Reliability of Mouse Behavioural Tests of Anxiety: a Systematic Review and Meta-Analysis on the Effects of Anxiolytics.

Animal research on anxiety and anxiety disorders relies on valid animal models of anxiety. However, the validity of widely used rodent behavioural tests of anxiety has repeatedly been questioned, as they often fail to produce consistent results across independent replicate studies using different study populations or different anxiolytic compounds. In this study, we assessed the sensitivity of behavioural tests of anxiety in mice to detect anxiolytic effects of drugs prescribed to treat anxiety in humans. To this end, we conducted a pre-registered systematic review of studies reporting tests of anxiolytic compounds against a control treatment using common behavioural tests of anxiety in mice. PubMed and EMBASE were searched on August 21 st 2019 for studies published in English and 814 papers were identified for inclusion. Risk of bias was assessed based on Syrcle’s risk of bias tool and the Camarades study quality checklist on a randomly selected subsample of 180 papers. Meta-analyses on effect sizes of treatments using standardized mean differences (Hedges’ g) showed that only two of 17 test measures reliably detected effects of anxiolytic compounds other than diazepam. Further, we report considerable variation in both direction and size of effects of most anxiolytics on most outcome variables, indicating poor replicability of test results. This was corroborated by high heterogeneity in most test measures. Finally, we found an overall high risk of bias. Our findings indicate a general lack of sensitivity of common behavioural tests of anxiety in mice to anxiolytic compounds and cast serious doubt on both construct and predictive validity of most of those tests. The use of animals to model human conditions can be justified only if the expected results are informative, reproducible, and translatable. In view of scientifically valid and ethically responsible research, we call for a revision of behavioural tests of anxiety in mice and the development of more predictive tests .

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Heart Rate Variability in Patients with Cirrhosis: A Systematic Review and Meta-analysis

10.1101/2021.01.20.21249506 ◽

2021 ◽

Author(s):

Tope Oyelade ◽

Gabriele Canciani ◽

Gabriele Carbone ◽

Jaber Alqahtani ◽

Kevin Moore ◽

...

Keyword(s):

Systematic Review ◽

Heart Rate ◽

Heart Rate Variability ◽

Liver Disease ◽

Autonomic Function ◽

Meta Analysis ◽

Risk Of Bias ◽

Newcastle Ottawa Scale ◽

Mean Differences ◽

Meta Analyses

AbstractBackgroundCirrhosis is associated with abnormal autonomic function and regulation of cardiac rhythm. Measurement of heart rate variability (HRV) provides an accurate and non-invasive measurement of autonomic function as well as liver disease severity currently calculated using the MELD, UKELD, or ChildPugh scores. This review assesses the methods employed for the measurement of HRV, and evaluates the alteration of HRV indices in cirrhosis, as well as their value in prognosis.MethodWe undertook a systematic review using Medline, Embase and Pubmed databases in July 2020. Data were extracted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias of included studies was assessed by a modified version of the Newcastle Ottawa Scale. The studies descriptive were analysed and the standardized mean differences of HRV indices were pooled.ResultsOf the 247 studies generated from our search, 14 studies were included. One of the 14 studies was excluded from meta-analysis because it reported only median of HRV indices. The studies included have a low risk of bias, and include 583 patients with cirrhosis and 349 healthy controls. The HRV time and frequency domains were significantly lower in cirrhotic patients. Between-studies heterogeneity was high in most of the pooled studies (P<0.05). Further, HRV indices predict survival independent of the severity of liver disease as assessed by MELD.ConclusionHRV is decreased in patients with cirrhosis compared with healthy matched controls. HRV correlated with severity of liver disease and independently predicted survival. There was considerable variation in the methods used for HRV analysis, and this impedes interpretation and clinical applicability. Based on the data analysed, SDNN (standard deviation of inter-beat intervals) and cSDNN (i.e. SDNN corrected for basal heart rate) are the most suitable indices for prognosis in patients with cirrhosis.

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Comparative efficacy and safety of interventions for treating head lice: a protocol for systematic review and network meta-analysis

BMJ Paediatrics Open ◽

10.1136/bmjpo-2021-001129 ◽

2021 ◽

Vol 5 (1) ◽

pp. e001129

Author(s):

Bill Stevenson ◽

Wubshet Tesfaye ◽

Julia Christenson ◽

Cynthia Mathew ◽

Solomon Abrha ◽

...

