Bioenergetic impairment in Gulf War illness assessed via 31P-MRS.

Time for post-exercise phosphocreatine-recovery (PCr-R), deemed a robust index of mitochondrial function in vivo, was previously reported to be elevated (signifying impaired ATP production) in veterans with Gulf War illness (GWI). Here we sought to replicate the finding and assess the impact of contravening previous eligibility requirements. The replication sample comprised white males. Cases reported ≥ moderate muscle-weakness to match the organ assessed to an organ affected; controls lacked recent headache or multiple symptoms. The expansion sample added cases without muscle-weakness, controls with recent headache, females, nonwhites. PCr-R, following pedal-depression-exercise, was compared in veterans with GWI versus controls (sample N = 38). In the replication sample, PCr-R results closely matched the prior report: PCr-R veterans with GWI mean(SD) = 47.7(16.5); control mean(SD) = 30.3(9.2), p = 0.017. (Prior-study PCr-R veterans with GWI mean(SD) = 46.1(17.9), control mean(SD) = 29.0(8.7), p = 0.023. Combined replication + prior samples: p = 0.001.) No case-control difference was observed in the expansion sample. In cases, PCr-R related to muscle-weakness: PCr-R = 29.9(7.1), 38.2(8.9), 47.8(15.2) for muscle-weakness rated none/low, intermediate, and high respectively (p for trend = 0.02), validating desirability of matching tissue assessed to tissue affected. In controls, headache/multiple symptoms, sex, and ethnicity each mattered (affecting PCr-R significantly). This study affirms mitochondrial/bioenergetic impairment in veterans with GWI. The importance of careful case/control selection is underscored.

Is Gulf War Illness a prolonged early phase tauopathy?

The work of the Gulf War Illness (GWI) Consortium and that of basic and clinical researchers across the USA have resulted in a better understanding in recent years of the pathological basis of GWI, as well as of the mechanisms underlying the disorder. Among the most concerning symptoms suffered by veterans with GWI are cognitive decrements including those related to memory functioning. These decrements are not severe enough to meet dementia criteria, but there is significant concern that the mild cognitive impairment of these veterans will progress to dementia as they become older. Recent studies on GWI using human brain organoids as well as a rat model suggest that one potential cause of the cognitive problems may be elevated levels of tau in the brain, and this is supported by high levels of tau autoantibodies in the blood of veterans with GWI. There is urgency in finding treatments and preventive strategies for these veterans before they progress to dementia, with added value in doing so because their current status may represent an early phase of tauopathy common to many neurodegenerative diseases.

The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness.

BACKGROUND: Since 1997, research on Gulf War illness (GWI) has predominantly used 3 case definitions-the original Research definition, the CDC definition, and modifications of the Kansas definition-but they have not been compared against an objective standard. METHODS: All 3 case definitions were measured in the U.S. Military Health Survey by a computer-assisted telephone interview in a random sample (n = 6,497) of the 1991 deployed U.S. military force. The interview asked whether participants had heard nerve agent alarms during the conflict. A random subsample (n = 1,698) provided DNA for genotyping the PON1 Q192R polymorphism. RESULTS: The CDC and the Modified Kansas definition without exclusions were satisfied by 41.7% and 39.0% of the deployed force, respectively, and were highly overlapping. The Research definition, a subset of the others, was satisfied by 13.6%. The majority of veterans meeting CDC and Modified Kansas endorsed fewer and milder symptoms; whereas, those meeting Research endorsed more symptoms of greater severity. The group meeting Research was more highly enriched with the PON1 192R risk allele than those meeting CDC and Modified Kansas, and Research had twice the power to detect the previously described gene-environment interaction between hearing alarms and RR homozygosity (adjusted relative excess risk due to interaction [aRERI] = 7.69; 95% CI 2.71-19.13) than CDC (aRERI = 2.92; 95% CI 0.96-6.38) or Modified Kansas without exclusions (aRERI = 3.84; 95% CI 1.30-8.52) or with exclusions (aRERI = 3.42; 95% CI 1.20-7.56). The lower power of CDC and Modified Kansas relative to Research was due to greater false-positive disease misclassification from lower diagnostic specificity. CONCLUSIONS: The original Research case definition had greater statistical power to detect a genetic predisposition to GWI. Its greater specificity favors its use in hypothesis-driven research; whereas, the greater sensitivity of the others favor their use in clinical screening for application of future diagnostic biomarkers and clinical care.

