Conduct and reporting of multivariate network meta-analyses: a scoping review.

OBJECTIVES: Combining multivariate and network meta-analysis methods simultaneously in a multivariate network meta-analysis (MVNMA) provides the methodological framework to analyze the largest amount of evidence relevant to decision-makers (i.e., from indirect evidence and correlated outcomes). The objectives of this scoping review were to summarize the characteristics of MVNMAs published in the health sciences literature and map the methodological guidance available for MVNMA. STUDY DESIGN AND SETTING: We searched MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature from inception to 28 August 2023, along with citations of included studies, for quantitative evidence syntheses that applied MVNMA and articles addressing MVNMA methods. Pairs of reviewers independently screened potentially eligible studies. Collected data included bibliographic, methodological, and analytical characteristics of included studies. We reported results as total numbers, frequencies, and percentages for categorical variables and medians and interquartile ranges for continuous variables that were not normally distributed. RESULTS: After screening 1,075 titles and abstracts, and 112 full texts, we included 38 unique studies, of which, 10 were quantitative evidence syntheses that applied MVNMA and 28 were articles addressing MVNMA methods. Among the 10 MVNMAs, the first was published in 2013, four used studies identified from already published systematic reviews, and eight addressed pharmacological interventions, which were the most common interventions. They evaluated interventions for metastatic melanoma, colorectal cancer, prostate cancer, oral hygiene, disruptive behavior disorders, rheumatoid arthritis, narcolepsy, type 2 diabetes, and overactive bladder syndrome. Five MVNMAs analyzed two outcomes simultaneously, and four MVNMAs analyzed three outcomes simultaneously. Among the articles addressing MVNMA methods, the first was published in 2007 and the majority provided methodological frameworks for conducting MVNMAs (26/28, 93%). One study proposed criteria to standardize reporting of MVNMAs and two proposed items relevant to the quality assessment of MVNMAs. Study authors used data from 18 different illnesses to provide illustrative examples within their methodological guidance. CONCLUSIONS: The application of MVNMA in the health sciences literature is uncommon. Many methodological frameworks are published; however, standardization and specific criteria to guide reporting and quality assessment are lacking. This overview of the current landscape may help inform future conduct of MVNMAs and research on MVNMA methods.

Impact of Allocation Concealment and Blinding in Trials Addressing Treatments for COVID-19: A Methods Study.

We aimed to assess the impact of allocation concealment and blinding on the results of coronavirus disease 2019 (COVID-19) trials, using the World Health Organization COVID-19 database (to February 2022). We identified 488 randomized trials comparing drug therapeutics with placebo or standard care in patients with COVID-19. We performed random-effects meta-regressions comparing the results of trials with and without allocation concealment and blinding of health-care providers and patients. We found that, compared with trials with allocation concealment, trials without allocation concealment may estimate treatments to be more beneficial for mortality, mechanical ventilation, hospital admission, duration of hospitalization, and duration of mechanical ventilation, but results were imprecise. We did not find compelling evidence that, compared with trials with blinding, trials without blinding produce consistently different results for mortality, mechanical ventilation, and duration of hospitalization. We found that trials without blinding may estimate treatments to be more beneficial for hospitalizations and duration of mechanical ventilation. We did not find compelling evidence that COVID-19 trials in which health-care providers and patients are blinded produce different results from trials without blinding, but trials without allocation concealment estimate treatments to be more beneficial compared with trials with allocation concealment. Our study suggests that lack of blinding may not always bias results but that evidence users should remain skeptical of trials without allocation concealment.

Measures of Retention in HIV Care: A Study Within a Review.

People living with HIV (PLHIV) need lifelong medical care. However, retention in HIV care is not measured uniformly, making it challenging to compare or pool data. The objective of this study within a review (SWAR) is to describe the assortment of definitions used for retention in HIV care in randomized controlled trials (RCTs). We conducted a SWAR, drawing data from an overview of systematic reviews on interventions to improve the HIV care cascade. Ethics review was not required for this analysis of secondary data. We identified RCTs of interventions used to improve retention in care for PLHIV, including all age groups and extracted the definitions used and their characteristics. We identified 50 trials that measured retention published between 2007 and 2021 and provided 59 definitions for retention in care. The definitions consisted of nine different characteristics with follow-up time (n = 47), and clinical visits (n = 36) most used. The definitions of retention in HIV care are highly heterogeneous. In this study, we present the pros and cons of characteristics used to measure retention in HIV care.

