Associations between cord blood acetaminophen biomarkers and childhood asthma with and without allergic comorbidities.

BACKGROUND: Previous studies have linked prenatal acetaminophen use to increased asthma risk in children. However, none have explored this association while differentiating between asthma cases with and without other allergic conditions or by employing objective biomarkers to assess acetaminophen exposure. OBJECTIVE: To evaluate whether the detection of acetaminophen biomarkers in cord blood is associated with the subgroups of asthma both with and without allergic comorbidities in children. METHODS: Acetaminophen biomarkers, including unchanged acetaminophen and acetaminophen glucuronide, were measured in neonatal cord blood samples from the Boston Birth Cohort. Asthma subgroups were defined on the basis of physician diagnoses of asthma and other allergic conditions (atopic dermatitis and allergic rhinitis). Multinomial regressions were used to evaluate the associations between acetaminophen biomarkers and asthma subgroups, adjusting for multiple confounders, including potential indications for maternal acetaminophen use such as maternal fever. RESULTS: The study included 142 children with asthma and at least 1 other allergic condition, 55 children with asthma but no other allergic condition, and 613 children free of asthma. Detection of acetaminophen in cord blood, reflecting maternal exposure to acetaminophen shortly before delivery, was associated with 3.73 times the odds of developing asthma without allergic comorbidities (95% CI: 1.79-7.80, P = .0004). In contrast, the detection of acetaminophen in cord blood was not associated with an elevated risk of asthma with allergic comorbidities. Analysis of acetaminophen glucuronide yielded consistent results. CONCLUSION: In a prospective birth cohort, cord blood acetaminophen biomarkers were associated with an increased risk of childhood asthma without allergic comorbidities, but were not associated with childhood asthma with allergic comorbidities.

Approaches to protocol standardization and data harmonization in the ECHO-wide cohort study.

The United States (U.S.) National Institutes of Health-funded Environmental influences on Child Health Outcomes (ECHO)-wide Cohort was established to conduct high impact, transdisciplinary science to improve child health and development. The cohort is a collaborative research design in which both extant and new data are contributed by over 57,000 children across 69 cohorts. In this review article, we focus on two key challenging issues in the ECHO-wide Cohort: data collection standardization and data harmonization. Data standardization using a Common Data Model and derived analytical variables based on a team science approach should facilitate timely analyses and reduce errors due to data misuse. However, given the complexity of collaborative research designs, such as the ECHO-wide Cohort, dedicated time is needed for harmonization and derivation of analytic variables. These activities need to be done methodically and with transparency to enhance research reproducibility. IMPACT: Many collaborative research studies require data harmonization either prior to analyses or in the analyses of compiled data. The Environmental influences on Child Health Outcomes (ECHO) Cohort pools extant data with new data collection from over 57,000 children in 69 cohorts to conduct high-impact, transdisciplinary science to improve child health and development, and to provide a national database and biorepository for use by the scientific community at-large. We describe the tools, systems, and approaches we employed to facilitate harmonized data for impactful analyses of child health outcomes.

Sociodemographic Differences in COVID-19 Pandemic Experiences Among Families in the United States.

