Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN) in World Trade Center exposed firefighters: a case-control observational study protocol.

BACKGROUND: Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. METHODS: Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. DISCUSSION: Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. TRIAL REGISTRATION: Name of Primary Registry: "Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BADBURN)". Trial Identifying Number: NCT05216133 . Date of Registration: January 31, 2022.

Association of firefighting exposures with lung function using a novel job exposure matrix (JEM).

OBJECTIVES: Characterisation of firefighters' exposures to dangerous chemicals in smoke from non-wildfire incidents, directly through personal monitoring and indirectly from work-related records, is scarce. The aim of this study was to evaluate the association between smoke particle exposures (P) and pulmonary function. METHODS: The study period spanned from January 2010 through September 2021. Routine firefighting P were estimated using fire incident characteristics, response data and emission factors from a novel job exposure matrix. Linear mixed effects modelling was employed to estimate changes in pulmonary function as measured by forced expiratory volume in one second (FEV1). Models controlled for age, race/ethnicity, height, smoking and weight. RESULTS: Every 1000 kg P was associated with 13 mL lower FEV1 (ß=-13.34; 95% CI=-13.98 to -12.70) over the entire 12-year follow-up period. When analysing exposures within 3 months before PFT measurements, 1000 kg P was associated with 27 mL lower FEV1 (ß=-26.87; 95% CI=-34.54 to -19.20). When evaluating P estimated within 3 months of a pulmonary function test (PFT), stronger associations were observed among those most highly exposed to the World Trade Center (WTC) disaster (ß=-12.90; 95% CI=-22.70 to -2.89); the association of cumulative exposures was similar for both highly and less highly exposed individuals. DISCUSSION: Smoke particle exposures were observed to have modest short-term and long-term associations with pulmonary function, particularly in those who, previously, had high levels of WTC exposure. Future work examining the association between P and pulmonary function among non-WTC exposed firefighters will be essential for disentangling the effects of ageing, routine firefighting and WTC exposures.

Development of a job-exposure matrix (JEM) for exposure to smoke particle mass among firefighters of the Fire Department of the City of New York (FDNY).

OBJECTIVES: A refined job exposure matrix (JEM) based on incident types and severities and response characteristics was developed for firefighters to estimate quantities of smoke particles emitted during structural and non-structural fire incidents from 2010 to 2021. METHODS: The cohort included a subset of 3237 Fire Department of the City of New York firefighters who responded to at least one incident between 2010 and 2021, prior to retirement. Fire incident data included dates, type, severity (alarm level) and location. Response data included dates worked, firehouse, position titles and shift lengths for each firefighter. The quantity of smoke particle mass generated during structural and non-structural fires adjusted by individual firefighter engagement was computed using the United States Environmental Protection Agency AP-42 emissions framework. Correlations between years of employment, fire responses and career total particle mass concentration by firefighter were examined. Linear regression models were fit and corresponding R2 values were calculated. RESULTS: Firefighters responded to a median of 424.7 (IQR=202.3-620.0) annual incidents/person; 17.6% were fire incidents (median=77.1; IQR=40.4-114.0). Structural fires were the most common type of fire incident (72.5% of annual incidents/person; median=55.9; IQR=29.6-85.5). Incident severity (alarm level) and firefighter engagement (position title) appeared to differentiate between high and low exposure regimes (R2=0.43). Incident severity explained most of the variability of particle exposures (R2=0.90). CONCLUSIONS: Using the JEM, job-related smoke particle concentrations were estimated to vary by incident type, incident severity and firefighter engagement, highlighting the importance of using refined measures, so that future studies can more accurately evaluate associations between firefighting and health outcomes.

Relationship between low serum immunoglobulin E levels and malignancies in 9/11 World Trade Center responders.

