Faculty Bibliography

Breast cancer represents the most common cancer diagnosis among World Trade Center (WTC)-exposed community members, residents, and cleanup workers enrolled in the WTC Environmental Health Center (WTC EHC). The primary aims of this study were (1) to compare blood DNA methylation profiles of WTC-exposed community members with breast cancer and WTC-unexposed pre-diagnostic breast cancer blood samples, and (2) to compare the DNA methylation differences among the WTC EHC breast cancer cases and WTC-exposed cancer-free controls. Gene pathway enrichment analyses were further conducted. There were significant differences in DNA methylation between WTC-exposed breast cancer cases and unexposed prediagnostic breast cancer cases. The top differentially methylated genes were Intraflagellar Transport 74 (IFT74), WD repeat-containing protein 90 (WDR90), and Oncomodulin (OCM), which are commonly upregulated in tumors. Probes associated with established tumor suppressor genes (ATM, BRCA1, PALB2, and TP53) were hypermethylated among WTC-exposed breast cancer cases compared to the unexposed group. When comparing WTC EHC breast cancer cases vs. cancer-free controls, there appeared to be global hypomethylation among WTC-exposed breast cancer cases compared to exposed controls. Functional pathway analysis revealed enrichment of several gene pathways in WTC-exposed breast cancer cases including endocytosis, proteoglycans in cancer, regulation of actin cytoskeleton, axon guidance, focal adhesion, calcium signaling, cGMP-PKG signaling, mTOR, Hippo, and oxytocin signaling. The results suggest potential epigenetic links between WTC exposure and breast cancer in local community members enrolled in the WTC EHC program.

BACKGROUND:The characteristics of community members exposed to World Trade Center (WTC) dust and fumes with Chronic Obstructive Pulmonary Disease (COPD) can provide insight into mechanisms of airflow obstruction in response to an environmental insult, with potential implications for interventions. METHODS:We performed a baseline assessment of respiratory symptoms, spirometry, small airway lung function measures using respiratory impulse oscillometry (IOS), and blood biomarkers. COPD was defined by the 2019 GOLD criteria for COPD. Patients in the WTC Environmental Health Center with <5 or ≥5 pack year smoking history were classified as nonsmoker-COPD (ns-COPD) or smoker-COPD (sm-COPD), respectively. MAIN RESULTS/RESULTS:= 0.007). CONCLUSIONS:Spirometry findings and small airway measures, as well as inflammatory markers, differed between patients with ns-COPD and sm-COPD. These findings suggest potential for differing mechanisms of airway injury in patients with WTC environmental exposures and have potential therapeutic implications.

The World Trade Center Environmental Health Center (WTC EHC), is a federally designated clinical center of excellence for surveillance and treatment of WTC disaster exposed community members (WTC Survivors). Cognitive impairment (CI) has been extensively described in WTC responders and a concern for progressive impairment in all WTC disaster exposed groups has been raised. Cognitive status, however, has not been systematically characterized in the WTC Survivor population. We describe cognitive status in a subgroup of the Survivor population referred for mental health evaluation (N = 480) in the WTC EHC as measured by scores on the Montreal Cognitive Assessment (MoCA) instrument, and examine their association with WTC exposures and individual-level covariates including PTSD and depression screening inventory scores. In regression analyses, probable cognitive impairment (MoCA score < 26) was found in 59% of the study subjects and was significantly associated with age, race/ethnicity, education, income, depression and PTSD scores. Being caught in the dust cloud on 11 September 2011 was significantly associated with cognitive impairment even after controlling for the above. These data suggest an association with cognitive dysfunction in WTC Survivors with exposure to the toxic dust/fumes and psychological stress from the 9/11 terrorist attack and warrant further systematic study.