Prognostic factors for streptococcal toxic shock syndrome: systematic review and meta-analysis.

OBJECTIVES: To quantify the prognostic effects of demographic and modifiable factors in streptococcal toxic shock syndrome (STSS). DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE and CINAHL from inception to 19 September 2022, along with citations of included studies. ELIGIBILITY CRITERIA: Pairs of reviewers independently screened potentially eligible studies of patients with Group A Streptococcus-induced STSS that quantified the association between at least one prognostic factor and outcome of interest. DATA EXTRACTION AND SYNTHESIS: We performed random-effects meta-analysis after duplicate data extraction and risk of bias assessments. We rated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: One randomised trial and 40 observational studies were eligible (n=1918 patients). We found a statistically significant association between clindamycin treatment and mortality (n=144; OR 0.14, 95% CI 0.06 to 0.37), but the certainty of evidence was low. Within clindamycin-treated STSS patients, we found a statistically significant association between intravenous Ig treatment and mortality (n=188; OR 0.34, 95% CI 0.15 to 0.75), but the certainty of evidence was also low. The odds of mortality may increase in patients ≥65 years when compared with patients 18-64 years (n=396; OR 2.37, 95% CI 1.47 to 3.84), but the certainty of evidence was low. We are uncertain whether non-steroidal anti-inflammatory drugs increase the odds of mortality (n=50; OR 4.14, 95% CI 1.13 to 15.14; very low certainty). Results failed to show a significant association between any other prognostic factor and outcome combination (very low to low certainty evidence) and no studies quantified the association between a prognostic factor and morbidity post-infection in STSS survivors. CONCLUSIONS: Treatment with clindamycin and within clindamycin-treated patients, IVIG, was each significantly associated with mortality, but the certainty of evidence was low. Future research should focus on morbidity post-infection in STSS survivors. PROSPERO REGISTRATION NUMBER: CRD42020166961.

Characterization of Extensively Drug-Resistant (XDR) Carbapenemase-Producing Enterobacterales (CPE) in Canada from 2019 to 2020.

Data regarding the epidemiology of extensively drug-resistant (XDR) carbapenemase-producing Enterobacterales (CPE) in Canada are scarce. Among CPE patients identified by the Canadian Nosocomial Infection Surveillance Program, the following were each significantly associated with XDR status: international travel history; CPE acquisition from a health care exposure abroad; presence of the New Delhi metallo-ß-lactamase (NDM) carbapenemase gene; E. coli sequence type (ST) 167, ST405, and ST648; E. cloaceae ST177; C. freundii ST22; and resistance to all antimicrobials except colistin, tigecycline, and ceftazidime-avibactam. IMPORTANCE Extensively drug-resistant (XDR) carbapenemase-producing Enterobacterales (CPE) are a global public health concern. XDR CPE are among the most drug-resistant and difficult-to-treat bacteria, and infected patients are likely to experience adverse outcomes. Because XDR status further reduces effective therapeutic options, it is critical for clinicians to consider resistance and therapeutic options not only in the context of a patient with CPE but also in the context of potential XDR status. Our study reports on patient characteristics associated with the acquisition of an XDR CPE. Our study also reports on the species and carbapenemases associated with XDR status among Enterobacterales identified in Canada. Among a panel of 22 antibiotics, including novel combination drugs, we showed which retained the highest activity against XDR CPE, which may help guide the selection of antibiotic treatments.

Patient-important outcomes reported in randomized controlled trials of pharmacologic treatments for COVID-19: a protocol of a META-epidemiological study.

BACKGROUND: The coronavirus disease 19 (covid-19) pandemic has underscored the need to expedite clinical research, which may lead investigators to shift away from measuring patient-important outcomes (PIO), limiting research applicability. We aim to investigate if randomized controlled trials (RCTs) of covid-19 pharmacological therapies include PIOs. METHODS: We will perform a meta-epidemiological study of RCTs that included people at risk for, or with suspected, probable, or confirmed covid-19, examining any pharmacological treatment or blood product aimed at prophylaxis or treatment. We will obtain data from all RCTs identified in a living network metanalysis (NMA). The main data sources are the living WHO covid-19 database up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Two reviewers independently will review each citation, full-text article, and abstract data. To categorize the outcomes according to their importance to patients, we will adapt a previously defined hierarchy: a) mortality, b) quality of life/ functional status/symptoms, c) morbidity, and d) surrogate outcomes. Outcomes within the category a) and b) will be considered critically important to patients, and outcomes within the category c) will be regarded as important. We will use descriptive statistics to assess the proportion of studies that report each category of outcomes. We will perform univariable and multivariable analysis to explore associations between trial characteristics and the likelihood of reporting PIOs. DISCUSSION: The findings from this meta-epidemiological study will help health care professionals and researchers understand if the current covid-19 trials are effectively assessing and reporting the outcomes that are important to patients. If a deficiency in capturing PIOs is identified, this information may help inform the development of future RCTs in covid-19. SYSTEMATIC REVIEW REGISTRATIONS: Open Science Framework registration: osf.io/6xgjz .

Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a data supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).

Clinical trials in COVID-19 management & prevention: A meta-epidemiological study examining methodological quality.

OBJECTIVE: To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. STUDY DESIGN: We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. RESULTS: We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. CONCLUSIONS: There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. REGISTRATION: CRD42020192095.

Prophylaxis against covid-19: living systematic review and network meta-analysis.

UPDATES: This is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity. OBJECTIVE: To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis (NMA). DATA SOURCES: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022. STUDY SELECTION: Randomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. RESULTS: The second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation­risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence. CONCLUSIONS: Much of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).

Are Sink Drainage Systems a Reservoir for Hospital-Acquired Gammaproteobacteria Colonization and Infection? A Systematic Review.

Increasing rates of antimicrobial-resistant organisms have focused attention on sink drainage systems as reservoirs for hospital-acquired Gammaproteobacteria colonization and infection. We aimed to assess the quality of evidence for transmission from this reservoir. We searched 8 databases and identified 52 studies implicating sink drainage systems in acute care hospitals as a reservoir for Gammaproteobacterial colonization/infection. We used a causality tool to summarize the quality of evidence. Included studies provided evidence of co-occurrence of contaminated sink drainage systems and colonization/infection, temporal sequencing compatible with sink drainage reservoirs, some steps in potential causal pathways, and relatedness between bacteria from sink drainage systems and patients. Some studies provided convincing evidence of reduced risk of organism acquisition following interventions. No single study provided convincing evidence across all causality domains, and the attributable fraction of infections related to sink drainage systems remains unknown. These results may help to guide conduct and reporting in future studies.

Drug treatments for covid-19: living systematic review and network meta-analysis

OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 3 December 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 1 December 2021 were included in the analysis. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 463 trials enrolling 166 581 patients were included; 267 (57.7%) trials and 89 814 (53.9%) patients are new from the previous iteration; 265 (57.2%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, three drugs reduced mortality in patients with mostly severe disease with at least moderate certainty: systemic corticosteroids (risk difference 23 fewer per 1000 patients, 95% credible interval 40 fewer to 7 fewer, moderate certainty), interleukin-6 receptor antagonists when given with corticosteroids (23 fewer per 1000, 36 fewer to 7 fewer, moderate certainty), and Janus kinase inhibitors (44 fewer per 1000, 64 fewer to 20 fewer, high certainty). Compared with standard care, two drugs probably reduce hospital admission in patients with non-severe disease: nirmatrelvir/ritonavir (36 fewer per 1000, 41 fewer to 26 fewer, moderate certainty) and molnupiravir (19 fewer per 1000, 29 fewer to 5 fewer, moderate certainty). Remdesivir may reduce hospital admission (29 fewer per 1000, 40 fewer to 6 fewer, low certainty). Only molnupiravir had at least moderate quality evidence of a reduction in time to symptom resolution (3.3 days fewer, 4.8 fewer to 1.6 fewer, moderate certainty); several others showed a possible benefit. Several drugs may increase the risk of adverse effects leading to drug discontinuation; hydroxychloroquine probably increases the risk of mechanical ventilation (moderate certainty). CONCLUSION: Corticosteroids, interleukin-6 receptor antagonists, and Janus kinase inhibitors probably reduce mortality and confer other important benefits in patients with severe covid-19. Molnupiravir and nirmatrelvir/ritonavir probably reduce admission to hospital in patients with non-severe covid-19. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is publicly available in the supplementary material. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fifth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.

Impact of maternal reproductive factors on cancer risks of offspring: A systematic review and meta-analysis of cohort studies.

