A case-crossover study of ST-elevation myocardial infarction and organic carbon and source-specific PM2.5 concentrations in Monroe County, New York.

Background: Previous work reported increased rates of cardiovascular hospitalizations associated with increased source-specific PM2.5 concentrations in New York State, despite decreased PM2.5 concentrations. We also found increased rates of ST elevation myocardial infarction (STEMI) associated with short-term increases in concentrations of ultrafine particles and other traffic-related pollutants in the 2014-2016 period, but not during 2017-2019 in Rochester. Changes in PM2.5 composition and sources resulting from air quality policies (e.g., Tier 3 light-duty vehicles) may explain the differences. Thus, this study aimed to estimate whether rates of STEMI were associated with organic carbon and source-specific PM2.5 concentrations. Methods: Using STEMI patients treated at the University of Rochester Medical Center, compositional and source-apportioned PM2.5 concentrations measured in Rochester, a time-stratified case-crossover design, and conditional logistic regression models, we estimated the rate of STEMI associated with increases in mean primary organic carbon (POC), secondary organic carbon (SOC), and source-specific PM2.5 concentrations on lag days 0, 0-3, and 0-6 during 2014-2019. Results: The associations of an increased rate of STEMI with interquartile range (IQR) increases in spark-ignition emissions (GAS) and diesel (DIE) concentrations in the previous few days were not found from 2014 to 2019. However, IQR increases in GAS concentrations were associated with an increased rate of STEMI on the same day in the 2014-2016 period (Rate ratio [RR] = 1.69; 95% CI = 0.98, 2.94; 1.73 µg/m3). In addition, each IQR increase in mean SOC concentration in the previous 6 days was associated with an increased rate of STEMI, despite imprecision (RR = 1.14; 95% CI = 0.89, 1.45; 0.42 µg/m3). Conclusion: Increased SOC concentrations may be associated with increased rates of STEMI, while there seems to be a declining trend in adverse effects of GAS on triggering of STEMI. These changes could be attributed to changes in PM2.5 composition and sources following the Tier 3 vehicle introduction.

Comparison of the rate of healthcare encounters for influenza from source-specific PM2.5 before and after tier 3 vehicle standards in New York state.

BACKGROUND: Influenza healthcare encounters in adults associated with specific sources of PM2.5 is an area of active research. OBJECTIVE: Following 2017 legislation requiring reductions in emissions from light-duty vehicles, we hypothesized a reduced rate of influenza healthcare encounters would be associated with concentrations of PM2.5 from traffic sources in the early implementation period of this regulation (2017-2019). METHODS: We used the Statewide Planning and Research Cooperative System (SPARCS) to study adult patients hospitalized (N = 5328) or treated in the emergency department (N = 18,247) for influenza in New York State. Using a modified case-crossover design, we estimated the excess rate (ER) of influenza hospitalizations and emergency department visits associated with interquartile range increases in source-specific PM2.5 concentrations (e.g., spark-ignition emissions [GAS], biomass burning [BB], diesel [DIE]) in lag day(s) 0, 0-3 and 0-6. We then evaluated whether ERs differed after Tier 3 implementation (2017-2019) compared to the period prior to implementation (2014-2016). RESULTS: Each interquartile range increase in DIE in lag days 0-6 was associated with a 21.3% increased rate of influenza hospitalization (95% CI: 6.9, 37.6) in the 2014-2016 period, and a 6.3% decreased rate (95% CI: -12.7, 0.5) in the 2017-2019 period. The GAS/influenza excess rates were larger in the 2017-2019 period than the 2014-2016 period for emergency department visits. We also observed a larger ER associated with increased BB in the 2017-2019 period compared to the 2014-2016 period. IMPACT STATEMENT: We present an accountability study on the impact of the early implementation period of the Tier 3 vehicle emission standards on the association between specific sources of PM2.5 air pollution on influenza healthcare encounters in New York State. We found that the association between gasoline emissions and influenza healthcare encounters did not lessen in magnitude between periods, possibly because the emissions standards were not yet fully implemented. The reduction in the rates of influenza healthcare encounters associated with diesel emissions may be reflective of past policies to reduce the toxicity of diesel emissions. Accountability studies can help policy makers and environmental scientists better understand the timing of pollution changes and associated health effects.

