Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

The Awesome Power of Human Genetics of Infectious Disease.

Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and susceptibility to infectious diseases. GWA studies enabled the identification of many common variants associated with small shifts in susceptibility to infectious diseases. This is exemplified by multiple loci associated with leprosy, malaria, HIV, tuberculosis, and coronavirus disease 2019 (COVID-19), which illuminate genetic architecture and implicate pathways underlying pathophysiology. Despite these successes, most of the heritability of infectious diseases remains to be explained. As the field advances, current limitations may be overcome by applying methodological innovations such as cellular GWA studies and phenome-wide association (PheWA) studies as well as by improving methodological rigor with more precise case definitions, deeper phenotyping, increased cohort diversity, and functional validation of candidate loci in the laboratory or human challenge studies.

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Stroke risk in women with atrial fibrillation.

BACKGROUND AND AIMS: Female sex is associated with higher rates of stroke in atrial fibrillation (AF) after adjustment for other CHA2DS2-VASc factors. This study aimed to describe sex differences in age and cardiovascular care to examine their relationship with stroke hazard in AF. METHODS: Population-based cohort study using administrative datasets of people aged ≥66 years diagnosed with AF in Ontario between 2007 and 2019. Cause-specific hazard regression was used to estimate the adjusted hazard ratio (HR) for stroke associated with female sex over a 2-year follow-up. Model 1 included CHA2DS2-VASc factors, with age modelled as 66-74 vs. ≥ 75 years. Model 2 treated age as a continuous variable and included an age-sex interaction term. Model 3 further accounted for multimorbidity and markers of cardiovascular care. RESULTS: The cohort consisted of 354 254 individuals with AF (median age 78 years, 49.2% female). Females were more likely to be diagnosed in emergency departments and less likely to receive cardiologist assessments, statins, or LDL-C testing, with higher LDL-C levels among females than males. In Model 1, the adjusted HR for stroke associated with female sex was 1.27 (95% confidence interval 1.21-1.32). Model 2 revealed a significant age-sex interaction, such that female sex was only associated with increased stroke hazard at age >70 years. Adjusting for markers of cardiovascular care and multimorbidity further decreased the HR, so that female sex was not associated with increased stroke hazard at age ≤80 years. CONCLUSION: Older age and inequities in cardiovascular care may partly explain higher stroke rates in females with AF.

Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression.

BACKGROUND AND AIMS: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin-protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. APPROACH AND RESULTS: We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed "undead") hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl 4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of 'undead' senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress. CONCLUSION: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

Days alive and out of hospital for adult female and male cardiac surgery patients: a population-based cohort study.

BACKGROUND: Research shows women experience higher mortality than men after cardiac surgery but information on sex-differences during postoperative recovery is limited. Days alive and out of hospital (DAH) combines death, readmission and length of stay, and may better quantify sex-differences during recovery. This main objective is to evaluate (i) how DAH at 30-days varies between sex and surgical procedure, (ii) DAH responsiveness to patient and surgical complexity, and (iii) longer-term prognostic value of DAH. METHODS: We evaluated 111,430 patients (26% female) who underwent one of three types of cardiac surgery (isolated coronary artery bypass [CABG], isolated non-CABG, combination procedures) between 2009 - 2019. Primary outcome was DAH at 30 days (DAH30), secondary outcomes were DAH at 90 days (DAH90) and 180 days (DAH180). Data were stratified by sex and surgical group. Unadjusted and risk-adjusted analyses were conducted to determine the association of DAH with patient-, surgery-, and hospital-level characteristics. Patients were divided into two groups (below and above the 10th percentile) based on the number of days at DAH30. Proportion of patients below the 10th percentile at DAH30 that remained in this group at DAH90 and DAH180 were determined. RESULTS: DAH30 were lower for women compared to men (22 vs. 23 days), and seen across all surgical groups (isolated CABG 23 vs. 24, isolated non-CABG 22 vs. 23, combined surgeries 19 vs. 21 days). Clinical risk factors including multimorbidity, socioeconomic status and surgical complexity were associated with lower DAH30 values, but women showed lower values of DAH30 compared to men for many factors. Among patients in the lowest 10th percentile at DAH30, 80% of both females and males remained in the lowest 10th percentile at 90 days, while 72% of females and 76% males remained in that percentile at 180 days. CONCLUSION: DAH is a responsive outcome to differences in patient and surgical risk factors. Further research is needed to identify new care pathways to reduce disparities in outcomes between male and female patients.