BACKGROUND: A number of studies have reported on associations between reproductive factors, such as delivery methods, number of birth and breastfeeding, and incidence of cancer in children, but systematic reviews addressing this issue to date have important limitations, and no reviews have addressed the impact of reproductive factors on cancer over the full life course of offspring. METHODS: We performed a comprehensive search in MEDLINE, and Embase up to January 2020 and Web of Science up to 2018 July, including cohort studies reporting the association between maternal reproductive factors of age at birth, birth order, number of births, delivery methods, and breastfeeding duration and cancer in children. Teams of two reviewers independently extracted data and assessed risk of bias. We conducted random effects meta-analyses to estimate summary relative estimates, calculated absolute differences between those with and without risk factors, and used the GRADE approach to evaluate the certainty of evidence. RESULTS: For most exposures and most cancers, we found no suggestion of a causal relation. We found low to very low certainty evidence of the following very small possible impact: higher maternal age at birth with adult multiple myeloma and lifetime uterine cervix cancer incidence; lower maternal age at birth with childhood overall cancer mortality (RR = 1.15, 95% CI = 1.01-1.30; AR/10,000 = 1, 95% CI = 0 to 2), adult leukemia and lifetime uterine cervix cancer incidence; higher birth order with adult melanoma, cervix uteri, corpus uteri, thyroid cancer incidence, lifetime lung, corpus uteri, prostate, testis, sarcoma, thyroid cancer incidence; larger number of birth with childhood brain (RR = 1.27, 95% CI = 1.06-1.52; AR/10,000 = 1, 95% CI = 0 to 2), leukemia (RR = 2.11, 95% CI = 1.62-2.75; AR/10,000 = 9, 95% CI = 5 to 14), lymphoma (RR = 4.66, 95% CI = 1.40-15.57; AR/10,000 = 11, 95% CI = 1 to 44) incidence, adult stomach, corpus uteri cancer incidence and lung cancer mortality, lifetime stomach, lung, uterine cervix, uterine corpus, multiple myeloma, testis cancer incidence; Caesarean delivery with childhood kidney cancer incidence (RR = 1.25, 95% CI = 1.01-1.55; AR/10,000 = 0, 95% CI = 0 to 1); and breastfeeding with adult colorectal cancer incidence. CONCLUSION: Very small impacts existed between a number of reproductive factors and cancer incidence and mortality in children and the certainty of evidence was low to very low primarily due to observational design.

Medical masks vs N95 respirators for preventing COVID-19 in healthcare workers: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Respiratory protective devices are critical in protecting against infection in healthcare workers at high risk of novel 2019 coronavirus disease (COVID-19); however, recommendations are conflicting and epidemiological data on their relative effectiveness against COVID-19 are limited. PURPOSE: To compare medical masks to N95 respirators in preventing laboratory-confirmed viral infection and respiratory illness including coronavirus specifically in healthcare workers. DATA SOURCES: MEDLINE, Embase, and CENTRAL from January 1, 2014, to March 9, 2020. Update of published search conducted from January 1, 1990, to December 9, 2014. STUDY SELECTION: Randomized controlled trials (RCTs) comparing the protective effect of medical masks to N95 respirators in healthcare workers. DATA EXTRACTION: Reviewer pair independently screened, extracted data, and assessed risk of bias and the certainty of the evidence. DATA SYNTHESIS: Four RCTs were meta-analyzed adjusting for clustering. Compared with N95 respirators; the use of medical masks did not increase laboratory-confirmed viral (including coronaviruses) respiratory infection (OR 1.06; 95% CI 0.90-1.25; I2  = 0%; low certainty in the evidence) or clinical respiratory illness (OR 1.49; 95% CI: 0.98-2.28; I2  = 78%; very low certainty in the evidence). Only one trial evaluated coronaviruses separately and found no difference between the two groups (P = .49). LIMITATIONS: Indirectness and imprecision of available evidence. CONCLUSIONS: Low certainty evidence suggests that medical masks and N95 respirators offer similar protection against viral respiratory infection including coronavirus in healthcare workers during non-aerosol-generating care. Preservation of N95 respirators for high-risk, aerosol-generating procedures in this pandemic should be considered when in short supply.