Tuberculosis screening for patients on biologic Medications: A Single-Center experience and Society guideline Review, Monroe County, New York, 2018-2021.

Rationale: Biologic medications for immune-mediated inflammatory diseases may increase the risk of tuberculosis (TB) reactivation, but data on screening for TB in low TB prevalence areas are limited. Objective: To assess the real-world practice patterns of TB screening among prescribers of biologic medications. Methods: We conducted a retrospective observational study at a single, university-based healthcare facility in a low TB prevalence area. We enrolled adult patients prescribed a biologic medication between October 2018 and December 2021, and collected data on demographics, biologic medications and TB test results. For patients with positive TB tests, further data including prescriber specialty and response to positive tests were obtained. We reviewed pertinent major society guidelines/ consensus statements regarding TB screening among patients treated with biologic medications. Results: 4,085 patients were included. 3024 (74.0%) had at least one screening TB test and 42 were positive. Among patients treated with tumor necrosis factor-alpha (TNFα) inhibitors, 1779 of 2129 patients (83.6%) underwent TB testing and 25 (1.4%) were positive. Most with positive TB test results were prescribed biologic medication by gastroenterology (11 patients, 26%), dermatology (12, 29%), or rheumatology (15, 36%) providers. 32 (76%) patients had imaging and roughly half were treated for latent TB infection. Biologic medications were temporarily held for 27 patients (67%). Nine out of 13 society guidelines recommend TB screening for TNFα inhibitors but have differing recommendations for other biologic medications. Conclusions: Significant practice pattern differences in TB screening for patients receiving biologic medications exist. Multiple society guidelines continue to recommend TB screening even for drugs with no known increased risk of TB reactivation.

PM2.5 and its components and respiratory disease healthcare encounters - Unanticipated increased exposure-response relationships in recent years after environmental policies.

Prior studies reported excess rates (ERs) of cardiorespiratory events associated with short-term increases in PM2.5 concentrations, despite implementation of pollution-control policies. In 2017, Federal Tier 3 light-duty vehicle regulations began, and to-date there have been no assessments of population health effects of the policy. Using the NYS Statewide Planning and Research Cooperative System (SPARCS) database, we obtained hospitalizations and ED visits with a principal diagnosis of asthma or chronic obstructive pulmonary disease (COPD) for residents living within 15 miles of six urban PM2.5 monitoring sites in NYS (2014-2019). We used a time-stratified case-crossover design and conditional logistic regression (adjusting for ambient temperature, relative humidity, and weekday) to estimate associations between PM2.5, POC (primary organic carbon), SOC (secondary organic carbon), and rates of respiratory disease hospitalizations and emergency department (ED) visits from 2014 to 2019. We evaluated demographic disparities in these relative rates and compared changes in ERs before (2014-2016) and after Tier 3 implementation (2017-2019). Each interquartile range increase in PM2.5 was associated with increased ERs of asthma or COPD hospitalizations and ED visits in the previous 7 days (ERs ranged from 1.1%-3.1%). Interquartile range increases in POC were associated with increased rates of asthma ED visits (lag days 0-6: ER = 2.1%, 95% CI = 0.7%, 3.6%). Unexpectedly, the ERs of asthma admission and ED visits associated with PM2.5, POC, and SOC were higher during 2017-2019 (after Tier 3) than 2014-2016 (before Tier-3). Chronic obstructive pulmonary disease analyses showed similar patterns. Excess Rates were higher in children (<18 years; asthma) and seniors (≥65 years; COPD), and Black, Hispanic, and NYC residents. In summary, unanticipated increases in asthma and COPD ERs after Tier-3 implementation were observed, and demographic disparities in asthma/COPD and PM2.5, POC, and SOC associations were also observed. Future work should confirm findings and investigate triggering of respiratory events by source-specific PM.

Triggering of ST-elevation myocardial infarction by ultrafine particles in New York: Changes following Tier 3 vehicle introduction.

