Evaluation of respondent-driven sampling in seven studies of people who use drugs from rural populations: findings from the Rural Opioid Initiative.

BACKGROUND: Accurate prevalence estimates of drug use and its harms are important to characterize burden and develop interventions to reduce negative health outcomes and disparities. Lack of a sampling frame for marginalized/stigmatized populations, including persons who use drugs (PWUD) in rural settings, makes this challenging. Respondent-driven sampling (RDS) is frequently used to recruit PWUD. However, the validity of RDS-generated population-level prevalence estimates relies on assumptions that should be evaluated. METHODS: RDS was used to recruit PWUD across seven Rural Opioid Initiative studies between 2018-2020. To evaluate RDS assumptions, we computed recruitment homophily and design effects, generated convergence and bottleneck plots, and tested for recruitment and degree differences. We compared sample proportions with three RDS-adjusted estimators (two variations of RDS-I and RDS-II) for five variables of interest (past 30-day use of heroin, fentanyl, and methamphetamine; past 6-month homelessness; and being positive for hepatitis C virus (HCV) antibody) using linear regression with robust confidence intervals. We compared regression estimates for the associations between HCV positive antibody status and (a) heroin use, (b) fentanyl use, and (c) age using RDS-1 and RDS-II probability weights and no weights using logistic and modified Poisson regression and random-effects meta-analyses. RESULTS: Among 2,842 PWUD, median age was 34 years and 43% were female. Most participants (54%) reported opioids as their drug of choice, however regional differences were present (e.g., methamphetamine range: 4-52%). Many recruitment chains were not long enough to achieve sample equilibrium. Recruitment homophily was present for some variables. Differences with respect to recruitment and degree varied across studies. Prevalence estimates varied only slightly with different RDS weighting approaches, most confidence intervals overlapped. Variations in measures of association varied little based on weighting approach. CONCLUSIONS: RDS was a useful recruitment tool for PWUD in rural settings. However, several violations of key RDS assumptions were observed which slightly impacts estimation of proportion although not associations.

Investigating peripheral blood monocyte and T-cell subsets as non-invasive biomarkers for asymptomatic hepatic steatosis: results from the Multi-Ethnic Study of Atherosclerosis.

Background: Circulating immune cells have gained interest as biomarkers of hepatic steatosis. Data on the relationships between immune cell subsets and early-stage steatosis in population-based cohorts are limited. Methods: This study included 1,944 asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with immune cell phenotyping and computed tomography measures of liver fat. Participants with heavy alcohol use were excluded. A liver-to-spleen ratio Hounsfield units (HU) <1.0 and liver attenuation <40 HU were used to diagnose liver fat presence and >30% liver fat content, respectively. Logistic regression estimated cross-sectional associations of immune cell subsets with liver fat parameters adjusted for risk factors. We hypothesized that higher proportions of non-classical monocytes, Th1, Th17, and memory CD4+ T cells, and lower proportions of classical monocytes and naive CD4+ T cells, were associated with liver fat. Exploratory analyses evaluated additional immune cell phenotypes (n = 19). Results: None of the hypothesized cells were associated with presence of liver fat. Higher memory CD4+ T cells were associated with >30% liver fat content, but this was not significant after correction for multiple hypothesis testing (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.03, 1.66). In exploratory analyses unadjusted for multiple testing, higher proportions of CD8+CD57+ T cells were associated with liver fat presence (OR: 1.21, 95% CI: 1.02, 1.44) and >30% liver fat content (OR: 1.34, 95% CI: 1.07, 1.69). Conclusions: Higher circulating memory CD4+ T cells may reflect liver fat severity. CD8+CD57+ cells were associated with liver fat presence and severity, but replication of findings is required.

Association of Alcohol Use with COVID-19 Infection and Hospitalization Among People Living with HIV in the United States, 2020.