Red and Processed Meat Consumption and Risk for All-Cause Mortality and Cardiometabolic Outcomes: A Systematic Review and Meta-analysis of Cohort Studies.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Dietary guidelines generally recommend limiting intake of red and processed meat. However, the quality of evidence implicating red and processed meat in adverse health outcomes remains unclear. Purpose: To evaluate the association between red and processed meat consumption and all-cause mortality, cardiometabolic outcomes, quality of life, and satisfaction with diet among adults. Data Sources: EMBASE (Elsevier), Cochrane Central Register of Controlled Trials (Wiley), Web of Science (Clarivate Analytics), CINAHL (EBSCO), and ProQuest from inception until July 2018 and MEDLINE from inception until April 2019, without language restrictions, as well as bibliographies of relevant articles. Study Selection: Cohort studies with at least 1000 participants that reported an association between unprocessed red or processed meat intake and outcomes of interest. Data Extraction: Teams of 2 reviewers independently extracted data and assessed risk of bias. One investigator assessed certainty of evidence, and the senior investigator confirmed the assessments. Data Synthesis: Of 61 articles reporting on 55 cohorts with more than 4 million participants, none addressed quality of life or satisfaction with diet. Low-certainty evidence was found that a reduction in unprocessed red meat intake of 3 servings per week is associated with a very small reduction in risk for cardiovascular mortality, stroke, myocardial infarction (MI), and type 2 diabetes. Likewise, low-certainty evidence was found that a reduction in processed meat intake of 3 servings per week is associated with a very small decrease in risk for all-cause mortality, cardiovascular mortality, stroke, MI, and type 2 diabetes. Limitation: Inadequate adjustment for known confounders, residual confounding due to observational design, and recall bias associated with dietary measurement. Conclusion: The magnitude of association between red and processed meat consumption and all-cause mortality and adverse cardiometabolic outcomes is very small, and the evidence is of low certainty. Primary Funding Source: None. (PROSPERO: CRD42017074074).

Reduction of Red and Processed Meat Intake and Cancer Mortality and Incidence: A Systematic Review and Meta-analysis of Cohort Studies.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Cancer incidence has continuously increased over the past few centuries and represents a major health burden worldwide. Purpose: To evaluate the possible causal relationship between intake of red and processed meat and cancer mortality and incidence. Data Sources: Embase, Cochrane Central Register of Controlled Trials, Web of Science, CINAHL, and ProQuest from inception until July 2018 and MEDLINE from inception until April 2019 without language restrictions. Study Selection: Cohort studies that included more than 1000 adults and reported the association between consumption of unprocessed red and processed meat and cancer mortality and incidence. Data Extraction: Teams of 2 reviewers independently extracted data and assessed risk of bias; 1 reviewer evaluated the certainty of evidence, which was confirmed or revised by the senior reviewer. Data Synthesis: Of 118 articles (56 cohorts) with more than 6 million participants, 73 articles were eligible for the dose-response meta-analyses, 30 addressed cancer mortality, and 80 reported cancer incidence. Low-certainty evidence suggested that an intake reduction of 3 servings of unprocessed meat per week was associated with a very small reduction in overall cancer mortality over a lifetime. Evidence of low to very low certainty suggested that each intake reduction of 3 servings of processed meat per week was associated with very small decreases in overall cancer mortality over a lifetime; prostate cancer mortality; and incidence of esophageal, colorectal, and breast cancer. Limitation: Limited causal inferences due to residual confounding in observational studies, risk of bias due to limitations in diet assessment and adjustment for confounders, recall bias in dietary assessment, and insufficient data for planned subgroup analyses. Conclusion: The possible absolute effects of red and processed meat consumption on cancer mortality and incidence are very small, and the certainty of evidence is low to very low. Primary Funding Source: None. (PROSPERO: CRD42017074074).

Methods for the Selection of Covariates in Nutritional Epidemiology Studies: A Meta-Epidemiological Review.

BACKGROUND: Observational studies provide important information about the effects of exposures that cannot be easily studied in clinical trials, such as nutritional exposures, but are subject to confounding. Investigators adjust for confounders by entering them as covariates in analytic models. OBJECTIVE: The aim of this study was to evaluate the reporting and credibility of methods for selection of covariates in nutritional epidemiology studies. METHODS: We sampled 150 nutritional epidemiology studies published in 2007/2008 and 2017/2018 from the top 5 high-impact nutrition and medical journals and extracted information on methods for selection of covariates. RESULTS: Most studies did not report selecting covariates a priori (94.0%) or criteria for selection of covariates (63.3%). There was general inconsistency in choice of covariates, even among studies investigating similar questions. One-third of studies did not acknowledge potential for residual confounding in their discussion. CONCLUSION: Studies often do not report methods for selection of covariates, follow available guidance for selection of covariates, nor discuss potential for residual confounding.

