Extracorporeal membrane oxygenation for COVID-19-associated severe acute respiratory distress syndrome in Canada: Analysis of data from the Canadian Nosocomial Infection Surveillance Program.

Background: Extracorporeal membrane oxygenation (ECMO) for COVID-19 across Canada has not been well-described. We studied trends for patients with COVID-19-related acute respiratory distress syndrome who received ECMO. Methods: Multicentre retrospective cohort study using data from the Canadian Nosocomial Infection Surveillance Program across four different waves. Surveillance data was collected between March 2020 and June 2022. We reported data stratified by ECMO status and wave. Results: ECMO recipients comprised 299 (6.8%) of the 4,408 critically ill patients included. ECMO recipients were younger (median age 49 versus 62 years, p < 0.001), less likely to be vaccinated against COVID-19 (Wave 4 data: 5.3% versus 19%; p = 0.002), and had fewer comorbidities compared to patients who did not receive ECMO. Thirty-day all-cause mortality was similar between the ECMO and non-ECMO groups (23% versus 26%; p = 0.25). Among ECMO recipients, mortality tended to decrease across Waves 1 to 4: 48%, 31%, 18%, and 16%, respectively (p = 0.04 for trend). However, this was no longer statistically significant when removing the high mortality during Wave 1 (p = 0.15). Conclusions: Our findings suggest that critically ill patients in Canadian hospitals who received ECMO had different characteristics from those who did not receive ECMO. We also observed a trend of decreased mortality over the waves for the ECMO group. Possible explanatory factors may include potential delay in ECMO initiation during Wave 1, evolution of the virus, better understanding of COVID-19 disease and ECMO use, and new medical treatments and vaccines available in later waves. These findings may provide insight for future potential pandemics.

Historique: L'oxygénation extracorporelle en cas de COVID-19 n'est pas bien décrite au Canada. Les chercheurs ont étudié les tendances des patients ayant un syndrome respiratoire aigu lié à la COVID-19 qui ont reçu une oxygénation extracorporelle. Méthodologie: Étude de cohorte rétrospective multicentrique à l'aide de données du Programme canadien de surveillance des infections nosocomiales lors de quatre différentes vagues. Les chercheurs ont recueilli les données de surveillance de mars 2020 à juin 2022. Ils ont rendu compte des données stratifiées en fonction de l'état d'oxygénation extracorporelle et de la vague. Résultats: Les receveurs d'une oxygénation extracorporelle représentaient 299 (6,8 %) des 4 408 patients participants gravement malades. Ils étaient plus jeunes (âge médian de 49 ans par rapport à 62 ans, p<0,001), moins susceptibles d'être vaccinés contre la COVID-19 (données de la quatrième vague 4 : 5,3 % par rapport à 19 %; p=0,002) et présentaient moins d'autres maladies que les patients qui avaient reçu une oxygénation extracorporelle. La mortalité toutes causes confondues au bout de 30 jours était semblable entre le groupe sous oxygénation extracorporelle et celui sans oxygénation extracorporelle (23 % par rapport à 26 %; p=0,25). Chez les receveurs d'une oxygénation extracorporelle, la mortalité avait tendance à diminuer d'une vague à l'autre, soit de 48 %, 31 %, 18 % et 16 % entre la première et la quatrième vague, respectivement (p=0,04 par tendance). Cependant, ces résultats n'étaient plus statistiquement significatifs lorsqu'on excluait le taux de mortalité élevé observé pendant la première vague (p=0,15). Conclusions: Selon les observations des chercheurs, les patients gravement malades des hôpitaux canadiens qui avaient reçu une oxygénation extracorporelle présentaient des caractéristiques différentes de ceux qui n'en avaient pas reçu. Dans le groupe sous oxygénation extracorporelle, ils ont également observé une tendance vers une diminution de la mortalité entre les vagues. Les facteurs explicatifs possibles peuvent inclure un retard potentiel de l'initiation de l'oxygénation extracorporelle pendant la première vague, l'évolution du virus, une meilleure compréhension de la COVID-19, le recours à l'oxygénation extracorporelle, les nouveaux traitements médicaux et les vaccins offerts lors de vagues plus tardives. Ces observations pourraient donner des indications intéressantes lors de futures pandémies. Summary: COVID-19 has affected millions of people. Some patients with COVID-19 develop extremely severe disease requiring advanced critical care. Extracorporeal Membrane Oxygenation (ECMO) is an advanced potentially life-saving technique that can support patients whose lungs are unable to function properly despite using a ventilator (breathing machine). ECMO temporarily takes over lung function, essentially acting as external lungs. ECMO can allow time for the body to heal and potentially improve survival for patients with severe lung failure. The decision to use ECMO is complex and always made by a team of medical professionals who factor in the patient's overall health, medical conditions, and disease severity.We studied the trends for critically ill patients with COVID-19 who received ECMO across Canadian hospitals. We used data collected by trained health care professionals through a Canada-wide program that monitors infections in Canadian hospitals. We compared data between critically ill patients who received and did not receive ECMO, and by wave of the COVID-19 pandemic.Our data found that critically ill patients who received ECMO tended to be younger, have fewer medical conditions, and be less likely to be vaccinated against COVID-19. For patients who received ECMO, the mortality was highest in Wave 1 (48%), then Wave 2 (31%), and similar during Waves 3 and 4 (18% and 16%, respectively). Possible explanations for this trend include potential ECMO delay in Wave 1, the evolution of the virus, a better understanding of ECMO use for COVID-19 and available treatments and vaccines during later waves.In conclusion, our study highlights that critically ill patients who received ECMO in Canada had different features and traits compared to those who did not receive ECMO. As well, our study reported mortality across the waves, with possible explanations for the findings offered. These trends may be helpful in providing insight for future potential pandemics.