BACKGROUND: Individuals with very low immunoglobulin E (IgE) levels have a high risk of developing malignancy. Previous studies have revealed that World Trade Center (WTC) responders exposed to carcinogens have an elevated risk of some cancers. OBJECTIVE: To evaluate the association between low-serum IgE levels and cancer development in WTC-exposed responders. METHODS: IgE levels were measured in 1851 WTC responders after September 11, 2001. This is the first pilot study in humans comparing the odds of developing cancer in this high-risk population, between the "low-IgE" (IgE in the lowest third percentile) vs "non-low-IgE" participants. RESULTS: A significantly higher proportion of hematologic malignancies was found in low-IgE (4/55, 7.3%) compared with non-low-IgE (26/1796, 1.5%, P < .01) responders. The proportion of solid tumors were similar in both groups (5.5% vs 11.4%, P > .05). After adjustment for relevant confounders (race, sex, age at blood draw, WTC arrival time, smoking status), the low-IgE participants had 7.81 times greater odds (95% confidence interval, 1.77-29.35) of developing hematologic cancer when compared with non-low-IgE participants. The hematologic cancers found in this cohort were leukemia (n = 1), multiple myeloma (n = 1), and lymphoma (n = 2). No statistical significance was found when estimating the odds ratio for solid tumors in relation to IgE levels. CONCLUSION: WTC responders with low serum IgE levels had the highest odds of developing hematologic malignancies. This hypothesis-generating study suggests that low serum IgE levels might be associated with the development of specific malignancies in at-risk individuals exposed to carcinogens. Larger, multicenter studies with adequate follow-up of individuals with different IgE levels are needed to better evaluate this relationship.

Dynamic Metabolic Risk Profiling of World Trade Center Lung Disease: A Longitudinal Cohort Study.

Rationale: Metabolic syndrome (MetSyn) increases the risk of World Trade Center (WTC) lung injury (LI). However, the temporal relationship of MetSyn, exposure intensity, and lung dysfunction is not well understood. Objective: To model the association of longitudinal MetSyn characteristics with WTC lung disease to define modifiable risk. Methods: Firefighters, for whom consent was obtained (N = 5,738), were active duty on September 11, 2001 (9/11). WTC-LI (n = 1,475; FEV1% predicted

Dietary phenotype and advanced glycation end-products predict WTC-obstructive airways disease: a longitudinal observational study.

BACKGROUND: Diet is a modifier of metabolic syndrome which in turn is associated with World Trade Center obstructive airways disease (WTC-OAD). We have designed this study to (1) assess the dietary phenotype (food types, physical activity, and dietary habits) of the Fire Department of New York (FDNY) WTC-Health Program (WTC-HP) cohort and (2) quantify the association of dietary quality and its advanced glycation end product (AGE) content with the development of WTC-OAD. METHODS: WTC-OAD, defined as developing WTC-Lung Injury (WTC-LI; FEV1 < LLN) and/or airway hyperreactivity (AHR; positive methacholine and/or positive bronchodilator response). Rapid Eating and Activity Assessment for Participants-Short Version (REAP-S) deployed on 3/1/2018 in the WTC-HP annual monitoring assessment. Clinical and REAP-S data of consented subjects was extracted (7/17/2019). Diet quality [low-(15-19), moderate-(20-29), and high-(30-39)] and AGE content per REAP-S questionnaire were assessed for association with WTC-OAD. Regression models adjusted for smoking, hyperglycemia, hypertension, age on 9/11, WTC-exposure, BMI, and job description. RESULTS: N = 9508 completed the annual questionnaire, while N = 4015 completed REAP-S and had spirometry. WTC-OAD developed in N = 921, while N = 3094 never developed WTC-OAD. Low- and moderate-dietary quality, eating more (processed meats, fried foods, sugary drinks), fewer (vegetables, whole-grains),and having a diet abundant in AGEs were significantly associated with WTC-OAD. Smoking was not a significant risk factor of WTC-OAD. CONCLUSIONS: REAP-S was successfully implemented in the FDNY WTC-HP monitoring questionnaire and produced valuable dietary phenotyping. Our observational study has identified low dietary quality and AGE abundant dietary habits as risk factors for pulmonary disease in the context of WTC-exposure. Dietary phenotyping, not only focuses our metabolomic/biomarker profiling but also further informs future dietary interventions that may positively impact particulate matter associated lung disease.