Importance: Few population-based studies in the US collected individual-level data from families during the COVID-19 pandemic. Objective: To examine differences in COVID-19 pandemic-related experiences in a large sociodemographically diverse sample of children and caregivers. Design, Setting, and Participants: The Environmental influences on Child Health Outcomes (ECHO) multi-cohort consortium is an ongoing study that brings together 64 individual cohorts with participants (24 757 children and 31 700 caregivers in this study) in all 50 US states and Puerto Rico. Participants who completed the ECHO COVID-19 survey between April 2020 and March 2022 were included in this cross-sectional analysis. Data were analyzed from July 2021 to September 2022. Main Outcomes and Measures: Exposures of interest were caregiver education level, child life stage (infant, preschool, middle childhood, and adolescent), and urban or rural (population <50 000) residence. Dependent variables included COVID-19 infection status and testing; disruptions to school, child care, and health care; financial hardships; and remote work. Outcomes were examined separately in logistic regression models mutually adjusted for exposures of interest and race, ethnicity, US Census division, sex, and survey administration date. Results: Analyses included 14 646 children (mean [SD] age, 7.1 [4.4] years; 7120 [49%] female) and 13 644 caregivers (mean [SD] age, 37.6 [7.2] years; 13 381 [98%] female). Caregivers were racially (3% Asian; 16% Black; 12% multiple race; 63% White) and ethnically (19% Hispanic) diverse and comparable with the US population. Less than high school education (vs master's degree or more) was associated with more challenges accessing COVID-19 tests (adjusted odds ratio [aOR], 1.88; 95% CI, 1.06-1.58), lower odds of working remotely (aOR, 0.04; 95% CI, 0.03-0.07), and more food access concerns (aOR, 4.14; 95% CI, 3.20-5.36). Compared with other age groups, young children (age 1 to 5 years) were least likely to receive support from schools during school closures, and their caregivers were most likely to have challenges arranging childcare and concerns about work impacts. Rural caregivers were less likely to rank health concerns (aOR, 0.77; 95% CI, 0.69-0.86) and social distancing (aOR, 0.82; 95% CI, 0.73-0.91) as top stressors compared with urban caregivers. Conclusions: Findings in this cohort study of US families highlighted pandemic-related burdens faced by families with lower socioeconomic status and young children. Populations more vulnerable to public health crises should be prioritized in recovery efforts and future planning.

Opportunities for understanding the COVID-19 pandemic and child health in the United States: the Environmental influences on Child Health Outcomes (ECHO) program.

Objective: Ongoing pediatric cohort studies offer opportunities to investigate the impact of the COVID-19 pandemic on children's health. With well-characterized data from tens of thousands of US children, the Environmental influences on Child Health Outcomes (ECHO) Program offers such an opportunity. Methods: ECHO enrolled children and their caregivers from community- and clinic-based pediatric cohort studies. Extant data from each of the cohorts were pooled and harmonized. In 2019, cohorts began collecting data under a common protocol, and data collection is ongoing with a focus on early life environmental exposures and five child health domains: birth outcomes, neurodevelopment, obesity, respiratory, and positive health. In April of 2020, ECHO began collecting a questionnaire designed to assess COVID-19 infection and the pandemic's impact on families. We describe and summarize the characteristics of children who participated in the ECHO Program during the COVID-19 pandemic and novel opportunities for scientific advancement. Results: This sample (n = 13,725) was diverse by child age (31% early childhood, 41% middle childhood, and 16% adolescence up to age 21), sex (49% female), race (64% White, 15% Black, 3% Asian, 2% American Indian or Alaska Native, <1% Native Hawaiian or Pacific Islander, 10% Multiple race and 2% Other race), Hispanic ethnicity (22% Hispanic), and were similarly distributed across the four United States Census regions and Puerto Rico. Conclusion: ECHO data collected during the pandemic can be used to conduct solution-oriented research to inform the development of programs and policies to support child health during the pandemic and in the post-pandemic era.

Characterizing changes in behaviors associated with chemical exposures during the COVID-19 pandemic.

The COVID-19 pandemic-and its associated restrictions-have changed many behaviors that can influence environmental exposures including chemicals found in commercial products, packaging and those resulting from pollution. The pandemic also constitutes a stressful life event, leading to symptoms of acute traumatic stress. Data indicate that the combination of environmental exposure and psychological stress jointly contribute to adverse child health outcomes. Within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort, a national consortium initiated to understand the effects of environmental exposures on child health and development, our objective was to assess whether there were pandemic-related changes in behavior that may be associated with environmental exposures. A total of 1535 participants from nine cohorts completed a survey via RedCap from December 2020 through May 2021. The questionnaire identified behavioral changes associated with the COVID-19 pandemic in expected directions, providing evidence of construct validity. Behavior changes reported by at least a quarter of the respondents include eating less fast food and using fewer ultra-processed foods, hair products, and cosmetics. At least a quarter of respondents reported eating more home cooked meals and using more antibacterial soaps, liquid soaps, hand sanitizers, antibacterial and bleach cleaners. Most frequent predictors of behavior change included Hispanic ethnicity and older age (35 years and older). Respondents experiencing greater COVID-related stress altered their behaviors more than those not reporting stress. These findings highlight that behavior change associated with the pandemic, and pandemic-related psychological stress often co-occur. Thus, prevention strategies and campaigns that limit environmental exposures, support stress reduction, and facilitate behavioral change may lead to the largest health benefits in the context of a pandemic. Analyzing biomarker data in these participants will be helpful to determine if behavior changes reported associate with measured changes in exposure.

