A comparison of the effectiveness of biologic therapies for asthma: A systematic review and network meta-analysis.

BACKGROUND: Trials have not directly compared biologics for the treatment of asthma. OBJECTIVE: To compare the relative efficacy of biologics in asthma. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to May 31, 2022 for randomized trials addressing biologic therapies for asthma. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. We present dichotomous outcomes as absolute risk differences per 1000 patients and relative risk with 95% confidence intervals (95% CI) and continuous outcomes as mean difference (MD) and 95% CI. RESULTS: We identified 64 trials, including 26,630 patients. For patients with eosinophilic asthma, tezepelumab (329 fewer exacerbations per 1000 [95% CI, 272.6-366.6 fewer]) and dupilumab (319.6 fewer exacerbations per 1000 [95% CI, 272.6-357.2 fewer]) reduce exacerbations compared with placebo (high certainty). Tezepelumab (MD, 0.24 L [95% CI, 0.16-0.32]) and dupilumab (0.25 L [95% CI, 0.21-0.29]) improve lung function compared with placebo (high certainty). Both tezepelumab (110.97 fewer hospital admissions per 1000 [95% CI, 94.53-120.56 fewer]) and dupilumab (97.27 fewer hospitalizations [4.11-124.67 fewer]) probably reduce hospital admissions compared with placebo (moderate certainty). For patients with low eosinophils, biologics probably do not improve asthma outcomes. For these patients, tezepelumab (MD, 0.1 L [95% CI, 0-0.19]) and dupilumab (MD, 0.1 L [95% CI, 0-0.20]) may improve lung function (low certainty). CONCLUSION: Tezepelumab and dupilumab are effective at reducing exacerbations. For patients with low eosinophils, however, clinicians should probably be more judicious in using biologics, including tezepelumab, because they probably do not confer substantial benefit.

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis.

BACKGROUND: Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear. METHODS: We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir-ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir-ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty). INTERPRETATION: Molnupiravir and nirmatrelvir-ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir-ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

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).

A Systematic Review and Meta-analysis of Systemic Antihypertensive Medications With Intraocular Pressure and Glaucoma.

PURPOSE: We synthesized the literature on the association between systemic antihypertensive medications with intraocular pressure (IOP) and glaucoma. Antihypertensive medications included ß-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. DESIGN: Systematic review and meta-analysis. METHODS: Databases were searched for relevant articles until December 5, 2022. Studies were eligible if they examined (1) the association between systemic antihypertensive medications with glaucoma or (2) the association between systemic antihypertensive medications with IOP in those without glaucoma or ocular hypertension. The protocol was registered at PROSPERO (International Prospective Register of Systematic Reviews; registration ID: CRD42022352028). RESULTS: A total of 11 studies were included in the review and 10 studies in the meta-analysis. The 3 studies on IOP were cross-sectional, whereas the 8 studies on glaucoma were primarily longitudinal. In the meta-analysis, ß-blockers were associated with a lower odds of glaucoma (odds ratio: 0.83, 95% CI: 0.75-0.92, 7 studies, n = 219,535) and lower IOP (ß: -0.53, 95% CI: -1.05 to -0.02, 3 studies, n = 28,683). Calcium channel blockers were associated with a higher odds of glaucoma (odds ratio: 1.13, 95% CI: 1.03-1.24, 7 studies, n = 219,535) but not with IOP (ß: -0.11, 95% CI: -0.25 to 0.03, 2 studies, n = 20,620). There were no consistent associations between angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or diuretics with glaucoma or IOP. CONCLUSIONS: Systemic antihypertensive medications have heterogeneous effects on glaucoma and IOP. Clinicians should be aware that systemic antihypertensive medications may mask elevated IOP or positively or negatively affect the risk of glaucoma.

