Longitudinal Patterns of Multimorbidity in Gulf War Era Veterans With and Without Gulf War Illness.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

Military exposures and Gulf War illness in veterans with and without posttraumatic stress disorder.

Gulf War illness (GWI) is a chronic multisymptom disorder of unknown etiology that is believed to be caused by neurotoxicant exposure experienced during deployment to the Gulf War. Posttraumatic stress disorder (PTSD) covaries with GWI and is believed to play a role in GWI symptoms. The present study examined the association between self-reported military exposures and GWI, stratified by PTSD status, in veterans from the Gulf War Era Cohort and Biorepository who were deployed to the Persian Gulf during the war. Participants self-reported current GWI and PTSD symptoms as well as military exposures (e.g., pyridostigmine [PB] pills, pesticides/insecticides, combat, chemical attacks, and oil well fires) experienced during the Gulf War. Deployed veterans' (N = 921) GWI status was ascertained using the Centers for Disease Control and Prevention definition. Individuals who met the GWI criteria were stratified by PTSD status, yielding three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression, adjusted for covariates, was used to examine associations between GWI/PTSD groups and military exposures. Apart from insect bait use, the GWI+/PTSD+ group had higher odds of reporting military exposures than the GWI+/PTSD- group, adjusted odds ratio (aOR) = 2.15, 95% CI [1.30, 3.56]-aOR = 6.91, 95% CI [3.39, 14.08]. Except for PB pills, the GWI+/PTSD- group had a higher likelihood of reporting military exposures than the GWI- group, aOR = 2.03, 95% CI [1.26, 3.26]-aOR = 4.01, 95% CI [1.57, 10.25]. These findings are consistent with roles for both PTSD and military exposures in the etiology of GWI.

Health outcomes and healthcare resource utilization among Veterans with stage IV non-small cell lung cancer treated with second-line chemotherapy versus immunotherapy.

BACKGROUND: Until recently, multi-agent chemotherapy (CT) was the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Clinical trials have confirmed benefits in overall survival (OS) and progression-free survival with immunotherapy (IO) compared to CT. This study compares real-world treatment patterns and outcomes between CT and IO administrations in second-line (2L) settings for patients with stage IV NSCLC. MATERIALS AND METHODS: This retrospective study included patients in the United States Department of Veterans Affairs healthcare system diagnosed with stage IV NSCLC during 2012-2017 and receiving IO or CT in the 2L. Patient demographics and clinical characteristics, healthcare resource utilization (HCRU), and adverse events (AEs) were compared between treatment groups. Logistic regression was used to examine differences in baseline characteristics between groups, and inverse probability weighting multivariable Cox proportional hazard regression was used to analyze OS. RESULTS: Among 4,609 Veterans who received first-line (1L) therapy for stage IV NSCLC, 96% received 1L CT alone. A total of 1,630 (35%) were administered 2L systemic therapy, with 695 (43%) receiving IO and 935 (57%) receiving CT. Median age was 67 years (IO group) and 65 years (CT group); most patients were male (97%) and white (76-77%). Patients administered 2L IO had a higher Charlson Comorbidity Index than those administered CT (p = 0.0002). 2L IO was associated with significantly longer OS compared with CT (hazard ratio 0.84, 95% CI 0.75-0.94). IO was more frequently prescribed during the study period (p < 0.0001). No difference in rate of hospitalizations was observed between the two groups. CONCLUSIONS: Overall, the proportion of advanced NSCLC patients receiving 2L systemic therapy is low. Among patients treated with 1L CT and without IO contraindications, 2L IO should be considered, as this supports potential benefit of IO for advanced NSCLC. The increasing availability and indications for IO will likely increase the administration of 2L therapy to NSCLC patients.

Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans.

