Population Health Research Institute

Antiphospholipid antibodies (aPL) are directed against phospholipids and phospholipid-binding proteins. Laboratory assays used to detect aPL include serological tests for aPL against β2-glycoprotein 1, cardiolipin and other molecules, as well as functional assays for lupus anticoagulant. The presence of aPL can lead to endothelial dysfunction or a hypercoagulable state through prothrombotic and antifibrinolytic mechanisms. These processes, often in conjunction with a 'second hit', such as trauma, surgery, or other causes of hypercoagulability or stasis, can lead to venous or arterial thrombosis. The thrombotic risk associated with aPL is best recognized in thrombotic antiphospholipid syndrome, characterized by a persistently positive test for lupus anticoagulant or seropositivity for aPL associated with venous, arterial or microvascular thrombosis. However, aPL seropositivity and its clinical effect on thrombotic events have been increasingly recognized in a broader group of individuals who do not meet traditional research criteria for thrombotic antiphospholipid syndrome. In this Review, we provide an overview of the evidence related to aPL seropositivity in individuals with or without previous thrombosis and the clinical relevance of aPL seropositivity in predicting the risk of thrombotic cardiovascular events. We discuss potential management strategies and identify key knowledge gaps that warrant further research.

Mendelian randomization leverages the random assortment of alleles at conception to investigate how genetically mediated changes in an exposure affect an outcome while minimizing concerns related to reverse causation and unmeasured confounding. Initially applied to assess the causal impact of modifiable traditional risk factors as mediators of disease risk, Mendelian randomization studies now incorporate large-scale multiomic datasets providing valuable insights for drug target discovery. By analyzing cis genetic changes that affect gene activity or protein levels—using advancing techniques like single-cell sequencing and proteomics—Mendelian randomization can identify new therapeutic targets, predict drug target efficacy and effect size before trial development, anticipate adverse effects, reduce late-stage trial failures, and identify opportunities for drug repurposing. This review explains the basic principles, broad applications, and inherent limitations of Mendelian randomization in drug-target identification, validation, and repurposing within the context of kidney disease. Many retrospective examples of concordant conclusions from clinical trials and Mendelian randomization studies have been reported including statins, allopurinol, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Genetic evidence should now be prospectively evaluated for all drugs attempting to traverse the “translational valley of death” in drug development. We summarize current examples, spotlight emerging analytic methodologies such as phenome-wide Mendelian randomization and integrated multiomics, and discuss future directions to accelerate drug development in nephrology.

Approximately one-third-of patients with transient new-onset atrial fibrillation (AF) during hospitalization for noncardiac surgery or medical illness will have recurrent AF within 1 year when assessed using two 14-day ECG monitors. The proportion of patients that would be diagnosed with recurrent AF with less monitoring is unknown. We used data from a prospective cohort of participants with transient new-onset AF while hospitalized for noncardiac surgery or medical illness, who wore one or two 14-day ECG monitors. We calculated the proportion of patients that would be diagnosed with recurrent AF with different durations of ECG monitoring and the median time-to-detection of recurrent AF lasting ≥30 s. A total of 139 participants (41.0 % female, median CHA2DS2-VASc 3) wore an ECG monitor a median of 1.5 months following hospital discharge; 83 (59.7 %) wore a second monitor at median of 5.8 months after the first monitor. Recurrent AF was detected in 5.0 % of participants by 1 day, 5.8 % by 2 days, 6.5 % by 3 days, 12.2 % by 7 days, 21.6 % by 14 days and in 28.8 % by the end of the second 14-day monitor. Median monitoring time to recurrent AF was 5.3 (IQR 1.4-9.7) days. In patients with transient new-onset AF during hospitalization for another reason, the rate of detection of recurrent AF increased with longer monitoring durations. Approximately 80 % of diagnoses were made after 2 days of monitoring; the likelihood of capturing recurrent AF was 4 times higher with 14 days of monitoring compared to 2 days.