Rationale: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, equally weighted, yes/no control tool that assesses symptom impairment and exacerbation risk. AIRQ control level (well-controlled [WC], not well-controlled [NWC], very poorly controlled [VPC]) predicts future 12-month exacerbations (odds-ratios [OR]95% Confidence Limits [CL] for >=1 exacerbation: NWC vs WC=2.1[1.6-2.9], VPC vs WC= 4.6[3.3-6.5]; AUC=0.70). We examined whether adding clinical and biomarker covariates to AIRQ improves exacerbation prediction.
Method(s): Patients completed monthly online surveys regarding exacerbation-related oral corticosteroid (OCS) use, emergency department/urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with relevant covariates (eg, sociodemographics, comorbidities, exacerbation history, FEV1, eosinophils, IgE, FeNO). Significant (p <=0.05) variables were included in a multivariable logistic regression with AIRQ control categories to predict exacerbations (OR[95%CL]).
Result(s): 1070 patients completed >=1 survey over 12 months (mean[SD] surveys 10.5[2.8]); 70.1% female; mean age 43.9[19.4] years; 21.5% non-White; BMI 30.6[8.7]; AIRQ WC 35%, NWC 38%, VPC 27%. 46% of patients reported >=1 exacerbation (WC 31.9%, NWC 56.6%, VPC 83.4%). In the multivariate analysis, AIRQ control category was predictive of exacerbations (NWC vs WC: OR=1.94[1.41, 2.66], VPC vs WC: OR=3.80[2.58, 5.60; AUC=0.72] as were age (10 year OR=1.12[1.02, 1.23], presence of sleep apnea (OR=1.48[1.00, 2.18]), FeNO <25 ppb (OR=1.36[1.02, 1.82]), and >=2 prior 12-month OCS courses (OR=2.46[1.50, 4.05]).
Conclusion(s): A history of multiple exacerbations and current asthma control as measured by AIRQ is strongly and independently associated with future exacerbations. Additional assessments do not significantly enhance the ability of AIRQ to predict exacerbations.
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BACKGROUND:Recurrent assessment of asthma control is essential to evaluating disease stability and intervention impacts. An assessment that can be administered between annual clinic visits is needed. The Asthma Impairment and Risk Questionnaire (AIRQ) is a cross-sectionally validated, 10-item, yes/no, composite control tool examining prior 2-week symptoms and prior 12-month exacerbations. OBJECTIVE:To determine the construct validity of the AIRQ utilizing a 3-month recall period for exacerbation-based risk questions and retaining the 2-week recall for symptom-based impairment items. METHODS:At baseline, patients completed the AIRQ with 12-month recall exacerbation items, Asthma Control Test (ACT), St. George's Respiratory Questionnaire (SGRQ), and global self-assessments of asthma risk, control, and symptom severity. Patientreported exacerbations were captured monthly. The AIRQ with 3-month recall exacerbation items, ACT, and global self-assessments were administered at months 3, 6, and 9, and SGRQ at month 6. RESULTS:1112 patients aged ≥12 years were enrolled (mean [standard deviation] age, 43.9 [19.5] years). The AIRQ and each administration of the AIRQ with 3-month recall exacerbation items classified asthma control similarly to an ACT + exacerbation validation standard. For both AIRQ versions, SGRQ scores were higher with worsening asthma control (P<0.001). At months 3, 6, and 9, worse AIRQ control levels were associated with higher proportions of patients with ≥1 and ≥2 exacerbations in the prior 3 months and patient global self-assessments indicating greater asthma morbidity (all P<0.001). CONCLUSION/CONCLUSIONS:The AIRQ utilizing exacerbation risk items with a 3-month recall period exhibits construct validity for classifying current asthma control and can be administered between annual AIRQ assessments.

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story 'Twin Towers'. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these 'WTC-affected' individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals.

Dyspnoea self-management is often suboptimal for patients with COPD. Many patients with COPD experience chronic dyspnoea as distressing and disabling, especially during physical activities. Breathing therapy is a behavioural intervention that targets reducing the distress and impact of dyspnoea on exertion in daily living. Using a qualitative design, we conducted interviews with 14 patients after they participated in a novel mind-body breathing therapy intervention adjunct, capnography-assisted respiratory therapy (CART), combined with outpatient pulmonary rehabilitation. Comprehensive CART consisted of patient-centred biofeedback, tailored breathing exercises, a home exercise programme and motivational interviewing counselling. We assessed participants' perceptions and reported experiences to gauge the acceptability of CART and refine CART based on feedback. Constant comparative analysis was used to identify commonalities and themes. We identified three main themes relating to the acceptability and reported benefits of CART: (1) self-regulating breathing; (2) impact on health; and (3) patient satisfaction. Our findings were used to refine and optimise CART (i.e. its intensity, timing and format) for COPD. By addressing dysfunctional breathing behaviours and dysregulated interoception, CART offers a promising new paradigm for relieving dyspnoea and related anxiety in patients with COPD.

