David J. Prezant

The World Trade Center (WTC) collapse produced an inhalation disaster. Body Mass index (BMI) is a risk-factor for WTC-related lung injury. Visit-to-visit-forced-expiratory-volume-at-one-second-variation (FEV₁-variation) is a mortality risk-factor in WTC-exposed Fire Department of New York (FDNY) workers. We hypothesized: worsened-FEV₁-variation with greater time post-9/11/2001 will be a mortality risk-factor associated with cross sectional BMI and longitudinal weight-variation. Annual WTC-monitoring measured lung function and weight. FEV₁-variation was quantified as individual-specific coefficient of variation (CV) and FEV₁-slope-SEM, among 9410 WTC-exposed workers who were alive at the 1/1/2019 Landmark and had ≥ 3 FEV₁-measurments early (9/12/2001 through 12/31/2009) and later (1/1/2010 through 12/31/2018). Weight-variation quantified as individual-specific weight-CV 9/12/2001 through 12/31/2018. Worsened-FEV₁-variation was defined as later/early FEV₁-variation ratio > 1. The outcome was all-cause mortality 1/1/2019 through 12/31/23. Cox regression assessed the 5-year mortality risk of Worsened-FEV₁-variation. Logistic regression assessed covariates associated with worsened-FEV₁-variation. Fourty-seven percent (4459/9410) of WTC-exposed FDNY-workers experienced worsened-FEV₁-variation. an exposure that was associated with 40% greater 5-year mortality risk (HR = 1.40; 95% CI 1.07, 1.89) in a Cox model adjusted for landmark, age, FEV₁, BMI, weight-variation, and smoking. Similarly, Worsened-FEV₁-variation defined by FEV₁-slope-SEM was a mortality risk factor (HR = 1.39; 95% CI 1.05, 1.83). Each 5 kg/m² increase in BMI and each 5%CV increased weight-variation was associated with 18% and 17% greater odds of worsened-FEV₁-variation (OR = 1.18; 95% CI 1.06, 1.27 and OR = 1.17; 95% CI 1.07, 1.27 respectively). Worsened-FEV₁-variation with greater time post-9/11/2001 is a mortality risk-factor associated with obesity and weight-variation. The association of Worsened-FEV₁-variation and weight-variation may reflect concurrent metabolic and pulmonary instability that increase vulnerability to death.

Posttraumatic stress disorder (PTSD) has been linked to impaired physical function, which in turn predicts falls, morbidity, and mortality. However, few studies have used objective measures such as handgrip strength to assess physical function. In this cross-sectional study, we investigated associations of average PTSD symptom severity and symptom domain severity with measures of maximum handgrip strength and handgrip asymmetry from 11/2021–12/2023, among 381 male firefighters and emergency medical responders who responded to the World Trade Center disaster, using covariate-adjusted linear regression models. PTSD was diagnosed using the Structured Clinical Interview for the DSM-5 in 17% of responders. Greater overall PTSD average symptom severity was associated with weaker maximum handgrip strength (β = −4.43 lbs; 95%; CI: −8.77, −0.09; p = 0.045). Higher re-experiencing symptom severity was associated with weaker maximum handgrip strength (β = −4.17 lbs; 95% CI: −8.13, −0.22; p = 0.039). Avoidance symptoms were associated with weaker handgrip strength in adjusted models (β = −4.14 lbs; 95% CI: −7.56, −0.73; p = 0.018), and associated with a larger negative difference assessing for hand asymmetry (β = −2.20 lbs; 95% CI: −4.18, −0.22; p = 0.029). Findings suggest that PTSD may contribute to long-term physical decline, even in populations with high baseline fitness.

Prevalence of somatic mutation (VAF ≤ 25%) in WTC-exposed responders

Mutational signatures for changes seen in WTC-exposed responders below the age of 60

Environmental exposures are linked to precancerous hematologic conditions, but studies in cohorts with well-defined exposures are limited. We sequenced blood samples from a large cohort of first responders exposed to the aerosolized dust and carcinogens from the 9/11 World Trade Center (WTC) disaster and observed a significantly higher prevalence of clonal hematopoiesis (CH) mutations when compared with two sets of control cohorts after controlling for age, race, and sex. Younger exposed first responders exhibited unconventional CH mutations, with defective DNA repair signatures. Leukemia risk was elevated (3.7% vs. 0.6%; OR = 5.73) in WTC-exposed responders with CH versus without CH. Exposure to particulate matter collected from WTC site impaired healthy stem cells while expanding Tet2-mutant CH clones in mice. The inflammation sensor IL1RAP was overexpressed in murine CH, and genetic knockdown inhibited mutant clone growth in vivo. This study links discrete environmental exposure to hematopoietic mutations and leukemia, identifying IL1RAP as a novel therapeutic target in CH.Significance:This study identifies elevated CH with distinct, nonclassical mutations in 9/11 first responders, particularly younger individuals, and links CH to increased leukemia risk. Findings suggest broader relevance to other genotoxic environmental exposures and highlight IL1RAP as a critical driver of CH expansion and a promising therapeutic target for inflammation-driven malignancies.See related commentary by Safina and van Galen, p. 2406

Mutational signatures for changes seen in WTC-exposed responders above the age of 60