Treatment and life goals among veterans with Gulf War illness.

Medically unexplained syndromes (MUS), also termed persistent physical symptoms, are both prevalent and disabling. Yet treatments for MUS are marked by high rates of patient dissatisfaction, as well as disagreement between patients and providers on the management of persistent physical symptoms. A better understanding of patient-generated goals could increase collaborative goal setting and promote person-centered care, a critical component of MUS treatment; yet research in this area is lacking. This paper aimed to develop a typology of treatment and life goals among Gulf War veterans with a medically unexplained syndrome (Gulf War Illness). We examined participants' responses to open-ended questions about treatment and life goals using Braun and Clarke's thematic analysis methodology. Results showed that treatment goals could be categorized into four overarching themes: 1) Get better/healthier, 2) Improve quality of life, 3) Improve or seek additional treatment, and 4) Don't know/Don't have any. Life goals were categorized into six overarching themes: 1) Live a fulfilling life, 2) Live a happy life, 3) Live a healthy life, 4) Be productive/financially successful, 5) Manage GWI, and 6) Don't know/Don't have any. Treatment goals were largely focused on getting better/healthier (e.g., improving symptoms), whereas life goals focused on living a fulfilling life. Implications for the treatment of Gulf War Illness and patient-provider communication are discussed. ClinicalTrials.gov Identifier: NCT02161133.

Ocular and inflammatory markers associated with Gulf War illness symptoms.

To examine the utility of ocular coherence tomography (OCT) metrics, in conjunction with systemic markers of inflammation, in identifying individuals with Gulf War Illness (GWI) symptoms. Prospective case-control study of 108 Gulf War Era veterans, split into 2 groups based on the presence of GWI symptoms, defined by the Kansas criteria. Information on demographics, deployment history, and co-morbidities were captured. 101 individuals underwent OCT imaging and 105 individuals provided a blood sample which was analyzed for inflammatory cytokines using an enzyme-linked immunosorbent assay-based chemiluminescent assay. The main outcome measure was predictors of GWI symptoms, examined with multivariable forward stepwise logistic regression analysis followed by receiver operating characteristic (ROC) analysis. The mean age of the population was 55 ± 4, 90.7% self-identified as male, 53.3% as White, and 54.3% as Hispanic. A multivariable model that considered demographics and co-morbidities found that a lower inferior temporal ganglion cell layer-inner plexiform layer (GCL‒IPL) thickness, higher temporal nerve fiber layer (NFL) thickness, lower interleukin (IL)-1ß levels, higher IL-1α levels, and lower tumor necrosis factor-receptor I levels correlated with GWI symptoms. ROC analysis demonstrated an area under the curve of 0.78 with the best cut-off value for the prediction model having a sensitivity of 83% and specificity of 58%. RNFL and GCL‒IPL measures, namely increased temporal thickness and decreased inferior temporal thickness, respectively, in conjunction with a number of inflammatory cytokines, had a reasonable sensitivity for the diagnosis of GWI symptoms in our population.

Examining the association between the gastrointestinal microbiota and Gulf War illness: A prospective cohort study.

Gulf War Illness (GWI) affects 25-35% of the 1991 Gulf War Veteran (GWV) population. Patients with GWI experience pain, fatigue, cognitive impairments, gastrointestinal dysfunction, skin disorders, and respiratory issues. In longitudinal studies, many patients with GWI have shown little to no improvement in symptoms since diagnosis. The gut microbiome and diet play an important role in human health and disease, and preliminary studies suggest it may play a role in GWI. To examine the relationship between the gut microbiota, diet, and GWI, we conducted an eight-week prospective cohort study collecting stool samples, medications, health history, and dietary data. Sixty-nine participants were enrolled into the study, 36 of which met the case definition for GWI. The gut microbiota of participants, determined by 16S rRNA sequencing of stool samples, was stable over the duration of the study and showed no within person (alpha diversity) differences. Between group analyses (beta diversity) identified statistically significant different between those with and without GWI. Several taxonomic lineages were identified as differentially abundant between those with and without GWI (n = 9) including a greater abundance of Lachnospiraceae and Ruminococcaceae in those without GWI. Additionally, there were taxonomic differences between those with high and low healthy eating index (HEI) scores including a greater abundance of Ruminococcaceae in those with higher HEI scores. This longitudinal cohort study of GWVs found that participants with GWI had significantly different microbiomes from those without GWI. Further studies are needed to determine the role these differences may play in the development and treatment of GWI.