No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection.

BACKGROUND: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. METHODS: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. RESULTS: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. CONCLUSIONS: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Meta-analysis under imbalance in measurement of confounders in cohort studies using only summary-level data.

BACKGROUND: Cohort collaborations often require meta-analysis of exposure-outcome association estimates across cohorts as an alternative to pooling individual-level data that requires a laborious process of data harmonization on individual-level data. However, it is likely that important confounders are not all measured uniformly across the cohorts due to differences in study protocols. This imbalance in measurement of confounders leads to association estimates that are not comparable across cohorts and impedes the meta-analysis of results. METHODS: In this article, we empirically show some asymptotic relations between fully adjusted and unadjusted exposure-outcome effect estimates, and provide theoretical justification for the same. We leverage these results to obtain fully adjusted estimates for the cohorts with no information on confounders by borrowing information from cohorts with complete measurement on confounders. We implement this novel method in CIMBAL (confounder imbalance), which additionally provides a meta-analyzed estimate that appropriately accounts for the dependence between estimates arising due to borrowing of information across cohorts. We perform extensive simulation experiments to study CIMBAL's statistical properties. We illustrate CIMBAL using National Children's Study (NCS) data to estimate association of maternal education and low birth weight in infants, adjusting for maternal age at delivery, race/ethnicity, marital status, and income. RESULTS: Our simulation studies indicate that estimates of exposure-outcome association from CIMBAL are closer to the truth than those from commonly-used approaches for meta-analyzing cohorts with disparate confounder measurements. CIMBAL is not too sensitive to heterogeneity in underlying joint distributions of exposure, outcome and confounders but is very sensitive to heterogeneity of confounding bias across cohorts. Application of CIMBAL to NCS data for a proof-of-concept analysis further illustrates the utility and advantages of CIMBAL. CONCLUSIONS: CIMBAL provides a practical approach for meta-analyzing cohorts with imbalance in measurement of confounders under a weak assumption that the cohorts are independently sampled from populations with the same confounding bias.

Suboptimal HIV suppression is associated with progression of coronary artery stenosis: The Multicenter AIDS Cohort Study (MACS) longitudinal coronary CT angiography study.

BACKGROUND AND AIMS: People living with HIV (HIV+) are surviving longer due to effective antiretroviral therapy. Cardiovascular disease is a leading cause of non-AIDS related clinical events. We determined HIV-related factors associated with coronary artery stenosis progression. METHODS: We performed serial coronary CT angiography among HIV+ and HIV-uninfected (HIV-) men in the Multicenter AIDS Cohort Study. The median inter-scan interval was 4.5 years. Stenosis was graded as 0, 1-29, 30-49, 50-69 or ≥70%. Progression was defined as an increase ≥2 categories. Suppressed HIV infection was consistent viral loads <50 copies/mL allowing 1 "blip" <500 copies/mL, otherwise considered viremic. Multivariable Poisson regression analysis assessed adjusted associations between HIV serostatus and viremia with coronary stenosis progression. RESULTS: The sample included 310 HIV+ (31% viremic) and 234 HIV- men. The median age was 53 years, 30% Black and 23% current smokers. Viremic men were 2.3 times more likely to develop coronary stenosis progression than HIV- men (adjusted RR 2.30; 95% CI, 1.32-4.00, p = 0.003), with no difference in progression between HIV+ suppressed and HIV- men (RR 1.10; 95% CI, 0.70-1.74, p = 0.67). There was a progressive increase in adjusted relative risk with greater viremia (p = 0.03). Men with >1 viral load >500 copies/ml demonstrated greatest stenosis progression (RR 3.01; 95% CI, 1.53-4.92, p = 0.001 compared with HIV- men). Suppressed HIV+ men with suboptimal antiretroviral adherence had greater stenosis progression (RR 1.91; 95% CI 1.12-3.24, p = 0.02) than HIV + suppressed men with optimal adherence. CONCLUSIONS: Coronary artery stenosis progression was associated with suboptimal HIV RNA suppression and antiretroviral therapy adherence. Effective ongoing HIV virologic suppression and antiretroviral therapy adherence may mitigate risk for coronary disease events among people living with HIV.