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.

Plasmid genomic epidemiology of blaKPC carbapenemase-producing Enterobacterales in Canada, 2010-2021.

Carbapenems are considered last-resort antibiotics for the treatment of infections caused by multidrug-resistant Enterobacterales, but carbapenem resistance due to acquisition of carbapenemase genes is a growing threat that has been reported worldwide. Klebsiella pneumoniae carbapenemase (blaKPC) is the most common type of carbapenemase in Canada and elsewhere; it can hydrolyze penicillins, cephalosporins, aztreonam, and carbapenems and is frequently found on mobile plasmids in the Tn4401 transposon. This means that alongside clonal expansion, blaKPC can disseminate through plasmid- and transposon-mediated horizontal gene transfer. We applied whole genome sequencing to characterize the molecular epidemiology of 829 blaKPC carbapenemase-producing isolates collected by the Canadian Nosocomial Infection Surveillance Program from 2010 to 2021. Using a combination of short-read and long-read sequencing, we obtained 202 complete and circular blaKPC-encoding plasmids. Using MOB-suite, 10 major plasmid clusters were identified from this data set which represented 87% (175/202) of the Canadian blaKPC-encoding plasmids. We further estimated the genomic location of incomplete blaKPC-encoding contigs and predicted a plasmid cluster for 95% (603/635) of these. We identified different patterns of carbapenemase mobilization across Canada related to different plasmid clusters, including clonal transmission of IncF-type plasmids (108/829, 13%) in K. pneumoniae clonal complex 258 and novel repE(pEh60-7) plasmids (44/829, 5%) in Enterobacter hormaechei ST316, and horizontal transmission of IncL/M (142/829, 17%) and IncN-type plasmids (149/829, 18%) across multiple genera. Our findings highlight the diversity of blaKPC genomic loci and indicate that multiple, distinct plasmid clusters have contributed to blaKPC spread and persistence in Canada.

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.

Trends in Severe Outcomes Among Adult and Pediatric Patients Hospitalized With COVID-19 in the Canadian Nosocomial Infection Surveillance Program, March 2020 to May 2022.