Serum Th-2 cytokines and FEV1 decline in WTC-exposed firefighters: A 19-year longitudinal study.

BACKGROUND: Accelerated-FEV1 -decline, defined as rate of decline in FEV1 > 64 ml/year, is a risk factor for asthma and chronic obstructive pulmonary disease in World Trade Center (WTC)-exposed firefighters. Accelerated-FEV1 -decline in this cohort is associated with elevated blood eosinophil concentrations, a mediator of Th-2 response. We hypothesized that an association exists between Th-2 biomarkers and FEV1 decline rate in those with accelerated-FEV1 -decline. METHODS: Serum was drawn from Fire Department of the City of New York (FDNY) firefighters 1-6 months (early) (N = 816) and 12-13 years (late) (N = 983) after 9/11/2001. Th-2 biomarkers IL-4, IL-13, and IL-5 were assayed by multiplex Luminex. Individual FEV1 decline rates were calculated using spirometric measurements taken: (1) between 9/11/2001 and 9/10/2020 for the early biomarker group and (2) between late measurement date and 9/10/2020 for the late biomarker group. Associations of early and late Th-2 biomarkers with subsequent FEV1 decline rates were analyzed using multivariable linear regression controlling for demographics, smoking status, and other potential confounders. RESULTS: In WTC-exposed firefighters with accelerated-FEV1 -decline, IL-4, IL-13, and IL-5 measured 1-6 months post-9/11/2001 were associated with greater FEV1 decline ml/year between 9/11/2001 and 9/10/2020 (-2.9 ± 1.4 ml/year per IL-4 doubling; -8.4 ± 1.2 ml/year per IL-13 doubling; -7.9 ± 1.3 ml/year per IL-5 doubling). Among late measured Th-2 biomarkers, only IL-4 was associated with subsequent FEV1 decline rate (-4.0 ± 1.6 ml/year per IL-4 doubling). CONCLUSIONS: In WTC-exposed firefighters with accelerated-FEV1 -decline, elevated serum IL-4 measured both 1-6 months and 12-13 years after 9/11 is associated with greater FEV1 decline/year. Drugs targeting the IL-4 pathway may improve lung function in this high-risk subgroup.

Lung function decline before and after treatment of World Trade Center associated obstructive airways disease with inhaled corticosteroids and long-acting beta agonists.

BACKGROUND: Greater than average loss of one-second forced expiratory volume (FEV1 ) is a risk factor for asthma, chronic obstructive pulmonary disease (COPD), and asthma/COPD overlap syndrome in World Trade Center (WTC)-exposed firefighters. Inhaled corticosteroids and long-acting beta agonists (ICS/LABA) are used to treat obstructive airways disease but their impact on FEV1 -trajectory in this population is unknown. METHODS: The study population included WTC-exposed male firefighters who were treated with ICS/LABA for 2 years or longer (with initiation before 2015), had at least two FEV1 measurements before ICS/LABA initiation and two FEV1 measurements posttreatment between September 11, 2001 and September 10, 2019. Linear mixed-effects models were used to estimate FEV1 -slope pre- and post-treatment. RESULTS: During follow-up, 1023 WTC-exposed firefighters were treated with ICS/LABA for 2 years or longer. When comparing intervals 6 years before and 6 years after treatment, participants had an 18.7 ml/year (95% confidence interval [CI]: 11.3-26.1) improvement in FEV1 -slope after adjustment for baseline FEV1 , race, height, WTC exposure, weight change, blood eosinophil concentration, and smoking status. After stratification by median date of ICS/LABA initiation (January 14, 2010), earlier ICS/LABA-initiators had a 32.5 ml/year (95% CI: 19.5-45.5) improvement in slope but later ICS/LABA-initiators had a nonsignificant FEV1 -slope improvement (7.9 ml/year, 95% CI: -0.5 to 17.2). CONCLUSIONS: WTC-exposed firefighters treated with ICS/LABA had improved FEV1 slope after initiation, particularly among those who started earlier. Treatment was, however, not associated with FEV1 -slope improvement if started after the median initiation date (1/14/2010), likely because onset of disease began before treatment initiation. Research on alternative treatments is needed for patients with greater than average FEV1 -decline who have not responded to ICS/LABA.

