Faculty Bibliography

IMPORTANCE/UNASSIGNED:Chronic exposure to arsenic in drinking water has been associated with increased chronic disease mortality. However, there is limited evidence on associations between reduced exposure and mortality risk. OBJECTIVE/UNASSIGNED:To examine whether reductions in arsenic exposure, measured using urinary arsenic levels, are associated with lower mortality from chronic diseases, including cancer and cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A prospective cohort of 11 746 adults was enrolled between 2000 and 2002 in Araihazar, Bangladesh, with levels of well-water arsenic ranging from less than 1 µg/L to 864 µg/L (mean, 102 µg/L), exceeding the Bangladesh standard of 50 µg/L. Arsenic levels declined over time as a result of community mitigation. Mortality was tracked through 2022. Analyses included 10 977 participants with calculable changes in urinary arsenic levels. EXPOSURES/UNASSIGNED:Urinary arsenic levels were measured up to 5 times per participant through 2018. Participants were categorized based on changes in urinary arsenic levels. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Adjusted hazard ratios (aHRs) and 95% CIs for mortality from chronic diseases, including cancer and CVD. RESULTS/UNASSIGNED:Among 10 977 participants (57% female; mean age, 37.0 [SD, 10.1] years), mean urinary arsenic levels declined from 283 (SD, 314) to 132 (SD, 161) µg/g creatinine from 2000 to 2018. Each IQR decrease in urinary arsenic (197 µg/g creatinine) was associated with 22% lower chronic disease mortality (aHR, 0.78 [95% CI, 0.75-0.82]), 20% lower cancer mortality (aHR, 0.80 [95% CI, 0.73-0.87]), and 23% lower CVD mortality (aHR, 0.77 [95% CI, 0.73-0.81]). Time-varying Cox and restricted cubic spline analyses showed larger reductions were associated with lower mortality, while increases were linked to higher risk. Compared with participants with consistently high urinary arsenic levels (above the baseline median of 199 µg/g creatinine [n = 1757]), those whose levels declined below the median (n = 3757) had lower mortality from chronic diseases (aHR, 0.46 [95% CI, 0.39-0.53]), including cancer (aHR, 0.51 [95% CI, 0.35-0.73]) and CVD (aHR, 0.43 [95% CI, 0.34-0.53]), similar to those consistently below the median (n = 4959) (aHR, 0.43-0.49). Findings were similar in propensity score-matched analyses. CONCLUSIONS AND RELEVANCE/UNASSIGNED:These findings support an association between reduced arsenic exposure and improved health outcomes in populations exposed to contaminated drinking water.

BACKGROUND:Sepsis is a life-threatening complication of infection with high mortality. A high-throughput analysis of circulating blood proteins may provide mechanistic insight and potent therapeutic targets for the prevention of sepsis. METHODS:We used multivariable Cox regression analysis to examine the association of 4955 plasma proteins, measured by SomaScan, with the risk of incident sepsis among 11 065 participants of the Atherosclerosis Risk in Communities (ARIC) Study (visit 3 in 1993 to 1995; mean age, 60.1 years, 54.4% female, 21.0% Black). Proteins (false discovery rate [FDR] of P < 0.05) discovered at visit 3 were replicated using data at visit 5 (n = 4869 in 2011 to 2013: mean age, 75.5 years) and in the Cardiovascular Health Study (CHS) (n = 3512 in 1992 to 1993; mean age, 74.5 years). Canonical pathways were identified by enrichment analyses. RESULTS:At ARIC visit three, 669 proteins were associated with the risk of sepsis; 175 were replicated at visit 5. Of these, 90 were validated in the CHS. The top 20 proteins ranked by P value were relevant to acute inflammatory signaling in innate immunity. Pathway analyses implicated activation of pro-inflammatory pathways (e.g., cytokine storm signaling) as well as inhibition of anti-inflammatory pathways (e.g., liver X receptor/retinoid X receptor [LXR/RXR] activation), which also play relevant roles in lipid metabolism. CONCLUSIONS:In this analysis, levels of acute inflammatory proteins measured during routine visits were associated with the subsequent incidence of sepsis. An increased risk of sepsis associated with the inhibition of anti-inflammatory pathways, such as LXR/RXR warrants further mechanistic investigation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Despite longstanding efforts to design, implement, and study parenting interventions early in life to address disparities in school readiness, gaps remain related to understanding their long-term effects and pathways of influence on child development. Here we describe sustained impacts at child age 6 of the innovative, tiered birth to age 3 Smart Beginnings (SB) model. METHODS:We performed a single-blind, 2-site randomized clinical trial of the SB model. SB integrates PlayReadVIP, a universal, pediatric primary care-based program, and Family Check-Up, a targeted secondary home-based parenting intervention. Mother-infant dyads (N = 403) were randomized at birth to standard pediatric care or the SB model. In line with SB's theory of change that supporting parents will promote their children's development, single and serial mediation pathways evaluated intervention effects of SB on age 6 child academic skills through parental cognitive stimulation at age 2 and child academic functioning at age 4. RESULTS:We found significant single and serially mediated indirect effects of SB on academic outcomes through parental cognitive stimulation in toddlerhood and preacademic skills in preschool. The total indirect pathways were positive and statistically significant for all academic outcomes at age 6, including receptive vocabulary (effect size [ES] = 0.04, P = .04), oral comprehension (ES = 0.05, P = .04), letter-word recognition (ES = 0.04, P = .04), phonemic decoding (ES = 0.04, P = .04), and applied problems (ES = 0.05, P = .04). CONCLUSIONS:Findings build on the demonstrated scalability of the SB model, support the cumulative process of academic functioning in childhood, and offer a promising model to address disparities early in life.