Alcohol use was associated with elevated COVID-19 risk in the general population. People with HIV (PWH) have high prevalences of alcohol use. To evaluate the effect of alcohol use on COVID-19 risks among PWH, we estimated the risk of COVID-19 diagnosis and COVID-19-related hospitalization among PWH in routine care at 8 HIV primary care centers that contributed data to the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort according to their alcohol use just prior to the COVID-19 pandemic. The CNICS data repository includes demographic characteristics, clinical diagnoses, and laboratory test results from electronic medical records and other sources. Alcohol use, substance use, and mental health symptoms were self-reported on tablet-based standardized surveys. Alcohol use was categorized according to standard, sex-specific Alcohol Use Disorder Identification Test-Consumption instrument cut-offs. We followed 5,496 PWH (79% male, 48% Black race, median age = 53 years) from March 1, 2020 to December 31, 2020. Relative to PWH with no baseline alcohol use, the adjusted hazard ratio (aHR) of COVID-19 diagnosis was 1.09 (95% confidence interval [CI]: 0.78, 1.51) for lower-risk drinking and 1.19 (95%CI: 0.81, 1.73) for unhealthy drinking. The aHR of COVID-19-related hospitalization was 0.82 (95%CI: 0.33, 1.99) for lower-risk drinking and 1.25 (95%CI: 0.50, 3.09) for unhealthy drinking. Results were not modified by recent cocaine or non-prescribed opioid use, depressive symptoms, or diagnoses of alcohol use disorder. The study suggested a slightly increased, but not statistically significant risk of COVID-19 diagnosis and hospitalization associated with unhealthy alcohol use.

Prescribing trends of proton pump inhibitors and histamine blockers among children in the United Kingdom (1998-2019): A population-based assessment.

PURPOSE: To describe the prescribing trends of proton pump inhibitors (PPIs) and H2 receptor antagonists (H2 RAs) among children with gastroesophageal reflux in the United Kingdom between 1998 and 2019. METHODS: We conducted a population-based retrospective cohort study using data from the Clinical Practice Research Datalink that included all children aged ≤18 years with a first ever diagnosis of gastroesophageal reflux between 1998 and 2019. Using negative binomial regression, we estimated crude and adjusted annual prescription rates per 1000 person-years and corresponding 95% confidence intervals (CIs) for PPIs and H2 RAs. We also assessed rate ratios of PPIs and H2 RAs prescription rates to examine changes in prescribing over time. RESULTS: Our cohort included 177 477 children with a first ever diagnosis of gastroesophageal reflux during the study period. The median age was 13 years (IQR: 1, 17) among children prescribed PPIs and 0.2 years (IQR: 0.1, 0.6) among those prescribed H2 RAs. The total prescription rate of all GERD drugs was 1468 prescriptions per 1000 person-years (PYs) (95% CI 1463-1472). Overall, PPIs had a higher prescription rate (815 per 1000 PYs, 95% CI 812-818) than H2 RAs (653 per 1000 PYs 95% CI 650-655). Sex- and age-adjusted rate ratios of 2019 versus 1998 demonstrated a 10% increase and a 76% decrease in the prescription rates of PPIs and H2 RAs, respectively. CONCLUSIONS: Prescription rates for PPIs increased, especially during the first half of the study period, while prescription rates for H2 RA decreased over time.

Retrospective Cohort Studies in Craniofacial Outcomes Research: An Epidemiologist's Approach to Mitigating Bias.

Retrospective cohort studies, defined as a follow-up study in which outcome occurred prior to study onset, are common in craniofacial outcomes research and will continue to be prevalent given the increasing availability of secondary datasets and inherent prospective study limitations. However, if available data are not adequately measured, or necessary variables are absent, retrospective cohort studies can be particularly prone to bias. This brief communication aims to highlight the primary sources of bias, including measurement error, selection bias, and confounding. Each source is clearly defined, examples pertinent to craniofacial outcomes are provided, and mitigation strategies are discussed.

Weight loss associated with semaglutide treatment among people with HIV.