Trajectories of P2Y12 inhibitor adherence in patients with acute coronary syndromes.

PURPOSE: P2Y12 inhibitors (P2Y12i) reduce cardiac events after acute coronary syndromes (ACS). However, suboptimal P2Y12i adherence persists. We aimed to examine P2Y12i non-adherence using group-based trajectory methods and to identify adherence predictors. METHODS: We conducted a population-based, retrospective cohort study using administrative data in Ontario, Canada of patients ≥65 years admitted for ACS between April 2014 and March 2018 with a P2Y12i dispensed within 7 days of discharge. We used group-based trajectory models to characterize longitudinal 1-year adherence patterns. Predictors associated with each adherence trajectory were identified by multinomial logistic regression. RESULTS: We included 11 917 patients using clopidogrel and 9763 using ticagrelor, aged [mean ± SD]: 77.33 ± 8.31/73.59 ± 6.79 years; men: 56.2%/65.4%, respectively. We identified 3 longitudinal adherence trajectories, that differed by agent: 75% of clopidogrel and 68% of ticagrelor patients showed a consistently adherent trajectory, while 13%/17% were gradually, and 12%/15% were rapidly non-adherent, respectively (p < 0.001). Differing baseline characteristics in each cohort were associated with observed adherence trajectories. Concomitant atrial fibrillation and prior bleeding history were associated with non-adherence among clopidogrel users. Among ticagrelor users, women and older persons were more likely to be rapidly non-adherent, adherence declining steeply starting 1 month post-ACS. CONCLUSIONS: We identified distinct adherence trajectories for clopidogrel and ticagrelor post-ACS, with 3 out of 4 clopidogrel patients but only 2 out of 3 ticagrelor patients in the consistently adherent trajectory. Intensive interventions targeted to the period of steep adherence decline post-ACS, particularly for women and older persons initiating ticagrelor, and patients with atrial fibrillation on clopidogrel should be considered and investigated further.

Development and Validation of the CANHEART Population-Based Laboratory Prediction Models for Atherosclerotic Cardiovascular Disease.

BACKGROUND: Prediction of atherosclerotic cardiovascular disease (ASCVD) in primary prevention assessments exclusively with laboratory results may facilitate automated risk reporting and improve uptake of preventive therapies. OBJECTIVE: To develop and validate sex-specific prediction models for ASCVD using age and routine laboratory tests and compare their performance with that of the pooled cohort equations (PCEs). DESIGN: Derivation and validation of the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) Lab Models. SETTING: Population-based cohort study in Ontario, Canada. PARTICIPANTS: A derivation and internal validation cohort of adults aged 40 to 75 years without cardiovascular disease from April 2009 to December 2015; an external validation cohort of primary care patients from January 2010 to December 2014. MEASUREMENTS: Age and laboratory predictors measured in the outpatient setting included serum total cholesterol, high-density lipoprotein cholesterol, triglycerides, hemoglobin, mean corpuscular volume, platelets, leukocytes, estimated glomerular filtration rate, and glucose. The ASCVD outcomes were defined as myocardial infarction, stroke, and death from ischemic heart or cerebrovascular disease within 5 years. RESULTS: Sex-specific models were developed and internally validated in 2 160 497 women and 1 833 147 men. They were well calibrated, with relative differences less than 1% between mean predicted and observed risk for both sexes. The c-statistic was 0.77 in women and 0.71 in men. External validation in 31 697 primary care patients showed a relative difference less than 14% and an absolute difference less than 0.3 percentage points in mean predicted and observed risks for both sexes. The c-statistics for the laboratory models were 0.72 for both sexes and were not statistically significantly different from those for the PCEs in women (change in c-statistic, -0.01 [95% CI, -0.03 to 0.01]) or men (change in c-statistic, -0.01 [CI, -0.04 to 0.02]). LIMITATION: Medication use was not available at the population level. CONCLUSION: The CANHEART Lab Models predict ASCVD with similar accuracy to more complex models, such as the PCEs. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Association of Neighborhood-Level Material Deprivation With Atrial Fibrillation Care in a Single-Payer Health Care System: A Population-Based Cohort Study.