Social inequalities contribute to racial/ethnic disparities in depressive symptomology among men who have sex with men.

PURPOSE: Racial/ethnic minorities experience disproportionate rates of depressive symptoms in the United States. The magnitude that underlying factors-such as social inequalities-contribute to these symptoms is unknown. We sought to identify exposures that explain racial/ethnic differences in clinically significant depressive symptomology among men who have sex with men (MSM). METHODS: Data from the Multicenter AIDS Cohort Study (MACS), a prospective cohort study, were used to examine clinically significant symptoms of depression (Center for Epidemiologic Studies Depression Scale score ≥ 20) among non-Latinx White, non-Latinx Black, and Latinx MSM. We included 44,823 person-visits by 1729 MSM seen in the study sites of Baltimore/Washington, DC; Chicago; Pittsburgh/Columbus; and Los Angeles from 2000 to 2017. Regression models estimated the percentage of depressive symptom risk explained by social, treatment, and health-related variables related to race/ethnicity. Machine-learning methods were used to predict the impact of mitigating differences in determinants of depressive symptoms by race/ethnicity. RESULTS: At the most recent non-missing MACS visit, 16% of non-Latinx White MSM reported clinically significant depressive symptoms, compared to 22% of non-Latinx Black and 25% of Latinx men. We found that income and social-environmental stress were the largest contributors to racial/ethnic disparities in risk for depressive symptoms. Similarly, setting the prevalence of these two exposures to be equal across racial/ethnic groups was estimated to be most effective at reducing levels of clinically significant depressive symptoms. CONCLUSION: Results suggested that reducing socioeconomic inequalities and stressful experiences may be effective public health targets to decrease racial/ethnic disparities in depressive symptoms among MSM.

Effect of Statin Use on Inflammation and Immune Activation Biomarkers in HIV-Infected Persons on Effective Antiretroviral Therapy.

Immune activation and inflammation are hallmarks of chronic HIV infection and are etiologically linked to major causes of morbidity and mortality among HIV-infected persons, including coronary artery disease and cancer. Systemic immune activation is dampened, but not resolved, with use of combination antiretroviral therapy (cART). Statins are cardioprotective drugs that also appear to have immunomodulatory and anti-inflammatory properties. We sought to understand the association between statin use, cART, and levels of circulating immune markers in a longitudinal cohort study. From 2004 to 2009, statin use was ascertained in male participants of the Multicenter AIDS Cohort Study (MACS) using interviewer-administered questionnaires. Twenty-four circulating markers of immune activation and inflammation were measured in archived serial samples from a subset of cohort members using multiplex assays. Propensity-adjusted generalized gamma models were used to compare biomarkers' distributions by statin use, and multivariable linear regression models were used to assess the effect of initiating statin on these biomarkers. Overall, 1,031 cART-exposed individuals with HIV infection were included in this study. Statin use was reported by 31.5% of cART-exposed participants. Compared to nonstatin users on cART, statin users on cART had lower levels of IP-10, IL-10, and IL-12p70, and the effect of statin use was decreased in participants using lipophilic statins (atorvastatin, simvastatin, fluvastatin, or lovastatin); these results were statistically significant (p < .05). Among cART users not on aspirin, starting statins decreased levels of high sensitivity c-reactive protein (hsCRP), IL-12p70, and IL-6. Statin therapy is associated with reduced levels of certain biomarkers of immune activation and inflammation in cART users, which may contribute to a lower burden of disease.

Economic Burden Among Gay, Bisexual, and Other Men Who Have Sex With Men Living With HIV or Living Without HIV in the Multicenter AIDS Cohort Study.