Keyword(s):

Systematic Review ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Grey Literature ◽

Risk Of Bias ◽

Controlled Trials ◽

Head Lice ◽

Efficacy And Safety ◽

Randomised Controlled ◽

Meta Analyses

BackgroundHead lice infestation is a major public health problem around the globe. Its treatment is challenging due to product failures resulting from rapidly emerging resistance to existing treatments, incorrect treatment applications and misdiagnosis. Various head lice treatments with different mechanism of action have been developed and explored over the years, with limited report on systematic assessments of their efficacy and safety. This work aims to present a robust evidence summarising the interventions used in head lice.MethodThis is a systematic review and network meta-analysis which will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for network meta-analyses. Selected databases, including PubMed, Embase, MEDLINE, Web of Science, CINAHL and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials exploring head lice treatments. Searches will be limited to trials published in English from database inception till 2021. Grey literature will be identified through Open Grey, AHRQ, Grey Literature Report, Grey Matters, ClinicalTrials.gov, WHO International Clinical Trials Registry and International Standard Randomised Controlled Trials Number registry. Additional studies will be sought from reference lists of included studies. Study screening, selection, data extraction and assessment of methodological quality will be undertaken by two independent reviewers, with disagreements resolved via a third reviewer. The primary outcome measure is the relative risk of cure at 7 and 14 days postinitial treatment. Secondary outcome measures may include adverse drug events, ovicidal activity, treatment compliance and acceptability, and reinfestation. Information from direct and indirect evidence will be used to generate the effect sizes (relative risk) to compare the efficacy and safety of individual head lice treatments against a common comparator (placebo and/or permethrin). Risk of bias assessment will be undertaken by two independent reviewers using the Cochrane Risk of Bias tool and the certainty of evidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations guideline for network meta-analysis. All quantitative analyses will be conducted using STATA V.16.DiscussionThe evidence generated from this systematic review and meta-analysis is intended for use in evidence-driven treatment of head lice infestations and will be instrumental in informing health professionals, public health practitioners and policy-makers.PROSPERO registration numberCRD42017073375.

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Influence of Coronal Preflaring on the Accuracy of Electronic Working Length Determination: Systematic Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm10132760 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2760

Author(s):

María León-López ◽

Daniel Cabanillas-Balsera ◽

Victoria Areal-Quecuty ◽

Jenifer Martín-González ◽

María C. Jiménez-Sánchez ◽

...

Keyword(s):

Systematic Review ◽

Science Studies ◽

Meta Analysis ◽

Experimental Studies ◽

Risk Of Bias ◽

Permanent Teeth ◽

Total Risk ◽

Human Teeth ◽

Working Length ◽

Meta Analyses

Aim. To conduct a systematic review and meta-analysis according to the following PICO question: in extracted human permanent teeth, does preflaring, compared with unflared canals, influence the accuracy of WL determination with EAL? Material and Methods. A systematic review was conducted according to the PRISMA checklist, using the following databases: PubMed, Science Direct, Scopus, and Web of Science. Studies related to WL determination using EAL both in preflared and unflared root canals of extracted human teeth were included. The outcome of interest was the accuracy of the electronic WL determination. A quality assessment of the included studies was performed, determining the risk of bias. The meta-analyses were calculated with the 5.4 RevMan software using the inverse variance method with random effects. PROSPERO registration: CRD42021243412. Results. Ten experimental studies fulfilled the inclusion criteria, and most of them found that preflaring increases the accuracy of the EALs in WL determination. The calculated OR was 1.98 (95% CI = 1.65–2.37; p < 0.00001; I2 = 10%), indicating that the determination of WL by EALs is almost twice as accurate in preflared canals. The accuracy of Root ZX in WL determination increases more than three times (OR = 3.25; p < 0.00001). Preflaring with Protaper files significantly increases the accuracy of EALs (OR = 1.76; p < 0.00001). The total risk of bias of the included studies was low. No obvious publication bias was observed. Conclusions. The results indicate a significant increase in the accuracy of WL determination with EAL after preflaring, doubling the percentage of exact measurements. Preflaring should be recommended as an important step during mechanical enlargement of the root canal, not only because it improves the access of the files to the canal, but also because it allows one to obtain more accurate electronic determinations of WL.

