.

Preoperative combined mechanical and oral antibiotic bowel preparation for preventing complications in elective colorectal surgery.

BACKGROUND: The success of elective colorectal surgery is mainly influenced by the surgical procedure and postoperative complications. The most serious complications include anastomotic leakages and surgical site infections (SSI)s, which can lead to prolonged recovery with impaired long-term health.  Compared with other abdominal procedures, colorectal resections have an increased risk of adverse events due to the physiological bacterial colonisation of the large bowel. Preoperative bowel preparation is used to remove faeces from the bowel lumen and reduce bacterial colonisation. This bowel preparation can be performed mechanically and/or with oral antibiotics. While mechanical bowel preparation alone is not beneficial, the benefits and harms of combined mechanical and oral antibiotic bowel preparation is still unclear. OBJECTIVES: To assess the evidence for the use of combined mechanical and oral antibiotic bowel preparation for preventing complications in elective colorectal surgery. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL and trial registries on 15 December 2021. In addition, we searched reference lists and contacted colorectal surgery organisations. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adult participants undergoing elective colorectal surgery comparing combined mechanical and oral antibiotic bowel preparation (MBP+oAB) with either MBP alone, oAB alone, or no bowel preparation (nBP). We excluded studies in which no perioperative intravenous antibiotic prophylaxis was given. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. Pooled results were reported as mean difference (MD) or risk ratio (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel method. The certainty of the evidence was assessed with GRADE. MAIN RESULTS: We included 21 RCTs analysing 5264 participants who underwent elective colorectal surgery. None of the included studies had a high risk of bias, but two-thirds of the included studies raised some concerns. This was mainly due to the lack of a predefined analysis plan or missing information about the randomisation process. Most included studies investigated both colon and rectal resections due to malignant and benign surgical indications. For MBP as well as oAB, the included studies used different regimens in terms of agent(s), dosage and timing.  Data for all predefined outcomes could be extracted from the included studies. However, only four studies reported on side effects of bowel preparation, and none recorded the occurrence of adverse effects such as dehydration, electrolyte imbalances or the need to discontinue the intervention due to side effects. Seventeen trials compared MBP+oAB with sole MBP. The incidence of SSI could be reduced through MBP+oAB by 44% (RR 0.56, 95% CI 0.42 to 0.74; 3917 participants from 16 studies; moderate-certainty evidence) and the risk of anastomotic leakage could be reduced by 40% (RR 0.60, 95% CI 0.36 to 0.99; 2356 participants from 10 studies; moderate-certainty evidence). No difference between the two comparison groups was found with regard to mortality (RR 0.87, 95% CI 0.27 to 2.82; 639 participants from 3 studies; moderate-certainty evidence), the incidence of postoperative ileus (RR 0.89, 95% CI 0.59 to 1.32; 2013 participants from 6 studies, low-certainty of evidence) and length of hospital stay (MD -0.19, 95% CI -1.81 to 1.44; 621 participants from 3 studies; moderate-certainty evidence). Three trials compared MBP+oAB with sole oAB. No difference was demonstrated between the two treatment alternatives in terms of SSI (RR 0.87, 95% CI 0.34 to 2.21; 960 participants from 3 studies; very low-certainty evidence), anastomotic leakage (RR 0.84, 95% CI 0.21 to 3.45; 960 participants from 3 studies; low-certainty evidence), mortality (RR 1.02, 95% CI 0.30 to 3.50; 709 participants from 2 studies; low-certainty evidence), incidence of postoperative ileus (RR 1.25, 95% CI 0.68 to 2.33; 709 participants from 2 studies; low-certainty evidence) or length of hospital stay (MD 0.1 respectively 0.2, 95% CI -0.68 to 1.08; data from 2 studies; moderate-certainty evidence). One trial (396 participants) compared MBP+oAB versus nBP. The evidence is uncertain about the effect of MBP+oAB on the incidence of SSI as well as mortality (RR 0.63, 95% CI 0.33 to 1.23 respectively RR 0.20, 95% CI 0.01 to 4.22; low-certainty evidence), while no effect on the risk of anastomotic leakages (RR 0.89, 95% CI 0.33 to 2.42; low-certainty evidence), the incidence of postoperative ileus (RR 1.18, 95% CI 0.77 to 1.81; low-certainty evidence) or the length of hospital stay (MD 0.1, 95% CI -0.8 to 1; low-certainty evidence) could be demonstrated. AUTHORS' CONCLUSIONS: Based on moderate-certainty evidence, our results suggest that MBP+oAB is probably more effective than MBP alone in preventing postoperative complications. In particular, with respect to our primary outcomes, SSI and anastomotic leakage, a lower incidence was demonstrated using MBP+oAB. Whether oAB alone is actually equivalent to MBP+oAB, or leads to a reduction or increase in the risk of postoperative complications, cannot be clarified in light of the low- to very low-certainty evidence. Similarly, it remains unclear whether omitting preoperative bowel preparation leads to an increase in the risk of postoperative complications due to limited evidence. Additional RCTs, particularly on the comparisons of MBP+oAB versus oAB alone or nBP, are needed to assess the impact of oAB alone or nBP compared with MBP+oAB on postoperative complications and to improve confidence in the estimated effect. In addition, RCTs focusing on subgroups (e.g. in relation to type and location of colon resections) or reporting side effects of the intervention are needed to determine the most effective approach of preoperative bowel preparation.

Good or best practice statements: proposal for the operationalisation and implementation of GRADE guidance.