BACKGROUND: With HIV now considered a chronic disease, economic burden for people living with HIV (LWH) may threaten long-term disease outcomes. We studied associations between economic burden (employment, income, insurance, and financial difficulty) and HIV status for gay, bisexual, and other men who have sex with men (GBMSM) and how economic burden relates to disease progression. SETTING: We analyzed data collected every 6 months through 2015 from GBMSM LWH and GBMSM living without HIV from 2 waves (2001-2003 cohort and 2010+ new recruit cohort) of the Multicenter AIDS Cohort Study. METHODS: Using generalized estimating equations, we first assessed the association between HIV status (exposure) and economic burden indicators since the last study visit (outcomes) of employment (working/student/retired versus not currently working), personal annual income of ≥$10,000, insurance (public/private versus none), and financial difficulty meeting basic expenses. Then among people LWH, we assessed the relationships between economic burden indicators (exposures), risk of progressive immune suppression (CD4 ≤500 cells/uL), and progression to AIDS (CD4 ≤200; outcomes). RESULTS: Of 1721 participants, 59.5% were LWH (n = 1024). GBMSM LWH were 12% less likely to be employed, 16% more likely to have health insurance, and 9% more likely to experience financial difficulty than GBMSM living without HIV. Among GBMSM LWH, employment was associated with a 6% and 32% lower likelihood of immune suppression or progression to AIDS, respectively, and the income was associated with a 15% lower likelihood of progression to AIDS. CONCLUSIONS: Interventions that stabilize employment, income, and offer insurance support may enrich GBMSM LWH's ability to prevent disease progression.

Partial Normalization of Biomarkers of Inflammation and Immune Activation Among Virally Suppressed Men With HIV Infection and High ART Adherence.

BACKGROUND: The objective of this study was to investigate whether 100% antiretroviral therapy (ART) adherence in men with HIV (MWH) is associated with normalization of concentrations of biomarkers of inflammation and immune activation compared with HIV-uninfected men. METHODS: We analyzed person-visits with available biomarker data from the Multicenter AIDS Cohort Study (MACS) among MWH receiving ART with HIV RNA <50 copies/mL and among HIV-uninfected men. Self-reported adherence was classified as 100% if no missed ART doses in the past 4 days were reported. We evaluated associations between ART adherence and concentrations of 24 serum biomarkers compared with HIV-uninfected visits using a generalized gamma model, adjusting for potential confounders. RESULTS: Person-visits (2565 from MWH reporting 100% ART adherence and 1588 from HIV-uninfected men) from a total of 1469 men were included in the analysis. Serum concentrations of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), IL-1ß, interferon-γ (IFN-γ), chemokine C-C motif ligand 2 (CCL2), and CCL14 from person-visits among MWH who reported 100% adherence were similar to HIV-uninfected person-visits. Comparatively higher concentrations of 11 biomarkers and lower concentrations of 7 biomarkers were observed in person-visits from MWH who reported 100% ART adherence, compared with HIV-uninfected person-visits. CONCLUSIONS: Although MWH with virologic suppression who reported 100% ART adherence exhibited overall higher concentrations of biomarkers of inflammation and immune activation compared with HIV-uninfected men, some biomarker concentrations were similar in both groups. These findings suggest that optimal ART adherence could have clinical implications beyond achieving and sustaining viral suppression.

Victimization in Early Adolescence, Stress, and Depressive Symptoms Among Aging Sexual Minority Men: Findings from the Multicenter AIDS Cohort Study.

Purpose: We investigated the relation between adversities in early adolescence and risk of a depressive phenotype in adulthood, and whether stress in adulthood modified these associations. Methods: A total of 1138 men who have sex with men (MSM) participated in a Multicenter AIDS Cohort substudy in which they reported on adversities in early adolescence. Poisson regression estimated prevalence ratios (PRs) for associations between adversities and a depressive phenotype in adulthood. Stratified analyses examined the effects of stress in the last year on the depressive phenotype. Results: In adjusted models, men who were verbally insulted; threatened by physical violence; had an object thrown at them; or punched, kicked, or beaten were at higher risk of having a depressive phenotype in adulthood (for ≥1 time per month vs. never, PR = 1.50, 95% confidence interval [CI] = 1.15-1.96; PR = 1.84, 95% CI = 1.45-2.34; PR = 2.00, 95% CI = 1.51-2.66; or PR = 1.78, 95% CI = 1.35-2.34, respectively.) Being threatened with a weapon approached statistical significance (PR = 1.89, 95% CI = 0.96-3.72). Although higher stress was associated with depression overall, early adolescent victimization was only associated with depression among MSM not reporting high levels of stress in the last year (for ≥1 time per month vs. never, PR = 1.68, 95% CI = 1.09-2.59; PR = 2.11, 95% CI = 1.40-3.17; PR = 2.24, 95% CI = 1.24-4.03; PR = 1.98, 95% CI = 1.22-3.22, respectively). Conclusion: The attenuation of relationships between adversities and depression among men reporting high stress may suggest that adult stress overshadows long-term effects of early adolescent victimization on adult depression. Victimization in early adolescence may increase the risk of sustained depressive symptoms in mid- to later life, reinforcing the need for preventive strategies.