Background: Despite robust evidence supporting intravascular imaging (IVI) to guide complex percutaneous coronary intervention (PCI), its adoption across Canada remains poorly defined.Methods: A standardized cross-sectional electronic survey was distributed to catheterization laboratory directors across Canada.Results: Sites were evenly distributed between academic 9 (43%) and non-academic 12 (57%) institutions, with a mean annual PCI volume of 1706722 procedures.IVI integration into the catheterization laboratory was reported in 38/56 (68%) of laboratories, with a median of 6 PCI operators (IQR 5-9) per site.Operator comfort levels were generally good, with the majority of catheterization laboratory directors describing their operators as somewhat 6 (29%) or very experienced 9 (43%).Most directors (90%) perceived IVI to have a positive impact on outcomes.Overall, there was a trend toward an increase in IVI-guided PCI between 2022 and 2024 (15.6% vs. 19.1%,p=0.7).The most cited barriers to broader IVI use were increased procedure time (76%), cost of equipment or devices (67%), and reimbursement challenges (48%), with no differences between Ontario and non-Ontario sites (40% vs. 33%, p=1.0).Over half (52%) of centers planned IVI upgrades within the next two years.Conclusions: Although IVI is widely available in Canadian catheterization laboratories, it remains underused due to barriers related to procedure time, workflow, and cost.A coordinated effort among key stakeholders is needed to reduce current barriers and promote broader guideline-concordant use IVI adoption.

Introduction: The spot sign identified on CT angiography (CTA), is a well-established predictor of hematoma expansion (HE), but its role in FXai-related intracerebral hemorrhage (ICH) remains poorly explored. We investigated the association between spot sign and HE in patients with acute FXai-associated ICH and to assess whether its presence modified the treatment effect of andexanet alfa. Methods: Participants with a qualifying ICH on baseline brain imaging and available CTA at baseline were included in this post-hoc analysis of the ANNEXa-I trial. Imaging analyses assessed the presence of spot sign and its features (e.g., number, maximum diameter, maximum density, co-localization with hypodensity). HE was defined as a hematoma volume increase of ≥12.5 mL or ≥35% between baseline and 12 hours after randomization. The association between spot sign presence and its characteristics with HE was assessed with logistic regression analysis adjusted for time from symptom onset to scan, baseline hematoma volume, and diastolic blood pressure. The treatment effect modification of andexanet on HE by these imaging variables was assessed with a multivariable regression analysis. Results: Of the 530 patients in the intention-to-treat population, 156 had CTA performed and were included in this study (66 [42.3%] female, mean [ + SD] age 78.5 [±7.8]) ( Table 1 ). HE was observed in 55 (35.7%) patients and 31 (20.1%) patients had a spot sign. Spot sign presence (adjusted odds ratio [aOR] 4.24 [95% CI=1.55-11.56]), as well as some of its features, such as diameter >5 mm (aOR 5.40 [95% CI=1.39-20.97]), central location (aOR 7.76 [95%CI=1.63-37.03]), and co-localization with a hypodensity (aOR 6.56, [95%CI=1.46-29.50]) were associated with HE following multivariable adjustment ( Table 2 ). HE occurred in 36 (29.3%) patients with no spot sign (andexanet 20% vs. usual care 38.1%; NNT with andexanet to prevent HE: 5.6) and in 19 (61.3%) with a spot sign (andexanet 45% vs. usual care 90.9%; NNT with andexanet to prevent HE: 2.2). No significant heterogeneity in the proportional reduction of HE with andexanet was observed based on spot sign presence (p-interaction=0.150) or its characteristics ( Figure 1 ). Conclusions: The presence of the spot sign and its features were significantly associated with HE in FXai-associated ICH. The treatment effect of andexanet was still consistent regardless of the presence of the spot sign and its features

Infliximab's efficacy as a second-line agent in moderate or severe ulcerative colitis after prior advanced therapy failure is unclear. Registration trials for infliximab did not assess its efficacy after exposure to other advanced therapies, a sequence in which it is increasingly used. We evaluate infliximab's second-line effectiveness, identify predictors of response, and compare outcomes to its first-line use. We conducted a retrospective cohort study of adults with ulcerative colitis treated with infliximab at a tertiary care center. Patients were categorized by line of therapy. Clinical and endoscopic outcomes at 1 year were compared between first-line and second-line users. Multivariable logistic regression was used to assess predictors of 1-year clinical remission. Among 225 included patients, 143 received infliximab first-line and 82 as second-line or subsequent therapy. Clinical response at 1 year was significantly lower in second-line users (odds ratio 0.53, 95% confidence interval: 0.28-0.99, P = 0.049) and remained significantly lower after adjustment for biosimilar and concurrent steroid use. Dose escalation was more common with second-line use (57.3% vs. 42.0%, P = 0.026). Endoscopic and histologic remission was numerically lower in second-line users (47.7% vs. 33.3% and 27.0% vs. 41.7%, respectively), though these were not statistically significant (P = 0.180 and 0.099, respectively). Infliximab remains effective as a second-line agent in ulcerative colitis, though with reduced response and higher rates of dose escalation as compared to use first-line. These findings support its continued use while highlighting the need for optimized patient selection and treatment strategies in therapy-exposed populations.