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After the terrorist attacks on September 11, 2001 (9/11), many rescue/recovery workers developed respiratory symptoms and pulmonary diseases due to their extensive World Trade Center (WTC) dust cloud exposure. Nearly all Fire Department of the City of New York (FDNY) workers were present within 48 h of 9/11 and for the next several months. Since the FDNY had a well-established occupational health service for its firefighters and Emergency Medical Services workers prior to 9/11, the FDNY was able to immediately start a rigorous monitoring and treatment program for its WTC-exposed workers. As a result, respiratory symptoms and diseases were identified soon after 9/11. This focused review summarizes the WTC-related respiratory diseases that developed in the FDNY cohort after 9/11, including WTC cough syndrome, obstructive airways disease, accelerated lung function decline, airway hyperreactivity, sarcoidosis, and obstructive sleep apnea. Additionally, an extensive array of biomarkers has been identified as associated with WTC-related respiratory disease. Future research efforts will not only focus on further phenotyping/treating WTC-related respiratory disease but also on additional diseases associated with WTC exposure, especially those that take decades to develop, such as cardiovascular disease, cancer, and interstitial lung disease.

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...

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), emerged in Wuhan, China, and rapidly led to a global pandemic that affected 213 countries, more than 5.8 million cases, and 360,000 deaths worldwide as of May 28, 2020. The United States currently has the highest number of COVID-19 cases in the world and contributes to nearly a third of the global death rate. The prevalence of COVID myocarditis is unclear but generally considered rare, with estimates up to 7% of COVID-related deaths. However, these patients suffered catastrophic worsening disease with respiratory compromise requiring intubation and often death. We report the case of a patient with COVID-19-induced myocarditis who was successfully treated with dexamethasone and review the literature.

Vascular changes occur early in the development of obstructive airways disease. However, the vascular remodeling and dysfunction due to World Trade Center-Particulate Matter (WTC-PM) exposure are not well described and are therefore the focus of this investigation. C57Bl/6 female mice oropharyngeally aspirated 200 µg of WTC-PM53 or phosphate-buffered saline (PBS) (controls). 24-hours (24-hrs) and 1-Month (1-M) after exposure, echocardiography, micro-positron emission tomography(µ-PET), collagen quantification, lung metabolomics, assessment of antioxidant potential and soluble-receptor for advanced glycation end products (sRAGE) in bronchoalveolar lavage(BAL) and plasma were performed. 24-hrs post-exposure, there was a significant reduction in (1) Pulmonary artery(PA) flow-velocity and pulmonary ejection time(PET) (2) Pulmonary acceleration time(PAT) and PAT/PET, while (3) Aortic ejection time(AET) and velocity time integral(VTI) were increased, and (4) Aortic acceleration time (AAT)/AET, cardiac output and stroke volume were decreased compared to controls. 1-M post-exposure, there was also significant reduction of right ventricular diameter as right ventricle free wall thickness was increased and an increase in tricuspid E, A peaks and an elevated E/A. The pulmonary and cardiac standard uptake value and volume 1-M post-exposure was significantly elevated after PM-exposure. Similarly, α-smooth muscle actin(α-SMA) expression, aortic collagen deposition was elevated 1-M after PM exposure. In assessment of the metabolome, prominent subpathways included advanced glycation end products (AGEs), phosphatidylcholines, sphingolipids, saturated/unsaturated fatty acids, eicosanoids, and phospholipids. BAL superoxide dismutase(SOD), plasma total-antioxidant capacity activity, and sRAGE (BAL and plasma) were elevated after 24-hrs. PM exposure and associated vascular disease are a global health burden. Our study shows persistent WTC-Cardiorespiratory and Vascular Dysfunction (WTC-CaRVD), inflammatory changes and attenuation of antioxidant potential after PM exposure. Early detection of vascular disease is crucial to preventing cardiovascular deaths and future work will focus on further identification of bioactive therapeutic targets.

Vascular changes occur early in the development of obstructive airways disease. However, the vascular remodeling and dysfunction due to World Trade Center-Particulate Matter (WTC-PM) exposure are not well described and are therefore the focus of this investigation. C57Bl/6 female mice oropharyngeally aspirated 200 µg of WTC-PM