BACKGROUND: Many severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive patients take commonly prescribed medications with properties which may affect mortality. OBJECTIVE: Assess if common medications postulated to affect clinical outcomes are associated with mortality in SARS-CoV-2 positive patients in the Veterans Health Administration (VHA). DESIGN: Observational national cohort analysis. PARTICIPANTS: Consecutive 26,508 SARS-CoV-2 positive Veterans (7% of 399,290 tested from March 1 to September 10, 2020) constitute the study cohort. MAIN MEASURES: The primary outcome was 30-day mortality from the first positive SARS-CoV-2 test date. In patients receiving medications or drug pairs within 2 weeks post-SARS-CoV-2 positive test, 30-day mortality was estimated as relative risk (RR) on the log-binomial scale or using multinomial models with and without adjusting for covariates. KEY RESULTS: The 26,508 SARS-CoV-2 positive patients were predominantly male (89%) and White (59%), and 82% were overweight/obese. Medications associated with decreased 30-day mortality risk included the following: metformin (aRR, 0.33; 95% CI, 0.25-0.43), colchicine, angiotensin-converting-enzyme inhibitors (ACEi), angiotensin II receptor blockers, statins, vitamin D, antihistamines, alpha-blockers, anti-androgens, and nonsteroidal anti-inflammatory drugs (aRR, 0.69; 95% CI, 0.61-0.78). The effect of co-prescribed medications on 30-day mortality risk revealed the lowest risk for combined statins and metformin (aRR, 0.21; 95% CI, 0.15-0.31), followed by ACEi and statins (aRR, 0.25; 95% CI, 0.18-0.35), ACEi and metformin (aRR, 0.26; 95% CI, 0.17-0.40), antihistamines and NSAIDs (aRR, 0.41; 95% CI, 0.32-0.52), and in men, combined alpha-blockers and anti-androgens (aRR, 0.51; 95% CI, 0.42-0.64). CONCLUSIONS: In this large national cohort, treatment of SARS-CoV-2 positive patients with individual or co-prescribed metformin and statins, ACEi and statins (or metformin) and other medications was associated with a markedly decreased 30-day mortality and can likely be continued safely. Clinical trials may assess their therapeutic benefit.

COVID-19-Associated Mortality in US Veterans with and without SARS-CoV-2 Infection.

BACKGROUND: We performed an observational Veterans Health Administration cohort analysis to assess how risk factors affect 30-day mortality in SARS-CoV-2-infected subjects relative to those uninfected. While the risk factors for coronavirus disease 2019 (COVID-19) have been extensively studied, these have been seldom compared with uninfected referents. METHODS: We analyzed 341,166 White/Black male veterans tested for SARS-CoV-2 from March 1 to September 10, 2020. The relative risk of 30-day mortality was computed for age, race, ethnicity, BMI, smoking status, and alcohol use disorder in infected and uninfected subjects separately. The difference in relative risk was then evaluated between infected and uninfected subjects. All the analyses were performed considering clinical confounders. RESULTS: In this cohort, 7% were SARS-CoV-2-positive. Age >60 and overweight/obesity were associated with a dose-related increased mortality risk among infected patients relative to those uninfected. In contrast, relative to never smoking, current smoking was associated with a decreased mortality among infected and an increased mortality in uninfected, yielding a reduced mortality risk among infected relative to uninfected. Alcohol use disorder was also associated with decreased mortality risk in infected relative to the uninfected. CONCLUSIONS: Age, BMI, smoking, and alcohol use disorder affect 30-day mortality in SARS-CoV-2-infected subjects differently from uninfected referents. Advanced age and overweight/obesity were associated with increased mortality risk among infected men, while current smoking and alcohol use disorder were associated with lower mortality risk among infected men, when compared with those uninfected.

Development of a Multi-Study Repository to Support Research on Veteran Health: The VA Cooperative Studies Program Epidemiology Center-Durham (CSPEC-Durham) Data and Specimen Repository.

Federal agencies, including the Department of Veterans Affairs (VA), have prioritized improved access to scientific data and results collected through federally funded research. Our VA Cooperative Studies Program Epidemiology Center in Durham, North Carolina (CSPEC-Durham) assembled a repository of data and specimens collected through multiple studies on Veteran health issues to facilitate future research in these areas. We developed a single protocol, request process that includes scientific and ethical review of all applications, and a database architecture using metadata (common variable descriptors) to securely store and share data across diverse studies. In addition, we created a mechanism to allow data and specimens collected through older studies in which re-use was not addressed in the study protocol or consent forms to be shared if the future research is within the scope of the original consent. Our CSPEC-Durham Data and Specimen Repository currently includes research data, genomic data, and study specimens (e.g., DNA, blood) for three content areas: colorectal cancer, amyotrophic lateral sclerosis, and Gulf War research. The linking of the study specimens and research data can support additional genetic analyses and related research to improve Veterans' health.

Biological measures and diagnostic tools for Gulf War Illness - A systematic review.

AIMS: Gulf War Illness (GWI) is a chronic multisymptom illness with debated etiology and pathophysiology. This systematic review catalogues studies of validated biological tests for diagnosing GWI and of associations between biological measures and GWI for their promise as biomarkers. MAIN METHODS: We searched multiple sources through February 2020 for studies of diagnostic tests of GWI and of associations between biological measures and GWI. We abstracted data on study design, demographics, and outcomes. We assessed the risk of bias of included studies. KEY FINDINGS: We did not identify any studies validating tests of biomarkers that distinguish cases of GWI from non-cases. We included the best-fitting studies, 32 completed and 24 ongoing or unpublished studies, of associations between GWI and biological measures. The less well-fitting studies (n = 77) were included in a Supplementary Table. Most studies were of the central nervous and immune systems and indicated a significant association of the biological measure with GWI case status. Biological measures were heterogeneous across studies. SIGNIFICANCE: Our review indicates that there are no existing validated biological tests to determine GWI case status. Many studies have assessed the potential association between a variety of biological measures and GWI, the majority of which pertain to the immune and central nervous systems. More importantly, while most studies indicated a significant association between biological measures and GWI case status, the biological measures across studies were extremely heterogeneous. Due to the heterogeneity, the focus of the review is to map out what has been examined, rather than synthesize information.