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness.

BACKGROUND: Nearly 250,000 veterans from the 1990-1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. METHODS: Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. RESULTS: An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. CONCLUSION: Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

The impact of post-traumatic stress on quality of life and fatigue in women with Gulf War Illness.

BACKGROUND: Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder characterized by fatigue, muscle pain, cognitive problems, insomnia, rashes, and gastrointestinal issues affecting an estimated 30% of the ~ 750,000 returning military Veterans of the 1990-1991 Persian Gulf War. Female Veterans deployed to combat in this war report medical symptoms, like cognition and respiratory troubles, at twice the rate compared to non-deployed female Veterans of the same era. The heterogeneity of GWI symptom presentation complicates diagnosis as well as the identification of effective treatments. This is exacerbated by the presence of co-morbidities. Defining subgroups of the illness may help alleviate these complications. One clear grouping is along the lines of gender. Our aim is to determine if women with GWI can be further subdivided into distinct subgroups based on post-traumatic stress disorder (PTSD) symptom presentation. METHODS: Veterans diagnosed with GWI (n = 35) and healthy sedentary controls (n = 35) were recruited through the Miami Veterans Affairs Medical Health Center. Symptoms were assessed via the RAND short form health survey, the multidimensional fatigue inventory, and the Davidson trauma scale. Hierarchal regression modeling was performed on measures of health and fatigue with PTSD symptoms as a covariate. This was followed by univariate analyses conducted with two separate GWI groups based on a cut-point of 70 for their total Davidson trauma scale value and performing heteroscedastic t-tests across all measures. RESULTS: Based on the distinct differences found in PTSD symptomology regarding all health and trauma symptoms, two subgroups were derived within female GWI Veterans. Hierarchical regression models displayed the comorbid effects of GWI and PTSD, as both conditions had measurable impacts on quality of life and fatigue (ΔR2 = 0.08-0.672), with notable differences in mental and emotional measures. Overall, a cut point analysis indicated poorer quality of life and greater fatigue within all measures for women with GWI and PTSD symptoms in comparison to those women with GWI without PTSD symptoms and healthy controls. CONCLUSIONS: Our current findings support the understanding that comorbid symptoms of GWI and PTSD subsequently result in poorer quality of life and fatigue, along with establishing the possibility of varying clinical presentations.

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.

Research tool for classifying Gulf War illness using survey responses: Lessons for writing replicable algorithms for symptom-based conditions.

AIMS: Gulf War illness (GWI), a chronic symptom-based disorder, affects up to 30% of Veterans who served in the 1990-1991 Gulf War1. Because no diagnostic test or code for GWI exists, researchers typically determine case status using self-reported symptoms and conditions according to Kansas2 and CDC3 criteria. No validated algorithm has been published and case definitions have varied slightly by study. This paper aims to standardize the application of the original CDC and Kansas case definitions by defining a framework for writing reliable code for complex case definitions, implementing this framework on a sample of 1343 Gulf War Veterans (GWVs), and validating the framework by applying the code to a sample of 41,077 GWVs. MAIN METHODS: Methods were drawn from software engineering: write pseudocode, write test cases, and write code; then test code. Code was examined for accuracy, flexibility, replicability, and reusability. KEY FINDINGS: The pseudocode promoted understanding of the planned algorithm, encouraging discussion and leading to agreement on the case definition algorithms among all team members. The completed SAS code was written for and tested in the Gulf War Era Cohort and Biorepository (GWECB)4. This code was adapted and tested in the Million Veteran Program (MVP)5. The code was documented for reproducibility and reusability. SIGNIFICANCE: Ease of reuse suggests that this method could be used to standardize the application of other case definitions, reducing time and resources spent by each study team. Documentation, code, and test cases are available through the Department of Veterans Affairs (VA) Phenomics catalog6.

Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC): A collaborative research infrastructure for intervention and implementation.

AIMS: There is an inadequate portfolio of treatments for Gulf War Illness (GWI), a complex disease involving multiple organ systems, and early-phase clinical trials are hampered by many logistical problems. To address these challenges, the Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC) was formed with the aims of (i) creating a collaborative consortium of clinical and scientific researchers that will rapidly implement rigorous and innovative phase I and II clinical trials for GWI, (ii) perform at least four phase I or II clinical trials, (iii) provide a foundation of scalable infrastructure and management in support of the efficient and successful operation of the GWICTIC, and (iv) partner with the Boston Biorepository, Recruitment & Integrated Network for GWI and other GWI investigators to develop a common data element platform for core assessments and outcomes. MAIN METHODS: The GWICTIC brings together a multidisciplinary team of researchers at several institutions to provide scientific innovation, statistical and computational rigor, and logistical efficiency in the development and implementation of early-phase low-risk clinical trials for GWI. The GWICTIC core trials adhere to a Veteran-centered philosophy and focus on interventions with multiple mechanistic targets to maximize the likelihood of efficacy. To support rapid and efficient study startup and implementation across the GWI research community, the GWICTIC will share infrastructure with investigator-initiated research studies funded under separate mechanisms. SIGNIFICANCE: The GWICTIC will leverage the efficiencies of centralized research support and innovative trial designs to address several longstanding needs in the GWI interventions research community.

Gulf War illness in the Gulf War Era Cohort and Biorepository: The Kansas and Centers for Disease Control definitions.

AIMS: This study characterizes Gulf War Illness (GWI) among U.S. veterans who participated in the Gulf War Era Cohort and Biorepository (GWECB). MAIN METHODS: Mailed questionnaires were collected between 2014 and 2016. Self-reported GWI symptoms, symptom domain criteria, exclusionary diagnoses, and case status were examined based on the originally published Kansas and Centers for Disease Control (CDC) definitions in the GWECB cohort (n = 849 deployed to Gulf and n = 267 non-deployed). Associations among GWI and deployment status, demographic, and military service characteristics were examined using logistic regression. KEY FINDINGS: Among deployed veterans in our sample, 39.9% met the Kansas criteria and 84.2% met the CDC criteria for GWI. Relative to non-deployed veterans, deployed veterans had a higher odds of meeting four GWI case status-related measures including the Kansas symptom criteria (aOR = 2.05, 95% CI = 1.50, 2.80), Kansas GWI case status (aOR = 1.42, 95% CI = 1.05, 1.93), the CDC GWI case status (aOR = 1.57, 95% CI = 1.07, 2.29) and the CDC severe criteria (aOR = 2.67, 95% CI = 1.79, 3.99). Forty percent met the Kansas exclusionary criteria, with no difference by deployment status. Some symptoms were nearly universally endorsed. SIGNIFICANCE: This analysis provides evidence of a sustained, multisymptom illness in veterans who deployed to the Persian Gulf War compared to non-deployed Gulf War era veterans nearly 25 years later. Differences in symptoms attributed to GWI by deployment status have diminished since initial reports, suggesting the need to update GWI definitions to account for aging-related conditions and symptoms. This study provides a foundation for future efforts to establish a single GWI case definition and analyses that employ the biorepository.

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.

Ocular manifestations and biomarkers of Gulf War Illness in US veterans.

Gulf War Illness (GWI) is a multisystem disease with variable presentations, making diagnosis difficult. Non-invasive biomarkers would aid in disease diagnosis. We hypothesized that the eye could serve as a biomarker for GWI. We performed a retrospective case-control study using a sample of 1246 patients seen during a 5-month period in an optometry clinic. We identified veterans who were active duty during the Gulf War Era and either had a questionnaire-based diagnosis of GWI (cases) or did not (controls). Medical records were reviewed for eye and medical co-morbidities, medication use, and retinal macular and nerve fiber layer (NFL) thicknesses based on optical coherence tomography (OCT) images. Compared to controls (n = 85), individuals with GWI (n = 60) had a higher frequency of dry eye symptoms (50% vs 32.9%, p = 0.039). Multivariable analysis revealed average retinal NFL thickness (odds ratio; OR = 0.95), cup-to-disc ratio (OR = 0.005), age (OR = 0.82), and PTSD (OR = 20.5) were predictors of a GWI diagnosis. We conclude that GWI is associated with dry eye symptoms and RNFL thinning may serve as a biomarker for disease.

