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To utilize the UK Biobank to identify genetic variants associated with the ICD10 (International Classification of Diseases10)-based diagnosis of cerebrovascular disease (CeVD). Cerebrovascular disease occurs because of a complex interplay between vascular, environmental, and genetic factors. It is the second leading cause of disability worldwide. Understanding who may be genetically predisposed to cerebrovascular disease can help guide preventative efforts. Moreover, there is considerable interest in the use of real-world data, such as EHR (electronic health records) to better understand disease mechanisms and to discover new treatment strategies, but whether ICD10-based diagnosis can be used to study CeVD genetics is unknown. Using the UK Biobank, we conducted a genome-wide association study (GWAS) where we analyzed the genomes of 11,155 cases and 122,705 controls who were sex, age and ancestry-matched in a 1:11 case: control design. Genetic variants were identified by Plink's firth logistic regression and assessed for association with the ICD10 codes corresponding to CeVD. We identified two groups of SNPs closely linked to PITX2 and LRRTM4 that were significantly associated with CeVD in this study (p < 5 x 10-8) and had a minor allele frequency of > 0.5%. Disease assignment based on ICD10 codes may underestimate prevalence; however, for CeVD, this does not appear to be the case. Compared to the age- and sex-matched control population, individuals with CeVD were more frequently diagnosed with comorbid conditions, such as hypertension, hyperlipidemia & atrial fibrillation or flutter, confirming their contribution to CeVD. The UK Biobank based ICD10 study identified 2 groups of variants that were associated with CeVD. The association between PITX2 and CeVD is likely explained by the increased rates of atrial fibrillation and flutter. While the mechanism explaining the relationship between LRRTM4 and CeVD is unclear, this has been documented in previous studies.

Stent thrombosis (ST) is an uncommon but serious complication of stent implantation. This study aimed to explore factors associated with early, late, and very late ST to help guide risk assessment and clinical decision-making on ST. The analysis included patients who received stent placement for the index acute coronary syndrome (ACS). Cumulative incidence of ST was assessed at 30 days (early ST), 31-360 days (late ST), 361-720 days (very late ST), and up to 720 days. Cox proportional hazards models were used to assess associations between ST and various factors, including patient characteristics [i.e., age, sex, ACS presentation, history of hypertension, smoking, diabetes, prior myocardial infarction (MI), heart failure, prior ischemic stroke, and cancer], laboratory tests [i.e., positive cardiac biomarker, hemoglobin, platelet count, white blood cell (WBC) count], and treatment [i.e., drug-eluting stent (DES) vs. bare-metal stent (BMS) and anticoagulant with rivaroxaban vs. placebo]. Among the 8,741 stented patients, 155 ST events (2.25%) occurred by Day 720. The cumulative incidences of early, late, and very late ST were 0.80%, 0.81%, and 0.77%, respectively. After multivariable adjustment, age ≥ 75 [hazard ratio (HR) = 2.13 (95% confidence interval, CI: 1.26-3.60)], a history of prior MI [HR = 1.81 (95% CI: 1.22-2.68)], low hemoglobin level [HR = 2.34 (95% CI: 1.59-3.44)], and high WBC count [HR = 1.58 (95% CI: 1.02-2.46)] were associated with a greater risk of overall ST, whereas DES [HR = 0.56 (95% CI: 0.38-0.83)] and rivaroxaban therapy [HR = 0.63 (95% CI: 0.44-0.88)] were associated with a lower risk of overall ST up to 720 days. Low hemoglobin level and high WBC count were associated with early ST (low hemoglobin: HR = 2.35 [95% CI: 1.34-4.12]; high WBC count: HR = 2.11 [95% CI: 1.17-3.81]). Low hemoglobin level and prior MI were associated with a greater risk of late ST (low hemoglobin: HR = 2.32 [95% CI: 1.26-4.27]; prior MI: HR = 2.98 [95% CI: 1.67-5.31]), whereas DES was associated with a lower risk of late ST [HR = 0.33 (95% CI: 0.16-0.67)]. Age ≥75 years was associated with very late ST. The study identified positive and negative associations with early, late, and very late ST. These variables may be useful in constructing risk assessment models for ST. http://www.clinicaltrials.gov, identifier NCT00809965.

The identification of acutely ill patients at high risk for venous thromboembolism (VTE) may be determined clinically or by use of integer‐based scoring systems. These scores demonstrated modest performance in external data sets. To evaluate the performance of machine learning models compared to the IMPROVE score. The APEX trial randomized 7513 acutely medically ill patients to extended duration betrixaban vs. enoxaparin. Including 68 variables, a super learner model (ML) was built to predict VTE by combining estimates from 5 families of candidate models. A “reduced” model (rML) was also developed using 16 variables that were thought, a priori, to be associated with VTE. The IMPROVE score was calculated for each patient. Model performance was assessed by discrimination and calibration to predict a composite VTE end point. The frequency of predicted risks of VTE were plotted and divided into tertiles. VTE risks were compared across tertiles. The ML and rML algorithms outperformed the IMPROVE score in predicting VTE (c‐statistic: 0.69, 0.68 and 0.59, respectively). The Hosmer‐Lemeshow goodness‐of‐fit P‐value was 0.06 for ML, 0.44 for rML, and <0.001 for the IMPROVE score. The observed event rate in the lowest tertile was 2.5%, 4.8% in tertile 2, and 11.4% in the highest tertile. Patients in the highest tertile of VTE risk had a 5‐fold increase in odds of VTE compared to the lowest tertile. The super learner algorithms improved discrimination and calibration compared to the IMPROVE score for predicting VTE in acute medically ill patients.