Biomarkers predict World Trade Center-Lung Injury (WTC-LI); however, there remains unaddressed multicollinearity in our serum cytokines, chemokines, and high-throughput platform datasets used to phenotype WTC-disease. To address this concern, we used automated, machine-learning, high-dimensional data pruning, and validated identified biomarkers. The parent cohort consisted of male, never-smoking firefighters with WTC-LI (FEV1, %Pred< lower limit of normal (LLN); n = 100) and controls (n = 127) and had their biomarkers assessed. Cases and controls (n = 15/group) underwent untargeted metabolomics, then feature selection performed on metabolites, cytokines, chemokines, and clinical data. Cytokines, chemokines, and clinical biomarkers were validated in the non-overlapping parent-cohort via binary logistic regression with 5-fold cross validation. Random forests of metabolites (n = 580), clinical biomarkers (n = 5), and previously assayed cytokines, chemokines (n = 106) identified that the top 5% of biomarkers important to class separation included pigment epithelium-derived factor (PEDF), macrophage derived chemokine (MDC), systolic blood pressure, macrophage inflammatory protein-4 (MIP-4), growth-regulated oncogene protein (GRO), monocyte chemoattractant protein-1 (MCP-1), apolipoprotein-AII (Apo-AII), cell membrane metabolites (sphingolipids, phospholipids), and branched-chain amino acids. Validated models via confounder-adjusted (age on 9/11, BMI, exposure, and pre-9/11 FEV1, %Pred) binary logistic regression had AUCROC [0.90(0.84–0.96)]. Decreased PEDF and MIP-4, and increased Apo-AII were associated with increased odds of WTC-LI. Increased GRO, MCP-1, and simultaneously decreased MDC were associated with decreased odds of WTC-LI. In conclusion, automated data pruning identified novel WTC-LI biomarkers; performance was validated in an independent cohort. One biomarker—PEDF, an antiangiogenic agent—is a novel, predictive biomarker of particulate-matter-related lung disease. Other biomarkers—GRO, MCP-1, MDC, MIP-4—reveal immune cell involvement in WTC-LI pathogenesis. Findings of our automated biomarker identification warrant further investigation into these potential pharmacotherapy targets., Author summary Disease related to air pollution causes millions of deaths annually. Large swathes of the general population, as well as certain occupations such as 1st responders and military personnel, are exposed to particulate matter (PM)—a major component of air pollution. Our longitudinal cohort of FDNY firefighters exposed to the World Trade Center dust cloud on 9/11 is a unique research opportunity to characterize the impact of a single, intense PM exposure by looking at pre- and post-exposure phenotype; however, PM-related lung disease and PM’s systemic effects are complex and call for a systems biological approach coupled with novel computational modelling techniques to fully understand pathogenesis. In the present study, we integrate clinical and environmental biomarkers with the serum metabolome, cytokines, and chemokines to develop a model for early disease detection and identification of potential signaling cascades of PM-related chronic lung disease.

Background Metabolic syndrome (MetSyn) predicted future development of World Trade Center lung injury (WTC-LI) in a subgroup of firefighters who never smoked and were male. An intracohort validation of MetSyn as a predictor of WTC-LI is examined in the cohort exposed to the World Trade Center (WTC) that has been followed longitudinally for 16 years. Methods Results of pulmonary function tests (n = 98,221) in workers exposed to the WTC (n = 9,566) were evaluated. A baseline cohort of firefighters who had normal FEV1 before 9/11 and who had had serum drawn before site closure on July 24, 2002 (n = 7,487) was investigated. Case subjects with WTC-LI (n = 1,208) were identified if they had at least two measured instances of FEV1 less than the lower limit of normal (LLN). Cox proportional hazards modeled early MetSyn biomarker ability to predict development of FEV1 less than the LLN. Results Case subjects were more likely to smoke, be highly exposed, and have MetSyn. There was a significant exposure dose response; the individuals most highly exposed had a 30.1% increased risk of developing WTC-LI, having MetSyn increased risk of developing WTC-LI by 55.7%, and smoking increased risk by 15.2%. There was significant interaction between smoking and exposure. Conclusions We validated the usefulness of MetSyn to predict future WTC-LI in a larger population of individuals who were exposed. MetSyn defined by dyslipidemia, insulin resistance, and cardiovascular disease suggests that systemic inflammation can contribute to future lung function loss.

RATIONALE The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 2019 (COVID-19), a new infectious disease, for which there are currently limited treatments. SARS-CoV-2 emerged in Wuhan, China in late 2019 and has expanded into a pandemic, which was declared on March 20, 2020. The United States (US) reported its first confirmed case on January 12, 2020, it has become the country with the greatest number of both cumulative and active COVID-19 cases. As of December 20, 2020, the US has over 17.9 million cases. As of April 11, 2020, the state of New York was the epicenter of the global health emergency with more confirmed cases of COVID-19 then any country worldwide. New York. Biomarkers have been studied in the context of COVID-19, but there have only been a few studies of a limited population. COVID-19 is a resource intensive disease with a high mortality. Therefore, being able to define predictive/associated biomarkers may not only facilitate early diagnosis of presumptive COVID, but also provide guidelines for early aggressive treatment and acuity of care triage.METHODS We examined all patients, admitted the MICU and adult medicine service for confirmed positive cases COVID or presumed COVID admitted to the Manhattan and Brooklyn campuses of our institution in the first 60 days of the COVID-19 pandemic, March 1-April 30, 2020. Our natural history study was accomplished by the review of the electronic medical records (EMR) of those diagnosed with COVID-19. Subjects were examined from the time of admission to discharge from each of the participating institutions. All data was collected in compliance with the Code of Federal Regulations, Title 21, Part 11 and approved by the NYU IRB#20-00473.RESULTS Of the N=13,307 COVID-19 positive patients admitted, N=4136 were of Hispanic/Latino descent, and N=932 were admitted to the ICU. The cohort was followed longitudinally with serial labs including inflammatory markers: d-dimers, ferritin, IL-1, IL-6, and CRP. Peak d-dimer, ferritin, and IL-6 was significantly associated with ICU admission (p