Antibiotic therapy for skin and soft tissue infections: a protocol for a systematic review and network meta-analysis.

BACKGROUND: Skin and soft tissue infections (SSTIs) in hospital and community settings impose a substantial socio-economic burden. Therapeutic uncertainty due to the availability of a wide range of antibiotics and the need for empirical treatment decisions complicate SSTI clinical management. Completion of numerous pairwise meta-analyses to account for this variability in antibiotics is impractical, and many head-to-head comparisons of potential interest are likely not available. In comparing multiple antibiotics simultaneously, this network meta-analysis aims to identify the antibiotic(s) with the greatest value in the treatment of SSTIs, in terms of patient-important outcomes such as efficacy and safety. METHODS: We will conduct a systematic review to identify randomized controlled trials of persons with suspected or confirmed SSTI assigned to orally or parenterally administered antibiotic therapy that report results on at least one outcome of interest. We will search MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL), along with trial registries. Our primary outcome of interest is clinical success at the test-of-cure visit. Secondary outcomes may include (1) early clinical success (2-3 days after the therapy starts), (2) mortality, (3) adverse events, (4) treatment duration, and (5) length of hospital stay. Independent reviewers will complete screening of titles, abstracts, and full texts, data extraction, risk of bias assessment (using the Cochrane Risk of Bias tool), and evaluation of the certainty of evidence (using the GRADE approach) in duplicate. We will complete pairwise and network meta-analyses within the Bayesian framework when possible using a random effects model. We will stratify SSTIs by severity into uncomplicated and complicated SSTIs when possible. Subgroup analyses by age, infection type, comorbidity, and suspected or confirmed methicillin-resistant Staphylococcus aureus (MRSA)-associated infection are planned. DISCUSSION: This study has several strengths compared to previous reviews: inclusion of a wider range of infection types, antibiotics, and outcomes; a comprehensive search strategy; a priori subgroup analyses; application of GRADE; and improved interpretability of findings through visual presentation of results. We hope our findings will inform future research, health care professionals, and policy makers resulting in improved evidence-based clinical management of SSTIs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018085607.

Does consecutive influenza vaccination reduce protection against influenza: A systematic review and meta-analysis.

INTRODUCTION: Vaccination against influenza on an annual basis is widely recommended, yet recent studies suggest consecutive vaccination may reduce vaccine effectiveness (VE). PURPOSE: To assess whether when examining the entirety of existing data consecutive influenza vaccination reduces VE compared to current season influenza vaccination. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 26, 2017; citations of included studies. STUDY SELECTION: Randomized, controlled trials (RCTs) and observational studies of children, adults and/or the elderly that reported laboratory-confirmed influenza infection over 2 or more consecutive influenza seasons were eligible. DATA EXTRACTION: Data related to study characteristics, participant demographics, cases of influenza infection by vaccination group and risk of bias assessment was extracted in duplicate. DATA SYNTHESIS: Five RCTs involving 11,987 participants did not show a significant reduction in VE when participants vaccinated in two consecutive seasons (VE 71%, 95% CI 62-78%) were compared to those vaccinated in the current season (VE 58%, 95% CI 48-66%) (odds ratio [OR] 0.88, 95% CI 0.62-1.26, p = 0.49, I2 = 39%). Twenty-eight observational studies involving 28,627 participants also did not show a reduction (VE for two consecutive seasons 41%, 95% CI 30-51% compared to VE for current season 47%, 95% CI 39-54%; OR 1.14, 95% CI 0.98-1.32, p = 0.09, I2 = 63%). Results from subgroup analyses by influenza type/subtype, vaccine type, age, vaccine match and co-morbidity support these findings; however, dose-response results were inconsistent. Certainty in the evidence was assessed to be very low due to unexplained heterogeneity and imprecision. LIMITATIONS: The inclusion of studies with relatively small sample sizes and low event rates contributed to the imprecision of summary VE and OR estimates, which were based on unadjusted data. CONCLUSION: Available evidence does not support a reduction in VE with consecutive influenza vaccination, but the possibility of reduced effectiveness cannot be ruled out due to very low certainty in this evidence. FUNDING SOURCE: CIHR Foundation Grant (PROSPERO: CRD42017059893).