Faculty Bibliography

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to look for microbial and host signatures in the lower airways associated with treatment response. We found that enrichment of the lower airway microbiome with oral commensals was associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short-chain fatty acids, methane, and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy, all of which could contribute to the poor response to immunotherapy. In a preclinical murine model of lung cancer with dysbiosis, inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways influence tumor-immune interactions via defined metabolic-immune axes.

Growing evidence suggests that exposure to air pollution during early life is associated with autism spectrum disorder (ASD). However, results have been inconsistent for autism-like traits and in low exposure settings. Here, we assessed sensitive windows of exposure to fine particulate matter (PM_2.5), nitrogen dioxide (NO₂), and ozone (O₃) and joint effects of exposure to sources and constituents of PM_2.5 on autism-like traits among 798 children in the Upstate KIDS cohort. Residential air pollution exposures were assessed with machine learning and land use regression models. Autism-like traits at age 10 were assessed via the ASD subscale on the Child Behavior Checklist. Treed distributed lag mixture model was used to identify critical windows of exposure to PM_2.5, NO₂, and O₃ and partial linear single index model was applied to estimate contributions of sources and constituents of PM_2.5 on autism-like traits. The median PM_2.5 exposures were 8.36 and 8.00 μg/m³ for pregnancy and the first year of life. We did not observe critical windows of exposure to PM_2.5, NO₂, or O₃ for autism-like traits. Exposures to elemental carbon (EC) PM_2.5 during gestation and to EC and traffic PM_2.5 during the first year of life were associated with higher odds of autism-like traits (prenatal EC adjusted odds ratio (aOR): 1.72, 95% CI: 1.04-2.83; first year EC aOR: 1.72, 95% CI: 1.21-2.46; traffic aOR: 1.31, 95% CI: 1.01-1.71). Our results suggest that exposure to motor vehicle traffic sources of PM_2.5 may drive previously reported associations between total PM_2.5 and autism-like traits.

RATIONALE & OBJECTIVE/UNASSIGNED:exposure and mortality, overall and by race and ethnicity. STUDY DESIGN/UNASSIGNED:Cohort study (2003-2019). SETTING & PARTICIPANTS/UNASSIGNED:National registry for patients with kidney failure. EXPOSURES/UNASSIGNED:), segregation scores (Theil's H method), deprivation scores (American Community Survey), and built environment factors (medically underserved areas [MUA] and urbanicity) by patients' residential ZIP code at dialysis initiation. OUTCOME/UNASSIGNED:All-cause mortality. ANALYTICAL APPROACH/UNASSIGNED:and mortality, overall and stratified by race and ethnicity. RESULTS/UNASSIGNED:< 0.001]). LIMITATIONS/UNASSIGNED:may not reflect individual-level exposures. CONCLUSIONS/UNASSIGNED:and reduce related mortality.

INTRODUCTION/BACKGROUND:Elevated concentrations of air pollutants in residential neighborhoods are associated with poorer survival, cognitive, and cardiovascular health among older adults. Older kidney transplant (KT) recipients may be more vulnerable due to chronic immunosuppression and age-related co-morbidities. Therefore, we quantified the associations between pollutant concentrations and post-KT outcomes among older recipients. METHODS:]) were obtained from the Center for Air, Climate and Energy Solutions, and matched by ZIP code and year of KT. We used shared frailty models (cluster = state) to estimate the adjusted hazard ratios (aHR) of mortality and death-censored graft failure (DCGF) and competing risk models with cluster-robust standard errors to estimate the adjusted subhazard ratios (aSHR) of dementia and stroke by pollutant concentrations. RESULTS:concentrations were associated with a 3% (aSHR = 1.03, 95% CI: 1.00-1.07) and 4% higher risk of stroke (aSHR = 1.04, 95% CI: 1.02-1.07), respectively. CONCLUSION/CONCLUSIONS:Residence in neighborhoods with high concentrations of ambient air pollutants can worsen patient and graft survival, as well as increase the risk of stroke among older KT recipients. Early screening and interventions targeting older recipients living in such neighborhoods may be crucial for preserving cognitive and cerebrovascular health, as well as improving longitudinal quality of life.

BACKGROUND:on dementia may be more severe in this population. METHODS:and dementia risk factors using a Wald test. Models were adjusted for confounders, including social determinants of health. RESULTS:was associated with 1.90-fold higher odds of global cognitive impairment (95% CI: 1.48-2.46), and 3.29-fold higher risk of dementia (95% CI: 1.14-9.55). CONCLUSION/CONCLUSIONS:neighborhoods should discuss cognitive assessments and ways to increase physical activity with providers.

BACKGROUND/UNASSIGNED:; environmental injustice) by racial/ethnic segregation (social injustice) on dementia diagnosis in ESKD. METHODS/UNASSIGNED:concentrations (annualized and matched to older adults' residential ZIP code at dialysis initiation) and by segregation scores (Theil's H method). FINDINGS/UNASSIGNED:and segregation. INTERPRETATION/UNASSIGNED:experienced an increased risk of dementia; this risk was particularly pronounced among individuals in high segregation and predominantly minority neighborhoods. Environmental and social injustices likely drive racial and ethnic disparities in dementia for older adults with ESKD, underscoring the need for interventions and policies to mitigate these injustices. FUNDING/UNASSIGNED:National Institutes of Health.