RATIONALE. Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China in late 2019 and has expanded into a global pandemic. This mass casualty triage, while requiring tremendous resources, also required early decision-making and ultimately allocation of critical care resources. Primary Objective was to ascertain risk factors of COVID-19 patients requiring ICU admission. Identify biomarkers, clinical risk factors, and comorbid conditions that can predict clinical outcome. METHODS. Setting and Study Design. We performed a natural history/retrospective chart review of patient admissions (n=5,568) at our facility for patients admitted between March 1-May 1, 2020, over 18 years of age, with a positive test less than 15 days before admission. We examined their inflammatory biomarker profile and clinical phenotype collected as part of their standard of care (n=90 variables). Analysis. Random forests used as a variable selector were assessed via a modified hamming distance between variable importance rankings of models with identical hyperparameters. The top 10% of variables (n=9) by mean decrease accuracy (MDA) were then included in a gradient-boosted tree model (xgboost package, R-Project) to build classifiers of ICU admissions and mortality. A random hyperparameter space search determined a final model that maximized 5-fold cross-validated AUCROC. All data was collected in compliance with the Code of Federal Regulations, Title 21, Part 11 and approved by the NYU IRB#20-00473. RESULTS. The classifiers of ICU admission and mortality had AUCROC = 0.93 and 0.90, and classification error = 15.6% and 20.2% based on the Youden's index-optimal probability threshold, respectively. Variables in the final predictive models of ICU admission and mortality are shown by rank (by MDA) in each model, with rank of 1 being the most important, Figure 1. In predicting ICU admission, the three most important variables were triglycerides, procalcitonin, and c-reactive protein;age, initial O2 flow (L/min), and blood O2 saturation were the three most important predictors of mortality. Procalcitonin, blood O2 saturation, lactate, and initial O2 flow (L/min) were predicted both ICU admission and mortality. CONCLUSION. Our models will be included in an online calculator that will be made available and can be used at point of care by providers to assist risk assessment and triage. Our analysis suggests that novel biomarker combinations may be important in assessment of COVID-19 severity. Future work will include validation of these models in other populations.

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 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.

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 &gt, 27 kg/m2 will be included. We will randomize subjects (1:1) to either: (1) Low Calorie Mediterranean (LoCalMed)&mdash, 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.

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-1&alpha, IL-10, TNF-&alpha, and NF-&kappa, B 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-&kappa, B, 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&rsquo, s inflammatory effects in vitro and was partly RAGE-mediated. Further research will focus on the intersection of MetSyn/PM exposure.

Pulmonary disease after World Trade Center particulate matter (WTC-PM) exposure is associated with dyslipidemia and the receptor for advanced glycation end products (RAGE); however, the mechanisms are not well understood. We used a murine model and a multiomics assessment to understand the role of RAGE in the pulmonary long-term effects of a single high-intensity exposure to WTC-PM. After 1 month, WTC-PM–exposed wild-type (WT) mice had airway hyperreactivity, whereas RAGE-deficient (Ager(−/−)) mice were protected. PM-exposed WT mice also had histologic evidence of airspace disease, whereas Ager(−/−) mice remained unchanged. Inflammatory mediators such as G-CSF (granulocyte colony–stimulating factor), IP-10 (IFN-γ–induced protein 10), and KC (keratinocyte chemoattractant) were differentially expressed after WTC-PM exposure. WTC-PM induced α-SMA, DIAPH1 (protein diaphanous homolog 1), RAGE, and significant lung collagen deposition in WT compared with Ager(−/−) mice. Compared with WT mice with PM exposure, relative expression of phosphorylated to total CREB (cAMP response element–binding protein) and JNK (c-Jun N-terminal kinase) was significantly increased in the lung of PM-exposed Ager(−/−) mice, whereas Akt (protein kinase B) was decreased. Random forests of the refined lung metabolomic profile classified subjects with 92% accuracy; principal component analysis captured 86.7% of the variance in three components and demonstrated prominent subpathway involvement, including known mediators of lung disease such as vitamin B(6) metabolites, sphingolipids, fatty acids, and phosphatidylcholines. Treatment with a partial RAGE antagonist, pioglitazone, yielded similar fold-change expression of metabolites (N(6)-carboxymethyllysine, 1-methylnicotinamide, N(1)+N(8)-acetylspermidine, and succinylcarnitine [C4-DC]) between WT and Ager(−/−) mice exposed to WTC-PM. RAGE can mediate WTC-PM–induced airway hyperreactivity and warrants further investigation.