To utilize the UK Biobank to identify genetic variants associated with the ICD10 (International Classification of Diseases10)-based diagnosis of cerebrovascular disease (CeVD). Cerebrovascular disease occurs because of a complex interplay between vascular, environmental, and genetic factors. It is the second leading cause of disability worldwide. Understanding who may be genetically predisposed to cerebrovascular disease can help guide preventative efforts. Moreover, there is considerable interest in the use of real-world data, such as EHR (electronic health records) to better understand disease mechanisms and to discover new treatment strategies, but whether ICD10-based diagnosis can be used to study CeVD genetics is unknown. Using the UK Biobank, we conducted a genome-wide association study (GWAS) where we analyzed the genomes of 11,155 cases and 122,705 controls who were sex, age and ancestry-matched in a 1:11 case: control design. Genetic variants were identified by Plink's firth logistic regression and assessed for association with the ICD10 codes corresponding to CeVD. We identified two groups of SNPs closely linked to PITX2 and LRRTM4 that were significantly associated with CeVD in this study (p 0.5%. Disease assignment based on ICD10 codes may underestimate prevalence; however, for CeVD, this does not appear to be the case. Compared to the age- and sex-matched control population, individuals with CeVD were more frequently diagnosed with comorbid conditions, such as hypertension, hyperlipidemia & atrial fibrillation or flutter, confirming their contribution to CeVD. The UK Biobank based ICD10 study identified 2 groups of variants that were associated with CeVD. The association between PITX2 and CeVD is likely explained by the increased rates of atrial fibrillation and flutter. While the mechanism explaining the relationship between LRRTM4 and CeVD is unclear, this has been documented in previous studies.

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.

An elevated white blood cell (WBC) count is associated with an increased risk of ischemic events among acute coronary syndrome (ACS) patients, but the association between WBC count and bleeding in ACS patients is not well established. The aim of this analysis was to assess and compare the association between WBC count and the occurrence of short- and long-term bleeding and ischemic events. This was a post hoc analysis of the ATLAS ACS2-TIMI 51 trial. A subset of patients had a WBC count measurement at baseline (n = 14,231, 91.6%). Univariate and multivariable Cox proportional hazard models were constructed to determine if there is an association between WBC count at baseline and a composite outcome of Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeds at 30 days and 1 year. Variables with a p <0.2 in the univariate analysis were included as potential parameters in the backward selection process A similar multivariable model was constructed to assess the association between WBC count and a composite ischemic endpoint of cardiovascular death, myocardial infarction and stroke. An increased risk of bleeding per a 1 × 109/L increase in WBC at baseline was observed at 30 days (Adjusted hazard ratio [HR] 1.08 95% confidence interval [CI] 1.01 to 1.17, p = 0.019) but not at 1 year (Adjusted HR 1.02 95% CI 0.97 to 1.08, p = 0.409). Additionally, an increased risk of ischemia per a 1 × 109/L increase in WBC at baseline was observed at 30 days (Adjusted HR 1.07, 95% CI: 1.03 to 1.12, p = 0.002) and at 1 year (Adjusted HR 1.05 95% CI 1.02 to 1.08, p = 0.001 at 1 year). In conclusion, a higher WBC count at baseline was associated with an increased risk of the composite bleeding endpoint by 30 days but not at 1 year. The association between WBC count and the risk of the composite ischemic endpoint was significant at 30 days and 1 year.

Background: While obesity is associated with an increased risk of venous thromboembolism (VTE), there is some data to suggest that higher BMI is also associated with decreased all-cause mortality in patients with a pulmonary embolism (PE). Methods: Using PE Response Team (PERT) activation data from a large tertiary hospital between 27 October 2020 and 28 August 2023, we constructed a multivariate Cox proportional hazards model to assess the association between obesity as a dichotomous variable (defined as BMI ≥ 30 vs. BMI 18.5–29.9), BMI as a continuous variable, and 30-day PE-related mortality. Results: A total of 248 patients were included in this analysis (150 with obesity and 98 who were in the normal/overweight category). Obesity was associated with a lower risk of 30-day PE-related mortality (adjusted HR 0.29, p = 0.036, 95% CI 0.09–0.92). A higher BMI was paradoxically associated with a lower risk of PE-related mortality (HR = 0.91 per 1 kg/m2 increase, p = 0.049, 95% CI 0.83–0.999). Conclusions: In our contemporary cohort of patients with a PERT activation, obesity was associated with a lower risk of PE-related mortality.

Despite the significant improvement in treatment options, cardiovascular disease (CVD), continues to be one of the leading causes of morbidity and mortality in the United States for almost a century. The increasing availability of more potent antithrombotic medication carries a significant therapeutic benefit in patients with acute coronary syndrome (ACS). However, this increased benefit comes with potentially significant side effects. Theoretically, rivaroxaban would have the greatest benefit in patients who are at a very high risk of another cardiovascular event but are at a very low risk of a bleeding event. While certain demographic characteristics may help risk stratify patients, this process can be further refined by incorporating biomarkers. This thesis will focus on both ischemic and bleeding outcomes, both highly relevant in a clinical setting. Additionally, we will demonstrate the applicability of these biomarkers in a new and growing population of patients with ACS, those who are also on rivaroxaban. Ultimately, our aim is to highlight the potential of biomarkers in aiding a physician decide on the appropriate treatment.