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The Effect of Plantago major on Wound Healing in Preclinical Studies: A Systematic Review

Wound Management & Prevention ◽

10.25270/wmp.2021.1.2734 ◽

2021 ◽

Vol 67 (1) ◽

pp. 27-34

Author(s):

Fernanda Cardoso ◽

Jéssica Breder ◽

Priscila Apolinário ◽

Henrique Oliveia ◽

Maria Saidel ◽

...

Keyword(s):

Systematic Review ◽

Wound Healing ◽

Meta Analysis ◽

Experimental Studies ◽

Risk Of Bias ◽

Preclinical Studies ◽

Plantago Major ◽

Best Response ◽

Meta Analyses

BACKGROUND: Plantago major is a medicinal plant that has been used for centuries to treat various health conditions including wounds. PURPOSE: To investigate the effectiveness of the topical use of P major in healing skin wounds in animal models. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted. Seven (7) electronic databases (Virtual Health Library, Public/Publisher MEDLINE, Scopus, Web of Science, Embase, Cumulative Index of Nursing and Allied Health Literature, and CAB Direct) were searched for controlled studies published in English from January 2006 to March 2020. The Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies tools guided the evaluation of the studies and determined their quality. The Systematic Review Center for Laboratory Animal Experimentation was used to assess the risk of bias. RESULTS: Of the 176 publications identified, 4 met the inclusion criteria. Studies included 20 to 100 animals and varying concentrations of P major. There were no reports of losses during research. Wound healing was assessed between 17 and 21 days following wounding. The best response in terms of wound contraction rate occurred with 10%, 20%, and 50% concentrations when compared with control groups. One (1) study did not have an animal ethics committee review. All studies had a high risk of bias and a lack of methodological rigor. CONCLUSION: The results of this review did not find evidence about the in vivo effectiveness of P major for wound healing. More rigorous preclinical studies with adequate sample sizes are required to identify the best concentrations and formulations as well as increase understanding about the mechanisms of action of P major in wound healing.

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Effectiveness of orthodontic temporary anchorage devices in canine retraction and anchorage preservation during the two-step technique: a systematic review and meta-analysis

BMC Oral Health ◽

10.1186/s12903-020-01271-8 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Haonan Tian ◽

Congman Xie ◽

Min Lin ◽

Hongmei Yang ◽

Aishu Ren

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Risk Of Bias ◽

Controlled Trials ◽

Cochrane Central Register ◽

Canine Retraction ◽

Temporary Anchorage Devices ◽

The Mean ◽

Mean Differences ◽

Implant Anchorage

Abstract Background Temporary anchorage devices have been used for decades in orthodontic practice for many applications. The aim of this systematic review was to assess the effectiveness of orthodontic temporary anchorage devices in canine retraction during the two-step technique. Methods A search was systematically performed for articles published prior to June 30, 2019 in five electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Scopus). The risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials (RCTs) and the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool for controlled clinical trials (CCTs). The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used for the quality assessment. Data concerning the mean difference in mesial molar movement and extent of canine retraction were extracted for statistical analysis. The mean differences and 95% confidence intervals were analyzed for continuous data. A meta-analysis with a random-effects model for comparable outcomes was carried out. Results Three RCTs and five CCTs were finally included. Meta-analysis showed a significant increase not only in anchorage preservation in the implant anchorage group in both the maxilla (1.56 mm, 95% CI: 1.14 to 1.98, P < 0.00001) and the mandible (1.62 mm, 95% CI: 1.24 to 2.01, P < 0.00001) but also in canine retraction in the implant anchorage group in both the maxilla (0.43 mm, 95% CI: 0.16 to 0.69, P = 0.001) and the mandible (0.26 mm, 95% CI: 0.02 to 0.49, P = 0.03). Conclusions There is very low-quality evidence showing that implant anchorage is more efficient than conventional anchorage during canine retraction. Additional high-quality studies are needed.