Association of High-Sensitivity Troponin with Cardiac CT Angiography Evidence of Myocardial and Coronary Disease in a Primary Prevention Cohort of Men: Results from MACS.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) elevations are associated with incident cardiovascular disease events in primary prevention samples. However, the mechanisms underlying this association remain unclear. METHODS: We studied 458 men without known cardiovascular disease who participated in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study and had cardiac CT angiography. We used multivariable linear and logistic regression models to examine the cross-sectional associations between coronary artery stenosis, coronary artery plaque, indexed left ventricular mass (LVMi), and the outcome of hs-cTnI. We also evaluated the associations between HIV serostatus or use of highly active antiretroviral therapy (HAART) and hs-cTnI. RESULTS: The mean age was 54 years, 54% were white, and 61% were HIV infected. In multivariable-adjusted logistic models, comparing the highest quartile of LVMi with the lowest quartile, the odds ratio (OR) of hs-cTnI ≥75th percentile was 2.59 (95% CI, 1.20-5.75). There was no significant association between coronary stenosis severity or plaque type and hs-cTnI in linear models; however, in logistic regression models, coronary artery stenosis ≥70% (8% of sample) was marginally associated with a higher likelihood (OR, 2.75 [95% CI, 1.03, 7.27]) of having hs-cTnI ≥75th percentile. There were no associations between HIV serostatus or HAART use and hs-cTnI in either linear or logistic models. CONCLUSION: Among primary prevention men with or at risk for HIV, hs-cTnI concentrations were strongly associated with LVMi but were not associated with HIV infection or treatment status or with coronary plaque type or stenosis until the extremes of severity (≥70% stenosis).

Inflammation and Risk of Depression in HIV: Prospective Findings From the Multicenter AIDS Cohort Study.

Studies suggest that inflammation might be involved in the pathogenesis of depression. Individuals with human immunodeficiency virus (HIV) have a higher risk of depression and elevated inflammatory profiles. Despite this, research on the link between inflammation and depression among this high-risk population is limited. We examined a sample of men who have sex with men from the Multicenter AIDS Cohort Study in prospective analyses of the association between inflammation and clinically relevant depression symptoms, defined as scores >20 on Center for Epidemiological Studies Depression Scale. We included 1,727 participants who contributed 9,287 person-visits from 1984 to 2010 (8,218 with HIV (HIV+) and 1,069 without (HIV-)). Exploratory factor analysis (EFA) was used to characterize underlying inflammatory processes from 19 immune markers. Logistic regression with generalized estimating equations was used to evaluate associations between inflammatory processes and depressive symptoms stratified by HIV serostatus. Three EFA-identified inflammatory processes (EIPs) were identified. EIP-1 scores-described by soluble tumor necrosis factor receptor 2 (sTNF-R2), soluble interleukin-2 receptor α (sIL-2Rα), sCD27, B-cell activating factor, interferon γ-induced protein 10 (IP-10), soluble interleukin-6 receptor (sIL-6R), sCD14, and sGP130-were significantly associated with 9% higher odds of depressive symptoms in HIV+ participants (odds ratio = 1.09; 95% confidence interval: 1.03, 1.16) and 33% higher odds in HIV- participants (odds ratio = 1.33; 95% confidence interval: 1.09, 1.61). Findings suggest that immune activation might be involved in depression risk among both HIV+ and HIV- men who have sex with men.

Recent Trends and Effectiveness of Antiretroviral Regimens Among Men Who Have Sex With Men Living With HIV in the United States: The Multicenter AIDS Cohort Study (MACS) 2008-2017.