BACKGROUND: Previously, we found increased rates of ST-elevation myocardial infarction (STEMI) associated with increased ultrafine particle (UFP; <100 nm) concentrations in the previous few hours in Rochester, New York. Relative rates were higher after air quality policies and a recession reduced pollutant concentrations (2014-2016 versus 2005-2013), suggesting PM composition had changed and the same PM mass concentration had become more toxic. Tier 3 light duty vehicles, which should produce less primary organic aerosols and oxidizable gaseous compounds, likely making PM less toxic, were introduced in 2017. Thus, we hypothesized we would observe a lower relative STEMI rate in 2017-2019 than 2014-2016. METHODS: Using STEMI events treated at the University of Rochester Medical Center (2014-2019), UFP and other pollutants measured in Rochester, a case-crossover design, and conditional logistic regression models, we estimated the rate of STEMI associated with increased UFP and other pollutants in the previous hours and days in the 2014-2016 and 2017-2019 periods. RESULTS: An increased rate of STEMI was associated with each 3111 particles/cm3 increase in UFP concentration in the previous hour in 2014-2016 (lag hour 0: OR = 1.22; 95% CI = 1.06, 1.39), but not in 2017-2019 (OR = 0.94; 95% CI = 0.80, 1.10). There were similar patterns for black carbon, UFP11-50nm, and UFP51-100nm. In contrast, increased rates of STEMI were associated with each 0.6 ppb increase in SO2 concentration in the previous 120 h in both periods (2014-2016: OR = 1.26, 95% CI = 1.03, 1.55; 2017-2019: OR = 1.21, 95% CI = 0.87, 1.68). CONCLUSIONS: Greater rates of STEMI were associated with short term increases in concentrations of UFP and other motor vehicle related pollutants before Tier 3 introduction (2014-2016), but not afterwards (2017-2019). This change may be due to changes in PM composition after Tier 3 introduction, as well as to increased exposure misclassification and greater underestimation of effects from 2017 to 2019.

The effect of air pollution on the transcriptomics of the immune response to respiratory infection.

Combustion related particulate matter air pollution (PM) is associated with an increased risk of respiratory infections in adults. The exact mechanism underlying this association has not been determined. We hypothesized that increased concentrations of combustion related PM would result in dysregulation of the innate immune system. This epidemiological study includes 111 adult patients hospitalized with respiratory infections who underwent transcriptional analysis of their peripheral blood. We examined the association between gene expression at the time of hospitalization and ambient measurements of particulate air pollutants in the 28 days prior to hospitalization. For each pollutant and time lag, gene-specific linear models adjusting for infection type were fit using LIMMA (Linear Models For Microarray Data), and pathway/gene set analyses were performed using the CAMERA (Correlation Adjusted Mean Rank) program. Comparing patients with viral and/or bacterial infection, the expression patterns associated with air pollution exposure differed. Adjusting for the type of infection, increased concentrations of Delta-C (a marker of biomass smoke) and other PM were associated with upregulation of iron homeostasis and protein folding. Increased concentrations of black carbon (BC) were associated with upregulation of viral related gene pathways and downregulation of pathways related to antigen presentation. The pollutant/pathway associations differed by lag time and by type of infection. This study suggests that the effect of air pollution on the pathogenesis of respiratory infection may be pollutant, timing, and infection specific.

Associations between Source-Specific Particulate Matter and Respiratory Infections in New York State Adults.

The response of respiratory infections to source-specific particulate matter (PM) is an area of active research. Using source-specific PM2.5 concentrations at six urban sites in New York State, a case-crossover design, and conditional logistic regression, we examined the association between source-specific PM and the rate of hospitalizations and emergency department (ED) visits for influenza or culture-negative pneumonia from 2005 to 2016. There were at most N = 14 764 influenza hospitalizations, N = 57 522 influenza ED visits, N = 274 226 culture-negative pneumonia hospitalizations, and N = 113 997 culture-negative pneumonia ED visits included in our analyses. We separately estimated the rate of respiratory infection associated with increased concentrations of source-specific PM2.5, including secondary sulfate (SS), secondary nitrate (SN), biomass burning (BB), pyrolyzed organic carbon (OP), road dust (RD), residual oil (RO), diesel (DIE), and spark ignition vehicle emissions (GAS). Increased rates of ED visits for influenza were associated with interquartile range increases in concentrations of GAS (excess rate [ER] = 9.2%; 95% CI: 4.3%, 14.3%) and DIE (ER = 3.9%; 95% CI: 1.1%, 6.8%) for lag days 0-3. There were similar associations between BB, SS, OP, and RO, and ED visits or hospitalizations for influenza, but not culture-negative pneumonia hospitalizations or ED visits. Short-term increases in PM2.5 from traffic and other combustion sources appear to be a potential risk factor for increased rates of influenza hospitalizations and ED visits.

