Faculty Bibliography

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.

BACKGROUND:Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. METHODS AND FINDINGS/RESULTS:Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. CONCLUSIONS:Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

Mounting evidence shows a disproportionate COVID-19 burden among Blacks. Early findings indicate pre-existing metabolic burden (eg, obesity, hypertension and diabetes) as key drivers of COVID-19 severity. Since Blacks exhibit higher prevalence of metabolic burden, we examined the influence of metabolic syndrome on disparate COVID-19 burden. We analyzed data from a NIH-funded study to characterize metabolic burden among Blacks in New York (Metabolic Syndrome Outcome Study). Patients (n=1035) were recruited from outpatient clinics, where clinical and self-report data were obtained. The vast majority of the sample was overweight/obese (90%); diagnosed with hypertension (93%); dyslipidemia (72%); diabetes (61%); and nearly half of them were at risk for sleep apnea (48%). Older Blacks (age≥65 years) were characterized by higher levels of metabolic burden and co-morbidities (eg, heart disease, cancer). In multivariate-adjusted regression analyses, age was a significant (p≤.001) independent predictor of hypertension (OR=1.06; 95% CI: 1.04-1.09), diabetes (OR=1.03; 95% CI: 1.02-1.04), and dyslipidemia (OR=0.98; 95% CI: 0.97-0.99), but not obesity. Our study demonstrates an overwhelmingly high prevalence of the metabolic risk factors related to COVID-19 among Blacks in New York, highlighting disparate metabolic burden among Blacks as a possible mechanism conferring the greater burden of COVID-19 infection and mortality represented in published data.

The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.

BACKGROUND:Statistical methods to study the joint effects of environmental factors are of great importance to understand the impact of correlated exposures that may act synergistically or antagonistically on health outcomes. This study proposes a family of statistical models under a unified partial-linear single-index (PLSI) modeling framework, to assess the joint effects of environmental factors for continuous, categorical, time-to-event, and longitudinal outcomes. All PLSI models consist of a linear combination of exposures into a single index for practical interpretability of relative direction and importance, and a nonparametric link function for modeling flexibility. METHODS:We presented PLSI linear regression and PLSI quantile regression for continuous outcome, PLSI generalized linear regression for categorical outcome, PLSI proportional hazards model for time-to-event outcome, and PLSI mixed-effects model for longitudinal outcome. These models were demonstrated using a dataset of 800 subjects from NHANES 2003-2004 survey including 8 environmental factors. Serum triglyceride concentration was analyzed as a continuous outcome and then dichotomized as a binary outcome. Simulations were conducted to demonstrate the PLSI proportional hazards model and PLSI mixed-effects model. The performance of PLSI models was compared with their counterpart parametric models. RESULTS:PLSI linear, quantile, and logistic regressions showed similar results that the 8 environmental factors had both positive and negative associations with triglycerides, with a-Tocopherol having the most positive and trans-b-carotene having the most negative association. For the time-to-event and longitudinal settings, simulations showed that PLSI models could correctly identify directions and relative importance for the 8 environmental factors. Compared with parametric models, PLSI models got similar results when the link function was close to linear, but clearly outperformed in simulations with nonlinear effects. CONCLUSIONS:We presented a unified family of PLSI models to assess the joint effects of exposures on four commonly-used types of outcomes in environmental research, and demonstrated their modeling flexibility and effectiveness, especially for studying environmental factors with mixed directional effects and/or nonlinear effects. Our study has expanded the analytical toolbox for investigating the complex effects of environmental factors. A practical contribution also included a coherent algorithm for all proposed PLSI models with R codes available.

Fire Department of New York (FDNY) rescue and recovery workers exposed to World Trade Center (WTC) particulates suffered loss of forced expiratory volume in 1 s (FEV₁). Metabolic Syndrome increased the risk of developing WTC-lung injury (WTC-LI)_. We aim to attenuate the deleterious effects of WTC exposure through a dietary intervention targeting these clinically relevant disease modifiers. We hypothesize that a calorie-restricted Mediterranean dietary intervention will improve metabolic risk, subclinical indicators of cardiopulmonary disease, quality of life, and lung function in firefighters with WTC-LI. To assess our hypothesis, we developed the Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE), a randomized controlled clinical trial (RCT). Male firefighters with WTC-LI and a BMI > 27 kg/m² will be included. We will randomize subjects (1:1) to either: (1) Low Calorie Mediterranean (LoCalMed)-an integrative multifactorial, technology-supported approach focused on behavioral modification, nutritional education that will include a self-monitored diet with feedback, physical activity recommendations, and social cognitive theory-based group counseling sessions; or (2) Usual Care. Outcomes include reduction in body mass index (BMI) (primary), improvement in FEV₁, fractional exhaled nitric oxide, pulse wave velocity, lipid profiles, targeted metabolic/clinical biomarkers, and quality of life measures (secondary). By implementing a technology-supported LoCalMed diet our FIREHOUSE RCT may help further the treatment of WTC associated pulmonary disease.