Zika virus (ZIKV) infection has been associated with Guillain-Barré Syndrome (GBS). Roughly 60% of people in countries such as the U.S. live in areas at risk for seasonal spread of ZIKV. ZIKV belongs to a class of diseases that is not typically seen in hospital settings across the U.S. and Europe. We describe the case presentation, management, and treatment of ZIKV infection complicated by GBS. A 64-year-old woman with recent travel to the Dominican Republic presented with rash followed by an acute, ascending polyneuropathy consistent with GBS. She was confirmed to have an acute ZIKV infection by detection of ZIKV nucleic acid by reverse transcription-polymerase chain reaction. She met Brighton Collaboration criteria level 1 evidence for GBS. She received two courses of intravenous immunoglobulin and slowly improved, though still had weakness at discharge. More research is needed to identify the pathophysiology behind ZIKV-associated GBS and its optimal treatment. Prevention is fundamental to limiting infection and spread of ZIKV.

Background In clinical practice, do-not-intubate (DNI) orders are generally accompanied by do-not-resuscitate (DNR) orders. Use of do-not-resuscitate (DNR) orders is associated with older patient age, more comorbid conditions, and the withholding of treatments outside of the cardiac arrest setting. Previous studies have not unpacked the factors independently associated with DNI orders. Objective To compare factors associated with combined DNR/DNI orders versus isolated DNR orders, as a means of elucidating factors associated with the addition of DNI orders. Design Retrospective chart review. Setting/subjects Patients who died on a General Medicine or MICU service (n = 197) at an urban public hospital over a 2-year period. Measurements Logistic regression was used to identify demographic and medical data associated with code status. Results Compared with DNR orders alone, DNR/DNI orders were associated with a higher median Charlson Comorbidity Index (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.13–1.43); older age (OR 1.02, 95% CI 1.01–1.04); malignancy (OR 2.27, 95% CI 1.18–4.37); and female sex (OR 1.98, 95% CI 1.02–3.87). In the last 3 days of life, they were associated with morphine administration (OR 2.76, 95% CI 1.43–5.33); and negatively associated with use of vasopressors/inotropes (OR 10.99, 95% CI 4.83–25.00). Conclusions Compared with DNR orders alone, combined DNR/DNI orders are more strongly associated with many of the same factors that have been linked to DNR orders. Awareness of the extent to which the two directives may be conflated during code status discussions is needed to promote patient-centered application of these interventions.

Gastroesophageal reflux disease (GERD) and Barrett’s Esophagus (BE), which are prevalent in the World Trade Center (WTC) exposed and general populations, negatively impact quality of life and cost of healthcare. GERD, a risk factor of BE, is linked to obstructive airways disease (OAD). We aim to identify serum biomarkers of GERD/BE, and assess the respiratory and clinical phenotype of a longitudinal cohort of never-smoking, male, WTC-exposed rescue workers presenting with pulmonary symptoms. Biomarkers collected soon after WTC-exposure were evaluated in optimized predictive models of GERD/BE. In the WTC-exposed cohort, the prevalence of BE is at least 6 times higher than in the general population. GERD/BE cases had similar lung function, D LCO , bronchodilator response and long-acting β-agonist use compared to controls. In confounder-adjusted regression models, TNF-α ≥ 6 pg/mL predicted both GERD and BE. GERD was also predicted by C-peptide ≥ 360 pg/mL, while BE was predicted by fractalkine ≥ 250 pg/mL and IP-10 ≥ 290 pg/mL. Finally, participants with GERD had significantly increased use of short-acting β-agonist compared to controls. Overall, biomarkers sampled prior to GERD/BE presentation showed strong predictive abilities of disease development. This study frames future investigations to further our understanding of aerodigestive pathology due to particulate matter exposure.

We present a case of severe symptomatic hyponatremia (94 mEq/L) in a male patient who presented with nausea, vomiting, and multiple falls. The patient was found with symptomatic hypo-osmolar hypovolemic hyponatremia secondary to volume loss from vomiting, diuretic use, and consumption of solute-free water. To manage such a severely hyponatremic patient, concomitant 3% hypertonic saline and DDAVP were initiated with successful slow and sustained correction of sodium without complications of osmotic demyelination syndrome.

