Faculty Bibliography

Experimental studies suggested per- and polyfluoroalkyl substances (PFASs) may disrupt estrogens in animals, however, the epidemiological evidence on the associations of PFASs with estrogens is sparse. We investigated the associations of legacy PFASs and their alternatives, including F-53B, the perfluorooctane sulfonate (PFOS) replacement that is specifically and commonly used in China, with estrogen concentrations in newborns. We quantified six PFASs and three estrogens in the cord sera of 942 newborns from a birth cohort in Wuhan, China, between 2013 and 2014. After adjusting for confounders and correcting for multiple comparisons, we observed that both legacy PFASs and their alternatives were associated with higher serum levels of estradiol (E2). Some of the PFASs were associated with increasing levels of estrone (E1) and estriol (E3). Analysis of PFASs in mixture using weighted quantile sum regressions showed that F-53B contributed 20.1% and 48.5% to the associations between PFASs and E1 and E2, respectively. This study provided epidemiological data on the associations between common PFAS exposures and estrogens in newborns. Additional toxicology studies are needed to fully understand the effects of PFASs on estrogens and the mechanisms.

OBJECTIVES/OBJECTIVE:Estimating the prevalence of drug use in the general population is important given its potential health consequences but is challenging. Self-reported surveys on drug use have inherent limitations that underestimate drug use. We evaluated the performance of linking urine drug testing with a local, representative health examination survey in estimating the prevalence of drug use in New York City (NYC). METHODS:We used urine drug testing from the NYC Health and Nutrition Examination Survey (NYC HANES) to estimate the prevalence of drug use (benzodiazepines, cocaine, heroin, and opioid analgesics) among the study sample and compare the findings with self-reported responses to questions about past-12-month drug use from the same survey. RESULTS:Of 1527 respondents to NYC HANES, urine drug testing was performed on 1297 (84.9%) participants who provided urine and consented to future studies. Self-reported responses gave past-12-month weighted estimates for heroin, cocaine, or any prescription drug misuse of 13.8% (95% CI, 11.6%-16.3%), for prescription drug misuse of 9.9% (95% CI, 8.1%-12.1%), and for heroin or cocaine use of 6.1% (95% CI, 4.7%-7.9%). Urine drug testing gave past-12-month weighted estimates for any drug use of 4.3% (95% CI, 3.0%-6.0%), for use of any prescription drug of 2.8% (95% CI, 1.9%-4.1%), and for heroin or cocaine use of 2.0% (95% CI, 1.2%-3.6%). CONCLUSION/CONCLUSIONS:Urine drug testing provided underestimates for the prevalence of drug use at a population level compared with self-report. Researchers should use other methods to estimate the prevalence of drug use on a population level.

Background: Zinc impairs replication of RNA viruses such as SARS-CoV-1, and may be effective against SARS-CoV-2. However, to achieve adequate intracellular zinc levels, administration with an ionophore, which increases intracellular zinc levels, may be necessary. We evaluated the impact of zinc with an ionophore (Zn+ionophore) on COVID-19 in-hospital mortality rates. Methods: A multicenter cohort study was conducted of 3,473 adult hospitalized patients with reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection admitted to four New York City hospitals between March 10 through May 20, 2020. Exclusion criteria were: death or discharge within 24h, comfort-care status, clinical trial enrollment, treatment with an IL-6 inhibitor or remdesivir. Patients who received Zn+ionophore were compared to patients who did not using multivariable time-dependent cox proportional hazards models for time to in-hospital death adjusting for confounders including age, sex, race, BMI, diabetes, week of admission, hospital location, sequential organ failure assessment (SOFA) score, intubation, acute renal failure, neurological events, treatment with corticosteroids, azithromycin or lopinavir/ritonavir and the propensity score of receiving Zn+ionophore. A sensitivity analysis was performed using a propensity score-matched cohort of patients who did or did not receive Zn+ionophore matched by age, sex and ventilator status. Results: Among 3,473 patients (median age 64, 1947 [56%] male, 522 [15%] ventilated, 545[16%] died), 1,006 (29%) received Zn+ionophore. Zn+ionophore was associated with a 24% reduced risk of in-hospital mortality (12% of those who received Zn+ionophore died versus 17% who did not; adjusted Hazard Ratio [aHR] 0.76, 95% CI 0.60-0.96, P=0.023). More patients who received Zn+ionophore were discharged home (72% Zn+ionophore vs 67% no Zn+ionophore, P=0.003) Neither Zn nor the ionophore alone were associated with decreased mortality rates. Propensity score-matched sensitivity analysis (N=1356) validated these results (Zn+ionophore aHR for mortality 0.63, 95%CI 0.44-0.91, P=0.015). There were no significant interactions for Zn+ionophore with other COVID-19 specific medications. Conclusions: Zinc with an ionophore was associated with increased rates of discharge home and a 24% reduced risk of in-hospital mortality among COVID-19 patients, while neither zinc alone nor the ionophore alone reduced mortality. Further randomized trials are warranted.

