Faculty Bibliography

Introduction/UNASSIGNED: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. Methods/UNASSIGNED: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 1s <lower 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. Results/UNASSIGNED: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. Conclusion/UNASSIGNED: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: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/METHODS:Retrospective chart review. SETTING/SUBJECTS/METHODS:Patients who died on a General Medicine or MICU service (n = 197) at an urban public hospital over a 2-year period. MEASUREMENTS/METHODS: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 beta-agonist use compared to controls. In confounder-adjusted regression models, TNF-alpha ≥ 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 beta-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.

World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)>/=97pg/mL, CRP>/=2.4mg/L, and MMP-9