BACKGROUND: There are limited data on the association of material deprivation with clinical care and outcomes after atrial fibrillation (AF) diagnosis in jurisdictions with universal health care. METHODS: This was a population-based cohort study of individuals ≥66 years of age with first diagnosis of AF between April 1, 2007, and March 31, 2019, in the Canadian province of Ontario, which provides public funding and prohibits private payment for medically necessary physician and hospital services. Prescription medications are subsidized for residents >65 years of age. The primary exposure was neighborhood material deprivation, a metric derived from Canadian census data to estimate inability to attain basic material needs. Neighborhoods were categorized by quintile from Q1 (least deprived) to Q5 (most deprived). Cause-specific hazards regression was used to study the association of material deprivation quintile with time to AF-related adverse events (death or hospitalization for stroke, heart failure, or bleeding), clinical services (physician visits, cardiac diagnostics), and interventions (anticoagulation, cardioversion, ablation) while adjusting for individual characteristics and regional cardiologist supply. RESULTS: Among 347 632 individuals with AF (median age 79 years, 48.9% female), individuals in the most deprived neighborhoods (Q5) had higher prevalence of cardiovascular disease, risk factors, and noncardiovascular comorbidity relative to residents of the least deprived neighborhoods (Q1). After adjustment, Q5 residents had higher hazards of death (hazard ratio [HR], 1.16 [95% CI, 1.13-1.20]) and hospitalization for stroke (HR, 1.16 [95% CI, 1.07-1.27]), heart failure (HR, 1.14 [95% CI, 1.11-1.18]), or bleeding (HR, 1.16 [95% CI, 1.07-1.25]) relative to Q1. There were small differences across quintiles in primary care physician visits (HR, Q5 versus Q1, 0.91 [95% CI, 0.89-0.92]), echocardiography (HR, Q5 versus Q1, 0.97 [95% CI, 0.96-0.99]), and dispensation of anticoagulation (HR, Q5 versus Q1, 0.97 [95% CI, 0.95-0.98]). There were more prominent disparities for Q5 versus Q1 in cardiologist visits (HR, 0.84 [95% CI, 0.82-0.86]), cardioversion (HR, 0.80 [95% CI, 0.76-0.84]), and ablation (HR, 0.45 [95% CI, 0.30-0.67]). CONCLUSIONS: Despite universal health care and prescription medication coverage, residents of more deprived neighborhoods were less likely to visit cardiologists or receive rhythm control interventions after AF diagnosis, even though they exhibited higher cardiovascular disease burden and higher risk of adverse outcomes.

Predicting left main stenosis in stable ischemic heart disease using logistic regression and boosted trees.

BACKGROUND: The ISCHEMIA trial showed similar cardiovascular outcomes of an initial conservative strategy as compared with invasive management in patients with stable ischemic heart disease without left main stenosis. We aim to assess the feasibility of predicting significant left main stenosis using extensive clinical, laboratory and non-invasive tests data. METHODS: All adult patients who had stress testing prior to undergoing an elective coronary angiography for stable ischemic heart disease in Ontario, Canada, between April 2010 and March 2019, were included. Candidate predictors included comprehensive demographics, comorbidities, laboratory tests, and cardiac stress test data. The outcome was stenosis of 50% or greater in the left main coronary artery. A traditional model (logistic regression) and a machine learning algorithm (boosted trees) were used to build prediction models. RESULTS: Among 150,423 patients included (mean age: 64.2 ± 10.6 years; 64.1% males), there were 9,225 (6.1%) with left main stenosis. The final logistic regression model included 24 predictors and 3 interactions, had an optimism-adjusted c-statistic of 0.72 and adequate calibration (optimism-adjusted Integrated Calibration Index 0.0044). These results were consistent in subgroups of males and females, diabetes and non-diabetes, and extent of ischemia. The boosted tree algorithm had similar accuracy, also resulting in a c-statistic of 0.72 and adequate calibration (Integrated Calibration Index 0.0054). CONCLUSIONS: In this large population-based study of patients with stable ischemic heart disease using extensive clinical data, only modest prediction of left main coronary artery disease was possible with traditional and machine learning modelling techniques.