AIMS/OBJECTIVE:We sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes. METHODS:in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR. RESULTS:Estimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index. CONCLUSIONS:Over the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.

Whether an OGTT reproducibly detects either type 2 diabetes (T2D) or prediabetes in Africans in unknown. Therefore, 131 Africans had two OGTT. Diagnostic reproducibility for T2D was excellent (κ = 0.84), but only moderate for prediabetes (κ = 0.51). A single OGTT positive for T2D may be sufficient to guide clinical care and inform epidemiologic study design. ClinicalTrials.gov Identifier: NCT00001853.

Background Functional decline (ie, a decrement in ability to perform everyday activities necessary to live independently) is common after acute myocardial infarction (AMI) and associated with poor long-term outcomes; yet, we do not have a tool to identify older AMI survivors at risk for this important patient-centered outcome. Methods and Results We used data from the prospective SILVER-AMI (Comprehensive Evaluation of Risk Factors in Older Patients With Acute Myocardial Infarction) study of 3041 patients with AMI, aged ≥75 years, recruited from 94 US hospitals. Participants were assessed during hospitalization and at 6 months to collect data on demographics, geriatric impairments, psychosocial factors, and activities of daily living. Clinical variables were abstracted from the medical record. Functional decline was defined as a decrement in ability to independently perform essential activities of daily living (ie, bathing, dressing, transferring, and ambulation) from baseline to 6 months postdischarge. The mean age of the sample was 82±5 years; 57% were men, 90% were White, and 13% reported activity of daily living decline at 6 months postdischarge. The model identified older age, longer hospital stay, mobility impairment during hospitalization, preadmission physical activity, and depression as risk factors for decline. Revascularization during AMI hospitalization and ability to walk a quarter mile before AMI were associated with decreased risk. Model discrimination (c=0.78) and calibration were good. Conclusions We identified a parsimonious model that predicts risk of activity of daily living decline among older patients with AMI. This tool may aid in identifying older patients with AMI who may benefit from restorative therapies to optimize function after AMI.

BACKGROUND:It is unknown whether transcatheter valves will have similar durability as surgical bioprosthetic valves. Definitions of structural valve deterioration (SVD), based on valve related reintervention or death, underestimate the incidence of SVD. OBJECTIVES:This study sought to determine and compare the 5-year incidence of SVD, using new standardized definitions based on echocardiographic follow-up of valve function, in intermediate-risk patients with severe aortic stenosis given transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) in the PARTNER (Placement of Aortic Transcatheter Valves) 2A trial and registry. METHODS:In the PARTNER 2A trial, patients were randomly assigned to receive either TAVR with the SAPIEN XT or SAVR, whereas in the SAPIEN 3 registry, patients were assigned to TAVR with the SAPIEN 3. The primary endpoint was the incidence of SVD, that is, the composite of SVD-related hemodynamic valve deterioration during echocardiographic follow-up and/or SVD-related bioprosthetic valve failure (BVF) at 5 years. RESULTS:Compared with SAVR, the SAPIEN-XT TAVR cohort had a significantly higher 5-year exposure adjusted incidence rates (per 100 patient-years) of SVD (1.61 ± 0.24% vs. 0.63 ± 0.16%), SVD-related BVF (0.58 ± 0.14% vs. 0.12 ± 0.07%), and all-cause (structural or nonstructural) BVF (0.81 ± 0.16% vs. 0.27 ± 0.10%) (p ≤ 0.01 for all). The 5-year rates of SVD (0.68 ± 0.18% vs. 0.60 ± 0.17%; p = 0.71), SVD-related BVF (0.29 ± 0.12% vs. 0.14 ± 0.08%; p = 0.25), and all-cause BVF (0.60 ± 0.15% vs. 0.32 ± 0.11%; p = 0.32) in SAPIEN 3 TAVR were not significantly different to a propensity score matched SAVR cohort. The 5-year rates of SVD and SVD-related BVF were significantly lower in SAPIEN 3 versus SAPIEN XT TAVR matched cohorts. CONCLUSIONS:Compared with SAVR, the second-generation SAPIEN XT balloon-expandable valve has a higher 5-year rate of SVD, whereas the third-generation SAPIEN 3 has a rate of SVD that was not different from SAVR. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII A [PARTNERII A]; NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate [PARTNERII S3i]; NCT03222128).