OBJECTIVE: There is limited real-world evidence about the effectiveness of semaglutide for weight loss among people with HIV (PWH). We aimed to investigate weight change in a US cohort of PWH who initiated semaglutide treatment. DESIGN: Observational study using the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. METHODS: We identified adult PWH who initiated semaglutide between 2018 and 2022 and with at least two weight measurements. The primary outcome was within-person bodyweight change in kilograms at 1 year. The secondary outcome was within-person Hemoglobin A1c percentage (HbA1c) change. Both outcomes were estimated using multivariable linear mixed model. RESULTS: In total, 222 new users of semaglutide met inclusion criteria. Mean follow-up was 1.1 years. Approximately 75% of new semaglutide users were men, and at baseline, mean age was 53 years [standard deviation (SD): 10], average weight was 108 kg (SD: 23), mean BMI was 35.5 kg/m 2 , mean HbA1c was 7.7% and 77% had clinically recognized diabetes. At baseline, 97% were on ART and 89% were virally suppressed (viral load < 50 copies/ml). In the adjusted mixed model analysis, treatment with semaglutide was associated with an average weight loss of 6.47 kg at 1 year (95% CI -7.67 to -5.18) and with a reduction in HbA1c of 1.07% at 1 year (95% CI -1.64 to -0.50) among the 157 PWH with a postindex HbA1c value. CONCLUSION: Semaglutide was associated with significant weight loss and HbA1c reduction among PWH, comparable to results of previous studies from the general population.

Venous Thromboembolism Among People With HIV: Design, Implementation, and Findings of a Centralized Adjudication System in Clinical Care Sites Across the United States.

BACKGROUND: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era. METHODS: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking. RESULTS: We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common. CONCLUSIONS: We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common.

Evaluating the Sick Quitting Hypothesis for Frailty Status and Reducing Alcohol Use Among People With HIV in a Longitudinal Clinical Cohort Study.

ABSTRACT: "Sick quitting," a phenomenon describing reductions in alcohol consumption following poor health, may explain observations that alcohol appears protective for frailty risk. We examined associations between frailty and reductions in drinking frequency among people with HIV (PWH). At six Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between January 2012 and August 2021, we assessed whether frailty, measured through validated modified frailty phenotype, precedes reductions in drinking frequency. We associated time-updated frailty with quitting and reducing frequency of any drinking and heavy episodic drinking (HED), adjusted for demographic and clinical characteristics in Cox models. Among 5,654 PWH reporting drinking, 60% reported >monthly drinking and 18% reported ≥monthly HED. Over an average of 5.4 years, frail PWH had greater probabilities of quitting (HR: 1.56, 95% confidence interval [95% CI] [1.13-2.15]) and reducing (HR: 1.35, 95% CI [1.13-1.62]) drinking frequency, as well as reducing HED frequency (HR: 1.58, 95% CI [1.20-2.09]) versus robust PWH. Sick quitting likely confounds the association between alcohol use and frailty risk, requiring investigation for control.

Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus.

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.

Developing a prediction model of children asthma risk using population-based family history health records.

BACKGROUND: Identifying children at high risk of developing asthma can facilitate prevention and early management strategies. We developed a prediction model of children's asthma risk using objectively collected population-based children and parental histories of comorbidities. METHODS: We conducted a retrospective population-based cohort study using administrative data from Manitoba, Canada, and included children born from 1974 to 2000 with linkages to ≥1 parent. We identified asthma and prior comorbid condition diagnoses from hospital and outpatient records. We used two machine-learning models: least absolute shrinkage and selection operator (LASSO) logistic regression (LR) and random forest (RF) to identify important predictors. The predictors in the base model included children's demographics, allergic conditions, respiratory infections, and parental asthma. Subsequent models included additional multiple comorbidities for children and parents. RESULTS: The cohort included 195,666 children: 51.3% were males and 17.7% had asthma diagnosis. The base LR model achieved a low predictive performance with sensitivity of 0.47, 95% confidence interval (0.45-0.48), and specificity of 0.67 (0.66-0.67) using a predicted probability threshold of 0.20. Sensitivity significantly improved when children's comorbidities were included using LASSO LR: 0.71 (0.69-0.72). Predictive performance further improved by including parental comorbidities (sensitivity = 0.72 [0.70-0.73], specificity = 0.69 [0.69-0.70]). We observed similar results for the RF models. Children's menstrual disorders and mood and anxiety disorders, parental lipid metabolism disorders and asthma were among the most important variables that predicted asthma risk. CONCLUSION: Including children and parental comorbidities to children's asthma prediction models improves their accuracy.

