Preparedness of Military Public Health for Epidemic and Pandemic Recognition and Response.

Disease epidemics have threatened American military preparedness and operational capabilities since 1775. The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19) pandemic, which began in 2019, again demonstrates the significant potential for infectious diseases to impact military units and threaten military readiness. We reviewed the historical and continuing threats to the U.S. Military from infectious disease outbreaks, as well as changes in U.S. Military capabilities for conducting meaningful surveillance and response. We concluded that a structured review of military public health and preventive medicine capabilities should be conducted to assess the response to the COVID-19 pandemic and determine the capabilities necessary for infectious disease surveillance and response to future threats.

Military Epidemics, Then and Now: Smallpox and COVID-19.

We compared the COVID-19 experience in the first year of the current pandemic in the US with the smallpox experience of the 18th century, focusing on the US military but recognizing civilian and military populations are not separate and distinct. Despite the epidemics being separated by 21/2 centuries and with great advancements in technology having occurred over that time, we observed similarities which led us to several conclusions: • Infectious disease outbreaks will continue to occur and novel agents, naturally occurring or manipulated by humans, will threaten military and civilian populations nationally and globally. • Infectious disease outbreaks can affect both military and civilian populations, persist for long periods, and be catastrophic to military peacetime and wartime operations. • Effective surveillance is a prerequisite for early identification and subsequent meaningful responses to novel and reemerging threat agents and diseases. • Socio-cultural, religious, or political factors may limit the implementation of effective interventions in military or civilian populations. Public health officials must assess impediments to implementation of interventions and develop plans to overcome them.

Hazardous Non-Combat Exposures in the U.S. Department of Defense.

Hazardous non-combat exposures are inherent to military service and occur in three settings: installation workplaces, installation environments, and deployment environments. Few military clinicians receive training in how to recognize, assess, and manage patients with these exposures, and systems improvements are needed to support clinicians with respect to exposure recognition and management. This commentary highlights key concepts surrounding military non-combat exposures by discussing three case examples of exposures occurring in each of these settings. In the workplace, well-coordinated, interdisciplinary occupational health teams improve identification of exposure-related illnesses, and these teams may be further supported by the development of automated clinical decision-support systems. Installation environmental exposures are characterized by high perceived risk, uncertainty in estimating actual risk, and a wide range of stakeholders including military family members and individuals in the surrounding community. Recognizing environmental exposure concerns, gathering a thorough environmental exposure history, and practicing exposure risk communication are vital skills to address these situations. During deployments, exposures may initially be perceived as low risk but then become a concern years later. A functional understanding of the capabilities and limitations of exposure monitoring and potential health effects of exposures helps the military clinician effectively communicate potential health risks to line leaders. For any of these exposure settings, service public health centers and OEM specialty leaders and consultants are available for consultation.

The Future of Military Occupational and Environmental Medicine in the Department of Defense.

OBJECTIVE: Transfer of military medical facilities to the Defense Health Agency is transforming the Military Health System. Our objective is to inform this transformation with respect to optimum application of occupational and environmental medicine (OEM) expertise. METHODS: We defined and analyzed the external influences on military OEM practice using a structured framework to identify key drivers. RESULTS: Key drivers are political and economic factors. These may change the size or military/civilian ratio of the specialty. Limited career development pathways should prompt consideration of making OEM a second or combined residency, and military-funded training of civilian physicians may be required. OEM specialist utilization should be reassessed. CONCLUSIONS: OEM is a highly adaptable specialty defined by the needs of its stakeholders. Comprehensive analysis of external influences can ensure that OEM practice remains in step with changing needs.

Training Occupational and Environmental Medicine (OEM) Residents at the Uniformed Services University.

OBJECTIVE: To develop an actionable plan to sustain and improve the quality of the Uniformed Services University of the Health Sciences (USU) Occupational and Environmental Medicine (OEM) Residency Program. METHODS: Program metrics were collected and analyzed to assess strengths, weaknesses, opportunities, and threats (SWOT analysis). RESULTS: Program strengths are stable funding, full-time faculty and large class size. Weaknesses are limited toxicology curriculum, and the lack of complex clinical cases. Opportunities include establishing an OEM referral clinic, collaborating with U.S. Department of Defense (DoD) toxicology programs, aligning OEM research priorities in DoD, and including DoD Civilian physicians in OEM residency training. Threats are Military Health System reorganization, budget, and personnel cuts. CONCLUSIONS: The USU OEM Residency is strong but must be flexible to adjust to personnel, fiscal, and organizational changes. Aggregating the SWOT analyses for all the OEM residency programs may help identify strategies to sustain OEM training in the United States.

Uniformed Services University Occupational and Environmental Medicine Residency Program.