OBJECTIVES/GOALS: Metabolic syndrome (MetSyn) is a risk for World Trade Center-Lung Injury (WTC-LI; defined as developing FEV11 LLN (N = 5,746). Data assessed from last pre-9/11 till August 1, 2017. Longitudinal MetSyn characteristics were assessed using 3 models: i. A linear mixed effect model to assess the effect size of longitudinal MetSyn and its components on longitudinal FEV1% predicted as an outcome; ii. a time-dependent Cox regression to assess the associations of MetSyn to time of onset of WTC-LI; iii. a novel, partially linear single index regression model with repeatedly measured MetSyn to assess their joint effects and delineate their relative contribution on the longitudinal lung function in the WTC-FDNY cohort. RESULTS/ANTICIPATED RESULTS: In Model I, BMI 30 kg/m2 had the largest effect size compared to ever-smoking, with −2.524 (95%CI: −2.708,−2.340) compared to −1.681(−2.325,−1.038) respectively. Having MetSyn, defined as 3/5 risk factors, had an effect size of −2.319(−2.526,−2.112). In Model II, hazards of triglycerides 150mg/dL were highest at 1.497(1.336, 1.677), followed by BMI 30 kg/m2 at 1.406(1.256, 1.575), and HDLModel III The proposed methods will be applied to our cohort study. DISCUSSION/SIGNIFICANCE OF IMPACT: MetSyn is both a predictor and concurrent marker of WTC-LI. The single index model can not only reduce dimensionality of the covariates, but also provides efficient estimates of the joint MetSyn effects, allowing linear or nonlinear effects. Future studies will investigate dietary intervention as a potential disease-modifying factor. CONFLICT OF INTEREST DESCRIPTION: NA, nothing to disclose.

Particulate matter (PM) exposure is associated with the development of cardiopulmonary disease. Our group has studied the adverse health effects of World Trade Center particulate matter (WTC-PM) exposure on firefighters. To fully understand the complex interplay between exposure, organism, and resultant disease phenotype, it is vital to analyze the underlying role of genomics in mediating this relationship. A PubMed search was performed focused on environmental exposure, genomics, and cardiopulmonary disease. We included original research published within 10 years, on epigenetic modifications and specific genetic or allelic variants. The initial search resulted in 95 studies. We excluded manuscripts that focused on work-related chemicals, heavy metals and tobacco smoke as primary sources of exposure, as well as reviews, prenatal research, and secondary research studies. Seven full-text articles met pre-determined inclusion criteria, and were reviewed. The effects of air pollution were evaluated in terms of methylation (n = 3), oxidative stress (n = 2), and genetic variants (n = 2). There is evidence to suggest that genomics plays a meditating role in the formation of adverse cardiopulmonary symptoms and diseases that surface after exposure events. Genomic modifications and variations affect the association between environmental exposure and cardiopulmonary disease, but additional research is needed to further define this relationship.

Airway hyperreactivity (AHR) related to environmental exposure is a significant public health risk worldwide. Similarly, metabolic syndrome (MetSyn), a risk factor for obstructive airway disease (OAD) and systemic inflammation, is a significant contributor to global adverse health. This prospective cohort study followed N = 7486 World Trade Center (WTC)-exposed male firefighters from 11 September 2001 (9/11) until 1 August 2017 and investigated N = 539 with newly developed AHR for clinical biomarkers of MetSyn and compared them to the non-AHR group. Male firefighters with normal lung function and no AHR pre-9/11 who had blood drawn from 9 September 2001&ndash, 24 July 2002 were assessed. World Trade Center-Airway Hyperreactivity (WTC-AHR) was defined as either a positive bronchodilator response (BDR) or methacholine challenge test (MCT). The electronic medical record (EMR) was queried for their MetSyn characteristics (lipid profile, body mass index (BMI), glucose), and routine clinical biomarkers (such as complete blood counts). We modeled the association of MetSyn characteristics at the first post-9/11 exam with AHR. Those with AHR were significantly more likely to be older, have higher BMIs, have high intensity exposure, and have MetSyn. Smoking history was not associated with WTC-AHR. Those present on the morning of 9/11 had 224% increased risk of developing AHR, and those who arrived in the afternoon of 9/11 had a 75.9% increased risk. Having &ge, 3 MetSyn parameters increased the risk of WTC-AHR by 65.4%. Co-existing MetSyn and high WTC exposure are predictive of future AHR and suggest that systemic inflammation may be a contributor.

Background Quantifying morphologic changes is critical to our understanding of the pathophysiology of the lung. Mean linear intercept (MLI) measures are important in the assessment of clinically relevant pathology, such as emphysema. However, qualitative measures are prone to error and bias, while quantitative methods such as mean linear intercept (MLI) are manually time consuming. Furthermore, a fully automated, reliable method of assessment is nontrivial and resource-intensive. Methods We propose a semi-automated method to quantify MLI that does not require specialized computer knowledge and uses a free, open-source image-processor (Fiji). We tested the method with a computer-generated, idealized dataset, derived an MLI usage guide, and successfully applied this method to a murine model of particulate matter (PM) exposure. Fields of randomly placed, uniform-radius circles were analyzed. Optimal numbers of chords to assess based on MLI were found via receiver-operator-characteristic (ROC)-area under the curve (AUC) analysis. Intraclass correlation coefficient (ICC) measured reliability. Results We demonstrate high accuracy (AUCROC > 0.8 for MLIactual > 63.83 pixels) and excellent reliability (ICC = 0.9998, p https://med.nyu.edu/nolanlab. Conclusions Our semi-automated method is reliable, equally fast as fully automated methods, and uses free, open-source software. Additionally, we quantified the optimal number of chords that should be measured per lung field.