Assessing the associations between known genetic variants and substance use in people with HIV in the United States.

BACKGROUND: The prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH. METHODS: We performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations. RESULTS: We observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation. CONCLUSIONS: Our analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population.

Methamphetamine use and utilization of medications for opioid use disorder among rural people who use drugs.

BACKGROUND: Methamphetamine use is common among persons with opioid use disorder. This study evaluated associations between methamphetamine use and treatment with agonist medications for opioid use disorder (MOUD, specifically buprenorphine, and/or methadone) in U.S. rural communities. METHODS: The Rural Opioid Initiative (ROI) is a consortium spanning 10 states and 65 rural counties that included persons who reported past 30-day use of opioids and/or injection drug use between 1/2018 and 3/2020. Analyses were restricted to participants who had ever used opioids and had data on past 30-day methamphetamine use. Multivariable models examined the relationship between methamphetamine use and utilization of agonist MOUD. RESULTS: Among 2899 participants, 2179 (75.2%) also reported recent methamphetamine use. Persons with methamphetamine use compared to those without were younger, more likely to have injected drugs, be unhoused, criminal justice involved, and less likely to have health insurance. Adjusted for age, sex, race, and study site, recent methamphetamine use was associated with lower relative odds of past 30-day methadone treatment (aOR=0.66; 95% CI: 0.45-0.99) and fewer methadone treatment days (aIRR=0.76; 0.57-0.99), but not past 30-day buprenorphine receipt (aOR=0.90; 0.67-1.20), buprenorphine treatment days in past 6 months: aIRR=0.88; 0.69-1.12) or perceived inability to access buprenorphine (aOR=1.12; 0.87-1.44) or methadone (aOR=1.06; 0.76-1.48). CONCLUSION: Methamphetamine use is common among persons who use opioids in rural U.S. areas and negatively associated with current treatment and retention on methadone but not buprenorphine. Future studies should examine reasons for this disparity and reduce barriers to methadone for persons who use opioids and methamphetamine.

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4+CD28- T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

Alcohol use and the longitudinal HIV care continuum for people with HIV who enrolled in care between 2011 and 2019.

PURPOSE: We described the impact of alcohol use on longitudinal engagement in HIV care including loss to follow-up, durability of viral suppression, and death. METHODS: We followed a cohort of 1781 people with HIV from enrolled in care at one of seven US clinics, 2011-2019 through 102 months. We used a multistate, time-varying Markov process and restricted mean time to summarize engagement in HIV care over follow-up according to baseline self-reported alcohol use (none, moderate, or unhealthy). RESULTS: Our sample (86% male, 54% White) had median age of 35 years. Over 102 months, people with no, moderate, and unhealthy alcohol use averaged 62.3, 61.1, and 59.5 months virally suppressed, respectively. People who reported unhealthy or moderate alcohol use spent 5.1 (95% confidence intervals (CI): 0.8, 9.3) and 7.6 (95%CI: 3.1, 11.7) more months lost to care than nondrinkers. Compared to no use, unhealthy alcohol use was associated with 3.4 (95%CI: -5.6, -1.6) fewer months in care, not virally suppressed. There were no statistically significant differences after adjustment for demographic and clinical characteristics. CONCLUSIONS: Moderate or unhealthy drinking at enrollment in HIV care was associated with poor retention in care. Alcohol use was not associated with time spent virally suppressed.