Risk Factors for Major Cardiovascular Events in Adult Sepsis Survivors: A Population-Based Cohort Study.

OBJECTIVES: To describe risk factors for major cardiovascular events in adults following hospital discharge after sepsis. DESIGN: Population-based cohort study. SETTING: Ontario, Canada (2008-2017). PATIENTS: Adult patients (age 18 yr or older) who survived a first sepsis hospitalization without preexisting cardiovascular disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary composite outcome was myocardial infarction, stroke, or cardiovascular death up to 5 years following hospital discharge. We used cause-specific Cox proportional hazards models that accounted for the competing risk of noncardiovascular death to describe factors associated with major cardiovascular events. We identified 268,259 adult patients without cardiovascular disease (median age, 72 yr), of whom 10.4% experienced a major cardiovascular event during a median follow-up of 3 years. After multivariable adjustment, age (hazard ratio [HR], 1.53 for every 10 yr; 95% CI, 1.51-1.54), male sex (HR, 1.23; 95% CI, 1.20-1.26), diabetes mellitus (HR, 1.24; 95% CI, 1.21-1.27), hypertension (HR, 1.34; 95% CI, 1.30-1.38), prevalent atrial fibrillation (HR, 1.46; 95% CI, 1.40-1.52), and chronic kidney disease (HR, 1.11; 95% CI, 1.06-1.16) were associated with major cardiovascular events during long-term follow-up. Sepsis characteristics such as site of infection (pneumonia vs other: HR, 1.09; 95% CI, 1.05-1.12), septic shock (HR, 1.08; 95% CI, 1.05-1.11), and renal replacement therapy (HR, 1.51; 95% CI, 1.38-1.64) were also associated with subsequent cardiovascular events. In an analysis restricting to patients with troponin values measured during the hospitalization (26,400 patients), an elevated troponin was also associated with subsequent cardiovascular events (HR, 1.23; 95% CI, 1.13-1.33). CONCLUSIONS: Classic cardiovascular risk factors, comorbid conditions, and characteristics of the sepsis episode were associated with a higher hazard of major cardiovascular events in adult sepsis survivors. These findings may inform enrichment strategies for future studies.

ARHGEF26 enhances Salmonella invasion and inflammation in cells and mice.

Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins affects Salmonella pathogenesis. Here we leveraged a candidate cellular GWAS screen to identify natural genetic variation in the ARHGEF26 (Rho Guanine Nucleotide Exchange Factor 26) gene that renders lymphoblastoid cells susceptible to Salmonella Typhi and Typhimurium invasion. Experimental follow-up redefined ARHGEF26's role in Salmonella epithelial cell infection. Specifically, we identified complex serovar-by-host interactions whereby ARHGEF26 stimulation of S. Typhi and S. Typhimurium invasion into host cells varied in magnitude and effector-dependence based on host cell type. While ARHGEF26 regulated SopB- and SopE-mediated S. Typhi (but not S. Typhimurium) infection of HeLa cells, the largest effect of ARHGEF26 was observed with S. Typhimurium in polarized MDCK cells through a SopB- and SopE2-independent mechanism. In both cell types, knockdown of the ARHGEF26-associated protein DLG1 resulted in a similar phenotype and serovar specificity. Importantly, we show that ARHGEF26 plays a critical role in S. Typhimurium pathogenesis by contributing to bacterial burden in the enteric fever murine model, as well as inflammation in the colitis infection model. In the enteric fever model, SopB and SopE2 are required for the effects of Arhgef26 deletion on bacterial burden, and the impact of sopB and sopE2 deletion in turn required ARHGEF26. In contrast, SopB and SopE2 were not required for the impacts of Arhgef26 deletion on colitis. A role for ARHGEF26 on inflammation was also seen in cells, as knockdown reduced IL-8 production in HeLa cells. Together, these data reveal pleiotropic roles for ARHGEF26 during infection and highlight that many of the interactions that occur during infection that are thought to be well understood likely have underappreciated complexity.