OBJECTIVE: We evaluated trends and population effectiveness (tolerability, HIV suppression) of current combination antiretroviral therapy (cART) regimens mindful of treatment guidelines. METHOD: Trend analyses included 18 017 person-visits (1457 men) on cART during 2008-2017 in the Multicenter AIDS Cohort Study. Effectiveness analyses of current regimens used 3598 person-visit-pairs (745 men) on cART in 2014-2017. Inverse-probability-of-treatment-and-censoring weighted Poisson regression with robust variances was used to evaluate the association between regimens and switching, adherence and HIV RNA <20 copies/mL. RESULTS: Integrase strand transfer inhibitor (INSTI)-based regimen usage has increased since 2008. Almost 90% of cART initiators started with INSTI-cART in 2016-2017; cART adherence was stable around 90% and 83%-85% suppressed virus (<20 cp/mL). Commonly used regimens in 2014-2017 contained disoproxil fumarate/emtricitabine (TDF/FTC) backbone with efavirenz (EFV, n = 1161 person-visits), elvitegravir/cobicistat (EVG/c, n = 551), rilpivirine (RPV, n = 492), darunavir/ritonavir (DRV/r, n = 351), or atazanavir (ATV)/r (n = 333). Others were dolutegravir/abacavir/lamivudine (DTG/ABC/3TC, n = 401) and EVG/c/tenofovir alafenamide/FTC (EVG/c/TAF/FTC, n = 309). Compared to EFV/TDF/FTC users, ATV/r+TDF/FTC users switched more (rate ratio [RR] = 1.80, 95% confidence interval (CI), 1.17-2.76), while those on DTG/ABC/3TC (RR [95% CI] = 0.16 [0.08-0.31]) or EVG/c/TAF/FTC (RR [95% CI] = 0.12 [0.06-0.27]) switched less. The rate of suppressed HIV RNA was 15% (95% CI, 2%-26%) lower among younger EVG/c/TDF/FTC users and 18% (95% CI, 3%-34%) higher in older DRV/r+TDF/FTC users; adherence did not differ by regimen. CONCLUSIONS: Consistent with guidelines, recent cART initiators started with INSTI-cART, which was associated with less switching early after initiation. Factors beyond those studied here, such as need for salvage therapy, unique personal characteristics, drug interactions, and cost may influence treatment decisions.

Midlife adiposity predicts cognitive decline in the prospective Multicenter AIDS Cohort Study.

OBJECTIVE: Obesity is a common, modifiable cardiovascular and cerebrovascular risk factor. Among people with HIV, obesity may contribute to multisystem dysregulation including cognitive impairment. We examined body mass index (BMI) and central obesity (waist circumference [WC]) in association with domain-specific cognitive function and 10-year cognitive decline in men with HIV infection (MWH) vs HIV-uninfected (HIV-) men. METHODS: A total of 316 MWH and 656 HIV- Multicenter AIDS Cohort Study participants ≥40 years at baseline, with neuropsychological testing every 2 years and concurrent BMI and WC measurements, were included. MWH were included if taking ≥2 antiretroviral agents and had HIV-1 RNA <400 copies/mL at >80% of visits. Mixed-effects models included all visits from 1996 to 2015, stratified by HIV serostatus, and adjusted for sociodemographic, behavioral, and clinical characteristics. At baseline and follow-up, 8% of MWH and 15% of HIV- men and 41% of MWH and 56% of HIV- men were ≥60 years, respectively. RESULTS: Cross-sectionally, higher BMI was inversely associated with motor function in MWH and HIV- men, and attention/working memory in HIV- men. WC was inversely associated with motor function in MWH and HIV- men. Longitudinal associations indicated an obese BMI was associated with a less steep decline in motor function in MWH whereas in HIV- men, obesity was associated with a greater decline in motor function, learning, and memory. WC, or central obesity, showed similar patterns of associations. CONCLUSION: Higher adiposity is associated with lower cognition cross-sectionally and greater cognitive decline, particularly in HIV- men. Overweight and obesity may be important predictors of neurologic outcomes and avenues for prevention and intervention.

Risk Factors for Falls, Falls With Injury, and Falls With Fracture Among Older Men With or at Risk of HIV Infection.