The Landmark Series: Axillary Management in Breast Cancer.

The evolution in axillary management for patients with breast cancer has resulted in multiple dramatic changes over the past several decades. The end result has been an overall deescalation of surgery in the axilla. Landmark trials that have formed the basis for the current treatment guidelines are reviewed herein.

Screening for Breast Cancer: What You Need to Know.

Significant controversy surrounds current recommendations for breast cancer screening. This has resulted in wide variation among national organizations in breast cancer screening guidelines. With the expanding field of breast imaging techniques, risk assessment and genetic testing, it has become clear that the recommendations for breast cancer screening need to be individualized in order to maximize the benefit and minimize harms of screening.

Low serum IgA and airway injury in World Trade Center-exposed firefighters: a 17-year longitudinal study.

Serum IgA ≤70 mg/dL (low IgA) is associated with exacerbations of chronic obstructive pulmonary disease. The association of low IgA with longitudinal lung function is poorly defined. This study included 917 World Trade Center (WTC)-exposed firefighters with longitudinal spirometry measured between September 2001 and September 2018 and IgA measured between October 2001 and March 2002. Low IgA, compared with IgA >70 mg/dL, was associated with lower forced expiratory volume in 1 s (FEV1) % predicted in the year following 11 September 2001 (94.1% vs 98.6%, p<0.001), increased risk of FEV1/FVC <0.70 (HR 3.8, 95% CI 1.6 to 8.8) and increased antibiotic treatment (22.5/100 vs 11.6/100 person-years, p=0.002). Following WTC exposure, early IgA ≤70 mg/dL was associated with worse lung function and increased antibiotic treatment.

Examining peer support and survivorship for African American women with breast cancer.

OBJECTIVE: More than 3.5 million female breast cancer (BrCa) survivors live in the United States, and the number continues to grow. Health status and quality of life among survivors are variable, and African American (AA) survivors suffer disproportionately from BrCa morbidity and mortality. Emerging evidence suggests that peer support is an effective strategy to promote positive survivorship outcomes for AA BrCa survivors. This study aimed to explore the role of peer support in the BrCa experiences of AA survivors. METHODS: Working collaboratively with The Breakfast Club, Inc. (BCI), a community-based BrCa peer support organization, we conducted a quasiexperiment to compare the BrCa experiences of AA survivors. We conducted in-depth interviews with two survivor groups (N = 12 per group), categorized according to receiving peer support during their BrCa experiences. RESULTS: Survivors who received peer support reported greater access to and utilization of alternative support sources, more capacity to process BrCa-related stress, and improved quality of life and adjustment to life as BrCa survivors compared with those who did not receive peer support. CONCLUSIONS: Peer relationships provide consistent, quality social support. Consistent peer support helps survivors cope with the continued stress of BrCa, with implications for psychosocial health and quality of life. Findings expand our current understanding of peer support and may enable public health and clinical practitioners to better recognize and intervene with those for whom additional support services are needed.

Geographic variations in racial disparities in postmastectomy breast reconstruction: A SEER database analysis.

