The Impact Of Provincial Proof- Of-Vaccination Policies On Age-Specific First-Dose Uptake Of COVID-19 Vaccines In Canada.

Requirements of proof of COVID-19 vaccination were mandated for nonessential businesses and venues by Canada's ten provinces throughout the fall of 2021. Leveraging variations in the timing of these measures across the provinces, we applied event study regression to estimate the impact the announcement of these measures had nationally on age-specific first-dose uptake in the subsequent seven-week period. Proof-of-vaccination mandate announcements were associated with a rapid, significant increase in first-dose uptake, particularly in people younger than age fifty. However, these behavioral changes were short-lived, with uptake returning to preannouncement levels-or lower-in all age groups within six weeks, despite mandates remaining in place for at least four months; this decline occurred earlier and was more apparent among adolescents ages 12-17. We estimated that nationally, 290,168 additional people received their first dose in the seven weeks after provinces announced proof-of-vaccination policies, for a 17.5 percent increase over the number of vaccinations estimated in the absence of these policies. This study provides novel age-specific evidence showing that proof-of-vaccination mandates led to an immediate, significant increase in national first-dose uptake and were particularly effective for increasing vaccination uptake in younger to middle-aged adults. Proof-of-vaccination mandates may be effective short-term policy measures for increasing population vaccination uptake, but their impact may differ across age groups.

Immunological effects and safety of live rotavirus vaccination after antenatal exposure to immunomodulatory biologic agents: a prospective cohort study from the Canadian Immunization Research Network.

BACKGROUND: People with inflammatory or autoimmune diseases are recommended to continue immunomodulatory biologic agents throughout pregnancy. However, concerns regarding potential immunosuppression in infants exposed to biologic agents have led to recommendations to avoid live vaccines in the first 6-12 months of life. We aimed to examine whether live rotavirus vaccine could be administered safely to infants exposed to biologic agents, assessed in the Canadian Special Immunization Clinic (SIC) Network. METHODS: In this prospective cohort study, infants exposed to biologic agents in utero were referred to one of six SIC sites in Canada for rotavirus vaccination recommendations. Children with other contraindications to rotavirus vaccination or older than 15 weeks were excluded. Clinical and laboratory evaluations were conducted according to a standard clinical pathway. Data were collected for relevant medical history, pregnancy outcomes, biologic agent exposure history, physical examination, laboratory results of the child, SIC recommendations for rotavirus vaccination, rotavirus vaccine series completion, and adverse events after immunisation. After parental consent, deidentified data were transferred to a central database for analysis. Children recommended for rotavirus vaccination were followed up for 8 months after series initiation to ascertain severe and serious adverse events, including severe diarrhoea, vomiting, and intussusception. FINDINGS: Between May 1, 2017, and Dec 31, 2021, 202 infants were assessed and 191 eligible infants were enrolled (97 [51%] were female and 94 [49%] were male). When including those exposed to multiple agents, the most common biologic agents to which infants were exposed were infliximab (67 [35%] of 191), adalimumab (49 [26%]), ustekinumab (18 [9%]), and vedolizumab (17 [9%]). Biologic agent exposure continued into the third trimester for 178 (93%) infants. No clinically significant abnormalities in lymphocyte subsets, quantitative immunoglobulins, or mitogen responses were detected. After SIC assessment, rotavirus vaccination was recommended for 187 (98%) of 191 infants, all of whom were followed up. By end of follow-up on Aug 19, 2022, 168 (90%) infants had initiated rotavirus vaccination; 150 (80%) completed the series. No serious adverse events after immunisation were reported, but three (2%) infants required medical attention, one for vomiting and change in stools who was subsequently diagnosed with gastroesophageal reflux disease, one for rash on labia unrelated to vaccination, and one for vomiting and diarrhoea associated with a milk allergy. INTERPRETATION: Findings from this study suggest that lymphocyte subsets and the safety of live rotavirus vaccination are generally not affected by in-utero exposure to biologic agents. Rotavirus vaccination can be offered to infants exposed to anti-TNF agents in utero. FUNDING: Public Health Agency of Canada and Canadian Institutes of Health Research through the Canadian Immunization Research Network.

Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

School Reopening And COVID-19 In The Community: Evidence From A Natural Experiment In Ontario, Canada.