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Leishmanicidal effects of resveratrol and its derivatives: a systematic review and meta-Analysis

10.21203/rs.3.rs-25274/v1 ◽

2020 ◽

Author(s):

Nasrin Amiri Dashatan ◽

Marzieh Ashrafmansouri ◽

Mehdi Koushki ◽

Nayebali Ahmadi

Keyword(s):

Systematic Review ◽

Publication Bias ◽

Data Extraction ◽

Meta Analysis ◽

Sensitivity Analyses ◽

Protective Effects ◽

Random Effects Models ◽

Important Health ◽

Mean Differences ◽

Meta Analyses

Abstract Background Leishmaniasis is one of the most important health problems worldwide. The evidence has suggested that resveratrol and its derivatives have anti-leishmanial effects; however, the results are inconsistent and inconclusive. The aim of this study was to assess the effect of resveratrol and its derivatives on the Leishmania viability through a systematic review and meta-analysis of available relevant studies. Methods The electronic databases PubMed, ScienceDirect, Embase, Web of Science and Scopus were queried between October 2000 and April 2020 using a comprehensive search strategy. The eligible articles selected and data extraction conducted by two reviewers. Mean differences of IC50 (concentration leading to reduction of 50% of Leishmania) for each outcome was calculated using random-effects models. Sensitivity analyses and prespecified subgroup were conducted to evaluate potential heterogeneity and the stability of the pooled results. Publication bias was evaluated using the Egger’s and Begg’s tests. We also followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for this review. Results Ten studies were included in the meta-analysis. We observed that RSV and its derivatives had significant reducing effects on Leishmania viability in promastigote [24.02 µg/ml; (95% CI 17.1, 30.8); P < 0.05; I2 = 99.8%; P heterogeneity = 0.00] and amastigote [18.3 µg/ml; (95% CI 13.5, 23.2); P < 0.05; I2 = 99.6%; P heterogeneity = 0.00] stages of Leishmania. A significant publication bias was observed in the meta-analysis. Sensitivity analyses showed a similar effect size while reducing the heterogeneity. Subgroup analysis indicated that the pooled effects of leishmanicidal of resveratrol and its derivatives were affected by type of stilbenes and Leishmania species. Conclusions Our findings clearly suggest that the strategies for the treatment of leishmaniasis should be focused on natural products such as RSV and its derivatives. Further study is needed to identify the mechanisms mediating this protective effects of RSV and its derivatives in leishmaniasis.

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Aromatherapy for Symptom Relief in Patients with Burn: A Systematic Review and Meta-Analysis

Medicina ◽

10.3390/medicina58010001 ◽

2021 ◽

Vol 58 (1) ◽

pp. 1

Author(s):

Hye Won Lee ◽

Lin Ang ◽

Jung Tae Kim ◽

Myeong Soo Lee

Keyword(s):

Systematic Review ◽

Data Extraction ◽

Meta Analysis ◽

Symptom Relief ◽

Routine Care ◽

Risk Of Bias ◽

Review Author ◽

Beneficial Effects ◽

Study Selection ◽

Meta Analyses

Background and Objectives: This review aimed to provide an updated review of evidence regarding the effects of aromatherapy in relieving symptoms of burn injuries, focusing on pain and physiological distress. Materials and Methods: Fifteen databases (including five English databases, four Korean medical databases, and four Iranian databases) and trial registries were searched for studies published between their dates of inception and July 2021. Two review authors individually performed study selection, data extraction, and risk of bias assessment, and any discrepancies were solved by a third review author. Results: Eight RCTs met our inclusion criteria and were analyzed in this updated systematic review. Our meta-analyses revealed that inhaled aromatherapy plus routine care showed beneficial effects in relieving pain after dressing, as compared to placebo plus routine care (p < 0.00001) and routine care alone (p = 0.02). Additionally, inhaled aromatherapy plus routine care (p < 0.00001) and aromatherapy massage plus routine care (p < 0.0001) also showed superior effects in calming anxiety, as compared to routine care alone. None of the included studies reported on AEs. Overall, the risk of bias across the studies was concerning. Conclusions: This updated review and synthesis of the studies had brought a more detailed understanding of the potential application of aromatherapy for easing the pain and anxiety of burn patients.