The purpose of this study was to determine whether racial disparities in reconstruction in the United States vary by geographic region. The SEER database years 2000-2013 was queried for all mastectomies in women ages 20-85+. Logistic regression was used to examine the main effects and interaction of race and geographic region on reconstruction. Hot spot Analysis was used to examine clustering of reconstruction across counties by race. We found large regional variation in racial differences in the rate of immediate postmastectomy reconstruction. Understanding how racial disparities vary by region can identify important factors for intervention to reduce disparities in practice.

Persistent self-reported ear and hearing problems among World Trade Center-exposed firefighters and emergency medical service workers, 2001-2017-A longitudinal cohort analysis.

BACKGROUND: The goal of this study was to estimate the impact of exposure to the World Trade Center (WTC) site on annual and persistent rates of otalgia and hearing impairment among Fire Department of the City of New York (FDNY) Firefighters and Emergency Medical Service Workers (EMS). METHODS: Responders completed routine physical health questionnaires at monitoring visits. We used logistic and marginal logistic regression models to explore the association between otalgia and hearing impairment and WTC arrival time. RESULTS: The highest-exposed group had greater odds of persistent ear symptoms (OR 1.33, 95%CI 1.11-1.59) compared with the least-exposed; the odds of persistent hearing problems between the groups were not significantly different. We found consistent WTC-exposure gradients when the average population odds of these outcomes were assessed each year. CONCLUSIONS: Our findings demonstrate that the odds of long-term ear symptoms were significantly associated with the intensity of WTC exposure.

Cigarette Smoke Regulates Calcium-Independent Phospholipase A2 Metabolic Pathways in Breast Cancer.

Phospholipase A2 (PLA2)-dependent pathways are important in the regulation of cell proliferation, differentiation, motility, and immune responses, and can be dysregulated during tumor development and progression. We show herein, for the first time, that cigarette smoking leads to an increase in platelet-activating factor (PAF) content and PAF receptor expression in human breast cancer cells and tissue. PAF production could be abrogated in triple-negative breast cancer cells by inhibition of calcium-independent PLA2 (iPLA2). We also demonstrate that cigarette smoke induces the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and reduces 15-hydroxyprostaglandin dehydrogenase, resulting in prostaglandin E2 release in human breast cancer. Increased cyclooxygenase-2 expression and prostaglandin E2 release could be abrogated in metastatic breast cancer cells by inhibition of iPLA2. These studies indicate that iPLA2-dependent metabolic pathways play an important role in tumor initiation or progression in smokers, representing novel therapeutic targets for breast cancer patients who smoke.

Risk factors for post-9/11 chronic rhinosinusitis in Fire Department of the City of New York workers.

OBJECTIVES: Chronic rhinosinusitis (CRS) has high socioeconomic burden but underexplored risk factors. The collapse of the World Trade Center (WTC) towers on 11 September 2001 (9/11) caused dust and smoke exposure, leading to paranasal sinus inflammation and CRS. We aim to determine which job tasks are risk factors for CRS in WTC-exposed Fire Department of the City of New York (FDNY) firefighters and emergency medical services (EMS) workers. METHODS: This cohort study included a 16-year follow-up of 11 926 WTC-exposed FDNY rescue/recovery workers with data on demographics, WTC exposure, job tasks and first post-9/11 complete blood counts. Using multivariable Cox regression, we assessed the associations of WTC exposure, work assignment (firefighter/EMS), digging and rescue tasks at the WTC site and blood eosinophil counts with subsequent CRS, adjusting for potential confounders. RESULTS: The rate of CRS was higher in firefighters than EMS (1.80/100 person-years vs 0.70/100 person-years; p<0.001). The combination of digging and rescue work was a risk factor for CRS (HR 1.54, 95% CI 1.23 to 1.94, p<0.001) independent of work assignment and WTC exposure. CONCLUSIONS: Compared with EMS, firefighters were more likely to engage in a combination of digging and rescue work, which was a risk factor for CRS. Chronic irritant exposures associated with digging and rescue work may account for higher post-9/11 CRS rates among firefighters.