In December 2020, Ontario, Canada, entered a provincewide shutdown to mitigate COVID-19 transmission. A regionalized approach was taken to reopen schools throughout early 2021 without any other opening of the economy, offering a unique natural experiment to estimate the impact of school reopening on community transmission. Estimated increases of 0.07, 0.08, 0.07, and 0.13 percentage points in community COVID-19 case growth rates occurred 11-15, 16-20, 21-25, and 26-30 days, respectively, after schools reopened. Although small, these changes were particularly evident among children younger than age fourteen, increased over time, and were greater when lag periods were considered, which points to a likely causal effect between in-person classes and a small increase in transmission. These findings suggest that although additional COVID-19 cases are to be expected after the reopening of schools, these risks may be manageable with sufficient, layered mitigation policies.

The federal government and Canada's COVID-19 responses: from 'we're ready, we're prepared' to 'fires are burning'.

Canada's experience with the coronavirus disease-2019 (COVID-19) pandemic has been characterized by considerable regional variation, as would be expected in a highly decentralized federation. Yet, the country has been beset by challenges, similar to many of those documented in the severe acute respiratory syndrome outbreak of 2003. Despite a high degree of pandemic preparedness, the relative success with flattening the curve during the first wave of the pandemic was not matched in much of Canada during the second wave. This paper critically reviews Canada's response to the COVID-19 pandemic with a focus on the role of the federal government in this public health emergency, considering areas within its jurisdiction (international borders), areas where an increased federal role may be warranted (long-term care), as well as its technical role in terms of generating evidence and supporting public health surveillance, and its convening role to support collaboration across the country. This accounting of the first 12 months of the pandemic highlights opportunities for a strengthened federal role in the short term, and some important lessons to be applied in preparing for future pandemics.

Challenges of using asthma admission rates as a measure of primary care quality in children: An international comparison.

OBJECTIVES: To demonstrate the challenges of interpreting cross-country comparisons of paediatric asthma hospital admission rates as an indicator of primary care quality. METHODS: We used hospital administrative data from >10 million children aged 6-15 years, resident in Austria, England, Finland, Iceland, Ontario (Canada), Sweden or Victoria (Australia) between 2008 and 2015. Asthma hospital admission and emergency department (ED) attendance rates were compared between countries using Poisson regression models, adjusted for age and sex. RESULTS: Hospital admission rates for asthma per 1000 child-years varied eight-fold across jurisdictions. Admission rates were 3.5 times higher when admissions with asthma recorded as any diagnosis were considered, compared with admissions with asthma as the primary diagnosis. Iceland had the lowest asthma admission rates; however, when ED attendance rates were considered, Sweden had the lowest rate of asthma hospital contacts. CONCLUSIONS: The large variations in childhood hospital admission rates for asthma based on the whole child population reflect differing definitions, admission thresholds and underlying disease prevalence rather than primary care quality. Asthma hospital admissions among children diagnosed with asthma is a more meaningful indicator for inter-country comparisons of primary care quality.

Family and Child Risk Factors for Early-Life RSV Illness.

BACKGROUND AND OBJECTIVES: Most infants hospitalized with respiratory syncytial virus (RSV) do not meet common "high-risk" criteria and are otherwise healthy. The objective of this study was to quantify the risks and relative importance of socioeconomic factors for severe, early-life RSV-related illness. We hypothesized several of these factors, particularly those indicating severe social vulnerability, would have statistically significant associations with increased RSV hospitalization rates and may offer impactful targets for population-based RSV prevention strategies, such as prophylaxis programs. METHODS: We used linked health, laboratory, and sociodemographic administrative data for all children born in Ontario (2012-2018) to identify all RSV-related hospitalizations occurring before the third birthday or end of follow-up (March 31, 2019). We estimated rate ratios and population attributable fractions using a fully adjusted model. RESULTS: A total of 11 782 RSV-related hospitalizations were identified among 789 484 children. Multiple socioeconomic factors were independently associated with increased RSV-related admissions, including young maternal age, maternal criminal involvement, and maternal history of serious mental health and/or addiction concerns. For example, an estimated 4.1% (95% confidence interval: 2.2 to 5.9) of RSV-related admissions could be prevented by eliminating the increased admissions risks among children whose mothers used welfare-based drug insurance. Notably, 41.6% (95% confidence interval: 39.6 to 43.5) of admissions may be prevented by targeting older siblings (eg, through vaccination). CONCLUSIONS: Many social factors were independently associated with early-life RSV-related hospitalization. Existing RSV prophylaxis and emerging vaccination programs should consider the importance of both clinical and social risk factors when determining eligibility and promoting compliance.

Palivizumab's real-world effectiveness: a population-based study in Ontario, Canada, 1993-2017.

OBJECTIVE: To evaluate the effectiveness of two palivizumab programmes targeting high-risk infants, defined by prematurity, diagnosis of comorbidities and geography, and assess potential disparities by neighbourhood income. DESIGN: Controlled, interrupted time series. SETTING: Ontario, Canada. PATIENTS: We used linked health and demographic administrative databases to identify all children born in hospitals 1 January 1993 through 31 December 2016. Follow-up ended at the earliest of second birthday or 30 June 2017. INTERVENTION: Palivizumab-eligibility: child was born very preterm and ≤6 months old during respiratory syncytial virus (RSV) season; <24 months old with significant chronic lung or congenital heart disease; or ≤6 months, born preterm or residents of remote regions. MAIN OUTCOME: Severe RSV-related illness, defined as hospitalisation or death with a diagnosis of bronchiolitis, RSV pneumonia or RSV. RESULTS: 3 million births and 87 000 RSV-related events were identified. Over the study period, rates of severe RSV-related illness declined 65.4% among the highest risk group, eligible infants <6 months (230.6 to 79.8 admissions per 1000 child-years). Relative to changes among ineligible infants <6 months, rates dropped 10.4% (95% CI -18.6% to 39.4%) among eligible infants immediately following introduction of a national palivizumab programme in 1998. Initially, rates were considerably higher among infants from low-income neighbourhoods, but income-specific rates converged over time among eligible infants <6 months; such convergence was not seen among other children. CONCLUSIONS: Incidence of severe RSV-related illness declined over the study period. While we cannot attribute causality, the timing and magnitude of these declines suggest impact of palivizumab in reducing RSV burden and diminishing social inequities among palivizumab-eligible infants.

Community-Based Antibiotic Prescribing Attributable to Respiratory Syncytial Virus and Other Common Respiratory Viruses in Young Children: A Population-Based Time-series Study of Scottish Children.

BACKGROUND: Inappropriate antibiotic prescribing, such as for viral illness, remains common in primary care. The objective of this study was to estimate the proportion of community-prescribed antibiotics to children aged less than 5 years attributable to common respiratory viruses. METHODS: We fitted time-series negative binomial models to predict weekly antibiotic prescribing rates from positive viral pathogen tests for the period 1 April 2009 through 27 December 2017 using comprehensive, population-based administrative data for all children (<5 years) living in Scotland. Multiple respiratory viral pathogens were considered, including respiratory syncytial virus (RSV), influenza, human metapneumovirus (HMPV), rhinovirus, and human parainfluenza (HPIV) types 1-4. We estimated the proportion of antibiotic prescriptions explained by virus circulation according to type of virus, by age group, presence of high-risk chronic conditions, and antibiotic class. RESULTS: We included data on 6 066 492 antibiotic prescriptions among 452 877 children. The antibiotic-prescribing rate among all Scottish children (<5 years) was 609.7 per 1000 child-years. Our final model included RSV, influenza, HMPV, HPIV-1, and HPIV-3. An estimated 6.9% (95% confidence interval, 5.6-8.3%), 2.4% (1.7-3.1%), and 2.3% (.8-3.9%) of antibiotics were attributable to RSV, influenza, and HMPV, respectively. RSV was consistently associated with the highest proportion of prescribed antibiotics, particularly among children without chronic conditions and for amoxicillin and macrolide prescriptions. CONCLUSIONS: Nearly 14% of antibiotics prescribed to children in this study were estimated to be attributable to common viruses for which antibiotics are not recommended. A future RSV vaccine could substantially reduce unnecessary antibiotic prescribing among children.

Development and validation of a simple algorithm to estimate common gestational age categories using standard administrative birth record data in Ontario, Canada.