BACKGROUND: Falls and fall risk factors are common among people living with HIV (PLWH). We sought to identify fall risk factors among men with and without HIV. METHODS: Men aged 50-75 years with (n = 279) and without HIV (n = 379) from the Bone Strength Substudy of the Multicenter AIDS Cohort Study were included. Multinomial logistic regression models identified risk factors associated with falling. RESULTS: One hundred fourteen (41%) PLWH and 149 (39%) of uninfected men had ≥1 fall; 54 (20%) PLWH and 66 (17%) of uninfected men experienced ≥2 falls over 2 years. Five and 3% of PLWH and uninfected men, respectively, had a fall-related fracture (P = 0.34). In multivariate models, the odds of ≥2 falls were greater among men reporting illicit drug use, taking diabetes or depression medications, and with peripheral neuropathy; obesity was associated with a lower risk (all P < 0.05). In models restricted to PLWH, detectable plasma HIV-1 RNA, current use of efavirenz or diabetes medications, illicit drug use, and peripheral neuropathy were associated with greater odds of having ≥2 falls (P < 0.05). Current efavirenz use was associated with increased odds of an injurious fall; longer duration of antiretroviral therapy was protective (both P < 0.05). Greater physical activity was associated with lower risk of falls with fracture (P < 0.05). CONCLUSIONS: Identified risk factors for recurrent falls or fall with fracture included low physical activity, detectable HIV-1 RNA, use of efavirenz, or use of medications to treat diabetes and depression. Fall risk reduction should prioritize interventions targeting modifiable risk factors including increased physical activity, antiretroviral therapy adherence, and transition off efavirenz.

Associations between lipids and subclinical coronary atherosclerosis.

OBJECTIVE: Whether HIV modifies the relationship of serum lipids with coronary atherosclerosis and coronary plaque subtypes is uncertain. We examined the associations between traditional lipids and coronary atherosclerosis among HIV-infected (HIV+) and HIV-uninfected (HIV-) men. DESIGN: The Multicenter AIDS Cohort Study is an observational cohort with a total of 429 HIV+ and 303 HIV- men who had non-contrast cardiac computed tomography performed to measure coronary artery calcium and coronary computed tomography angiography to measure coronary stenosis, coronary plaque presence, and composition. METHODS: We used multivariable adjusted prevalence ratios to examine the relationship between the SD difference in each lipid parameter and coronary atherosclerosis. RESULTS: Total cholesterol (TC)/HDL-cholesterol had the strongest associations with coronary atherosclerosis regardless of HIV status. Overall, lipid parameters were most strongly associated with the presence of mixed plaque, stenosis more than 50%, and coronary artery calcium for both HIV+ and HIV- men. HIV+ men had similar, but weaker associations, between lipid parameters and coronary atherosclerosis compared with HIV- men. The strongest association was between the TC/HDL-cholesterol and stenosis more than 50% for both HIV+ [prevalence ratios 1.25 per SD (95% confidence interval 1.07-1.43)] and HIV- men [prevalence ratios 1.46 per SD (95% confidence interval 1.08-1.85)]. CONCLUSION: The associations between lipids and coronary atherosclerosis tended to be weaker for HIV+ compared with HIV- men, although TC/HDL had the strongest association for both HIV+ and HIV- men. A weaker association between lipid levels and coronary atherosclerosis for HIV+ men may contribute to the decreased discrimination of cardiovascular disease risk observed in HIV+ individuals.

Increasing Levels of Serum Heat Shock Protein 70 Precede the Development of AIDS-Defining Non-Hodgkin Lymphoma Among Carriers of HLA-B8-DR3.

BACKGROUND: We hypothesized that carriage of presumably high Hsp70-producing gene variants on a specific human major histocompatibility complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-non-Hodgkin lymphoma (NHL). SETTING: We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n = 151 pairs) nested in the Multicenter AIDS Cohort Study. METHODS: We tested the impact of 8.1AH-specific single-nucleotide polymorphism (SNP) and joint SNP-human leukocyte antigen extended haplotypes previously associated with AIDS-NHL in the Multicenter AIDS Cohort Study on the circulating Hsp70 levels in mixed linear models. RESULTS: We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH, but not in noncarrier cases and not in carrier- or non-carrier-matched controls. The strongest predictor of higher serum Hsp70 was the haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster, and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; standard error = 0.182; P = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing tumor necrosis factor-alpha haplotype rs909253(G)-rs1800629(A) (beta = 0.308; standard error = 0.140; P = 0.032) were observed only with NHL identified as an AIDS-defining condition, but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases. CONCLUSION: Our combined genetic and functional approach suggests that the altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy.