Olfactory and cognitive decrements in 1991 Gulf War veterans with gulf war illness/chronic multisymptom illness.

BACKGROUND: Gulf War illness (GWI)/Chronic Multisymptom Illness (CMI) is a disorder related to military service in the 1991 Gulf War (GW). Prominent symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI/CMI symptom, anecdotally some GW veterans have reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson's and Alzheimer's disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans. METHODS: Eighty deployed GW veterans (mean age: 59.9 ±7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from healthy control (HC) participants from the Parkinson's Progression Markers Initiative (PPMI) study were downloaded for comparison. RESULTS: GW veterans had a mean UPSIT score of 27.8 ± 6.3 (range 9-37) and a mean MoCA score of 25.3 ± 2.8 (range 19-30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman's ρ = 0.39, p < 0.001). There were no significant differences in UPSIT or MoCA scores between GW veterans with and without history of COVID or between those with and without Kansas GWI exclusionary conditions. CONCLUSIONS: We found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans, 99% of whom had CMI. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available.

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.

Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts.

BACKGROUND: During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community. METHODS: The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI. RESULTS: Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans. CONCLUSIONS: This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures.

Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.

BACKGROUND: Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years. METHODS: Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures. RESULTS: Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time. CONCLUSION: This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.

Stability of symptom patterns in Australian Gulf War veterans: 10-year longitudinal study.

OBJECTIVES: Previously we established that symptoms reported by 1990-1991 Gulf War veterans were correlated and exhibited a pattern with 3 factors (psychophysiological distress, somatic distress and arthroneuromuscular distress), and this pattern was similar to that observed in a military comparison group. In this follow-up study, we examined whether the patterns of symptomatology have changed over time. METHODS: Using data on 56 symptoms that was collected in 2000-2003 (wave 1) and 2011-2012 (wave 2) from an Australian cohort of Gulf War veterans (veterans) and a military comparison group, exploratory factor analysis was conducted and Tucker's Congruence Coefficient (TCC) was used to determine factor structure similarity across study groups and waves. RESULTS: The results showed that the 3 factors observed at wave 1 were still present at wave 2, and factor structures across study groups and study waves were fairly similar, with TCC ranging 0.86-0.92. Veterans consistently reported more symptoms across all 3 factors. Veterans' symptomatology specific to psychophysiological distress increased between waves 1 and 2 (ratio of means 1.15; 95% CI 1.07 to 1.25) but psychophysiological distress symptomatology was constant in the comparison group (ratio of means 0.97; 95% CI 0.89 to 1.06). Somatic and arthroneuromuscular distress symptomatology significantly increased over time for both study groups, although at a similar rate. CONCLUSIONS: While the symptom groupings (measured by the 3 factors) remained unchanged at 10 years of follow-up, and remained comparable between Gulf War and comparison group, symptomatology continued to be elevated in Gulf War veterans than in the comparison group, and was most evident for psychophysiological distress.

Gulf War Illness: Challenges Persist.

It has been more than 20 years since the United States and coalition forces entered Kuwait and Iraq. Actual combat was of remarkably short duration: less than 1 week of sustained ground activity and 6 weeks of air missions. Thus, it was surprising when approximately 200,000 returning US veterans were affected by a chronic multi-symptom illness that came to be known as Gulf War Illness (GWI). There were many challenges in investigating GWI, not least of which was that it took several years before the condition was officially taken seriously. There were multiple exposures to potentially causal agents on and off the battlefield, but these exposures were documented incompletely if at all, leaving epidemiologists to rely on self-report for information. In the past 2 years, significant controversy has arisen over the future directions of the field. Despite these challenges, several studies have implicated exposure to acetylcholinesterase inhibitors such as pyridostigmine bromide in the genesis of the condition. The story of GWI can inform research into other conditions and guide future work on veterans' health.

Increased symptom reporting persists in 1990-1991 Gulf War veterans 20 years post deployment.

BACKGROUND: Following the 1990-1991 Gulf War, Gulf War veterans (veterans) reported health symptoms more commonly than non-deployed groups. This article examines symptom persistence, incidence and prevalence 20 years on. METHODS: In 2000-2003 and 2011-2012, a 63-item symptom checklist was administered to 697 veterans and 659 comparison group. Symptomatology was compared using log-binomial regression. RESULTS: Both veterans and comparison group reported significantly increased prevalence (3-52%) over time in more than half the symptoms, with a similar overall rate of increase. Half the symptoms had higher incidence (risk-ratios ranged 1.43-1.50) and a quarter were more persistent (risk-ratios ranged 1.12-1.20) in veterans than the comparison group. CONCLUSIONS: Symptomatology increased in both groups over time, but persisted to a similar extent and had higher incidence among veterans than the comparison group. The gap in symptom prevalence between the two groups remained unchanged. These findings suggest enduring health consequences of Gulf War service.

Susceptibility to radiation adverse effects in veterans with Gulf War illness and healthy civilians.

We evaluated whether veterans with Gulf War illness (VGWI) report greater ionizing radiation adverse effects (RadAEs) than controls; whether radiation-sensitivity is tied to reported chemical-sensitivity; and whether environmental exposures are apparent risk factors for reported RadAEs (rRadAEs). 81 participants (41 VGWI, 40 controls) rated exposure to, and rRadAEs from, four radiation types. The relations of RadAE-propensity (defined as the ratio of rRadAEs to summed radiation exposures) to Gulf War illness (GWI) presence and severity, and to reported chemical-sensitivity were assessed. Ordinal logistic regression evaluated exposure prediction of RadAE-propensity in the full sample, in VGWI, and stratified by age and chemical-sensitivity. RadAE-propensity was increased in VGWI (vs. controls) and related to GWI severity (p < 0.01) and chemical-sensitivity (p < 0.01). Past carbon monoxide (CO) exposure emerged as a strong, robust predictor of RadAE-propensity on univariable and multivariable analyses (p < 0.001 on multivariable assessment, without and with adjustment for VGWI case status), retaining significance in age-stratified and chemical-sensitivity-stratified replication analyses. Thus, RadAE-propensity, a newly-described GWI-feature, relates to chemical-sensitivity, and is predicted by CO exposure-both features reported for nonionizing radiation sensitivity, consistent with shared mitochondrial/oxidative toxicity across radiation frequencies. Greater RadAE vulnerability fits an emerging picture of heightened drug/chemical susceptibility in VGWI.

Epidemiologic evidence of health effects from long-distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War.

BACKGROUND: Military intelligence data published in a companion paper explain how chemical fallout from US and Coalition bombing of Iraqi chemical weapons facilities early in the air campaign transited long distance, triggering nerve agent alarms and exposing US troops. We report the findings of a population-based survey designed to test competing hypotheses on the impact on chronic Gulf War illness of nerve agent from early-war bombing versus post-war demolition. METHODS: The US Military Health Survey performed computer-assisted telephone interviews of a stratified random sample of Gulf War-era veterans (n = 8,020). Early-war exposure was measured by having heard nerve agent alarms and post-war exposure, by the computer-generated plume from the Khamisiyah demolition. Gulf War illness was measured by two widely published case definitions. RESULTS: The OR (95% CI) for the association of alarms with the Factor case definition was 4.13 (95% CI 2.51-6.80) compared with 1.21 (95% CI 0.86-1.69) for the Khamisiyah plume. There was a dose-related trend for the number of alarms (p(trend) < 0.001) but not for the number of days in the Khamisiyah plume (p(trend) = 0.17). CONCLUSIONS: Exposure to low-level sarin nerve agent in fallout from bombing early in the air campaign contributed more to chronic illness than post-war demolition.

Women of the Gulf War: Understanding Their Military and Health Experiences Over 30 Years.

INTRODUCTION: Women Veterans of the Persian Gulf War (GW) expanded the military roles they had filled in previous military eras, with some women engaging in direct combat for the first time. Many GW service members, including women, had unique combat exposures to hazardous agents during deployment, which might have contributed to the development of chronic health problems. This study aims to understand the experiences of women GW Veterans (GWVs) as it is related to their military service and subsequent health in order to better inform and improve their clinical care. MATERIALS AND METHODS: We conducted in-depth interviews with 10 women GWVs to understand their experiences and perspectives about how their military service in the Gulf has impacted their lives and health. We used an integrated approach of content analysis and inductive thematic analysis to interpret interview data. RESULTS: Besides having many of the same war-related exposures as men, women faced additional challenges in a military that was inadequately prepared to accommodate them, and they felt disadvantaged as women within the military and local culture. After service, participants had emergent physical and mental health concerns, which they described as developing into chronic and complex conditions, affecting their relationships and careers. While seeking care and service connection at Veterans Health Administration (VA), women voiced frustration over claim denials and feeling dismissed. They provided suggestions of how VA services could be improved for women and GWVs. Participants found some nonpharmacological approaches for symptom management and coping strategies to be helpful. CONCLUSIONS: Women in the GW encountered challenges in military and healthcare systems that were inadequately prepared to address their needs. Women faced chronic health conditions common to GWV and voiced the desire to be understood as a cohort with unique needs. There is an ongoing need to expand services within the VA for women GWVs, particularly involving psychosocial support and management of chronic illness. While the small sample size can limit generalizability, the nature of these in-depth, minimally guided interviews provides a rich narrative of the women GWVs in this geographically diverse sample.

The Gulf War Illness and the Iraqi Population's Forgotten Pain and Suffering.

Exposure to chemical warfare agents results in long-term biopsychosocial complaints. A recent study has revealed an association between exposure to a low dose of Sarin and Gulf War illness in American veterans from the Gulf War. The prevalence of Gulf War illness has not been studied in the Iraqi population. In light of recent research results, Iraqi chemical warfare agent survivors' multiple physical and mental illnesses should be highlighted. For this reason, establishing both legislation and medical commissions is most needed.

Association of Atherosclerotic Cardiovascular Disease, Hypertension, Diabetes, and Hyperlipidemia With Gulf War Illness Among Gulf War Veterans.

BACKGROUND: Approximately 30% of the 700 000 Gulf War veterans report a chronic symptom-based illness of varying severity referred to as Gulf War illness (GWI). Toxic deployment-related exposures have been implicated in the cause of GWI, some of which contribute to metabolic dysregulation and lipid abnormalities. As this cohort ages, the relationship between GWI and atherosclerotic cardiovascular disease (ASCVD) is a growing concern. We evaluated associations between GWI and ASCVD, diabetes, hyperlipidemia, and hypertension in veterans of the Gulf War (1990-1991). METHODS AND RESULTS: Analysis of survey data collected in 2014 to 2016 from a national sample of deployed Gulf War veterans (n=942) and Veterans Health Administration electronic health record data (n=669). Multivariable logistic regression models tested for associations of GWI with self-reported ASCVD, diabetes, hyperlipidemia, and hypertension, controlling for confounding factors. Separate models tested for GWI associations with ASCVD and risk factors documented in the electronic health record. GWI was associated with self-reported hypertension (adjusted odds ratio [aOR], 1.67 [95% CI, 1.18-2.36]), hyperlipidemia (aOR, 1.46 [95% CI, 1.03-2.05]), and ASCVD (aOR, 2.65 [95% CI, 1.56-4.51]). In the subset of veterans with electronic health record data, GWI was associated with documented diabetes (aOR, 2.34 [95% CI, 1.43-3.82]) and hypertension (aOR, 2.84 [95% CI, 1.92-4.20]). Hyperlipidemia and hypertension served as partial mediators of the association between GWI and self-reported ASCVD. CONCLUSIONS: Gulf War veterans with GWI had higher odds of hyperlipidemia, hypertension, diabetes, and ASCVD compared with Gulf War veterans without GWI. Further examination of the mechanisms underlying this association, including a possible shared exposure-related mechanism, is necessary.

Association of Gulf War Illness with Characteristics in Deployed vs. Non-Deployed Gulf War Era Veterans in the Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis.

