Purpose SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) provide cardiovascular (CV) benefits, but their first-line use among adults with severe mental illness (SMI) is not well characterized. We evaluated selective prescribing of SGLT2i, GLP-1 RA, and metformin among adults with SMI and type 2 diabetes (T2D).Methods Using 2017-2022 Medicare claims, we identified adults with SMI and T2D who initiated first-line SGLT2i, GLP-1 RA, or metformin during 1/1/2018-12/31/2021. By calendar year, standardized mean differences (SMD) assessed baseline characteristic differences, and propensity score overlap coefficients (OVL) assessed group comparability between SGLT2i or GLP-1 RA initiators and metformin initiators.Results We identified 1322 SGLT2i, 2306 GLP-1 RA, and 21 144 metformin initiators. From 2018 to 2021, SGLT2i initiators shifted from younger to older than metformin initiators (SMD, -0.11 to 0.19), while differences in CVD (0.10 to 0.50) and CKD (0.18 to 0.62) increased. GLP-1 RA initiators consistently had higher prevalence of obesity (SMD, 0.33 to 0.41) and CKD (0.42 to 0.28) than metformin initiators. Compared with metformin initiators, both SGLT2i and GLP-1 RA initiators had lower prevalence of schizophrenia, antipsychotic use, and recent psychiatrist visits but higher prevalence of major depressive disorder; these differences generally persisted over time. OVL increased from 42.7% to 50.7% for SGLT2i and from 42.3% to 50.0% for GLP-1 RA versus metformin.Conclusions First-line SGLT2i and GLP-1 RA prescribing among adults with SMI was selective according to cardiometabolic and mental health-related characteristics. Future comparative studies should account for these differences and temporal prescribing changes to mitigate confounding.
Background The triglyceride glucose (TyG) index and related obesity metrics are commonly recognized as important indicators of insulin resistance. However, the associations of several novel TyG-related obesity indices developed with venous thromboembolism (VTE) risk and their interactions with genetic susceptibility remain unclear. Methods Cox proportional hazards models were applied to evaluate the associations between TyG-related obesity indices and VTE risk. Restricted cubic spline analyses were conducted to examine the linear and nonlinear relationships. Kaplan-Meier curves were performed to assess the cumulative risk of VTE. The additive interactions were assessed using the relative excess risk due to interaction, attributable proportion due to interaction. Discriminative performance was assessed using receiver operating characteristic curves. Results Participants in the highest quartiles of TyG, TyG-BMI, TyG-WC, TyG-WHtR, TyG-BRI, TyG-ABSI, TyG-WWI, and TyG-VAI exhibited elevated risk of VTE, with HRs (95% CIs) of 1.11 (1.04-1.17), 1.86 (1.76-1.98), 2.08 (1.94-2.22), 1.78 (1.67-1.89), 1.80 (1.70-1.92), 1.24 (1.17-1.33), 1.37 (1.29-1.46), and 1.19 (1.12-1.25), respectively. Individuals in the highest quartiles of TyG-related obesity indices had a higher cumulative incidence of VTE. ROC analysis indicated that TyG-WC and TyG-BRI showed comparatively better discriminative performance for VTE risk compared with other TyG-related obesity indices. Participants with both high genetic risk and high TyG-related obesity indices showed an increased risk of VTE. Conclusion Higher TyG-related obesity indices were associated with an increased risk of VTE. Individuals with both higher quartiles of TyG-related obesity indices and high genetic susceptibility exhibited the highest VTE risk. Additive interactions were observed between TyG-related obesity indices and high genetic risk.