Importance: Trends in COVID-19 severe outcomes have significant implications for the health care system and are key to informing public health measures. However, data summarizing trends in severe outcomes among patients hospitalized with COVID-19 in Canada are not well described. Objective: To describe trends in severe outcomes among patients hospitalized with COVID-19 during the first 2 years of the COVID-19 pandemic. Design, Setting, and Participants: Active prospective surveillance in this cohort study was conducted from March 15, 2020, to May 28, 2022, at a sentinel network of 155 acute care hospitals across Canada. Participants included adult (aged ≥18 years) and pediatric (aged 0-17 years) patients hospitalized with laboratory-confirmed COVID-19 at a Canadian Nosocomial Infection Surveillance Program (CNISP)-participating hospital. Exposures: COVID-19 waves, COVID-19 vaccination status, and age group. Main Outcomes and Measures: The CNISP collected weekly aggregate data on the following severe outcomes: hospitalization, admission to an intensive care unit (ICU), receipt of mechanical ventilation, receipt of extracorporeal membrane oxygenation, and all-cause in-hospital death. Results: Among 1 513 065 admissions, the proportion of adult (n = 51 679) and pediatric (n = 4035) patients hospitalized with laboratory-confirmed COVID-19 was highest in waves 5 and 6 of the pandemic compared with waves 1 to 4 (77.3 vs 24.7 per 1000 patient admissions). Despite this, the proportion of patients with positive test results for COVID-19 who were admitted to an ICU, received mechanical ventilation, received extracorporeal membrane oxygenation, and died were each significantly lower in waves 5 and 6 when compared with waves 1 through 4. Admission to the ICU and in-hospital all-cause death rates were significantly higher among those who were unvaccinated against COVID-19 when compared with those who were fully vaccinated (incidence rate ratio, 4.3 and 3.9, respectively) or fully vaccinated with an additional dose (incidence rate ratio, 12.2 and 15.1, respectively). Conclusions and Relevance: The findings of this cohort study of patients hospitalized with laboratory-confirmed COVID-19 suggest that COVID-19 vaccination is important to reduce the burden on the Canadian health care system as well as severe outcomes associated with COVID-19.

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.

Nonpharmaceutical interventions to prevent viral respiratory infection in community settings: an umbrella review.

Background: Respiratory viruses pose an important public health threat to most communities. Nonpharmaceutical interventions (NPIs) such as masks, hand hygiene or physical distancing, among others, are believed to play an important role in reducing transmission of respiratory viruses. In this umbrella review, we summarise the evidence of the effectiveness of NPIs for the prevention of respiratory virus transmission in the community setting. Observations: A systematic search of PubMed, Embase, Medline and Cochrane reviews resulted in a total of 24 studies consisting of 11 systematic reviews and meta-analyses, 12 systematic reviews without meta-analyses and one standalone meta-analysis. The current evidence from these data suggests that hand hygiene is protective against respiratory viral infection. The use of hand hygiene and facemasks, facemasks alone and physical distancing were interventions with inconsistent evidence. Interventions such as school closures, oral hygiene or nasal saline rinses were shown to be effective in reducing the risk of influenza; however, the evidence is sparse and mostly of low and critically low quality. Conclusions: Studies on the effectiveness of NPIs for the prevention of respiratory viral transmission in the community vary in study design, quality and reported effectiveness. Evidence for the use of hand hygiene or facemasks is the strongest; therefore, the most reasonable suggestion is to use hand hygiene and facemasks in the community setting.