Noninvasive Oxygenation Strategies in Adult Patients With Acute Hypoxemic Respiratory Failure: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Several recently published randomized controlled trials have evaluated various noninvasive oxygenation strategies for the treatment of acute hypoxemic respiratory failure. RESEARCH QUESTION: Which available noninvasive oxygen strategies are effective for acute hypoxic respiratory failure? STUDY DESIGN AND METHODS: A systematic review of Medline, Embase, Cochrane CENTRAL, CINAHL, Web of Science, MedRxiv, and Research Square was conducted from inception to October 1, 2022. A random effects frequentist network meta-analysis was performed, and the results are presented using absolute risk difference per 1,000 patients. The Grading of Recommendations, Assessment, Development and Evaluation framework was used to rate the certainty of the evidence. Mortality, invasive mechanical ventilation, duration of hospitalization and ICU stay, ventilator-free days, and level of comfort are reported. RESULTS: Thirty-six trials (7,046 patients) were included. It was found that helmet CPAP probably reduces mortality compared with standard oxygen therapy (SOT) (231 fewer deaths per 1,000; 95% CI, 126-273 fewer) (moderate certainty). A high-flow nasal cannula (HFNC) probably reduces the need for invasive mechanical ventilation (103.5 fewer events per 1,000; 95% CI, 40.5-157.5 fewer) (moderate certainty). All noninvasive oxygenation strategies may reduce the duration of hospitalization as compared with SOT (low certainty). Helmet bilevel ventilation (4.84 days fewer; 95% CI, 2.33-7.36 days fewer) and helmet CPAP (1.74 days fewer; 95% CI, 4.49 fewer-1.01 more) may reduce the duration of ICU stay as compared with SOT (both low certainty). SOT may be more comfortable than face mask noninvasive ventilation and no different in comfort compared with an HFNC (both low certainty). INTERPRETATION: A helmet interface for noninvasive ventilation probably reduces mortality and the risk of mechanical ventilation, as well as the duration of hospital and ICU stay. An HFNC probably reduces the risk of invasive mechanical ventilation and may be as comfortable as SOT. Further research is necessary to understand the role of these interfaces in acute hypoxemic respiratory failure.

Methodology and design of platform trials: a meta-epidemiological study.

OBJECTIVES: Adaptive platforms allow for the evaluation of multiple interventions at a lower cost and have been growing in popularity, especially during the COVID-19 pandemic. The objective of this review is to summarize published platform trials, examine specific methodological design features among these studies, and hopefully aid readers in the evaluation and interpretation of platform trial results. METHODS: We performed a systematic review of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov from January 2015 to January 2022 for protocols or results of platform trials. Pairs of reviewers, working independently and in duplicate, collected data on trial characteristics of trial registrations, protocols, and publications of platform trials. We reported our results using total numbers and percentages, as well as medians with interquartile range (IQR) when appropriate. RESULTS: We identified 15,277 unique search records and screened 14,403 titles and abstracts after duplicates were removed. We identified 98 unique randomized platform trials. Sixteen platform trials were sourced from a systematic review completed in 2019, which included platform trials reported prior to 2015. Most platform trials (n = 67, 68.3%) were registered between 2020 and 2022, coinciding with the COVID-19 pandemic. The included platform trials primarily recruited or plan to recruit patients from North America or Europe, with most subjects being recruited from the United States (n = 39, 39.7%) and the United Kingdom (n = 31, 31.6%). Bayesian methods were used in 28.6% (n = 28) of platform RCTs and frequentist methods in 66.3% (n = 65) of trials, including 1 (1%) that used methods from both paradigms. Out of the twenty-five trials with peer-reviewed publication of results, seven trials used Bayesian methods (28%), and of those, two (8%) used a predefined sample size calculation while the remainder used pre-specified probabilities of futility, harm, or benefit calculated at (pre-specified) intervals to inform decisions about stopping interventions or the entire trial. Seventeen (68%) peer-reviewed publications used frequentist methods. Out of the seven published Bayesian trials, seven (100%) reported thresholds for benefit. The threshold for benefit ranged from 80% to >99%. CONCLUSION: We identified and summarized key components of platform trials, including the basics of the methodological and statistical considerations. Ultimately, improving standardization and reporting in platform trials require an understanding of the current landscape. We provide the most updated and rigorous review of platform trials to date.