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome.

Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share many symptoms of fatigue, pain, and cognitive dysfunction that are not relieved by rest. Patterns of serum metabolites in ME/CFS and GWI are different from control groups and suggest potential dysfunction of energy and lipid metabolism. The metabolomics of cerebrospinal fluid was contrasted between ME/CFS, GWI and sedentary controls in 2 sets of subjects who had lumbar punctures after either (a) rest or (b) submaximal exercise stress tests. Postexercise GWI and control subjects were subdivided according to acquired transient postexertional postural tachycardia. Banked cerebrospinal fluid specimens were assayed using Biocrates AbsoluteIDQ® p180 kits for quantitative targeted metabolomics studies of amino acids, amines, acylcarnitines, sphingolipids, lysophospholipids, alkyl and ether phosphocholines. Glutamate was significantly higher in the subgroup of postexercise GWI subjects who did not develop postural tachycardia after exercise compared to nonexercise and other postexercise groups. The only difference between nonexercise groups was higher lysoPC a C28:0 in GWI than ME/CFS suggesting this biochemical or phospholipase activities may have potential as a biomarker to distinguish between the 2 diseases. Exercise effects were suggested by elevation of short chain acylcarnitine C5-OH (C3-DC-M) in postexercise controls compared to nonexercise ME/CFS. Limitations include small subgroup sample sizes and absence of postexercise ME/CFS specimens. Mechanisms of glutamate neuroexcitotoxicity may contribute to neuropathology and "neuroinflammation" in the GWI subset who did not develop postural tachycardia after exercise. Dysfunctional lipid metabolism may distinguish the predominantly female ME/CFS group from predominantly male GWI subjects.

An analysis of 2-day cardiopulmonary exercise testing to assess unexplained fatigue.

Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (2-day CPET protocol) are increasingly used to evaluate post-exertional malaise (PEM) and related disability among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This protocol may extend to other fatiguing illnesses with similar characteristics to ME/CFS; however, 2-day CPET protocol reliability and minimum change required to be considered clinically meaningful (i.e., exceeding the standard error of the measure) are not well characterized. To address this gap, we evaluated the 2-day CPET protocol in Gulf War Illness (GWI) by quantifying repeatability of seven CPET parameters, establishing their thresholds of clinically significant change, and determining whether changes differed between veterans with GWI and controls. Excluding those not attaining peak effort criteria (n = 15), we calculated intraclass correlation coefficients (ICCs), the smallest real difference (SRD%), and repeated measures analysis of variance (RM-ANOVA) at the ventilatory anaerobic threshold (VAT) and peak exercise in 15 veterans with GWI and eight controls. ICC values at peak ranged from moderate to excellent for veterans with GWI (mean [range]; 0.84 [0.65 - 0.92]) and were reduced at the VAT (0.68 [0.37 - 0.78]). Across CPET variables, the SRD% at peak exercise for veterans with GWI (18.8 [8.8 - 28.8]) was generally lower than at the VAT (28.1 [9.5 - 34.8]). RM-ANOVAs did not detect any significant group-by-time interactions (all p > .05). The methods and findings reported here provide a framework for evaluating 2-day CPET reliability, and reinforce the importance of carefully considering measurement error in the population of interest when interpreting findings.

Systemic Hyperalgesia in Females with Gulf War Illness, Chronic Fatigue Syndrome and Fibromyalgia.