Biomarkers of metabolic syndrome expressed soon after World Trade Center (WTC) exposure predict development of WTC Lung Injury (WTC-LI). The metabolome remains an untapped resource with potential to comprehensively characterise many aspects of WTC-LI. This case-control study identified a clinically relevant, robust subset of metabolic contributors of WTC-LI through comprehensive high-dimensional metabolic profiling and integration of machine learning techniques.Never-smoking, male, WTC-exposed firefighters with normal pre-9/11 lung function were segregated by post-9/11 lung function. Cases of WTC-LI (forced expiratory volume in 1slower limit of normal, n=15) and controls (n=15) were identified from previous cohorts. The metabolome of serum drawn within 6 months of 9/11 was quantified. Machine learning was used for dimension reduction to identify metabolites associated with WTC-LI.580 metabolites qualified for random forests (RF) analysis to identify a refined metabolite profile that yielded maximal class separation. RF of the refined profile correctly classified subjects with a 93.3% estimated success rate. 5 clusters of metabolites emerged within the refined profile. Prominent subpathways include known mediators of lung disease such as sphingolipids (elevated in cases of WTC-LI), and branched-chain amino acids (reduced in cases of WTC-LI). Principal component analysis of the refined profile explained 68.3% of variance in five components, demonstrating class separation.Analysis of the metabolome of WTC-exposed 9/11 rescue workers has identified biologically plausible pathways associated with loss of lung function. Since metabolites are proximal markers of disease processes, metabolites could capture the complexity of past exposures and better inform treatment. These pathways warrant further mechanistic research.

Background: The study of sepsis is hindered by its heterogeneous time course and evolution. A subgroup of patients with severe sepsis develops shock soon after the initiation of treatment while others present hypotensive. We sought to determine the incidence of hypotension after the initiation of treatment for sepsis, and characterize their clinical features and course. Methods: A retrospective review of electronic medical record of all septic patients (n = 542) that met the definition of septic shock within 24 hours of admission (2011 - 2012) at an urban Veteran Affairs Hospital was performed. Subjects either had 1) initial normotension (INT) with hypotension developing within 24 hours or 2) initial hypotension (IH). Logistic regression was used to model associated factors of INT/IH. Results: INT occurred in 62 patients (11%) with average initial blood pressure of 120/71 mm Hg and developed hypotension to 79/48 mm Hg. IH was identified in 52 patients (10%) with average presenting blood pressure of 81/46 mm Hg. INT showed evidence of increased sympathetic tone with significantly higher heart rate, blood pressure and temperature. INT patients were younger, more frequently on alpha-blockers, and more likely septic from pneumonia compared to IH patients. INT and IH patients had similar timing of antibiotic initiation, amount of 24-hour fluid resuscitation, vasopressor use, organ dysfunction and mortality at 28 days. Using alpha-blockers, being Caucasian, and having higher temperatures were independent predictors of INT. Conclusion: INT is a distinctive presentation of septic shock characterized by rapid deterioration during early treatment. By further studying this subgroup, mediators of septic shock may be identified that clarify pathophysiology and provide timely targeted treatment. J Clin Med Res. 2016;8(8):575-581 doi: http://dx.doi.org/10.14740/jocmr2597w

In the August issue of JAMA , Gordon and colleagues compared the outcomes of renal failure in septic shock between early vasopressin and norepinephrine treatment (1).

BackgroundOur group has identified the receptor for advanced glycation end-products (RAGE) as a predictor of World Trade Center particulate matter associated lung injury. The aim of this systematic review is to assess the relationship between RAGE and obstructive airways disease secondary to environmental exposure.MethodsA comprehensive search using PubMed and Embase was performed on January 5, 2018 utilising keywords focusing on environmental exposure, obstructive airways disease and RAGE and was registered with PROSPERO (CRD42018093834). We included original human research studies in English, focusing on pulmonary end-points associated with RAGE and environmental exposure.ResultsA total of 213 studies were identified by the initial search. After removing the duplicates and applying inclusion and exclusion criteria, we screened the titles and abstracts of 61 studies. Finally, 19 full-text articles were included. The exposures discussed in these articles include particulate matter (n=2) and cigarette smoke (n=17).ConclusionRAGE is a mediator of inflammation associated end-organ dysfunction such as obstructive airways disease. Soluble RAGE, a decoy receptor, may have a protective effect in some pulmonary processes. Overall, RAGE is biologically relevant in environmental exposure associated lung disease. Future investigations should focus on further understanding the role and therapeutic potential of RAGE in particulate matter exposure associated lung disease.