Systemic corticosteroids in fibrotic lung disease: a systematic review and meta-analysis.

OBJECTIVES: We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023. ELIGIBILITY CRITERIA: We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD. DATA EXTRACTION AND SYNTHESIS: We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs. RESULTS: Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence). CONCLUSIONS: The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap.

Ambient Air Pollution and Age-Related Eye Disease: A Systematic Review and Meta-Analysis.

Purpose: To compare the burden of age-related eye diseases among adults exposed to higher versus lower levels of ambient air pollutants. Methods: MEDLINE, EMBASE, and Scopus were searched for relevant articles until September 30, 2021. Inclusion criteria included studies of adults, aged 40+ years, that provided measures of association between the air pollutants (nitrogen dioxide, carbon monoxide [CO], sulfur dioxide, ozone [O3], particulate matter [PM] less than 2.5 µm in diameter [PM2.5], and PM less than 10 µm in diameter [PM10]) and the age-related eye disease outcomes of glaucoma, age-related macular degeneration (AMD), or cataract. Pooled odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated using a random-effects meta-analysis model. PROSPERO registration ID: CRD42021250078. Results: A total of eight studies were included in the review. Consistent evidence for an association was found between PM2.5 and glaucoma, with four of four studies reporting a positive association. The pooled OR for each 10-µg/m3 increase of PM2.5 on glaucoma was 1.18 (95% CI, 0.95-1.47). Consistent evidence was also found for O3 and cataract, with three of three studies reporting an inverse association. Two of two studies reported a null association between PM2.5 and cataract, while one of one studies reported a positive association between PM10 and cataract. One of one studies reported a positive relationship between CO and AMD. Other relationships were less consistent between studies. Conclusions: Current evidence suggests there may be an association between some air pollutants and cataract, AMD, and glaucoma.

Systematic review and meta-analysis of 3D-printing in otolaryngology education.

INTRODUCTION: Three-dimensional (3D) printing has received increased attention in recent years and has many applications. In the field of otolaryngology surgery, 3D-printed models have shown potential educational value and a high fidelity to actual tissues. This provides an opportunity for trainees to gain additional exposure, especially as conventional educational tools, such as cadavers, are expensive and in limited supply. The purpose of this study was to perform a meta-analysis of the uses of 3D-printing in otolaryngology education. The primary outcomes of investigation were surgical utility, anatomical similarity, and educational value of 3D-printed models. Secondary outcomes of interest included country of implementation, 3D-printer materials and costs, types of surgical simulators, and the levels of training of participants. METHODS: MEDLINE, Embase, Web of Science, Google Scholar and previous reviews were searched from inception until June 2021 for eligible articles. Title, abstract, and data extraction were performed in duplicate. Data were analyzed using random-effects models. The National Institute of Health Quality Assessment Tool was used to rate the quality of the evidence. RESULTS: A total of 570 abstracts were identified and screened by 2 independent reviewers. Of the 274 articles reviewed in full text, 46 articles met the study criteria and were included in the meta-analysis. Surgical skill utility was reported in 42 studies (563 participants) and had a high degree of acceptance (84.8%, 95% CI: 81.1%-88.4%). The anatomical similarity was reported in 39 studies (484 participants) and was received positively at 80.6% (95% CI: 77.0%-84.2%). Educational value was described in 36 studies (93 participants) and had the highest approval rating by participants at 90.04% (87.20%-92.88%). A subgroup analysis by year of publication demonstrated that studies published after 2015 had higher ratings across all outcomes compared to those published prior to 2015. CONCLUSION: This study found that 3D-printing interventions in otolaryngology demonstrated surgical, anatomical, and educational value. In addition, the approval ratings of 3D-printed models indicate a positive trend over time. Future educational programs may consider implementing 3D-printing on a larger scale within the medical curriculum to enhance exposure to otolaryngology.

Inverse Association of APOE ε4 and Glaucoma Modified by Systemic Hypertension: The Canadian Longitudinal Study on Aging.