Gestational age is often incompletely recorded in administrative records, despite being critical to paediatric and maternal health research. Several algorithms exist to estimate gestational age using administrative databases; however, many have not been validated or use complicated methods that are not readily adaptable. We developed a simple algorithm to estimate common gestational age categories from routine administrative data. We leveraged a population-based registry of all hospital births occurring in Ontario, Canada over 2002-2016 including 1.8 million birth records. In this sample, this simple algorithm had excellent performance compared to a verified measure of gestational age; 87.61% agreement (95% CI: 87.49, 87.74). The accuracy of the algorithm exceeded 98% for all of the gestational age categories. Agreement notably increased over time and was greatest among singleton births and infants born at 2500-2999 g. This study provides a straight-forward algorithm for accurately estimating common gestational age categories that is easily adaptable for use in other countries.Impact StatementWhat is already known on this subject? Gestational age is often incompletely or inaccurately recorded in administrative health databases, despite being critical to the study of many paediatric and maternal health outcomes. Consequently, researchers must rely on various methods to estimate gestational age, many of these methods are either overly simple (i.e. assuming a uniform duration) or analytically complicated and difficult to adapt for new populations (e.g. regression-based approaches).What the results of this study add? This study, based on a population-based registry of all 1.8 million births occurring in Ontario, Canada 2003-2016, found that a simple, sex-specific algorithm using three commonly recorded birth record characteristics performs almost perfectly compared to a clinical estimate recorded near birth.What the implications are of these findings for clinical practice and/or further research? This study suggests that a straight-forward, sex-specific algorithm based on routinely collected birth record data is able to accurately estimate common gestational age categories (i.e. extreme preterm, <28 weeks; very preterm, 28-32 weeks; moderate-to-late preterm, 33-26 weeks; and term, 37 weeks of completed gestational age). This work will be of greatest interest to perinatal researchers using routinely collected health administrative data.

Deprivation and mortality related to pediatric respiratory tract infection: a cohort study in 3 high-income jurisdictions.

BACKGROUND: Deaths from respiratory tract infections (RTIs) in children are preventable through timely access to public health and medical interventions. We aimed to assess whether socioeconomic disparities in mortality related to pediatric RTI persisted after accounting for health status at birth. METHODS: We compared the prevalence of and risk factors for RTI-related death in singletons aged 28 days to 4 years across Ontario (Canada), Scotland and England (jurisdictions with universal health care) using linked administrative data for 2003-2013. We estimated rates of RTI-related mortality for children living in deprived areas and those born to teenage girls; we estimated both crude rates and those adjusted for health status at birth. RESULTS: A total of 1 299 240 (Ontario), 547 556 (Scotland) and 3 910 401 (England) children were included in the study. Across all jurisdictions, children born in the most deprived areas experienced the highest rates of RTI-related mortality. After adjustment for high-risk chronic conditions and prematurity, we observed differences in mortality according to area-level deprivation in Ontario and England but not in Scotland. In Ontario, teenage motherhood was also an independent risk factor for RTI-related mortality. INTERPRETATION: Socioeconomic disparities played a substantial role in child mortality related to RTI in all 3 jurisdictions. Context-specific investigations around the mechanisms of this increased risk and development of programs to address socioeconomic disparities are needed.

Vancomycin-resistant enterococci (VRE) screening and isolation in the general medicine ward: a cost-effectiveness analysis.

Background: Vancomycin-resistant enterococci (VRE) are a serious antimicrobial resistant threat in the healthcare setting. We assessed the cost-effectiveness of VRE screening and isolation for patients at high-risk for colonisation on a general medicine ward compared to no VRE screening and isolation from the healthcare payer perspective. Methods: We developed a microsimulation model using local data and VRE literature, to simulate a 20-bed general medicine ward at a tertiary-care hospital with up to 1000 admissions, approximating 1 year. Primary outcomes were accrued over the patient's lifetime, discounted at 1.5%, and included expected health outcomes (VRE colonisations, VRE infections, VRE-related bacteremia, and deaths subsequent to VRE infection), quality-adjusted life years (QALYs), healthcare costs, and incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analysis (PSA) and scenario analyses were conducted to assess parameter uncertainty. Results: In our base-case analysis, VRE screening and isolation prevented six healthcare-associated VRE colonisations per 1000 admissions (6/1000), 0.6/1000 VRE-related infections, 0.2/1000 VRE-related bacteremia, and 0.1/1000 deaths subsequent to VRE infection. VRE screening and isolation accrued 0.0142 incremental QALYs at an incremental cost of $112, affording an ICER of $7850 per QALY. VRE screening and isolation practice was more likely to be cost-effective (> 50%) at a cost-effectiveness threshold of $50,000/QALY. Stochasticity (randomness) had a significant impact on the cost-effectiveness. Conclusion: VRE screening and isolation can be cost-effective in majority of model simulations at commonly used cost-effectiveness thresholds, and is likely economically attractive in general medicine settings. Our findings strengthen the understanding of VRE prevention strategies and are of importance to hospital program planners and infection prevention and control.