An evidence-based approach is considered the gold standard for health decision-making. Sometimes, a guideline panel might judge the certainty that the desirable effects of an intervention clearly outweigh its undesirable effects as high, but the body of supportive evidence is indirect. In such cases, the application of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach for grading the strength of recommendations is inappropriate. Instead, the GRADE Working Group has recommended developing ungraded best or good practice statement (GPS) and developed guidance under which circumsances they would be appropriate.Through an evaluation of COVID-1- related recommendations on the eCOVID Recommendation Map (COVID-19.recmap.org), we found that recommendations qualifying a GPS were widespread. However, guideline developers failed to label them as GPS or transparently report justifications for their development. We identified ways to improve and facilitate the operationalisation and implementation of the GRADE guidance for GPS.Herein, we propose a structured process for the development of GPSs that includes applying a sequential order for the GRADE guidance for developing GPS. This operationalisation considers relevant evidence-to-decision criteria when assessing the net consequences of implementing the statement, and reporting information supporting judgments for each criterion. We also propose a standardised table to facilitate the identification of GPS and reporting of their development. This operationalised guidance, if endorsed by guideline developers, may palliate some of the shortcomings identified. Our proposal may also inform future updates of the GRADE guidance for GPS.

The GIN-McMaster guideline tool extension for the integration of quality improvement and quality assurance in guidelines: a description of the methods for its development.

BACKGROUND AND OBJECTIVES: Our objective was to develop an extension of the widely used GIN-McMaster Guideline Development Checklist and Tool for the integration of quality assurance and improvement (QAI) schemes with guideline development. METHODS: We used a mixed-methods approach incorporating evidence from a systematic review, an expert workshop and a survey of experts to iteratively create an extension of the checklist for QAI through three rounds of feedback. As a part of this process, we also refined criteria of a good guideline-based quality indicator. RESULTS: We developed a 40-item checklist extension addressing steps for the integration of QAI into guideline development across the existing 18 topics and created one new topic specific to QAI. The steps span from 'organization, budget, planning and training', to updating of QAI and guideline implementation. CONCLUSION: The tool supports integration of QAI schemes with guideline development initiatives and it will be used in the forthcoming integrated European Commission Initiative on Colorectal Cancer. Future work should evaluate this extension and QAI items requiring additional support for guideline developers and links to QAI schemes.

Interventions for preventing back pain among office workers - a systematic review and network meta-analysis.

OBJECTIVE: Back pain is common in the working population. This systematic review with network meta-analysis (NMA) aimed to compare the effects of interventions for preventing back pain among office workers. METHODS: We searched eight databases and additional sources up to March 2021. We included randomized controlled trials (RCT) and cluster RCT focusing on office workers, comparing work-related interventions aimed at preventing back pain (defined as pain in any part of the spine) to a control condition and assessing back pain and/or work absence. Further outcomes considered were adverse events and participants' satisfaction. We performed both frequentist and component NMA. Risk of bias (RoB) was evaluated using RoB 2 and certainty of the evidence (CoE) was assessed using GRADE. RESULTS: We screened 9809 records and included 24 studies with a total of 7080 participants. RoB was assessed as "some concerns" or "high" for all studies and outcomes. Included studies investigated multicomponent interventions, ergonomics, physical activity, education, behavioral interventions and no/minimal interventions. Effects were mostly not statistically significant and based on low/very low CoE. Physical activity probably reduces days of work absence slightly [mean difference (MD) -1.10, 95% confidence interval (CI) -2.07- -0.13], and combining physical activity and ergonomics may reduce back pain intensity (standardized MD -0.41, 95% CI -0.80- -0.02) when compared to no/minimal intervention. A large proportion of participants were satisfied with the interventions, adverse events were rarely assessed. CONCLUSIONS: We observed mostly minor effects of interventions on back pain and work absence among office workers. The practical relevance of these effects is questionable.

Evidence-based guidelines for hypertension and diabetes in sub-Saharan Africa: a scoping review.

OBJECTIVE: The Collaboration for Evidence-Based Healthcare and Public Health in sub-Saharan Africa (CEBHA+), a research network, aims to build capacities for evidence-based healthcare. Hypertension (HTN) and diabetes mellitus (DM) are two priority areas of the network, both are major causes of burden of disease in this region. This review aimed to: (1) identify existing evidence-based guidelines for HTN and DM, (2) map their recommendations and (3) assess their quality. SETTING: Sub-Saharan Africa. DESIGN: Scoping review. METHODS: Systematic searches for evidence-based guidelines, developed with systematic review of evidence and certainty of evidence assessment, were undertaken in electronic databases and grey literature, and ministries of health of all countries in this region were contacted. Included guidelines were assessed with the Appraisal of Guidelines for research and evaluation II (AGREE-II) tool. Searches were conducted between 7 December 2021 and 14 January 2022. Results are presented descriptively. RESULTS: 66 potentially relevant guidelines were identified, developed in 23, out of 49 sub-Saharan African countries. Of these, only two guidelines (on DM) reported the use of systematic review of evidence and certainty of evidence assessment. Their quality appraisal showed that both have relatively similar scores on domains of AGREE-II, with higher scores on Scope and Purpose and Clarity and Presentation domains, and lower on Stakeholder Involvement, Applicability, Rigour of Development and Editorial independence domains. The overall scores of both guidelines were 50% and 58%, respectively. CONCLUSIONS: Less than half of the countries in sub-Saharan Africa developed and published their own guidelines for HTN or DM. The quality appraisal showed that the two included guidelines scored relatively low in several crucial domains of AGREE-II. Countries in this region could consider adopting or adapting already published high-quality recommendations, in order to facilitate a more efficient and faster development of much needed trustworthy evidence-based guidance.

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.