Abstract Hip fracture is a disabling event experienced disproportionately by older adults with Alzheimer’s disease or related dementias (ADRD). Understanding how to better prognosticate outcomes for this population could drive more tailored clinical decision making. Our objective was to identify distinct trajectories of health before a hip fracture and determine their influences on post-fracture recovery trajectories and 1-year mortality rates among older adults with Alzheimer’s disease or related dementias (ADRD). We conducted a cohort study of 16,576 community-dwelling Medicare beneficiaries living with ADRD who experienced hip fracture between 2010 and 2017. We used latent mixture modeling to evaluate trajectories of days at home assessed monthly up to 180 days prior to hospitalization, and their associations with post-fracture days at home and 1-year mortality. Before a hip fracture, 3 distinct trajectories were identified: Robust (n=14,980, 90.3%), Impaired but Improving (n=809, 5.3%), and Impaired and Declining (n=787, 4.7%). Membership in the Impaired and Declining pre-fracture trajectory was strongly associated with membership in less favorable post-fracture recovery trajectories and 65% higher 1-year mortality rate (hazard ratio 1.65, 95% confidence interval 1.45-1.87) as compared to those in the Robust trajectory group. Similar albeit weaker associations were observed between membership in the Impaired but Improving pre-fracture trajectory and post-fracture outcomes. Overall, our results indicate that pre-fracture days at home trajectories are highly associated with post-hospitalization outcomes among older adults with ADRD and could be used to guide care management decisions.

OBJECTIVE:To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects.METHODS:Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype.RESULTS:Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses.CONCLUSIONS:Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Abstract Background Polygenic risk scores (PRS) for coronary artery disease (CAD) are emerging as a potential method to improve cardiovascular risk prediction. Questions remain about their applicability to diverse populations as well as their correlation with coronary histopathology. Purpose To assess whether high genetic risk associates with histopathologic coronary plaque morphology. Methods We assessed 122 known CAD risk loci in 954 Black and White subjects within our sudden death registry to generate a PRS. The cohort was divided into quintiles according to z-score-standardized PRS, both in a race-stratified fashion and in the pooled sample. Detailed histopathologic examination of the coronary arteries was performed in all subjects. Results Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared to subjects in the lowest quintile, with greater mean cross-sectional luminal narrowing (71.5% (95% CI, 66.6%-76.5%) vs. 56.6% (95% CI, 51.1%-62.1%); adjusted p<0.001; Figure 1) and a higher frequency of calcification (adjusted OR 2.19; 95% CI 1.31–3.68; p=0.003) after adjustment for the first 10 principal components, age, sex, and race. Higher z-score-standardized PRS was predictive for the finding of severe atherosclerosis (i.e., ≥75% cross-sectional luminal narrowing) even after additional controlling for traditional CAD risk factors including hypertension, smoking, diabetes mellitus, and hyperlipidemia (adjusted OR 1.39; 95% CI 1.19–1.63; p<0.001; Figure 2). Among Black subjects, higher PRS was associated with higher odds of plaque rupture (adjusted OR 1.31; 95% CI 1.03–1.66; p=0.03) and predicted CAD-associated cause of death among subjects younger than 50 years old (adjusted OR 1.26; 95% CI 1.01–1.58; p=0.04). Conclusions This is the first autopsy study investigating associations between PRS and atherosclerotic plaque morphology at a histopathologic level. Our pathological analysis suggests PRS correlates with plaque burden and coronary artery calcification and may be useful as a method for CAD risk stratification, especially in younger subjects. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): R01 HL141425 Leducq Foundation Grant

Introduction PRONTO!, Victoria’s community based rapid point of care (RPOC) testing service, opened in August 2013. RPOC syphilis testing was introduced in June 2014. To assess the need and feasibility of comprehensive STI testing at PRONTO! a Neisseria gonorrhoea (NG) and Chlamydia trachomatis (CT) testing trial was conducted in November–December 2014. We describe site specific positivity of NG and CT infection and the characteristics of gay, bisexual and other men who have sex with men (GBM) testing positive. Methods All GBM testing for HIV between November 7-December 23 2014 were offered NG and CT testing, with clients instructed in the self-collection of anal, genital and throat swabs. Client characteristics were collected using standard PRONTO! client surveys and matched to test results. All clients with an infection were notified by telephone and referred to a high caseload clinic for treatment. Results Among 239 clients, 186 (78%) opted to receive NG and CT tests and 35 (18.8%) tested positive for at least one of NG or CT. Of the 22 (11.8%) positive NG results, there were nine anal (5.0%), two urethral (1.1%), and 15 throat (8.2%) infections. Of the 17 (9.1%) positive CT results, there were 12 anal (6.6%), eight urethral (4.3%), and three throat (1.6%) infections. Twelve men (6.4%) tested positive for more than one STI or at multiple sites. Demographic and risk characteristics were largely similar between men testing positive or negative for NG and/or CT with the exception that group sex in the previous six months was associated with both CT (OR = 4.65; 95% CI = 0.96–7.3) and NG (OR = 2.54; 95% CI = 1.02–6.33) positivity. Conclusion STI testing using self-collected samples is a feasible model for screening in a community-based RPOC testing service. The high prevalence of infections and acceptability testing for bacterial STIs supports the introduction of comprehensive STI screening at PRONTO!. Disclosure of interest statement All authors have no conflicts to declare. The Victorian Department of Health funds the PRONTO! service which is run by the Victorian AIDS Council. The authors would like to acknowledge the NHMRC who provide funding to Kathleen Ryan as a public health scholarship recipient and Mark Stoové through a Career Development Fellowship. The authors gratefully acknowledge the contribution to this work of Victorian Operational Infrastructure Support Program received by the Burnet Institute.

Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively.

A common functional variant in paraoxonase 1 (PON1), Q192R, was recently reported to be a major determinant of clopidogrel response. This variant was genotyped in 566 participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) study and in 227 percutaneous coronary intervention (PCI) patients. Serum paraoxonase activity was measured in a subset of 79 PAPI participants. PON1 Q192R was not associated with pre- or post-clopidogrel platelet aggregation in the PAPI study (P = 0.16 and P = 0.21, respectively) or the PCI cohort (P = 0.47 and P = 0.91, respectively). The Q192 allele was not associated with cardiovascular events (hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.20-1.06; P = 0.07). No correlation was observed between paraoxonase activity and post-clopidogrel platelet aggregation (r(2) < 0.01, P = 0.78). None of 49 additional PON1 variants evaluated was associated with post-clopidogrel platelet aggregation. These findings do not support a role for PON1 as a determinant of clopidogrel response.