Tobacco Smoking and Pack-Years Are Associated With Frailty Among People With HIV.

BACKGROUND: Tobacco smoking increases frailty risk among the general population and is common among people with HIV (PWH) who experience higher rates of frailty at younger ages than the general population. METHODS: We identified 8608 PWH across 6 Centers for AIDS Research Network of Integrated Clinical Systems sites who completed ≥2 patient-reported outcome assessments, including a frailty phenotype measuring unintentional weight loss, poor mobility, fatigue, and inactivity, and scored 0-4. Smoking was measured as baseline pack-years and time-updated never, former, or current use with cigarettes/day. We used Cox models to associate smoking with risk of incident frailty (score ≥3) and deterioration (frailty score increase by ≥2 points), adjusted for demographics, antiretroviral medication, and time-updated CD4 count. RESULTS: The mean follow-up of PWH was 5.3 years (median: 5.0), the mean age at baseline was 45 years, 15% were female, and 52% were non-White. At baseline, 60% reported current or former smoking. Current (HR: 1.79; 95% confidence interval: 1.54 to 2.08) and former (HR: 1.31; 95% confidence interval: 1.12 to 1.53) smoking were associated with higher incident frailty risk, as were higher pack-years. Current smoking (among younger PWH) and pack-years, but not former smoking, were associated with higher risk of deterioration. CONCLUSIONS: Among PWH, smoking status and duration are associated with incident and worsening frailty.

Polygenic risk scores point toward potential genetic mechanisms of type 2 myocardial infarction in people with HIV.

BACKGROUND: People with human immunodeficiency virus (HIV) infection (PWH) are at higher risk of myocardial infarction (MI) than those without HIV. About half of MIs in PWH are type 2 (T2MI), resulting from mismatch between myocardial oxygen supply and demand, in contrast to type 1 MI (T1MI), which is due to primary plaque rupture or coronary thrombosis. Despite worse survival and rising incidence in the general population, evidence-based treatment recommendations for T2MI are lacking. We used polygenic risk scores (PRS) to explore genetic mechanisms of T2MI compared to T1MI in PWH. METHODS: We derived 115 PRS for MI-related traits in 9541 PWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort with adjudicated T1MI and T2MI. We applied multivariate logistic regression analyses to determine the association with T1MI and T2MI. Based on initial findings, we performed gene set enrichment analysis of the top variants composing PRS associated with T2MI. RESULTS: We found that T1MI was strongly associated with PRS for cardiovascular disease, lipid profiles, and metabolic traits. In contrast, PRS for alcohol dependence and cholecystitis, significantly enriched in energy metabolism pathways, were predictive of T2MI risk. The association remained after the adjustment for actual alcohol consumption. CONCLUSIONS: We demonstrate distinct genetic traits associated with T1MI and T2MI among PWH further highlighting their etiological differences and supporting the role of energy regulation in T2MI pathogenesis.

Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study.

BACKGROUND AND OBJECTIVES: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS). METHODS: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1,298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-SD increase in the log2-transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and noncardioembolic IS and proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation. RESULTS: Of 2,983 eligible participants, the mean age was 74.3 (±4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal probrain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, p = 2.08 × 10-08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, p = 4.55 × 10-06) were independently associated with IS risk. These 2 associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident noncardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction. DISCUSSION: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and noncardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

Associations between alcohol and cigarette use and type 1 and 2 myocardial infarction among people with HIV.

OBJECTIVES: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. DESIGN AND METHODS: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. RESULTS: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. CONCLUSIONS: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

Preterm birth and stillbirth rates associated with socioeconomic disparities during COVID-19 pandemic: a population-based cross-sectional study.