Variation and clinical consequences of wait-times for atrial fibrillation ablation: population level study in Ontario, Canada.

AIMS: Atrial fibrillation (AF) is the most common cardiac rhythm disorder. Emerging evidence supporting the efficacy of catheter ablation in managing AF has led to increased demand for this therapy, potentially outpacing the capacity to perform this procedure. Mismatch between demand and capacity for AF ablation results in wait-times which have not been comprehensively evaluated at a population level. Additionally, the consequences of such delays in AF ablation, namely the risk of hospitalization or adverse events, have not been studied. METHODS AND RESULTS: This observational cohort study included adults referred for catheter ablation to treat AF in Ontario, Canada, between 1 April 2016 and 31 March 2020. Wait-time was defined from referral to the earliest of ablation, death, off-list, or the study endpoint of 31 March 2022. The outcomes of interest included a composite of death, hospitalization for AF/heart failure, and emergency department visit for AF/heart failure. Our study cohort included 6253 patients referred for de novo AF ablation. The median wait-time for patients who received and who did not receive ablation was 218 days (IQR: 112-363) and 520 days (IQR: 270-763), respectively. Wait-time increased consistently for patients referred between October 2017 and March 2020. Mortality was rare, but significant morbidity was observed, affecting 19.2% of patients on the waitlist for AF ablation. Paroxysmal AF was associated with a statistically significant greater risk for adverse outcomes on the waitlist (HR 1.51, 95% CI 1.18-1.93). CONCLUSION: Wait-times for AF ablation are increasing and are associated with significant morbidity.

A review of the use of propensity score methods with multiple treatment groups in the general internal medicine literature.

BACKGROUND: Propensity score (PS) methods with two treatment groups (e.g., treated vs. control) is a well-established technique for reducing the effects of confounding in nonrandomized studies. However, researchers are often interested in comparing multiple interventions. PS methods have been modified to incorporate multiple exposures. We described available techniques for PS methods in multicategory exposures (≥3 groups) and examined their use in the medical literature. METHODS: A comprehensive search was conducted for studies published in PubMed, Embase, Google Scholar, and Web of Science until February 27, 2023. We included studies using PS methods for multiple groups in general internal medicine research. RESULTS: The literature search yielded 4088 studies (2616 from PubMed, 86 from Embase, 85 from Google Scholar, 1671 from Web of Science, five from other sources). In total, 264 studies using PS method for multiple groups were identified; 61 studies were on general internal medicine topics and included. The most commonly used method was that of McCaffrey et al., which was used in 26 studies (43%), where the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) method and corresponding inverse probabilities of treatment weights were estimated via generalized boosted models. The next most commonly used method was pairwise propensity-matched comparisons, which was used in 20 studies (33%). The method by Imbens et al. using a generalized propensity score was implemented in six studies (10%). Four studies (7%) used a conditional probability of being in a particular group given a set of observed baseline covariates where a multiple propensity score was estimated using a non-parsimonious multinomial logistic regression model. Four studies (7%) used a technique that estimates generalized propensity scores and then creates 1:1:1 matched sets, and one study (2%) used the matching weight method. CONCLUSIONS: Many propensity score methods for multiple groups have been adopted in the literature. The TWANG method is the most commonly used method in the general medical literature.

Association Between Hospital Postoperative Troponin Use and Patient Outcomes After Vascular Surgery.