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Effects of the endocrine disruptor vinclozolin in male reproduction: a systematic review and meta-analysis†

Biology of Reproduction ◽

10.1093/biolre/ioab018 ◽

2021 ◽

Author(s):

Mariana Feijó ◽

Roberta V L Martins ◽

Sílvia Socorro ◽

Luísa Pereira ◽

Sara Correia

Keyword(s):

Systematic Review ◽

Publication Bias ◽

Meta Analysis ◽

Endocrine Disrupting Chemicals ◽

Reproductive Organs ◽

Male Reproduction ◽

Mean Differences ◽

Trim And Fill ◽

Meta Analyses ◽

Q Statistic

Abstract Endocrine-disrupting chemicals have become an issue of scientific and public discussion. Vinclozolin (VNZ) is a fungicide that competitively antagonizes the binding of natural androgens to their receptor, disturbing the function of tissues that are sensitive to these hormones, as is the case of the male reproductive organs. A systematic review with meta-analyses of rodent studies was conducted to answer the following question: Does exposure to VNZ affect sperm parameters and testicular/epididymal weight? The methodology was prespecified according to the Cochrane Handbook for Systematic Reviews and PRISMA recommendations. Sixteen articles met the inclusion criteria, comprising a total of 1189 animals. The risk of publication bias was assessed using the Trim and Fill adjustment, funnel plot, and Egger regression test. Heterogeneity and inconsistency across the findings were tested using the Q-statistic and I2 of Higgins, respectively. Sensitivity was also analyzed. Statistical analysis was performed on Comprehensive Meta-Analysis software (Version 2.0), using random models and weighted mean differences along with a 95% confidence interval. Sperm motility, counts, daily sperm production (evidence of publication bias), and epididymis weight were decreased in VNZ-treated animals. Exposure length and dose, as well as the time point of exposure, influenced the obtained results. Despite the moderate/high heterogeneity observed, the sensitivity analysis overall demonstrated the robustness of the findings. The quality scores of the included studies were superior to 4 in a total of 9, then classified as good. The obtained data corroborate the capability of VNZ exposure to disrupt spermatogenic output and compromise male fertility.

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Systematic Review and Meta-analyses of Effects of Phosphate-lowering Agents in Non-dialysis Chronic Kidney Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.2021040554 ◽

2021 ◽

pp. ASN.2021040554

Author(s):

Nicole Lioufas ◽

Elaine Pascoe ◽

Carmel Hawley ◽

Grahame Elder ◽

Sunil Badve ◽

...

Keyword(s):

Systematic Review ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Clinical Outcomes ◽

Serum Phosphate ◽

Risk Of Bias ◽

Lowering Therapy ◽

Mean Differences ◽

Meta Analyses

Background: Benefits of phosphate-lowering interventions on clinical outcomes in patients with chronic kidney disease (CKD) are unclear; systematic reviews have predominantly involved dialysis patients. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of non-calcium-based phosphate-lowering treatment in non-dialysis CKD. Methods: We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared to placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes, with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence. Results: Twenty trials involving 2,498 participants (median sample size 120, median follow up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, non calcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37, 95% CI -0.58,-0.15 mg/dL, low certainty evidence) and urinary phosphate excretion (8 trials, SMD -0.61, 95% CI -0.90,-0.31, low certainty evidence), but resulted in increased constipation (9 trials, log odds ratio [OR] 0.93, 95% CI 0.02, 1.83, low certainty evidence) and greater vascular calcification score (3 trials, SMD 0.47, 95% CI 0.17, 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR 0.51 [95% CI -0.51, 1.17]) and death were scant. Conclusions: Non-calcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end-points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.

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Vaccines to prevent COVID-19: a protocol for a living systematic review with network meta-analysis including individual patient data (The LIVING VACCINE Project)

Systematic Reviews ◽

10.1186/s13643-020-01516-1 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Steven Kwasi Korang ◽

Sophie Juul ◽

Emil Eik Nielsen ◽

Joshua Feinberg ◽

Faiza Siddiqui ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Randomized Clinical Trials ◽

Individual Patient Data ◽

Viral Vector ◽

Meta Analysis ◽

Risk Of Bias ◽

Serious Adverse Events ◽

Meta Analyses ◽

Harmful Effects

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. Methods/design We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; “active placebo;” no intervention; standard care; an “active” intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. Discussion COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. Systematic review registration PROSPERO CRD42020196492

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