AIMS/HYPOTHESIS/OBJECTIVE:plus FPG. METHODS:, individually and in combination, for diagnosing diabetes. Random-effects meta-analyses were applied to pooled data to summarise the overall diagnostic accuracy across studies. RESULTS:, with pooled AUCs (95% CI) of 0.97 (0.96, 0.98) vs 0.85 (0.82, 0.88). CONCLUSIONS/INTERPRETATION/CONCLUSIONS:for diagnosing type 2 diabetes.

Cisgender women are underserved by current HIV prevention efforts, and substantial gender disparities persist in pre-exposure prophylaxis (PrEP) use. Recent diagnoses with a bacterial sexually transmitted infection (STI) are objective, readily available indicators of PrEP-eligibility that could be used to improve PrEP prescribing for cisgender women. To better understand missed opportunities for prescribing, we examined the prevalence and correlates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) diagnoses among cisgender women seeking care at a New York City obstetrics and gynecology (Ob/Gyn) clinic, along with the number of PrEP prescriptions provided post-STI diagnosis. A cross-sectional, retrospective review of electronic health record data was conducted for all HIV-negative cisgender women tested for CT and/or NG at the clinic between September 1, 2021 and September 19, 2022. Counts and prevalence for CT and NG infection were calculated, and multivariable log-binomial regression was used to examine associated factors. Among 7593 cisgender women receiving CT/NG testing during the study period, 186 had ≥ 1 CT infection (prevalence: 2.45%) and 18 had ≥ 1 NG infection (prevalence: 0.24%). In a multivariable model, CT/NG infection was significantly associated with age, having Spanish as a primary language, and a marital status of divorced, widowed, or separated. No cisgender women who received CT or NG diagnoses were prescribed PrEP during the study period. These findings highlight how opportunities to prescribe PrEP to cisgender women continue to be missed, even with readily available indicators for PrEP eligibility. More effective strategies are needed to promote PrEP prescribing among diverse populations of cisgender women, particularly in Ob/Gyn settings.

Previous studies have developed proteomic aging clocks to estimate biological age and predict mortality and age-related diseases. However, these earlier clocks were based on cross-sectional data, capturing only the cumulative aging burden at a single time point but were unable to reflect the dynamic trajectory of biological aging over time. We constructed a longitudinal proteomic aging index (LPAI) using data from 4684 plasma proteins measured by the SomaScan 5K Array across three visits in the Atherosclerosis Risk in Communities (ARIC) study (ages 67-90 at last visit). Our two-step approach applied functional principal component analysis (FPCA) to capture protein-level change patterns over time, followed by elastic net penalized Cox regression for protein selection. LPAI was constructed in a randomly selected training set of ARIC participants (N = 2954), tested among the remaining ARIC participants (N = 1267), and validated externally in Multi-Ethnic Study of Atherosclerosis (MESA) participants (N = 3726, ages 53-94 at last exam). Using Cox proportional hazards model, higher LPAI was associated with increased all-cause mortality (HR = 2.50, 95% CI: [2.15, 2.92] per SD), CVD mortality (HR = 1.79, 95% CI: [1.34, 2.39] per SD), and cancer mortality (HR = 1.96, 95% CI: [1.45, 2.64] per SD) risk in ARIC, with statistically significant and directionally consistent associations also observed in MESA. Additionally, higher LPAI was associated with increased multimorbidity and frailty. This study demonstrates the feasibility of developing biological aging measures from longitudinal proteomics data and supports LPAI as a biomarker for aging-related health risks.