Assessment of Long-term Follow-up of Randomized Trial Participants by Linkage to Routinely Collected Data: A Scoping Review and Analysis.

Importance: Follow-up of participants in randomized trials may be limited by logistic and financial factors. Some important randomized trials have been extended well beyond their original follow-up period by linkage of individual participant information to routinely collected data held in administrative records and registries. Objective: To perform a scoping review of randomized clinical trials extended by record linkage to characterize this literature and explore any additional insights into treatment effectiveness provided by long-term follow-up using record linkage. Data Sources: A literature search in Embase, CINAHL, MEDLINE, and the Cochrane Register of Controlled Trials was performed for the period January 1, 1945, through November 25, 2016. Study Selection: Various combinations of search terms were used, as there is no accepted terminology. Determination of study eligibility and extraction of information about trial characteristics and outcomes, for both original and extended trial reports, were performed in duplicate. Data Extraction and Synthesis: Assessment of study eligibility and data extraction were performed independently by 2 reviewers. All analyses were descriptive. Main Outcomes and Measures: Outcomes in the pairs of original and extended trials were categorized according to whether any benefits or harms from interventions were sustained, were lost, or emerged during long-term follow-up. Results: A total of 113 extended trials were included in the study. Linkage to administrative and registry data extended follow-up by between 1 and 55 years. The most common interventions were pharmaceuticals (47 [41.6%]), surgery (19 [16.8%]), and disease screening (19 [16.8%]). End points most frequently studied through record linkage included mortality (88 [77.9%]), cancer (41 [36.3%]), and cardiovascular events (37 [32.7%]). One hundred four trial extensions (92.0%) were analyzed according to the original trial randomization. The reports provided details of 155 analyses of study outcomes. Seventy-four analyses (47.7%) identified statistically significant benefits in the trial extension phase. In 21 of these (28.4%), benefits were significant only in this period. Null results in both the original and extended trials were seen in 34 of the analyses (21.9%). Loss of significant benefits of an intervention were seen in 12 analyses (7.7%). Statistically significant harms were seen in 16 trial extension analyses (10.3%), and in 14 of these (87.5%), the harms were significant only in the trial extension phase. Conclusions and Relevance: Trial extension by linkage to routinely collected data is a versatile underused approach that may add critical insights beyond those of the original trial. Some beneficial and harmful outcomes of interventions are captured only in the extension phase of randomized trials.

Risk factors for serious outcomes associated with influenza illness in high- versus low- and middle-income countries: Systematic literature review and meta-analysis.

AIM: To determine factors associated with a serious outcome (hospital admission or severe outcome: critical care or death) and associated with illness caused by laboratory-confirmed influenza, with a specific interest in low- and middle-income countries (LMIC). METHOD: Databases were searched on 11 March 2016 for reports of influenza and factors associated with mortality or morbidity in humans, with no language restrictions. Pooled risks were estimated using random-effects models. RESULTS: Despite the heterogeneity of results across studies, known risk factors for serious disease were associated with both hospital admission and severe outcomes (critical care and/or death). In LMIC, but not in high income countries (HIC), pregnant women, people with HIV/AIDS and children < 5 years old (compared with older children) were at increased risk of a severe outcome. Also, although all patients with neurological conditions were at higher risk of severe outcomes than those without, children were at higher risk than adults and children who lived in a LMIC were at significantly higher risk than those living in HIC. Adults were more likely than children to suffer a severe outcome if they had diabetes or a hematologic condition, were obese or had liver disease. Asthma is a risk factor for hospital admission but not for severe outcomes. CONCLUSION: Known risk factors for serious disease remain important predictors of hospital admission and severe outcomes with few differences between HIC and LMIC countries. These differences likely reflect differences in health-seeking behaviours and health services, but high heterogeneity between studies limits conclusions about the effect size.

Characterising violent deaths of undetermined intent: a population-based study, 1999-2012.

