A chief concern over the first months of the coronavirus disease 2019 (COVID-19) pandemic was the capacity to provide care for acutely ill patients in hospitals and intensive care units (ICUs). The variability in outcomes of patients with COVID-19 internationally has been striking, with some reports describing ICU mortality in ranges between 40 and 90%. 1-3 Systematic reviews including Characteristics and outcomes of patients with COVID-19 admitted to hospital and intensive care in the first phase of the pandemic in Canada: a national cohort study

Risk prediction scores are important tools to support clinical decision-making for patients with coronavirus disease (COVID-19). The objective of this paper was to validate the 4C mortality score, originally developed in the United Kingdom, for a Canadian population, and to examine its performance over time. We conducted an external validation study within a registry of COVID-19 positive hospital admissions in the Kitchener-Waterloo and Hamilton regions of southern Ontario between March 4, 2020 and June 13, 2021. We examined the validity of the 4C score to prognosticate in-hospital mortality using the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals calculated via bootstrapping. The study included 959 individuals, of whom 224 (23.4%) died in-hospital. Median age was 72 years and 524 individuals (55%) were male. The AUC of the 4C score was 0.77, 95% confidence interval 0.79–0.87. Overall mortality rates across the pre-defined risk groups were 0% (Low), 8.0% (Intermediate), 27.2% (High), and 54.2% (Very High). Wave 1, 2 and 3 values of the AUC were 0.81 (0.76, 0.86), 0.74 (0.69, 0.80), and 0.76 (0.69, 0.83) respectively. The 4C score is a valid tool to prognosticate mortality from COVID-19 in Canadian hospitals and can be used to prioritize care and resources for patients at greatest risk of death.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments.MethodsWe searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework.ResultsWe identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (–88.35 to 411.12)), pirfenidone (2.47% (–0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty).Conclusion and relevanceFuture guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.

Most trials addressing the treatment of patients with COVID-19 have targeted patients admitted to hospital with severe or critical disease. 1 However, more recently, several treatments, including antiviral drugs, antidepressants, monoclonal anti bodies and inhaled corticosteroids, have been studied for patients with nonsevere COVID-19. 2 Preliminary evidence from ongoing or recently completed trials suggests that 2 novel antiviral drugsmolnupiravir and nirmatrelvir-ritonavir (Paxlovid) -may be effective at reducing risk of hospital admission. [3][4][5] To date, evidence on antiviral drugs for nonsevere COVID-19 has not been systematically synthesized or appraised. Furthermore, although efficacy data from trials of molnupiravir, nirmatrelvir-ritonavir and remdesivir are promising, no head-to-head trials have compared these drugs.A network meta-analysis allows for comparison of treatments that have not been compared in randomized controlled trials (RCTs), using pooled estimates from direct and indirect evidence.They can provide guidance to clinicians and evidence users in determining which treatments are superior. This is particularly important as health care systems attempt to prioritize access to effective COVID-19 treatments in the early stages of the disease.We sought to compare the effectiveness of antiviral drugs for patients with nonsevere COVID-19. MethodsWe conducted a systematic review and network meta-analysis, that included a rigorous appraisal of the evidence. We registered a protocol on Open Science Framework and uploaded the data used for this analysis (https://osf.io/zbcf9). We report our systematic review and network meta-analysis in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) extension statement for reporting of sys tematic reviews incorporating network meta-analyses. 6

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ObjectiveTo 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.DesignRetrospective review.Data sourcesWorld 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 measuresComparison 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.ResultsOf 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.ConclusionNo 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.

Background Magnesium supplementation is often purported to improve sleep; however, as both an over-the-counter sleep aid and a complementary and alternative medicine, there is limited evidence to support this assertion. The aim was to assess the effectiveness and safety of magnesium supplementation for older adults with insomnia. Methods A search was conducted in MEDLINE, EMBASE, Allied and Complementary Medicine, clinicaltrials.gov and two grey literature databases comparing magnesium supplementation to placebo or no treatment. Outcomes were sleep quality, quantity, and adverse events. Risk of bias and quality of evidence assessments were carried out using the RoB 2.0 and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approaches. Data was pooled and treatment effects were quantified using mean differences. For remaining outcomes, a modified effects direction plot was used for data synthesis. Results Three randomized control trials (RCT) were identified comparing oral magnesium to placebo in 151 older adults in three countries. Pooled analysis showed that post-intervention sleep onset latency time was 17.36 min less after magnesium supplementation compared to placebo (95% CI − 27.27 to − 7.44, p = 0.0006). Total sleep time improved by 16.06 min in the magnesium supplementation group but was statistically insignificant. All trials were at moderate-to-high risk of bias and outcomes were supported by low to very low quality of evidence. Conclusion This review confirms that the quality of literature is substandard for physicians to make well-informed recommendations on usage of oral magnesium for older adults with insomnia. However, given that oral magnesium is very cheap and widely available, RCT evidence may support oral magnesium supplements (less than 1 g quantities given up to three times a day) for insomnia symptoms.

Objective: Assess the impact of allocation concealment and blinding on the results of trials addressing COVID-19 therapeutics. Data sources: World Health Organization (WHO) COVID-19 database and the Living Overview of the Evidence (L-OVE) COVID-19 platform by the Epistemonikos Foundation (up to February 4th 2022) Methods: We included trials that compared drug treatments, antiviral antibodies and cellular therapies with placebo or standard care. For the five most commonly reported outcomes, if sufficient data were available, we performed random-effects meta-regression comparing the results of trials with and without allocation concealment and trials in which both healthcare providers and patients were blinded with trials in which healthcare providers and/or patients were aware of the intervention. A ratio of odds ratios (ROR) > 1 or a difference in mean difference (DMD) > 0 indicates that trials without allocation concealment or open-label trials produced larger effects than trials with allocation concealment or blinded trials. Results: As of February 4th 2022, we have identified 488 trials addressing COVID-19 drug treatments and antiviral antibodies and cellular therapies. Of these, 436 trials reported on one or more of our outcomes of interest and were included in our analyses. We found that trials without allocation concealment probably overestimate mortality (ROR 1.14 [95% CI 0.92 to 1.41]), need for mechanical ventilation (ROR 1.26 [95% CI 0.97 to 1.64]), admission to hospital (ROR 1.93 [95% CI 0.83 to 4.48]), duration of hospitalization (DMD 1.94 [95% CI 0.86 to 3.02]), and duration of mechanical ventilation (DMD 2.64 [95% CI -0.90 to 6.18]), but results were imprecise. We did not find compelling evidence that double-blind and open-label trials produce consistently different results for mortality (ROR 1.00 [95% CI 0.87 to 1.15]), need for mechanical ventilation (ROR 1.03 [95% CI 0.84 to 1.26]), and duration of hospitalization (DMD 0.47 days [95% CI -0.38 to 1.32]). We found that open-label trials may overestimate the beneficial effects of interventions for hospitalizations (ROR 1.87 [95% CI 0.95 to 3.67] and duration of mechanical ventilation (DMD 1.02 days [95% CI -1.30 to 3.35]), but results were imprecise. Conclusion: We found compelling evidence that, compared to trials with allocation concealment, trials without allocation concealment may overestimate the beneficial effects of treatments. We did not find evidence that trials without blinding addressing COVID-19 interventions produce consistently different results from trials with blinding. Our results suggest that consideration of blinding status may not be sufficient to judge risk of bias due to imbalances in co-interventions. Evidence users may consider evidence of differences in co-interventions between trial arms when judging the trustworthiness of open-label trials. We suggest, however, evidence users to remain skeptical of trials without allocation concealment.