Changes in the hospitalization and ED visit rates for respiratory diseases associated with source-specific PM2.5 in New York State from 2005 to 2016.

Prior work found increased rates for emergency department (ED) visits for asthma and hospitalizations for chronic obstructive pulmonary disease per unit mass of PM2.5 across New York State (NYS) during 2014-2016 after significant reductions in ambient PM2.5 concentrations had occurred following implementation of various policy actions and major economic disruptions. The associations of source-specific PM2.5 concentrations with these respiratory diseases were assessed with a time-stratified case-cossover design and logistic regression models to identify the changes in the PM2.5 that have led to the apparently increased toxicity per unit mass. The rates of ED visits and hospitalizations for asthma and COPD associated with increases in source-specific PM2.5 concentrations in the prior 1, 4, and 7 days were estimated for 6 urban sites in New York State. Overall, there were similar numbers of significantly increased (n = 9) and decreased rates (n = 8) of respiratory events (asthma and COPD hospitalizations and ED visits) associated with increased source-specific PM2.5 concentrations in the previous 1, 4, and 7 days. Associations of source-specific PM2.5 concentrations with excess rates of hospitalizations for COPD for spark- and compression ignition vehicles increased in the 2014-2016 period, but the values were not statistically significant. Other source types showed inconsistent patterns of excess rates. For asthma ED visits, only biomass burning and road dust showed consistent positive associations with road dust having significant values for most lag times. Secondary nitrate also showed significant positive associations with asthma ED visits in the AFTER period compared to no associations in the prior periods. These results suggest that the relationships of asthma and COPD exacerbation with source-specific PM2.5 are not well defined and further work will be needed to determine the causes of the apparent increases in the per unit mass toxicity of PM2.5 in New York State in the 2014-16 period.

Use of Biomarkers to Assess Environmental Exposures and Health Outcomes in Deployed Troops.

OBJECTIVE: This paper provides an overview of our Military Biomarkers Research Study (MBRS) designed to assess whether biomarkers can be used to retrospectively assess deployment exposures and health impacts related to deployment environmental exposures. METHODS: The MBRS consists of four phases. Phase I was a feasibility study of stored sera. Phase II looks at associations between exposures and biomarkers. Phase III examines relationships of biomarkers and health outcomes, and Phase IV investigates in vitro biomarker changes associated with exposures to chemicals of interest. This paper briefly summarizes work already published and introduces the new reports contained in this supplement. RESULTS: Novel biomarkers were identified. These were associated with deployment exposures. CONCLUSIONS: Significant associations were noted between deployment exposures, microRNA biomarkers and metabolomic biomarkers, and deployment health outcomes.

Advances in Comprehensive Exposure Assessment: Opportunities for the US Military.

OBJECTIVE: Review advances in exposure assessment offered by the exposome concept and new -omics and sensor technologies. METHODS: Narrative review of advances, including current efforts and potential future applications by the US military. RESULTS: Exposure assessment methods from both bottom-up and top-down exposomics approaches are advancing at a rapid pace, and the US military is engaged in developing both approaches. Top-down approaches employ various -omics technologies to identify biomarkers of internal exposure and biological effect. Bottom-up approaches use new sensor technology to better measure external dose. Key challenges of both approaches are largely centered around how to integrate, analyze, and interpret large datasets that are multidimensional and disparate. CONCLUSIONS: Advances in -omics and sensor technologies may dramatically enhance exposure assessment and improve our ability to characterize health risks related to occupational and environmental exposures, including for the US military.