OBJECTIVES: Violent deaths classified as undetermined intent (UD) are sometimes included in suicide counts. This study investigated age and sex differences, along with socioeconomic gradients in UD and suicide deaths in the province of Ontario between 1999 and 2012. METHODS: We used data from the Institute for Clinical Evaluative Sciences, which has linked vital statistics from the Office of the Registrar General Deaths register with Census data between 1999 and 2012. Socioeconomic status was operationalised through the four dimensions of the Ontario Marginalization Index. We computed age-specific and annual age-standardised mortality rates, and risk ratios to calculate risk gradients according to each of the four dimensions of marginalization. RESULTS: Rates of UD-classified deaths were highest for men aged 45-64 years residing in the most materially deprived (7.9 per 100 000 population (95% CI 6.8 to 9.0)) and residentially unstable (8.1 (95% CI 7.1 to 9.1)) neighbourhoods. Similarly, suicide rates were highest among these same groups of men aged 45-64 living in the most materially deprived (28.2 (95% CI 26.1 to 30.3)) and residentially unstable (30.7 (95% CI 28.7 to 32.6)) neighbourhoods. Relative to methods of death, poisoning was the most frequently used method in UD cases (64%), while it represented the second most common method (27%) among suicides after hanging (40%). DISCUSSION: The similarities observed between both causes of death suggest that at least a proportion of UD deaths may be misclassified suicide cases. However, the discrepancies identified in this analysis seem to indicate that not all UD deaths are misclassified suicides.

Protocol for a scoping review of post-trial extensions of randomised controlled trials using individually linked administrative and registry data.

INTRODUCTION: Well-conducted randomised controlled trials (RCTs) provide the least biased estimates of intervention effects. However, RCTs are costly and time-consuming to perform and long-term follow-up of participants may be hampered by lost contacts and financial constraints. Advances in computing and population-based registries have created new possibilities for increasing the value of RCTs by post-trial extension using linkage to routinely collected administrative/registry data in order to determine long-term interventional effects. There have been recent important examples, including 20+ years follow-up studies of trials of pravastatin and mammography. Despite the potential value of post-trial extension, there has been no systematic study of this literature. This scoping review aims to characterise published post-trial extension studies, assess their value, and identify any potential challenges associated with this approach. METHODS AND ANALYSIS: This review will use the recommended methods for scoping reviews. We will search MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. A draft search strategy is included in this protocol. Review of titles and abstracts, full texts of potentially eligible studies and data/information extraction will be conducted independently by pairs of investigators. Eligible studies will be RCTs that investigated healthcare interventions that were extended by individual linkage to administrative/registry/electronic medical records data after the completion of the planned follow-up period. Information concerning the original trial, characteristics of the extension study, any clinical, policy or ethical implications and methodological or practical challenges will be collected using standardised forms. ETHICS AND DISSEMINATION: As this study uses secondary data, and does not include person-level data, ethics approval is not required. We aim to disseminate these findings through journals and conferences targeting triallists and researchers involved in health data linkage. We aim to produce guidance for investigators on the conduct of post-trial extensions using routinely collected data.

Risk of Bias in Systematic Reviews of Non-Randomized Studies of Adverse Cardiovascular Effects of Thiazolidinediones and Cyclooxygenase-2 Inhibitors: Application of a New Cochrane Risk of Bias Tool.

BACKGROUND: Systematic reviews of the effects of healthcare interventions frequently include non-randomized studies. These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results. Our aims were to assess the reliability and usability of a new Cochrane risk of bias (RoB) tool for non-randomized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the reviews. METHODS AND FINDINGS: We selected two systematic reviews of population-based, controlled non-randomized studies of the relationship between the use of thiazolidinediones (TZDs) and cyclooxygenase-2 (COX-2) inhibitors and major cardiovascular events. Two epidemiologists applied the Cochrane RoB tool and made assessments across the seven specified domains of bias for each of 37 component studies. Inter-rater agreement was measured using the weighted Kappa statistic. We grouped studies according to overall RoB and performed statistical pooling for (a) all studies and (b) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0. In the COX-2 inhibitor review, two studies had low overall RoB, 14 had moderate RoB, and five had serious RoB. In the TZD review, six studies had low RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. The pooled odds ratios for myocardial infarction, heart failure, and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However, the estimate for myocardial infarction declined from 1.14 (95% CI 1.07-1.24) to 1.06 (95% CI 0.99-1.13) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were confined to studies with low or moderate RoB. The exception was a rise in the relative risk associated with ibuprofen from 1.07 (95% CI 0.97-1.18) to 1.14 (95% CI 1.03-1.26). The main limitation of our study was testing the instrument on a narrow range of pharmacoepidemiological studies; we cannot assume our findings extend to a broader range of interventions and settings. CONCLUSIONS: The Cochrane RoB tool highlighted a wide range of risks of bias in studies included in two widely cited reviews and had the potential to change the conclusions of the reviews. Systematic reviews that incorporate non-randomized studies of medical interventions should include a detailed assessment of RoB for each included study.