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx-], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx-, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

Health-Related Quality of Life by Gulf War Illness Case Status.

This study examines how health-related quality of life (HRQOL) and related indices vary by Gulf War illness (GWI) case status. The study population included veterans from the Gulf War Era Cohort and Biorepository (n = 1116). Outcomes were physical and mental health from the Veterans RAND 12 and depression, post-traumatic stress (PTSD), sleep disturbance, and pain. Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions were used. Kansas GWI derived subtypes included GWI (met symptom criteria; no exclusionary conditions (KS GWI: Sym+/Dx−)) and those without GWI: KS noncase (1): Sym+/Dx+, KS noncase (2): Sym−/Dx+, and noncase (3): Sym−/Dx−. CDC-derived subtypes included CDC GWI severe, CDC GWI mild-to-moderate and CDC noncases. Case status and outcomes were examined using multivariable regression adjusted for sociodemographic and military-related characteristics. Logistic regression analysis was used to examine associations between GWI case status and binary measures for depression, PTSD, and severe pain. The KS GWI: Sym+/Dx− and KS noncase (1): Sym+/Dx+ groups had worse mental and physical HRQOL outcomes than veterans in the KS noncase (2): Sym−/Dx+ and KS noncase (3): Sym−/Dx− groups (ps < 0.001). Individuals who met the CDC GWI severe criteria had worse mental and physical HRQOL outcomes than those meeting the CDC GWI mild-to-moderate or CDC noncases (ps < 0.001). For other outcomes, results followed a similar pattern. Relative to the less symptomatic comparison subtypes, veterans who met the Kansas symptom criteria, regardless of exclusionary conditions, and those who met the CDC GWI severe criteria experienced lower HRQOL and higher rates of depression, PTSD, and severe pain.

Complementary/integrative healthcare utilization in US Gulf-War era veterans: Descriptive analyses based on deployment history, combat exposure, and Gulf War Illness.

Complementary and integrative health (CIH) approaches have gained empirical support and are increasingly being utilized among veterans to treat a myriad of conditions. A cluster of medically unexplained chronic symptoms including fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems, often referred to as Gulf War Illness (GWI) prominently affect US Gulf War era (GWE) veterans, yet little is known about CIH use within this population. Using data collected as part of a larger study (n = 1153), we examined the influence of demographic characteristics, military experiences, and symptom severity on CIH utilization, and utilization differences between GWE veterans with and without GWI. Over half of the sample (58.5%) used at least one CIH modality in the past six months. Women veterans, white veterans, and veterans with higher levels of education were more likely to use CIH. GWE veterans with a GWI diagnosis and higher GWI symptom severity were more likely to use at least one CIH treatment in the past six months. Over three quarters (82.7%) of veterans who endorsed using CIH to treat GWI symptoms reported that it was helpful for their symptoms. Almost three quarters (71.5%) of veterans indicated that they would use at least one CIH approach if it was available at VA. Results provide a deeper understanding of the likelihood and characteristics of veterans utilizing CIH to treat health and GWI symptoms and may inform expansion of CIH modalities for GWE veterans, particularly those with GWI.

Evaluation of a Gene-Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case-Control Study Drawn from the U.S. Military Health Survey's National Population Sample.

BACKGROUND: Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias. OBJECTIVES: We investigated a prestated hypothesis of the association of GWI with a gene-environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure. METHODS: A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment. RESULTS: The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18; 95% CI: 0.81, 1.73; p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine. DISCUSSION: Given gene-environment independence and monotonicity, the unconfounded aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009.

Dry Eye Symptoms and Signs in US Veterans With Gulf War Illness.