Purpose: Studies examining the apolipoprotein E (APOE) ε4 allele and glaucoma are inconsistent, which could be due to interactions with other factors. We examined the relationship between the APOE ε4 allele and glaucoma and intraocular pressure in a large, population-based random sample and explored whether the APOE ε4 allele interacted with systemic hypertension. Methods: Data came from the Canadian Longitudinal Study on Aging, a population-based study that included 24,655 adults ages 45 to 85 years old in the European ancestry cohort. APOE genotypes were derived from single-nucleotide polymorphisms rs429358 and rs7412. Participants were asked about a prior diagnosis of glaucoma from a doctor. Corneal compensated intraocular pressure (IOP) was measured using the Reichart Ocular Response Analyzer. Results: Having an APOE ε4 allele was associated with a lower odds of glaucoma after adjusting for age, sex, IOP, and the top 10 population structure principal components (odds ratio [OR] = 0.83; 95% confidence interval [CI], 0.69-0.98; P = 0.033). A novel statistically significant interaction was found in that having an APOE ε4 allele was only associated with glaucoma in those without systemic hypertension (OR = 0.62; 95% CI, 0.46-0.85) although it was not associated in those with it (OR = 0.97; 95% CI, 0.79-1.21) (interaction term P value = 0.017). APOE ε4 was not associated with IOP (ß = -0.01; 95% CI, -0.13 to 0.10). Conclusions: Evidence increasingly points to the APOE ε4 allele having protective benefits against glaucoma, but this association was limited to those without systemic hypertension. Further research is needed to understand the biological mechanisms for these findings and the treatment potential they hold.

Causal language use in systematic reviews of observational studies is often inconsistent with intent: a systematic survey.

OBJECTIVES: We systematically evaluated causal language use in systematic reviews of observational studies and explored the relation between language use and the intent of the investigation. STUDY DESIGN AND SETTING: We searched EMBASE, MEDLINE, and Epistemonikos. We randomly selected 199 reviews published in 2019, stratified in a 1:1 ratio by use and nonuse of the Grading of Recommendations Assessment, Development and Evaluation approach to rating quality of evidence. RESULTS: Of 199 reviews of observational studies 56.8% had causal intent. Reviews with causal intent were more likely to investigate therapeutic clinical intervention (33.6% vs. 12.8%). Although 78.8% of those with causal intent used causal language in one or more sections of the title, abstract, or main text, only 4.4% consistently used causal language throughout the manuscript, and 21.2% did not use causal language at all. Of reviews without causal intent, 51.2% used causal language somewhere in the manuscript. CONCLUSION: Systematic reviews of observational studies sometimes do and sometimes do not have causal intent. Both those are inconsistent in causal language use and often use language inconsistent with the intent. Journal policies would better serve clarity of thinking and appropriateness of inferences by demanding authors clearly specify their intent and consistently use language consistent with that intent.

Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis.

BACKGROUND: There is no consensus on the most effective treatments of pulmonary arterial hypertension (PAH). Our objective was to compare effects of medications for PAH. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception to December 2021. We performed a frequentist random-effects network meta-analysis on all included trials. We rated the certainty of the evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS: We included 53 randomised controlled trials with 10 670 patients. Combination therapy with endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) reduced clinical worsening (120.7 fewer events per 1000, 95% CI 136.8-93.4 fewer; high certainty) and was superior to either ERA or PDE5i alone, both of which reduced clinical worsening, as did riociguat monotherapy (all high certainty). PDE5i (24.9 fewer deaths per 1000, 95% CI 35.2 fewer to 2.1 more); intravenous/subcutaneous prostanoids (18.3 fewer deaths per 1000, 95% CI 28.6 fewer deaths to 0) and riociguat (29.1 fewer deaths per 1000, 95% CI 38.6 fewer to 8.7 more) probably reduce mortality as compared to placebo (all moderate certainty). Combination therapy with ERA+PDE5i (49.9 m, 95% CI 25.9-73.8 m) and riociguat (49.5 m, 95% CI 17.3-81.7 m) probably increase 6-min walk distance as compared to placebo (moderate certainty). CONCLUSION: Current PAH treatments improve clinically important outcomes, although the degree and certainty of benefit vary between treatments.

Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies.

OBJECTIVE: To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and CENTRAL from inception to 1 April 2020. STUDY SELECTION: Non-randomised studies reporting on harms of medical cannabis or cannabinoids in adults or children living with chronic pain with ≥4 weeks of follow-up. DATA EXTRACTION AND SYNTHESIS: A parallel guideline panel provided input on the design and interpretation of the systematic review, including selection of adverse events for consideration. Two reviewers, working independently and in duplicate, screened the search results, extracted data and assessed risk of bias. We used random-effects models for all meta-analyses and the Grades of Recommendations, Assessment, Development and Evaluation approach to evaluate the certainty of evidence. RESULTS: We identified 39 eligible studies that enrolled 12 143 adult patients with chronic pain. Very low certainty evidence suggests that adverse events are common (prevalence: 26.0%; 95% CI 13.2% to 41.2%) among users of medical cannabis for chronic pain, particularly any psychiatric adverse events (prevalence: 13.5%; 95% CI 2.6% to 30.6%). Very low certainty evidence, however, indicates serious adverse events, adverse events leading to discontinuation, cognitive adverse events, accidents and injuries, and dependence and withdrawal syndrome are less common and each typically occur in fewer than 1 in 20 patients. We compared studies with <24 weeks and ≥24 weeks of cannabis use and found more adverse events reported among studies with longer follow-up (test for interaction p<0.01). Palmitoylethanolamide was usually associated with few to no adverse events. We found insufficient evidence addressing the harms of medical cannabis compared with other pain management options, such as opioids. CONCLUSIONS: There is very low certainty evidence that adverse events are common among people living with chronic pain who use medical cannabis or cannabinoids, but that few patients experience serious adverse events.

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.

Epidemiological Study of COVID-19 Fatalities and Vaccine Uptake: Insight From a Public Health Database in Ontario, Canada.

Coronavirus disease (COVID-19) has reached millions of people worldwide and is responsible for millions of deaths around the world. Research on fatalities in rural communities remains limited. In addition, the scientific literature has not yet reported on the distribution of vaccines in Canada and compared the findings to the age distribution of COVID-19 fatalities in Canada to see whether the vaccines have been distributed to the highest age category populations. This research article used data from the Government of Ontario and Statistics Canada to analyze the number of cases, fatalities, case fatality rates (CFRs) by demographic factors, such as age, gender, urban-rural status, and compared the findings to national vaccination rates by age. As of June 11, 2021, this study found that among the 528,819 cases among 14.8 million people. Among this population, there were 8875 fatalities in Ontario with 82.208% (n=7296) of fatalities occurred in people over 70 years, and 93.183% in people over 60 years (n=8,270). Additionally, the odds ratio of a fatal event was 9,652 times higher in people over 90 years (95% CI: 4418, 31124, p<0.001) as compared with less than 20 years. Men had a higher number of fatalities (n=4,490, CFR=1.721%) compared with women (n=4,385, CFR=1.692%), and a higher odd of fatal events only when adjusted for age and gender (OR=1.66, 95% CI: 1.57, 1.74, p<0.001). Urban areas had 92.034% of fatalities (n=8,168) and had a CFR of 1.632%. In contrast, rural areas comprised 4.451% of total fatalities (n=395) and had the highest CFR (2.267%). The unadjusted odds of a fatality were 1.41 (95% CI: 1.27, 1.56) in rural areas compared with urban areas. Across Canada as of May 29, 2021, people over 80 years old received 1,530,318 vaccines with 91.98% of this population age group receiving at least one and 457,664 being fully vaccinated (27.51%). In Ontario, as the number of people with at least one vaccine increased for people over 90 years, the number of fatalities was reduced from about 8 per day prior to vaccines to approximately two per day. Furthermore, once the vaccination rates exceeded 75% in ages 60 years and over 50% in the younger age groups, the number of fatalities per day among all age groups was approximately one per day. In summary, age was found to be a significant factor for COVID-19 mortality in Ontario and vaccine uptake in Ontario was followed by decreases in COVID-19 mortality.