Particulate matter (PM) exposure and metabolic syndrome (MetSyn) are both significant global health burdens. PM exposure has been implicated in the pathogenesis of MetSyn and cardiopulmonary diseases. Individuals with pre-existing MetSyn may be more susceptible to the detrimental effects of PM exposure. Our aim was to provide a narrative review of MetSyn/PM-induced systemic inflammation in cardiopulmonary disease, with a focus on prior studies of the World Trade Center (WTC)-exposed Fire Department of New York (FDNY). We included studies (1) published within the last 16-years; (2) described the epidemiology of MetSyn, obstructive airway disease (OAD), and vascular disease in PM-exposed individuals; (3) detailed the known mechanisms of PM-induced inflammation, MetSyn and cardiopulmonary disease; and (4) focused on the effects of PM exposure in WTC-exposed FDNY firefighters. Several investigations support that inhalation of PM elicits pulmonary and systemic inflammation resulting in MetSyn and cardiopulmonary disease. Furthermore, individuals with these preexisting conditions are more sensitive to PM exposure-related inflammation, which can exacerbate their conditions and increase their risk for hospitalization and chronic disease. Mechanistic research is required to elucidate biologically plausible therapeutic targets of MetSyn- and PM-induced cardiopulmonary disease.

World Trade Center (WTC) exposure caused airflow obstruction years after exposure. Chitinases and IgE are innate and humoral mediators of obstructive airway disease. We investigated if serum expression of chitinases and IgE early after WTC exposure predicts subsequent obstruction.With a nested case-control design, 251 FDNY personnel had chitotriosidase, YKL-40 and IgE measured in serum drawn within months of 9/11/2001. The main outcome was subsequent Forced Expiratory Volume after 1 second/Forced Vital Capacity (FEV1/FVC) less than the lower limit of normal (LLN). Cases (N = 125) had abnormal FEV1/FVC whereas controls had normal FEV1/FVC (N = 126). In a secondary analysis, resistant cases (N = 66) had FEV1 (≥107%) one standard deviation above the mean. Logistic regression adjusted for age, BMI, exposure intensity and post-exposure FEV1/FVC modeled the association between early biomarkers and later lung function.Cases and Controls initially lost lung function. Controls recovered to pre-9/11 FEV1 and FVC while cases continue to decline. Cases expressed lower serum chitotriosidase and higher IgE levels. Increase in IgE increased the odds of airflow obstruction and decreased the odds of above average FEV1. Alternately, increasing chitotriosidase decreased the odds of abnormal FEV1/FVC and increased the odds of FEV1 ≥ 107%. Serum YKL-40 was not associated with FEV1/FVC or FEV1 in this cohort.Increased serum chitotriosidase reduces the odds of developing obstruction after WTC-particulate matter exposure and is associated with recovery of lung function. Alternately, elevated IgE is a risk factor for airflow obstruction and progressive lung function decline.

RATIONALE: Metabolic syndrome (MetSyn) is common in industrialized areas with high concentration of ambient particulate matter (PM). Mediators of metabolic syndrome (MetSyn) predict abnormal FEV in firefighters exposed to PM while performing rescue and recovery activities at the World Trade Center (WTC). RAGE is highly expressed in the lung, a strong predictor of FEV, and a key MetSyn mediator. METHODS: Wild type (WT) and RAGE -/- mice were exposed to WTC-PM or PBS control by oropharyngeal aspiration. Lung function, MCT were quantified 24 hours after PM exposure using Flexivent. Lung stereology was assessed for biovolume to airspace ratio and mean chord length (MCL). BAL cytokine profiles were also determined with Luminex. MEASUREMENTS AND MAIN RESULTS: One day after PM exposure, WT mice had: increased neutrophilia, loss of FEV, decreased compliance, increased resistance and reactivity, and elevation of IL-1a, IL-5, IP-10, MCP-1, MIP-2, IL-9, IL-10 and LIF. RAGE -/- mice are protected from these changes. PM-exposed RAGE -/- had lower BAL levels of IL-10 but higher levels of LIF when compared to WT-PM mice. Histology shows loss of alveolar space in WT-PM, but no differences in architecture between RAGE -/- PM and control. Area fraction was not different between WT-PBS and PM, but had significantly shorter MCL for WT-PM. CONCLUSIONS: A single dose of PM can cause increased neutrophilia, elastance, resistance, and hyperreactivity, and decreased FEV one day after exposure. PM induced lung injury is mitigated in the absence of RAGE.

Background The WTC collapse exposed FDNY-workers to caustic airborne particulates that likely resulted in upper and lower airway injury resulting in sinus disease. Aims To identify risk factors for sinus disease in order to focus interventions on WTC-exposed persons at greatest risk. Methods Using information from the FDNY WTC medical monitoring and treatment program database we assessed the impact of initial WTC-arrival time, duration of WTC-rescue/recovery work and blood eosinophil concentration on incident chronic rhinosinusitis (CRS) in 9394 FDNY rescue/recovery workers using Cox proportional hazard models. Results Multiple-predictor Cox regression models adjusted for age, race, and smoking history predicting CRS showed an increased hazard of CRS with higher eosinophil concentration(HR 1.13 (1.04-1.22),P=0.004), as well as high intensity exposures defined by arrival on the morning of 9/11 (HR 1.26 (1.15-1.38),P Conclusions A circumscribed but intense irritant exposure can produce non-resolving inflammation of the upper airway yielding increased rates of CRS years later. FDNY-workers who arrived the morning of 9/11 and had a high blood eosinophil concentration are at higher risk to develop CRS.