Environmental Chemicals Altered in Association With Deployment for High Risk Areas.

OBJECTIVE: A study was conducted using serum samples and high-resolution metabolomics (HRM) to test for changes in abundance of environmental chemicals in deployment in high-risk areas (Balad, Iraq; Bagram, Afghanistan). METHODS: Pre and Post-deployment serum samples for deployment (cases) and matched controls stationed domestically were analyzed by HRM and bioinformatics for the relative abundance of 271 environmental chemicals. RESULTS: Of the 271 chemicals, 153 were measurable in at least 80% of the samples in one of the pre- or post-deployment groups. Several pesticides and other chemicals were modestly elevated post-deployment in the Control as well as the Bagram and Balad samples. Similarly, small decreases were seen for some chemicals. CONCLUSION: These results using serum samples show that for the 271 environmental chemicals studied, 56% were detected and small differences occurred with deployment to high-risk areas.

Metabolome-Wide Association Study of Deployment to Balad, Iraq or Bagram, Afghanistan.

OBJECTIVE: To use high-resolution metabolomics (HRM) to identify metabolic changes in military personnel associated with deployment to Balad, Iraq, or Bagram, Afghanistan. METHODS: Pre- and post-deployment samples were obtained from the Department of Defense Serum Repository (DoDSR). HRM and bioinformatics were used to identify metabolic differences associated with deployment. RESULTS: Differences at baseline (pre-deployment) between personnel deployed to Bagram compared with Balad or Controls included sex hormone and keratan sulfate metabolism. Deployment to Balad was associated with alterations to amino acid and lipid metabolism, consistent with inflammation and oxidative stress, and pathways linked to metabolic adaptation and repair. Difference associated with deployment to Bagram included lipid pathways linked to cell signaling and inflammation. CONCLUSIONS: Metabolic variations in pre- and post-deployment are consistent with deployment-associated responses to air pollution and other environmental stressors.

Associations of Benzo(ghi)perylene and Heptachlorodibenzo-p-dioxin in Serum of Service Personnel Deployed to Balad, Iraq, and Bagram, Afghanistan Correlates With Perturbed Amino Acid Metabolism in Human Lung Fibroblasts.

OBJECTIVE: A study was conducted to identify metabolic-related effects of benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), on primary human fibroblasts to verify biological associations previously found in occupational health research. METHODS: Human lung fibroblasts were exposed to BghiP or HpCDD and extracts were analyzed with a metabolome-wide association study to test for pathways and metabolites altered relative to controls. Gene expression was measured by quantitative-real time polymerase chain reaction. RESULTS: Metabolic perturbations in amino-acid, oxidative stress, and fatty-acid pathways were observed for BghiP and HpCDD. HpCDD but not BghiP exposure increased gene expression of the amino acid transporters SLC7A5 and SLC7A11. CONCLUSIONS: Exposure to polycyclic aromatic hydrocarbons (PAH) or dioxins perturbs amino acid pathways at physiologically relevant concentrations with different mechanisms. These findings imply an effect on central homeostatic systems by environmental exposures which could have implications on disease susceptibility.

Analysis of Postdeployment Serum Samples Identifies Potential Biomarkers of Exposure to Burn Pits and Other Environmental Hazards.

OBJECTIVE: The potential health risks of deployment to sites with open burn pits remain poorly understood, in part, because personal exposure monitoring was not performed. Here, we investigated whether postdeployment serum samples contain biomarkers associated with exposure to burn pits. METHODS: A total of 237 biomarkers were measured in 800 serum samples from deployed and never-deployed subjects. We used a regression model and a supervised vector machine to identify serum biomarkers with significant associations with exposures and deployment. RESULTS: We identified 101 serum biomarkers associated with polycyclic aromatic hydrocarbons, dioxins or furans, and 54 biomarkers associated with deployment. Twenty-six of these biomarkers were shared in common by the exposure and deployment groups. CONCLUSIONS: We identify a potential signature of exposure to open burn pits, and provide a framework for using postexposure sera to identify exposures when contemporaneous monitoring was inadequate.

Machine Learning Approach for Predicting Past Environmental Exposures From Molecular Profiling of Post-Exposure Human Serum Samples.