The destruction of World Trade Center on 11 September 2001 exposed local community members to a complex mixture of known carcinogens and potentially carcinogenic substances. To date, breast cancer has not been characterized in detail in the WTC-exposed civilian populations. The cancer characteristics of breast cancer patients were derived from the newly developed Pan-Cancer Database at the WTC Environmental Health Center (WTC EHC). We used the Surveillance, Epidemiology, and End Results (SEER) Program breast cancer data as a reference source. Between May 2002 and 31 December 2019, 2840 persons were diagnosed with any type of cancer at the WTC EHC, including 601 patients with a primary breast cancer diagnosis (592 women and 9 men). There was a higher proportion of grade 3 (poorly differentiated) tumors (34%) among the WTC EHC female breast cancers compared to that of the SEER-18 data (25%). Compared to that of the SEER data, female breast cancers in the WTC EHC had a lower proportion of luminal A (88% and 65%, respectively), higher proportion of luminal B (13% and 15%, respectively), and HER-2-enriched (5.5% and 7%, respectively) subtypes. These findings suggest considerable differences in the breast cancer characteristics and distribution of breast cancer intrinsic subtypes in the WTC-exposed civilian population compared to that of the general population. This is important because of the known effect of molecular subtypes on breast cancer prognosis.

Rationale: The Asthma Impairment and Risk Questionnaire (AIRQTM) is a 10-item, equally-weighted, yes/no, composite control tool. The AIRQTM was validated in a cross-sectional study of 442 patients with asthma aged >=12 years recruited from specialty practices. The combination of selected AIRQTM questions and score range (Well-controlled: 0-1, Not Well-controlled: 2-4, and Very Poorly Controlled: 5-10 yes responses) demonstrated high sensitivity and specificity to differentiate patients on either end of the control spectrum. The current study assessed construct validity of the AIRQTM in primary and specialty care patients recruited from web-based panels by evaluating systemic corticosteroid and rescue therapy use as measures of asthma control.
Method(s): Participants aged >=18 years self-reporting asthma and use of therapies across all Global Initiative for Asthma (GINA)-step severities were included. Sociodemographic and medical history forms, the Asthma Control Test (ACTTM), and AIRQTM were completed electronically. To determine AIRQTM construct validity, ACTTM score, prior-year self-reported systemic corticosteroids for exacerbations, and rescue inhaler/nebulizer use were analyzed within provider groups relative to AIRQTM control level (general linear models with Scheffe's post hoc adjustment for pairwise comparisons).
Result(s): 1153 patients (538 primary and 615 specialty care) were included: mean (SD) age 49 (15) years; 60% female; 68% White, 15% African American, 15% Hispanic/Latino; 33% GINA 3-5; and 43% with less than college degrees. Among the panel primary and specialty care patients, the AIRQTM identified 48.7% and 25.4% as well-controlled, 33.5% and 32.8% as not well-controlled, and 17.8% and 41.8% as very poorly controlled, respectively. Control differences were supported by more primary care patients having well-controlled ACTTM scores (60.8% vs 32.4%) and fewer having >=2 courses of oral corticosteroids (21.0% vs 50.7%) or steroid injections (7.6% vs 35.3%) for asthma exacerbations or rescue inhaler use (26.2% vs 44.2%) or nebulizer treatments (8.0% vs 26.8%) >=3 times/week (p<0.0001, for each). Within provider groups, the proportion of patients with each of these indices of morbidity increased with worsening AIRQTM control level (p<0.0001, for each) (Table).
Conclusion(s): These data demonstrate the construct validity of the AIRQTM among patients in primary and specialty care, as differences in AIRQTM control levels were associated with differential proportions of patients reporting use of systemic corticosteroids for exacerbations and rescue therapy for uncontrolled symptoms. In addition to being a robust composite control tool, AIRQTM can increase awareness for all providers as to their patients' burden of disease