Background Pulmonary embolism (PE) is frequently suspected in emergency departments (EDs). Safely ruling out PE without additional testing could reduce imaging use and ED crowding. Machine learning (ML) may improve accuracy and efficiency. Objectives To evaluate ML models for ruling out PE without additional testing in ED patients with suspected PE, while maintaining a failure rate <2%. Methods We retrospectively analyzed pooled data from four prospective European studies of ED patients with suspected PE (2000-2013). A total of 5,038 patients were randomly split into training (n = 2,400) and validation (n = 2,638) datasets. ML models classified patients into low, intermediate, and high pre-test probability groups. In intermediate-risk patients, post-test probability was refined using either a fixed D-dimer threshold or a second ML model. The primary outcome was the failure rate assessed in the validation cohort and defined as the proportion of missed PE diagnoses. Results The best-performing algorithm combined weighted ridge regression (pre-test) with weighted random forest (posttest), achieving a failure rate of 1.44% (95% CI: 1.04-1.99) and a Matthews correlation coefficient of 0.470 (95% CI: 0.440-0.500). This model ruled out PE without any testing in 9.7% of patients, with an estimated imaging proportion of 54.1%, comparable to 4-level Pulmonary Embolism Clinical Probability Score (4PEPS; 52.9%) and lower than Pulmonary Embolism Rule-out Criteria (PERC; 66.8%). Conclusion A two-step ML algorithm performed comparably to the best existing clinical decision rules, with a failure rate whose confidence interval remained below the prespecified 2% criterion and an estimated imaging proportion similar to 4PEPS. Prospective external validation is warranted.
Background Protein C (PC) is a key anticoagulant protein that regulates hemostatic balance. Hereditary PC deficiency increases the risk of thrombosis. We identified the same mutation, c.1099G > A:p.V325 M (V325 M), in the PROC gene in four unrelated patients with thrombotic events and one patient with recurrent pregnancy loss, prompting further investigation. Objective The objective of this study was to decipher the molecular basis of the clotting defect in patients carrying the V325 M mutation. Methods We expressed and purified both wild-type and mutant PC/activated protein C (APC) in mammalian cells and characterized their properties in established coagulation and cytoprotective assay systems. Results Functional characterization of the recombinant mutant APC revealed multiple defects, including reduced catalytic efficiency toward chromogenic substrates, decreased affinity for Na & thorn;, impaired anticoagulant activity in both purified and plasma systems, and diminished barrier-protective function. In parallel, electrophoretic analysis showed that the mutant APC exhibited an altered isoform distribution compared with wild-type; this difference was eliminated upon treatment with PNGase F for deglycosylation. Conclusion Our studies demonstrate that the V325 M mutation directly impairs the anticoagulant and cytoprotective functions of PC, together with altered Nglycosylation patterns, providing a molecular mechanism for the prothrombotic phenotype observed in the carriers with this mutation.
Background In vitro studies have suggested prothrombotic properties of very low-density lipoproteins (VLDL). Whether differences in VLDL particle size and lipid composition are related to venous thromboembolism (VTE) risk has been scarcely investigated. We aimed to investigate the association between chylomicron and VLDL subfractions and the risk of incident VTE in a population-based cohort. Methods Participants (n = 17,032) from the third survey of the Tr & oslash;ndelag Health Study (HUNT3, 2006-08) were followed through December 31, 2019, and all incident VTE events during follow-up were validated and recorded. Nuclear magnetic resonance (NMR) spectroscopy was used to measure chylomicron and VLDL subfractions (including particle size, concentration, and lipid composition) in serum collected at cohort baseline. Associations between VLDL subfractions and risk of VTE were assessed using Cox regression models, adjusted for age, sex, and body mass index. Results In total, 342 incident VTE cases occurred during a median follow-up of 12.0 years. No associations were found between VLDL particle size, VLDL concentration, VLDL lipid composition, and total triglycerides and VTE risk. All hazard ratios (HRs) per 1 standard deviation increase in VLDL metrics were within the range 0.87 to 1.16 and all 95% confidence intervals (CIs) included 1. Increasing quartiles of total VLDL particles (Q4 vs. Q1 HR: 1.12, 95% CI: 0.80-1.56) and the proportion of larger VLDL particles (Q4 vs. Q1: HR: 1.09, 95% CI: 0.81-1.45) were not associated with VTE risk. Conclusion Total triglycerides and VLDL subfractions, including particle size, concentration, and lipid composition, were not associated with risk of incident VTE.