OBJECTIVE: To develop an approach for a retrospective analysis of post-exposure serum samples using diverse molecular profiles. METHODS: The 236 molecular profiles from 800 de-identified human serum samples from the Department of Defense Serum Repository were classified as smokers or non-smokers based on direct measurement of serum cotinine levels. A machine-learning pipeline was used to classify smokers and non-smokers from their molecular profiles. RESULTS: The refined supervised support vector machines with recursive feature elimination predicted smokers and non-smokers with 78% accuracy on the independent held-out set. Several of the identified classifiers of smoking status have previously been reported and four additional miRNAs were validated with experimental tobacco smoke exposure in mice, supporting the computational approach. CONCLUSIONS: We developed and validated a pipeline that shows retrospective analysis of post-exposure serum samples can identify environmental exposures.

Integrative Network Analysis Linking Clinical Outcomes With Environmental Exposures and Molecular Variations in Service Personnel Deployed to Balad and Bagram.

OBJECTIVE: To develop a computational approach to link clinical outcomes with environmental exposures and molecular variations measured in Department of Defense (DOD) serum-repository samples. METHODS: International Classification of Diseases, Ninth Division codes which corresponded to cardiopulmonary symptoms for service personnel were selected to test for associations with deployment-related inhalation hazards and metabolomics, micro-RNA, cytokine, plasma markers, and environmental exposure analyses for corresponding samples. xMWAS and Mummichog were used for integrative network and pathway analysis. RESULTS: Comparison between 41 personnel exhibiting new cardio-pulmonary diagnoses after deployment start-date to 25 personnel exhibiting no symptoms identified biomarkers associated with cardiopulmonary conditions. Integrative network and pathway analysis showed communities of clinical, molecular, and environmental markers associated with fatty acid, lipid, nucleotide, and amino acid metabolism pathways. CONCLUSIONS: The current proof of principle study establishes a computational framework for integrative analysis of deployment-related exposures, molecular responses, and health outcomes.

Benzo[a]pyrene Perturbs Mitochondrial and Amino Acid Metabolism in Lung Epithelial Cells and Has Similar Correlations With Metabolic Changes in Human Serum.

OBJECTIVE: A study was conducted to identifymetabolic-related effects of benzo[a]pyrene (BaP) on human lung epithelial cells and validate these findings using human sera. METHODS: Human lung epithelial cells were treated with BaP, and extracts were analyzed with a global metabolome-wide association study (MWAS) to test for pathways and metabolites altered relative to vehicle controls. RESULTS: MWAS results showed that BaP metabolites were among the top metabolites differing between BaP-treated cells and controls. Pathway enrichment analysis further confirmed that fatty acid, lipid, and mitochondrial pathways were altered by BaP. Human sera analysis showed that lipids varied with BaP concentration. BaP associations with amino acid metabolism were found in both models. CONCLUSIONS: These findings show that BaP has broad metabolic effects, and suggest that air pollution exacerbates disease processes by altered mitochondrial and amino acid metabolism.

Exposure to Heptachlorodibenzo-p-dioxin (HpCDD) Regulates microRNA Expression in Human Lung Fibroblasts.

OBJECTIVE: Benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin (HpCDD) were elevated in serum from personnel deployed to sites with open burn pits. Here, we investigated the ability of BghiP and HpCDD to regulate microRNA (miRNA) expression through the aryl hydrocarbon receptor (AHR). METHODS: Human lung fibroblasts (HLFs) were exposed to BghiP and HpCDD. AHR activity was measured by reporter assay and gene expression. Deployment related miRNA were measured by quantitative polymerase chain reaction. AHR expression was depleted using siRNA. RESULTS: BghiP displayed weak AHR agonist activity. HpCDD induced AHR activity in a dose-dependent manner. Let-7d-5p, miR-103-3p, miR-107, and miR-144-3p levels were significantly altered by HpCDD. AHR knockdown attenuated these effects. CONCLUSIONS: These studies reveal that miRNAs previously identified in sera from personnel deployed to sites with open burn pits are altered by HpCDD exposure in HLFs.