The Interaction of Vitamin D and Corticosteroids: A Mortality Analysis of 26,508 Veterans Who Tested Positive for SARS-CoV-2.

This data-based cohort consisted of 26,508 (7%) United States veterans out of the 399,290 who tested positive for SARS-CoV-2 from 1 March to 10 September 2020. We aimed to assess the interaction of post-index vitamin D (Vit D) and corticosteroid (CRT) use on 30-day mortality among hospitalized and non-hospitalized patients with coronavirus disease 2019 (COVID-19). Combination Vit D and CRT drug use was assessed according to four multinomial pairs (-|+, -|-, +|+, +|-). Respective categorical effects were computed on a log-binomial scale as adjusted relative risk (aRR). Approximately 6% of veterans who tested positive for SARS-CoV-2 died within 30 days of their index date. Among hospitalized patients, a significantly decreased aRR was observed for the use of Vit D in the absence of CRTs relative to patients who received CRTs but not Vit D (aRR = 0.30; multiplicity corrected, p = 0.0004). Among patients receiving systemically administered CRTs (e.g., dexamethasone), the use of Vit D was associated with fewer deaths in hospitalized patients (aRR = 0.51) compared with non-hospitalized patients (aRR = 2.5) (P-for-Interaction = 0.0071). Evaluating the effect of modification of these compounds in the context of hospitalization may aid in the management of COVID-19 and provide a better understanding of the pathophysiological mechanisms underlying this and future infectious disease outbreaks.

A Systematic Review of Therapeutic Interventions and Management Strategies for Gulf War Illness.

INTRODUCTION: After the 1990 to 1991 conflict in the Persian Gulf, many Gulf War Veterans began reporting numerous unexplained symptoms including, but not limited to, systemic pain, fatigue, flu-like symptoms, and difficulty with memory/concentration. These symptom clusters are now referred to as Gulf War Illness (GWI). Although the etiology of GWI is still debated, as many as 250,000 former service members have been continually suffering from GWI since 1991, making the need for treatment urgent. A broad variety of treatments have been considered for GWI, but there has not been a broad and comprehensive assessment of what is known and not known about GWI treatment. We conducted a systematic review to catalogue the types of treatments that have been examined for GWI, to evaluate the effectiveness and harms of these interventions, and to identify promising and ongoing areas of future GWI treatment research. MATERIALS AND METHODS: We searched electronic databases, trial registries, and reference lists through September 2019 for randomized controlled trial and nonrandomized controlled trial and cohort studies directly comparing interventions for Veterans with GWI to each other, placebo, or usual care. We abstracted data on study design, demographics, interventions, and outcomes. Two reviewers independently assessed studies for inclusion, quality, and strength of evidence (SOE) using prespecified criteria. We resolved discordant ratings by discussion and consensus. RESULTS: We identified 12 randomized controlled trials, each of which examined a different intervention for GWI. We found moderate SOE that cognitive behavioral therapy and exercise, separately and in combination, were associated with improvements in several GWI symptom domains. There was low SOE of benefit from two mindfulness-based interventions and continuous positive airway pressure (CPAP). Mindfulness-based stress reduction improved pain, cognitive functioning, fatigue, depression, and posttraumatic stress disorder (PTSD), whereas mind-body bridging improved fatigue, depression, posttraumatic stress disorder, and sleep, although pain and other outcomes did not improve. Continuous positive airway pressure improved overall physical health, pain, cognitive functioning, fatigue, mental health, and sleep quality in a small study of Veterans with sleep-disordered breathing and GWI. We found moderate SOE that doxycycline is ineffective for GWI in mycoplasma DNA-positive Veterans and increases the risk of adverse events compared with placebo. We also found 33 ongoing, single-arm pilot, or unpublished studies examining a variety of interventions. CONCLUSION: Cognitive behavioral therapy (moderate SOE), exercise (moderate SOE), and mindfulness-based interventions (low SOE) may be effective in improving several symptom domains in patients with GWI. Doxycycline was ineffective and associated with harms (moderate SOE). Larger, more rigorous studies are needed to confirm the benefits found in completed trials. A wide array of treatments are being assessed in ongoing trials. A sufficient evidence base will need to be developed to guide clinicians about which treatments are most likely to be effective in clinical practice and which treatments should be avoided.