BACKGROUND: Acute myocardial injury after noncardiac surgery, which is most often symptomatically silent, is associated with increased mortality and morbidity. However, it is not known if routine postoperative troponin testing will affect patient outcomes. METHODS: We assembled a cohort of patients who underwent carotid endarterectomy or abdominal aortic aneurysm repair in Ontario, Canada, from 2010 to 2017. Hospitals were categorized into high, medium, and low troponin testing intensity based on the proportion of patients who received postoperative troponin testing. Cox proportional hazards modeling was used to assess the association between hospital-specific testing intensity and 30-day and 1-year major adverse cardiovascular events (MACEs) while adjusting for patient-, surgery-, and hospital-level factors. RESULTS: The cohort consisted of 18,467 patients from 17 hospitals. Mean age was 72 years, and 74.0% were men. Rates of postoperative troponin testing were 77.5%, 35.8%, and 21.6% in the high-, medium-, and low-testing intensity hospitals, respectively. At 30 days, 5.3%, 5.3%, and 6.5% of patients in high-, medium-, and low-testing intensity hospitals experienced MACE, respectively. Higher troponin testing rate was associated with lower adjusted hazard ratios (HRs) for MACE at 30 days (0.94; 95% confidence interval [CI], 0.89-0.98) and at 1 year (0.97; 95% CI, 0.94-0.99) for each 10% increase in hospital troponin rate. Hospitals with high-testing intensity had higher rates of postoperative cardiology referrals, cardiovascular testing, and rates of new cardiovascular prescriptions. CONCLUSIONS: Patients undergoing vascular surgery at hospitals with higher postoperative troponin testing intensity experienced fewer adverse outcomes than patients who had surgery at hospitals with lower testing intensity.

Differences in Treatment Patterns and Outcomes of Acute Myocardial Infarction for Low- and High-Income Patients in 6 Countries.

Importance: Differences in the organization and financing of health systems may produce more or less equitable outcomes for advantaged vs disadvantaged populations. We compared treatments and outcomes of older high- and low-income patients across 6 countries. Objective: To determine whether treatment patterns and outcomes for patients presenting with acute myocardial infarction differ for low- vs high-income individuals across 6 countries. Design, Setting, and Participants: Serial cross-sectional cohort study of all adults aged 66 years or older hospitalized with acute myocardial infarction from 2013 through 2018 in the US, Canada, England, the Netherlands, Taiwan, and Israel using population-representative administrative data. Exposures: Being in the top and bottom quintile of income within and across countries. Main Outcomes and Measures: Thirty-day and 1-year mortality; secondary outcomes included rates of cardiac catheterization and revascularization, length of stay, and readmission rates. Results: We studied 289 376 patients hospitalized with ST-segment elevation myocardial infarction (STEMI) and 843 046 hospitalized with non-STEMI (NSTEMI). Adjusted 30-day mortality generally was 1 to 3 percentage points lower for high-income patients. For instance, 30-day mortality among patients admitted with STEMI in the Netherlands was 10.2% for those with high income vs 13.1% for those with low income (difference, -2.8 percentage points [95% CI, -4.1 to -1.5]). One-year mortality differences for STEMI were even larger than 30-day mortality, with the highest difference in Israel (16.2% vs 25.3%; difference, -9.1 percentage points [95% CI, -16.7 to -1.6]). In all countries, rates of cardiac catheterization and percutaneous coronary intervention were higher among high- vs low-income populations, with absolute differences ranging from 1 to 6 percentage points (eg, 73.6% vs 67.4%; difference, 6.1 percentage points [95% CI, 1.2 to 11.0] for percutaneous intervention in England for STEMI). Rates of coronary artery bypass graft surgery for patients with STEMI in low- vs high-income strata were similar but for NSTEMI were generally 1 to 2 percentage points higher among high-income patients (eg, 12.5% vs 11.0% in the US; difference, 1.5 percentage points [95% CI, 1.3 to 1.8 ]). Thirty-day readmission rates generally also were 1 to 3 percentage points lower and hospital length of stay generally was 0.2 to 0.5 days shorter for high-income patients. Conclusions and Relevance: High-income individuals had substantially better survival and were more likely to receive lifesaving revascularization and had shorter hospital lengths of stay and fewer readmissions across almost all countries. Our results suggest that income-based disparities were present even in countries with universal health insurance and robust social safety net systems.