PURPOSE: To examine dry eye (DE) symptoms and signs in individuals with vs without Gulf War illness (GWI). DESIGN: Prospective cross-sectional study. METHODS: We performed a prospective, cross-sectional study of South Florida veterans who were active duty during the Gulf War era (GWE; 1990-1991) and seen at an eye clinic between October 1, 2020, and March 13, 2021. Veterans were split into 2 groups: those who met Kansas criteria for GWI (cases, n = 30) and those who did not (controls, n = 41). DE symptoms were assessed via standardized questionnaires whereas DE signs were assessed using a series of ocular surface parameters. Differences between groups were assessed via Mann-Whitney U test. Linear regression analyses were used to examine which GWI symptoms most closely aligned with DE symptoms. RESULTS: Veterans with GWI had higher DE symptoms scores compared to controls (Ocular Surface Disease Index [OSDI] scores: mean 41.20±22.92 vs 27.99±24.03, P = .01). In addition, veterans with GWI had higher eye pain scores compared with controls (average eye pain over past week: 2.63±2.72 vs 1.22±1.50, P = .03), including on neuropathic ocular pain questionnaires (Neuropathic Pain Symptom Inventory modified for the Eye [NPSI-E]: 17.33±17.20 vs 9.63±12.64, P = .03). DE signs were mostly similar between the groups. GWI symptoms "nausea or upset stomach" (ß=14.58, SE = 3.02, P < .001) and "headache" (ß=7.90, SE = 2.91, P = .011) correlated with higher OSDI scores. CONCLUSION: Individuals with GWI have more severe DE symptoms and ocular pain scores but similar tear and ocular surface parameters compared to controls without GWI. This finding suggests that mechanisms beyond tear dysfunction drive eye symptoms in GWI.

Validation of a research case definition of Gulf War illness in the 1991 US military population.

BACKGROUND: A case definition of Gulf War illness with 3 primary variants, previously developed by factor analysis of symptoms in a US Navy construction battalion and validated in clinic veterans, identified ill veterans with objective abnormalities of brain function. This study tests prestated hypotheses of its external validity. METHODS: A stratified probability sample (n = 8,020), selected from a sampling frame of the 3.5 million Gulf War era US military veterans, completed a computer-assisted telephone interview survey. Application of the prior factor weights to the subjects' responses generated the case definition. RESULTS: The structural equation model of the case definition fit both random halves of the population sample well (root mean-square error of approximation = 0.015). The overall case definition was 3.87 times (95% confidence interval, 2.61-5.74) more prevalent in the deployed than the deployable nondeployed veterans: 3.33 (1.10-10.10) for syndrome variant 1; 5.11 (2.43-10.75) for variant 2, and 4.25 (2.33-7.74) for variant 3. Functional status on SF-12 was greatly reduced (effect sizes, 1.0-2.0) in veterans meeting the overall and variant case definitions. CONCLUSIONS: The factor case definition applies to the full Gulf War veteran population and has good characteristics for research.

A US-UK comparison of health in 1990-1991 Gulf War veterans.

BACKGROUND: UK and US military personnel appear to have different health profiles yet direct comparisons of health status and deployment exposures between US and UK military populations have never been performed. AIMS: To compare US and UK military personnel deployed to the 1991 Persian Gulf War (PGW) for rates of symptom reporting, medical conditions and health status [Short Form-36 general health perception (GHP) and physical functioning (PF) subscales] and self-report military exposures. METHODS: We analysed representative cross-sectional samples of military personnel from the Iowa Persian Gulf Study (n = 3626) and the UK Health Survey of Military Personnel (n = 5573) that included directly comparable measures and stratified by those who had been deployed to PGW and those who had not been deployed to PGW. RESULTS: Although UK veterans had similar mean PF scores as US veterans (mean differences in PGW: 0.86, 95% CI -0.36 to 2.07 and in non-deployed -0.61, 95% CI -1.84 to 0.62), they had worse mean GHP scores (mean differences in PGW: -5.62, 95% CI -7.44 to -3.80 and in non-deployed -3.83, 95% CI -5.40 to -2.27). UK PGW veterans were more likely to report Gulf specific exposures, and this was associated with worse GHP (UK mean difference -9.05, 95% CI -11.49 to -6.61 versus US mean difference -4.30, 95% CI -6.62 to -1.98). CONCLUSIONS: This study observed transatlantic variations in health status in military populations that may reflect cultural differences in the reporting of health.