In 2019, the Uniformed Services University of the Health Sciences (USU) F. Edward Hébert School of Medicine celebrated the 30th anniversary of its Occupational and Environmental Medicine (OEM) Residency program. This unique program is among the largest preventive medicine residency programs in the United States. Residents from the US Army, Navy, Air Force, other federal institutions, and the Canadian Forces come to Bethesda, Maryland, to become OEM specialists in a unique training program encompassing both military and civilian OEM settings. This publication describes the historical development and practice of OEM in the military leading to the development of the USU OEM Residency Program, along with the program's past accomplishments and current operation. Finally, the publication explores potential future directions for this relatively small but important preventive medicine specialty in the practice of military medicine, considering the impacts of reorganization of the Military Health System along with the opportunities this reorganization presents for the USU OEM Residency program.

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.

The U.S. Army Occupational and Environmental Medicine Residency at Aberdeen Proving Ground, Maryland: 1960-1996.

BACKGROUND: Reorganization of the Army and critical assessment of Army Graduate Medical Education programs prompted the Occupational and Environmental Medicine (OEM) Consultant to the Army Surgeon General to initiate a review of current Army OEM residency training. Available information indicated the Army OEM residency at Aberdeen Proving Ground, MD, was the first and longest operating Army OEM residency. Describing this residency was identified as the first step in the review, with the objectives of determining why the residency was started and sustained and its relevance to the needs of the Army. METHODS: Records possibly related to the residency were reviewed, starting with 1954 since certification of physicians as Occupation Medicine specialists began in 1955. Interviews were conducted with selected physicians who had strong affiliations with the Army residency and the practice of Army OEM. FINDINGS: The Army OEM residency began in 1960 and closed in 1996 with the transfer of Army OEM residency training to the Uniformed Services University of the Health Sciences, Bethesda, MD. Over 36 years, 47 uniformed residency graduates were identified; 44 were from the Army. Forty graduated between 1982 and 1996. The OEM residency was part of a dynamic cycle. Uniformed OEM leaders identified the knowledge and skills required of military OEM physicians and where these people should be stationed in the global Army. Rotations at military sites to acquire the needed knowledge and skills were integrated into the residency. Residency graduates were assigned to positions where they were needed. Having uniformed residents and preceptors facilitated the development of trust with military leaders and access to areas where OEM physician skills and knowledge could have a positive impact. Early reports indicated the residency was important in recruiting and retaining OEM physicians, with emphasis placed on supporting the Army industrial base. The late 1970s into the 1990s was a more dynamic period. There was heightened interest in environmental protection and restoration of military installations, and in the threats posed by nuclear, biological and chemical weapons. Additionally, President Reagan initiated a military buildup that brought new health risks to soldiers who would use and maintain modern equipment. Army OEM physicians were required to possess competencies in many areas, to include depots in the Army industrial base, occupational health for the soldier for exposures like carbon monoxide in armored vehicles, military unique exposures like those from chemical threat agents, and environmental medicine to assess health risks on contaminated U.S. military sites and from exposures of deployed forces. These offered interesting OEM training opportunities that challenged residents in the program and helped recruit new residents. DISCUSSION: The strength of the first Army OEM residency was that it was part of a dynamic cycle that consisted of identifying and defining Army OEM needs, training physicians to meet those needs and assigning residency graduates to positions where they would have a positive impact. This paradigm can be used as the basis for contemporary assessments of the Army's need for uniformed OEM physicians and a uniformed OEM residency program.

High-Resolution Metabolomics Assessment of Military Personnel: Evaluating Analytical Strategies for Chemical Detection.

OBJECTIVE: The aim of this study was to maximize detection of serum metabolites with high-resolution metabolomics (HRM). METHODS: Department of Defense Serum Repository (DoDSR) samples were analyzed using ultrahigh resolution mass spectrometry with three complementary chromatographic phases and four ionization modes. Chemical coverage was evaluated by number of ions detected and accurate mass matches to a human metabolomics database. RESULTS: Individual HRM platforms provided accurate mass matches for up to 58% of the KEGG metabolite database. Combining two analytical methods increased matches to 72% and included metabolites in most major human metabolic pathways and chemical classes. Detection and feature quality varied by analytical configuration. CONCLUSIONS: Dual chromatography HRM with positive and negative electrospray ionization provides an effective generalized method for metabolic assessment of military personnel.

MicroRNAs as Novel Biomarkers of Deployment Status and Exposure to Polychlorinated Dibenzo-p-Dioxins/Dibenzofurans.

OBJECTIVE: To determine if service members deployed to locations with open air burn pits have different serum microRNA (miRNA) profiles after deployment compared with length-of-service matched, non-deployed individuals. We also tested for correlations between miRNA and serum levels of Polychlorinated Dibenzo-p-Dioxins/Dibenzofurans (PCDD/PCDFs). METHODS: MiRNAs were isolated and quantified by PCR array. Groups were analyzed for differences in miRNA expression. Correlations between serum miRNA and PCDD/PCDFs were assessed with a linear regression model. RESULTS: Several miRNAs were differentially expressed after deployment and a partially overlapping set of miRNAs were identified between deployed and non-deployed individuals. Significant correlations between miRNAs and PCDD/PCDFs were identified. CONCLUSIONS: Serum miRNA levels show a link between deployment to locations with open burn pits and environmental exposures that can take place during deployment.