The Importance of Race and Ethnicity Data in Cardiovascular Health Research.

The COVID-19 pandemic has underscored the importance of addressing race and ethnic disparities in healthcare worldwide. In Canada, however, the lack of consistent capture of race and ethnicity data has hindered a comprehensive understanding of these potential disparities. This article explores the importance of and current progress in collecting race and ethnic data in Canada and provides examples of its importance in cardiovascular health outcomes. We believe that a successful implementation of standardized data collection tools on race and ethnicity data will shape evidence-based policies to minimize health disparities in Canada in the future.

Restrictive versus liberal transfusion in patients with diabetes undergoing cardiac surgery: An open-label, randomized, blinded outcome evaluation trial.

AIM: To characterize the association between diabetes and transfusion and clinical outcomes in cardiac surgery, and to evaluate whether restrictive transfusion thresholds are harmful in these patients. MATERIALS AND METHODS: The multinational, open-label, randomized controlled TRICS-III trial assessed a restrictive transfusion strategy (haemoglobin [Hb] transfusion threshold <75 g/L) compared with a liberal strategy (Hb <95 g/L for operating room or intensive care unit; or <85 g/L for ward) in patients undergoing cardiac surgery on cardiopulmonary bypass with a moderate-to-high risk of death (EuroSCORE ≥6). Diabetes status was collected preoperatively. The primary composite outcome was all-cause death, stroke, myocardial infarction, and new-onset renal failure requiring dialysis at 6 months. Secondary outcomes included components of the composite outcome at 6 months, and transfusion and clinical outcomes at 28 days. RESULTS: Of the 5092 patients analysed, 1396 (27.4%) had diabetes (restrictive, n = 679; liberal, n = 717). Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes (OR [95% CI] 1.10 [0.93-1.31]) nor the restrictive strategy increased the risk for the primary composite outcome (diabetes OR [95% CI] 1.04 [0.68-1.59] vs. no diabetes OR 1.02 [0.85-1.22]; Pinteraction  = .92). In patients with versus without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion (diabetes OR [95% CI] 0.28 [0.21-0.36]; no diabetes OR [95% CI] 0.40 [0.35-0.47]; Pinteraction  = .04). CONCLUSIONS: The presence of diabetes did not modify the effect of a restrictive transfusion strategy on the primary composite outcome, but improved its efficacy on red cell transfusion. Restrictive transfusion triggers are safe and effective in patients with diabetes undergoing cardiac surgery.

COVID-19 and its Cardiac and Neurological Complications among Ontario Visible Minorities.

BACKGROUND: Due to lack of data on the epidemiology, cardiac, and neurological complications among Ontario visible minorities (Chinese and South Asians) affected by coronavirus disease (COVID-19), this population-based retrospective study was undertaken to study them systematically. METHODS: From January 1, 2020 to September 30, 2020 using the last name algorithm to identify Ontario Chinese and South Asians who were tested positive by PCR for COVID-19, their demographics, cardiac, and neurological complications including hospitalization and emergency visit rates were analyzed compared to the general population. RESULTS: Chinese (N = 1,186) with COVID-19 were found to be older (mean age 50.7 years) compared to the general population (N = 42,547) (mean age 47.6 years) (p < 0.001), while South Asians (N = 3,459) were younger (age of 42.1 years) (p < 0.001). The 30-day crude rate for cardiac complications among Chinese was 169/10,000 (p = 0.069), while for South Asians, it was 64/10,000 (p = 0.008) and, for the general population, it was 112/10,000. For neurological complications, the 30-day crude rate for Chinese was 160/10,000 (p < 0.001); South Asians was 40/10,000 (p = 0.526), and general population was 48/10,000. The 30-day all-cause mortality rate was significantly higher for Chinese at 8.1% vs 5.0% for the general population (p < 0.001), while it was lower in South Asians at 2.1% (p < 0.001). CONCLUSIONS: Chinese and South Asians in Ontario affected by COVID-19 during the first wave of the pandemic were found to have a significant difference in their demographics, cardiac, and neurological outcomes.