Background Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure hospitalizations, with limited data on predictors of mortality by sex and race. We evaluated for differences in predictors of all-cause mortality by sex and race among hospitalized patients with HFpEF in the ARIC (Atherosclerosis Risk in Communities) Community Surveillance Study. Methods and Results Adjudicated HFpEF hospitalization events from 2005 to 2013 were analyzed from the ARIC Community Surveillance Study, comprising 4 US communities. Comparisons between clinical characteristics and mortality at 1 year were made by sex and race. Of 4335 adjudicated acute decompensated heart failure cases, 1892 cases (weighted n=8987) were categorized as HFpEF. Men had an increased risk of 1-year mortality compared with women in adjusted analysis (hazard ratio [HR], 1.27; 95% CI, 1.06-1.52 [P=0.01]). Black participants had lower mortality compared with White participants in unadjusted and adjusted analyses (HR, 0.79; 95% CI, 0.64-0.97 [P=0.02]). Age, heart rate, worsening renal function, and low hemoglobin were associated with increased mortality in all subgroups. Higher body mass index was associated with improved survival in men, with borderline interaction by sex. Higher blood pressure was associated with improved survival among all groups, with significant interaction by race. Conclusions In a diverse HFpEF population, men had worse survival compared with women, and Black participants had improved survival compared with White participants. Age, heart rate, and worsening renal function were associated with increased mortality across all subgroups; high blood pressure was associated with decreased mortality with interaction by race. These insights into sex- and race-based differences in predictors of mortality may help strategize targeted management of HFpEF.

BACKGROUND:Diabetes prevalence and incidence vary by neighborhood socioeconomic environment (NSEE) and geographic region in the United States. Identifying modifiable community factors driving type 2 diabetes disparities is essential to inform policy interventions that reduce the risk of type 2 diabetes. OBJECTIVE:This paper aims to describe the Diabetes Location, Environmental Attributes, and Disparities (LEAD) Network, a group funded by the Centers for Disease Control and Prevention to apply harmonized epidemiologic approaches across unique and geographically expansive data to identify community factors that contribute to type 2 diabetes risk. METHODS:The Diabetes LEAD Network is a collaboration of 3 study sites and a data coordinating center (Drexel University). The Geisinger and Johns Hopkins University study population includes 578,485 individuals receiving primary care at Geisinger, a health system serving a population representative of 37 counties in Pennsylvania. The New York University School of Medicine study population is a baseline cohort of 6,082,146 veterans who do not have diabetes and are receiving primary care through Veterans Affairs from every US county. The University of Alabama at Birmingham study population includes 11,199 participants who did not have diabetes at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort study with oversampling of participants from the Stroke Belt region. RESULTS:The Network has established a shared set of aims: evaluate mediation of the association of the NSEE with type 2 diabetes onset, evaluate effect modification of the association of NSEE with type 2 diabetes onset, assess the differential item functioning of community measures by geographic region and community type, and evaluate the impact of the spatial scale used to measure community factors. The Network has developed standardized approaches for measurement. CONCLUSIONS:The Network will provide insight into the community factors driving geographical disparities in type 2 diabetes risk and disseminate findings to stakeholders, providing guidance on policies to ameliorate geographic disparities in type 2 diabetes in the United States. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)/UNASSIGNED:DERR1-10.2196/21377.

Importance/UNASSIGNED:Children of parents expressing limited comfort with English (LCE) or limited English proficiency may be at increased risk of adverse events (harms due to medical care). No prior studies have examined, in a multicenter fashion, the association between language comfort or language proficiency and systematically, actively collected adverse events that include family safety reporting. Objective/UNASSIGNED:To examine the association between parent LCE and adverse events in a cohort of hospitalized children. Design, Setting, and Participants/UNASSIGNED:This multicenter prospective cohort study was conducted from December 2014 to January 2017, concurrent with data collection from the Patient and Family Centered I-PASS Study, a clinician-family communication and patient safety intervention study. The study included 1666 Arabic-, Chinese-, English-, and Spanish-speaking parents of general pediatric and subspecialty patients 17 years and younger in the pediatric units of 7 North American hospitals. Data were analyzed from January 2018 to May 2020. Exposures/UNASSIGNED:Language-comfort data were collected through parent self-reporting. LCE was defined as reporting any language besides English as the language in which parents were most comfortable speaking to physicians or nurses. Main Outcomes and Measures/UNASSIGNED:The primary outcome was adverse events; the secondary outcome was preventable adverse events. Adverse events were collected using a systematic 2-step methodology. First, clinician abstractors reviewed patient medical records, solicited clinician reports, hospital incident reports, and family safety interviews. Then, review and consensus classification were completed by physician pairs. To examine the association of LCE with adverse events, a multivariable logistic regression was conducted with random intercepts to adjust for clustering by site. Results/UNASSIGNED:Of 1666 parents providing language-comfort data, 1341 (80.5%) were female, and the mean (SD) age of parents was 35.4 (10.0) years. A total of 147 parents (8.8%) expressed LCE, most of whom (105 [71.4%]) preferred Spanish. Children of parents who expressed LCE had higher odds of having 1 or more adverse events compared with children whose parents expressed comfort with English (26 of 147 [17.7%] vs 146 of 1519 [9.6%]; adjusted odds ratio, 2.1; 95% CI, 1.2-3.7), after adjustment for parent race and education, complex chronic conditions, length of stay, site, and the intervention period. Similarly, children whose parents expressed LCE were more likely to experience 1 or more preventable adverse events (adjusted odds ratio, 2.3; 95% CI, 1.2-4.2). Conclusions and Relevance/UNASSIGNED:Hospitalized children of parents expressing LCE were twice as likely to experience harms due to medical care. Targeted strategies are needed to improve communication and safety for this vulnerable group of children.