Pain is a diagnostic criterion for Gulf War Illness (GWI), Chronic Fatigue Syndrome (CFS), and fibromyalgia (FM). The physical sign of systemic hyperalgesia (tenderness) was assessed in 920 women who were stratified by 2000 Kansas GWI, 1994 CFS, and 1990 FM criteria. Pressure was applied by dolorimetry at 18 traditional tender points and the average pressure causing pain determined. GWI women were the most tender (2.9 ± 1.6 kg, mean ± SD, n = 70), followed by CFS/FM (3.1 ± 1.4 kg, n = 196), FM (3.9 ± 1.4 kg, n = 56), and CFS (5.8 ± 2.1 kg, n = 170) compared to controls (7.2 ± 2.4 kg, significantly highest by Mann-Whitney tests p < 0.0001, n = 428). Receiver operating characteristics set pressure thresholds of 4.0 kg to define GWI and CFS/FM (specificity 0.85, sensitivities 0.80 and 0.83, respectively), 4.5 kg for FM, and 6.0 kg for CFS. Pain, fatigue, quality of life, and CFS symptoms were equivalent for GWI, CFS/FM and CFS. Dolorimetry correlated with symptoms in GWI but not CFS or FM. Therefore, women with GWI, CFS and FM have systemic hyperalgesia compared to sedentary controls. The physical sign of tenderness may complement the symptoms of the Kansas criteria as a diagnostic criterion for GWI females, and aid in the diagnosis of CFS. Molecular mechanisms of systemic hyperalgesia may provide new insights into the neuropathology and treatments of these nociceptive, interoceptive and fatiguing illnesses.

Gulf War Illness Symptom Severity and Onset: A Cross-Sectional Survey.

INTRODUCTION: Gulf War illness (GWI) affects 25 to 32% of the 693,826 veterans of the First Persian Gulf War. The etiology and pathophysiology of GWI remain controversial, but the condition is attributed to toxic exposures and stress in the deployed setting. The Kansas criteria used for GWI diagnosis highlight 37 symptoms that were more prevalent in deployed compared to nondeployed veterans. This study employed the Kansas criteria to identify recent symptom severity, assess the perceived burden of disease for veterans with GWI, and characterize disease course over the past three decades. MATERIALS AND METHODS: The Kansas criteria were operationalized into a questionnaire to provide a summary of symptom severity, approximate year of onset, and an aid for diagnosis. The online version of the questionnaire was completed by 485 veterans with GWI. Symptom data were grouped for analysis based on observed trends. This study received approval from the Georgetown University Institutional Review Board (IRB 2018-0430). RESULTS: Symptom severity for the past 6 months demonstrated a high burden of disease for veteran participants. Frequency analysis of total severity scores (out of 148) showed a unimodal distribution with a median score of 95 (1st quartile = 78, 3rd quartile = 110), minimum score of 19, and maximum of 146. Over 89% of respondents had moderate or severe fatigue, sleep disturbances, pain, and abdominal symptoms over the past 6 months. The veterans who participated in this study reported cumulative frequencies higher than those in a meta-analysis of 21 GWI large epidemiologic cross-sectional studies for symptoms around 1998. The cumulative frequency of symptoms indicated long duration of symptoms, although recall bias must be taken into consideration. CONCLUSIONS: This cross-sectional sample of self-selected veterans with GWI demonstrates a high current burden of disease and reveals symptom onset patterns. The information from this study can be used to better understand the long-term trajectory of GWI and be integrated into the treatment and diagnosis of impacted veterans. It can also be used as historical deployed health data and inform the future medical care of combat veterans experiencing health effects from war exposures.

Sex Differences in Gulf War Illness: A Reanalysis of Data From the CDC Air Force Study Using CDC and Modified Kansas Case Definitions.

OBJECTIVE: Estimate and compare the prevalence of Gulf War Illness (GWI) in male and female Gulf War veterans using Centers for Disease Control and Prevention (CDC) and modified Kansas case definitions. METHODS: Data from the landmark CDC Air Force Study of GW Air Force veterans is used. RESULTS: Nearly half of the deployed veterans met the GWI CDC case definition compared with 14% of non-deployed veterans. Only 29% met the definition using the modified Kansas criteria compared with 8% of non-deployed veterans. Deployed veterans and female veterans exhibited significantly higher GWI risk. Female GW veterans had higher rates of severe and mild-to-moderate cases of GWI. CONCLUSION: Results suggest increased GWI rates based on CDC and modified Kansas criteria among deployed and female veterans. Further research is needed to examine the chronic health outcomes of female GW veterans independently.