Troponin testing after noncardiac surgery: a population-based historical cohort study on variation and factors associated with testing in Ontario.

BACKGROUND: International practice guidelines make different recommendations for postoperative troponin testing to detect perioperative myocardial infarction and myocardial injury after noncardiac surgery. To gain insights into current testing patterns, we evaluated predictors of routine troponin testing after three commonly performed major noncardiac surgeries. METHODS: We conducted a population-based historical cohort study of adults having major orthopedic, colorectal, or vascular surgery in Ontario, Canada from 1 January 2010 to 31 December 2017. We used hierarchical logistic regression modelling to assess the association of patient, surgery, and hospital factors with postoperative troponin testing, while accounting for clustering at the hospital level. We characterized hospital-level variation by the intraclass correlation coefficient (ICC), which was adjusted for various characteristics. RESULTS: The cohort included 176,454 eligible patients. Hospital-specific adjusted testing rates ranged from 0-20.1% for orthopedic surgery, 0-43.8% for colorectal surgery, and 19.6-88.0% for vascular surgery. Older age, urgent surgery status, and surgery duration were consistently associated with higher rates of testing for all three surgeries. Higher Revised Cardiac Risk Index scores were associated with higher odds of testing for orthopedic and colorectal surgery, but not for vascular surgery. Even after adjustment, the ICCs were 9.2%, 7.4%, and 24.1% for orthopedic, general, and vascular surgery, respectively. CONCLUSIONS: Troponin testing varied substantially across hospitals for selected major noncardiac surgery procedures even after accounting for differences in patient-level cardiac risk factors. Our observations lend support to a more standardized approach for troponin testing after noncardiac surgery.

RéSUMé: CONTEXTE: Les directives de pratique internationales émettent différentes recommandations en ce qui concerne les dosages postopératoires de troponines afin de détecter l'infarctus du myocarde et les lésions myocardiques périopératoires après une chirurgie non cardiaque. Pour mieux comprendre les habitudes de test actuelles, nous avons évalué les prédicteurs de dosage de troponines de routine après trois chirurgies non cardiaques majeures couramment réalisées. MéTHODE: Nous avons réalisé une étude de cohorte historique basée sur la population d'adultes bénéficiant d'une chirurgie orthopédique, colorectale ou vasculaire majeure en Ontario, au Canada, entre le 1er janvier 2010 et le 31 décembre 2017. Nous avons utilisé un modèle de régression logistique hiérarchique afin d'évaluer l'association des facteurs liés au patient, à la chirurgie et à l'hôpital avec les dosages de troponines postopératoires, tout en tenant compte des groupements au niveau hospitalier. Nous avons caractérisé la variation hospitalière par le coefficient de corrélation intraclasse (CCI), qui a été ajusté pour tenir compte de diverses caractéristiques. RéSULTATS: La cohorte comprenait 176 454 patients éligibles. Les taux de tests ajustés propres à l'hôpital variaient de 0 à 20,1 % pour les chirurgies orthopédiques, de 0 à 43,8 % pour les chirurgies colorectales et de 19,6 à 88,0 % pour les chirurgies vasculaires. Un âge plus avancé, un statut de chirurgie urgente et la durée de la chirurgie étaient systématiquement associés à des taux plus élevés de dosages pour les trois chirurgies. Des scores plus élevés sur l'Indice de risque cardiaque révisé étaient associés à des probabilités plus élevées de dosages pour les chirurgies orthopédiques et colorectales, mais pas pour les chirurgies vasculaires. Même après ajustement, les CCI étaient de 9,2 %, 7,4 % et 24,1 % pour les chirurgies orthopédiques, générales et vasculaires, respectivement. CONCLUSION: Les dosages de troponines varient considérablement d'un hôpital à l'autre pour certaines interventions chirurgicales non cardiaques majeures, même après avoir pris en compte les différences dans les facteurs de risque cardiaques liés au patient. Nos observations appuient une approche plus standardisée des dosages de troponines après une chirurgie non cardiaque.