Retinoblastoma Survival Following Primary Enucleation by AJCC Staging.

Primary enucleation of the eye with retinoblastoma is a widely accessible, life-saving treatment for retinoblastoma. This study evaluated the survival of patients following primary enucleation based on AJCC 8th edition staging. Included were 700 consecutive patients (700 eyes) treated with primary enucleation at 29 Chinese treatment centers between 2006 and 2015. Excluded were patients with less than one year follow-up, bilateral retinoblastoma, clinical evidence of extraocular disease at diagnosis, or prior focal or systemic therapy. The 5-year overall survival was 95.5%, and 5-year disease-specific survival (DSS) was 95.7%. Survival was better when enucleation was <26 days from diagnosis than delayed >26 days (96.1% vs. 86.9%; p = 0.017). Patients with eyes presenting with raised intraocular pressure with neovascularization and/or buphthalmos (cT3c) had worse 5-year DSS (87.1%) than those without (cT2b, 99.1%; cT3b, 98.7%; cT3d, 97.2%) (p < 0.05). The 5-year DSS based on pathological staging was pT1 (99.5%), pT2a (95.5%), pT3a (100%), pT3b (93.0%), pT3c/d (92.3%), and pT4 (40.9%). Patients with pT3 pathology who received six cycles of adjuvant chemotherapy had better 5-year DSS (97.7%) than those with no chemotherapy (88.1%; p = 0.06) and those who underwent 1-3 cycles (86.9%, p = 0.02) or 4-5 cycles (89.3%, p = 0.06). Patients with pT4 pathology who received six cycles of chemotherapy had better 5-year DSS than those with 0-5 cycles (63.6% vs. 16.7%; p = 0.02). Prompt primary enucleation yielded high long-term survival for children with retinoblastoma. The AJCC 8th edition staging is predictive of survival.

Fine Particulate Matter and Age-Related Eye Disease: The Canadian Longitudinal Study on Aging.

Purpose: To determine the relationship between fine particulate matter (PM2.5) and ocular outcomes such as visual impairment and age-related eye disease. Methods: Baseline data were used from the Canadian Longitudinal Study on Aging. The Comprehensive Cohort consisted of 30,097 adults ages 45 to 85 years. Annual mean PM2.5 levels (µg/m3) for each participant's postal code were estimated from satellite data. Ozone, sulfur dioxide, and nitrogen dioxide levels were also estimated. Binocular presenting visual acuity was measured using a visual acuity chart. Intraocular pressure (IOP) was measured in millimeters of mercury using the Reichart Ocular Response Analyzer. Participants were asked about a diagnosis of glaucoma, macular degeneration, or cataract. Logistic and linear regression models were used. Results: The overall mean PM2.5 level was 6.5 µg/m3 (SD = 1.8). In the single pollutant models, increased PM2.5 levels (per interquartile range) were associated with visual impairment (odds ratio [OR] = 1.12; 95% confidence interval [CI], 1.02-1.24), glaucoma (OR = 1.14; 95% CI, 1.01-1.29), and visually impairing age-related macular degeneration (OR = 1.52; 95% CI, 1.10-2.09) after adjustment for sociodemographics and disease. PM2.5 had a borderline adjusted association with cataract (OR = 1.06; 95% CI, 0.99-1.14). In the multi-pollutant models, increased PM2.5 was associated with glaucoma and IOP only after adjustment for sociodemographics and disease (OR = 1.24; 95% CI, 1.05-1.46 and ß = 0.24; 95% CI, 0.12-0.37). Conclusions: Increased PM2.5 is associated with glaucoma and IOP. These associations should be confirmed using longitudinal data and potential mechanisms should be explored. If confirmed, this work may have relevance for revision of World Health Organization thresholds to protect human health.

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.