Introduction: Metabolic biomarkers predict World Trade Center lung injury (WTC-LI), FEV 1 less than the lower limit of normal (LLN), in a pilot study. We now validate these findings in the larger cohort. We identify distinct phenotypic clusters to further isolate endotypes that would benefit different treatment strategies. Methods: Using hierarchical clustering and principal component analysis we identified clinically relevant patterns in the larger cohort. Firefighters had FEV 1 ≥LLN prior to 9/11 and database was closed as of March 2015. Of the remaining N=7711, N=787 developed WTC-LI and N=6813 had FEV≥LLN. We modeled the ability of biomarkers at the first post-9/11 exam to predict FEV below LLN at the most recent PFT with binary logistic regression. Results: Two-step clustering identified one group with high triglycerides, glucose, and exposure intensity as strongly associated with WTC-LI, Figure 1A. Systolic blood pressure, dyslipidemia, glucose, and smoking are significant predictors in a regression after adjusting for age and exposure intensity, Figure 1B. Conclusion: We have validated biomarkers of metabolic syndrome also seen in our prior pilot to predict WTC-lung injury in a larger population of exposed individuals. These biomarkers are associated with dyslipidemia, insulin resistance, and cardiovascular disease, and suggest that systemic inflammation can contribute to future lung function loss.

Background: World Trade Center (WTC) exposed firefighters developed aerodigestive disease. This pilot study focuses on identifying predictive biomarkers of GERD and Barrett9s in firefighters with WTC exposure. Methods: Retrospective analysis of electronic medical records identified those with incident GERD, Barrett9s and short-acting (SABA)/ long-acting beta-agonists (LABA) use in never smoking firefighters. Serum was analyzed on a subcohort (Luminex). Regression was used to identify the association of SABA/LABA and analytes that could predict GERD and/or Barrett9s. Results: Lung function (FEV 1 ) at the time of presentation was no different in those with GERD/Barrett9s compared to controls. After adjusting for age, BMI, and exposure, SABA use was a significant predictor of GERD, but not Barrett9s. C-peptide and Insulin predicted GERD as continuous variables. CRP, Fractalkine, G-CSF, Insulin, IP-10, and Triglyceride significantly predicted Barrett9s. Cutpoints were optimized in this population to determine clinically useful levels. Conclusion: Although there is an association between SABA use and GERD in this population, there is no increased incidence of Barrett9s. We demonstrate that metabolically active mediators, insulin and triglycerides, have a strong association with GERD and Barrett9s. This pilot study frames future studies to further our understanding of aerodigestive pathology due to particulate exposure.

The World Trade Center (WTC) collapse generated caustic airborne particulates that caused chronic rhinosinusitis in exposed Fire Department of New York firefighters. Surgery was performed when symptoms remained uncontrolled despite medical management.To identify predictors of surgical intervention for chronic rhinosinusitis in firefighters exposed to airborne irritants at the WTC collapse site.We assessed in 8,227 firefighters with WTC exposure between September 11, 2001 (9/11), and September 25, 2001, including WTC-site arrival time, months of rescue and recovery work, and eosinophil concentration measured between 9/11 and March 10, 2003. We assessed the association of serum cytokines and immunoglobulins with eosinophil concentration and surgery for rhinosinusitis in 112 surgical cases and 376 control subjects with serum available from the first 6 months after exposure to the WTC collapse site.Between 9/11 and March 10, 2015, the surgery rate was 0.47 cases per 100 person-years. In the first 18 months post-9/11, surgical patients had higher mean blood eosinophil levels than study cohort patients (219 ± 155 vs. 191 ± 134; P 0.0001). Increased surgery risk was associated with increasing blood eosinophil counts (hazard ratio [HR], 1.12 per 100 cells/μl; 95% confidence interval [CI], 1.07-1.17; P 0.001); arriving at the WTC site on 9/11 or September 12, 2001 (HR, 1.43; 95% CI, 1.04-1.99; P = 0.03); and working 6 months or longer at the WTC site (HR, 1.48; 95% CI, 1.14-1.93; P 0.01). Median blood eosinophil levels for surgical patients were above levels for the cohort in all 18-month intervals March 11, 2000, through March 10, 2015, using 51,163 measurements representing 97,733 person-years of observation. Increasing age, increasing IL-17A, and low IgA in serum from 2001 to 2002 predicted blood eosinophil concentration in surgical patients but not in control subjects (R(2) = 0.26, P 0.0001; vs. R(2) = 0.008, P = 0.56).Increasing blood eosinophil concentration predicts surgical intervention for chronic rhinosinusitis, particularly in those with intense acute and prolonged exposure to airborne irritants. WTC-exposed Fire Department of New York firefighters who underwent irritant-associated sinus surgery are immunologically different from the cohort. Surgical patients have a higher blood eosinophil levels that is associated with mediators of mucosal immunity.