BACKGROUND: Conflicting evidence exists on the impact of the COVID-19 pandemic restrictions on preterm birth (PTB) and stillbirth rates. We aimed to evaluate changes in PTB and stillbirth rates before and during the pandemic period and assess the potential effect modification of socioeconomic status (SES). METHODS: Using the linked administrative health databases from Manitoba, Canada, we conducted a cross-sectional study among all pregnant women, comparing 3.5 years pre-pandemic (1 October 2016 to 29 February 2020) to the first year of the pandemic (1 March 2020 to 31 March 2021). We used generalised linear models to assess the quarterly rates of PTB (<37 weeks) and stillbirths. We calculated the predicted trends based on pre-pandemic period data. Finally, we evaluated the PTB and stillbirth rates among lower and higher SES pregnant women (average annual household income) using subgroup analysis and interaction models. RESULTS: We examined 70 931 pregnancies in Manitoba during the study period. The risk of PTB increased by 7.7% (95%CI 1.01 to 1.13) and stillbirths by 33% (95% CI 1.08 to 1.64) during the pandemic period. Following COVID-19 restrictions implemented in March 2020, there were increases in the quarterly rates of both PTB (immediate increase (ß2)=1.37; p=0.0247) and stillbirths (immediate increase (ß2)=0.12; p=0.4434). Among the lower income groups, the pandemic restrictions resulted in an immediate relative increase in PTB and stillbirth rates by 20.12% (immediate increase (ß2)=3.17; p=0.0057) and 27.19% (immediate increase (ß2)=0.48; p=0.0852). However, over the pandemic, the overall PTB rate significantly decreased as a rebound effect by 0.85% per quarter (p=0.0004), whereas the overall stillbirth rate did not decrease significantly (slope decrease (ß3) =-0.01; p=0.8296) compared with the pre-pandemic period. The quarterly rates during the pandemic among the higher income group decreased by 0.39% (p=0.1296) for PTB and increased by 0.07% (p=0.1565) for stillbirth. We observed an effect modification by SES for PTB rates (p=0.047). CONCLUSION: While the onset of COVID-19 pandemic restrictions was not associated with significant effects on stillbirth rates, we observed an immediate and rebound effect on PTB rates. The impact of COVID-19 on preterm birth was dependent on SES, with higher influence on families with lower SES. Further studies are needed to detect future trend changes during pandemic waves after 2021 and assess potential underlying mechanisms.

Development of Frail RISC-HIV: a Risk Score for Predicting Frailty Risk in the Short-term for Care of People with HIV.

OBJECTIVE: Frailty is common among people with HIV (PWH), so we developed frail risk in the short-term for care (RISC)-HIV, a frailty prediction risk score for HIV clinical decision-making. DESIGN: We followed PWH for up to 2 years to identify short-term predictors of becoming frail. METHODS: We predicted frailty risk among PWH at seven HIV clinics across the United States. A modified self-reported Fried Phenotype captured frailty, including fatigue, weight loss, inactivity, and poor mobility. PWH without frailty were separated into training and validation sets and followed until becoming frail or 2 years. Bayesian Model Averaging (BMA) and five-fold-cross-validation Lasso regression selected predictors of frailty. Predictors were selected by BMA if they had a greater than 45% probability of being in the best model and by Lasso if they minimized mean squared error. We included age, sex, and variables selected by both BMA and Lasso in Frail RISC-HIV by associating incident frailty with each selected variable in Cox models. Frail RISC-HIV performance was assessed in the validation set by Harrell's C and lift plots. RESULTS: Among 3170 PWH (training set), 7% developed frailty, whereas among 1510 PWH (validation set), 12% developed frailty. BMA and Lasso selected baseline frailty score, prescribed antidepressants, prescribed antiretroviral therapy, depressive symptomology, and current marijuana and illicit opioid use. Discrimination was acceptable in the validation set, with Harrell's C of 0.76 (95% confidence interval: 0.73-0.79) and sensitivity of 80% and specificity of 61% at a 5% frailty risk cutoff. CONCLUSIONS: Frail RISC-HIV is a simple, easily implemented tool to assist in classifying PWH at risk for frailty in clinics.