Rationale & Objectives/UNASSIGNED:Recent data demonstrate that center volume is not a factor in the outcomes of adult kidney transplant recipients. This study assessed whether center volume affects graft survival in pediatric patients who received a kidney transplant. Study Design/UNASSIGNED:Case-cohort study. Setting & Participants/UNASSIGNED:Kidney transplantation centers, recipients younger than 18 years. Results/UNASSIGNED: = 0.02. Although outcomes for deceased donor kidney recipients were similar in the 3 volume categories, outcomes in patients who received a living kidney donation were better in the high-volume centers. Low household income was associated with poorer outcomes. However, 3-year graft survival was similar in the 3 center volume categories in high and low mean household income states. Limitations/UNASSIGNED:Lack of information for complications and individual family household income of recipients. Conclusions/UNASSIGNED:Transplantation outcomes are worse in pediatric patients treated at lower-volume centers. The difference was more pronounced for patients receiving living versus deceased donor kidneys. The distribution of household income in pediatric transplant recipients may also be a factor that contributes to lower 3-year graft survival in low-volume centers.

World Trade Center particulate matter (WTC-PM)-exposed firefighters with metabolic syndrome (MetSyn) have a higher risk of WTC lung injury (WTC-LI). Since macrophages are crucial innate pulmonary mediators, we investigated WTC-PM/lysophosphatidic acid (LPA) co-exposure in macrophages. LPA, a low-density lipoprotein metabolite, is a ligand of the advanced glycation end-products receptor (AGER or RAGE). LPA and RAGE are biomarkers of WTC-LI. Human and murine macrophages were exposed to WTC-PM, and/or LPA, and compared to controls. Supernatants were assessed for cytokines/chemokines; cell lysate immunoblots were assessed for signaling intermediates after 24 h. To explore the translatability of our in-vitro findings, we assessed serum cytokines/chemokines and metabolites of symptomatic, never-smoking WTC-exposed firefighters. Agglomerative hierarchical clustering identified phenotypes of WTC-PM-induced inflammation. WTC-PM induced GM-CSF, IL-8, IL-10, and MCP-1 in THP-1-derived macrophages and induced IL-1α, IL-10, TNF-α, and NF-κB in RAW264.7 murine macrophage-like cells. Co-exposure induced synergistic elaboration of IL-10 and MCP-1 in THP-1-derived macrophages. Similarly, co-exposure synergistically induced IL-10 in murine macrophages. Synergistic effects were seen in the context of a downregulation of NF-κB, p-Akt, -STAT3, and -STAT5b. RAGE expression after co-exposure increased in murine macrophages compared to controls. In our integrated analysis, the human cytokine/chemokine biomarker profile of WTC-LI was associated with discriminatory metabolites (fatty acids, sphingolipids, and amino acids). LPA synergistically elaborated WTC-PM's inflammatory effects in vitro and was partly RAGE-mediated. Further research will focus on the intersection of MetSyn/PM exposure.

Mean residual life (MRL) is the remaining life expectancy of a subject who has survived to a certain time point and can be used as an alternative to hazard function for characterizing the distribution of a time-to-event variable. Inference and application of MRL models have primarily focused on full-cohort studies. In practice, case-cohort and nested case-control designs have been commonly used within large cohorts that have long follow-up and study rare diseases, particularly when studying costly molecular biomarkers. They enable prospective inference as the full-cohort design with significant cost-saving benefits. In this paper, we study the modeling and inference of a family of generalized MRL models under case-cohort and nested case-control designs. Built upon the idea of inverse selection probability, the weighted estimating equations are constructed to estimate regression parameters and baseline MRL function. Asymptotic properties of the proposed estimators are established and finite-sample performance is evaluated by extensive numerical simulations. An application to the New York University Women's Health Study is presented to illustrate the proposed models and demonstrate a model diagnostic method to guide practical implementation.