Effectiveness of the influenza vaccine at reducing adverse events in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: The association between influenza and adverse vascular events in patients with heart failure is well documented. The effect of the influenza vaccine on preventing such adverse events is uncertain. This systematic review and meta-analysis addressed whether vaccination against influenza reduces adverse vascular events and mortality in heart failure patients. METHODS: MEDLINE and EMBASE databases were comprehensively searched, study screening and quality assessment were completed, and data was synthesized. Eligible studies investigated heart failure patients who received the influenza vaccine, and reported outcomes within 12 months, compared to heart failure patients who did not receive the influenza vaccine. The following 6 outcomes were assessed: all-cause mortality, cardiovascular-related mortality, all-cause hospitalization, cardiovascular-related hospitalization, non-fatal myocardial infarction, and non-fatal stroke. Risk of bias was assessed using the Newcastle-Ottawa Scale and a GRADE assessment was completed. A random-effects meta-analysis was performed to estimate the pooled risk ratio (RR), 95% confidence intervals (CIs), and heterogeneity using I2 statistics. RESULTS: After synthesizing data from 7 non-randomized studies (247,842 patients), the results demonstrate the risk of all-cause mortality is significantly reduced within 12 months of a heart failure patient receiving the influenza vaccine (RR = 0.75, 95% CI 0.71-0.79; P<0.0001); very low certainty of evidence. The risk of cardiovascular-related mortality was significantly reduced (RR = 0.77, 95% CI 0.73-0.81; P<0.0001); low certainty of evidence. The pooled risk of all-cause hospitalization was higher among vaccinated heart failure patients (RR = 1.24, 95% CI 1.13-1.35; P<0.0001), based on two studies; very low certainty of evidence and considerable heterogeneity (I2 = 90%). No eligible studies assessed cardiovascular-related hospitalization, non-fatal myocardial infarction, or non-fatal stroke. CONCLUSIONS: Influenza vaccination appears to reduce adverse cardiovascular events, although the certainty of the evidence is low or very low. Rigorous randomized controlled trial evidence is needed to further examine the protective effect of the influenza vaccine in heart failure patients.

Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials.

BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19. METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach. RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo. DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis.

Objective: To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design: Systematic review and network meta-analysis. Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods: Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results: Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion: These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.

Consistency of covid-19 trial preprints with published reports and impact for decision making: retrospective review.

Objective: To assess the trustworthiness (ie, complete and consistent reporting of key methods and results between preprint and published trial reports) and impact (ie, effects of preprints on meta-analytic estimates and the certainty of evidence) of preprint trial reports during the covid-19 pandemic. Design: Retrospective review. Data sources: World Health Organization covid-19 database and the Living Overview of the Evidence (L-OVE) covid-19 platform by the Epistemonikos Foundation (up to 3 August 2021). Main outcome measures: Comparison of characteristics of covid-19 trials with and without preprints, estimates of time to publication of covid-19 preprints, and description of differences in reporting of key methods and results between preprints and their later publications. For the effects of eight treatments on mortality and mechanical ventilation, the study comprised meta-analyses including preprints and excluding preprints at one, three, and six months after the first trial addressing the treatment became available either as a preprint or publication (120 meta-analyses in total, 60 of which included preprints and 60 of which excluded preprints) and assessed the certainty of evidence using the GRADE framework. Results: Of 356 trials included in the study, 101 were only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. The median time to publication of preprints was about six months. Key methods and results showed few important differences between trial preprints and their subsequent published reports. Apart from two (3.3%) of 60 comparisons, point estimates were consistent between meta-analyses including preprints versus those excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. For nine (15%) of 60 comparisons, the rating of the certainty of evidence was different when preprints were included versus being excluded-the certainty of evidence including preprints was higher in four comparisons and lower in five comparisons. Conclusion: No compelling evidence indicates that preprints provide results that are inconsistent with published papers. Preprints remain the only source of findings of many trials for several months-an unsuitable length of time in a health emergency that is not conducive to treating patients with timely evidence. The inclusion of preprints could affect the results of meta-analyses and the certainty of evidence. Evidence users should be encouraged to consider data from preprints.

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).

A living WHO guideline on drugs to prevent covid-19.

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

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.

The burden of influenza in older adults: meeting the challenge.

Influenza is an acute respiratory infection for which vaccination is our best prevention strategy. Small seasonal changes in circulating influenza viruses (antigenic drift) result in the need for annual influenza vaccination, in which the vaccine formulation is updated to better match the predominant circulating influenza viruses that have undergone important antigenic changes. Although the burden of influenza infection and its complications is the highest in older adults, vaccine effectiveness is the lowest in this vulnerable population. This is largely due to waning of the immune response with age known as "immune senescence", and presents an important, unmet challenge. Possible strategies to tackle this include adjuvant and high-dose vaccines, and herd immunity induced by greater vaccine uptake.