Effect of Vitamin D3 Supplementation on Inflammatory Markers and Glycemic Measures among Overweight or Obese Adults: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Obesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with cardiometabolic risk. This systematic review examines the association between oral vitamin D (VD) supplementation and circulating inflammatory biomarkers and glycemic outcomes from randomized controlled trials (RCTs) of overweight and/or obese adults. METHODS: MEDLINE OVID, EMBASE and the Cochrane Central Register of Controlled Trials were searched according to a predefined protocol. Eligible RCTs included adults randomized to receive either oral VD or placebo. Two reviewers independently assessed RCTs for inclusion. Bias was assessed using the Cochrane Collaboration risk of bias tool. Mean differences were calculated comparing end-of-study sample means between the independent VD and placebo groups. RESULTS: Eleven unique RCTs met inclusion criteria from a total of 3,383 identified citations, including 79 screened articles and 14 full text data extractions. Inflammatory and glycemic measures were reported in 7 and 10 RCTs, respectively. Most trial findings were non-significant with considerable heterogeneity in design, participants and outcomes. All but one trial was rated as either high or unclear risk of bias. Two RCTs reported significant changes in inflammatory biomarkers; however, the mean difference between groups was not statistically significant: C-reactive protein 0.19 mg/L (p = 0.88); Tumor Necrosis Factor -0.54 pg/ml (p = 0.20). Two other trials found significant mean differences in fasting plasma glucose -0.32 mmol/L (p = 0.03), Hemoglobin A1c -0.13% (p = 0.04), and Homeostatic Model Assessment -0.86 (p = 0.02) following VD supplementation. CONCLUSIONS: Overall, there is no clear established benefit of VD supplementation on inflammatory biomarkers among overweight/obese adults. Baseline serum VD possibly influences the effect of VD repletion on inflammatory markers. Risk of bias was present in most studies, thus supporting the need for higher quality studies in this area to more conclusively understand the role VD supplementation has on inflammatory pathways.

Narrowing mortality gap between men and women over two decades: a registry-based study in Ontario, Canada.

BACKGROUND: Historically, women have lower all-cause mortality than men. It is less understood that sex differences have been converging, particularly among certain subgroups and causes. This has implications for public health and health system planning. Our objective was to analyse contemporary sex differences over a 20-year period. METHODS: We analysed data from a population-based death registry, the Ontario Registrar's General Death file, which includes all deaths recorded in Canada's most populous province, from 1992 to 2012 (N=1 710 080 deaths). We calculated absolute and relative mortality sex differences for all-cause and cause-specific mortality, age-adjusted and age-specific, including the following causes: circulatory, cancers, respiratory and injuries. We used negative-binomial regression of mortality on socioeconomic status with direct age adjustment for the overall population. RESULTS: In the 20-year period, age-adjusted mortality dropped 39.2% and 29.8%, respectively, among men and women. The age-adjusted male-to-female mortality ratio dropped 41.4%, falling from 1.47 to 1.28. From 2000 onwards, all-cause mortality rates of high-income men were lower than those seen among low-income women. Relative mortality declines were greater among men than women for cancer, respiratory and injury-related deaths. The absolute decline in circulatory deaths was greater among men, although relative deciles were similar to women. The largest absolute mortality gains were seen among men over the age of 85 years. CONCLUSIONS: The large decline in mortality sex ratios in a Canadian province with universal healthcare over two decades signals an important population shift. These narrowing trends varied according to cause of death and age. In addition, persistent social inequalities in mortality exist and differentially affect men and women. The observed change in sex ratios has implications for healthcare and social systems.