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.

Changes in Epidemiology of Acetaminophen Overdoses in an Urban County Hospital After 20 Years.

INTRODUCTION: Acetaminophen (APAP) toxicity is the main cause of acute liver failure in the United States. A prior series (1992-1995) identified 71 hospitalized adults with APAP toxicity through the International Statistical Classification of Disease and Related Health Problems, 9th revision (ICD-9) code at Parkland Hospital, Dallas, TX. METHODS: We used a laboratory database search of serum APAP levels from 2011 to 2015 to identify patients with APAP toxicity in the same hospital. RESULTS: We identified 140 patients hospitalized for APAP toxicity from 27,143 APAP levels obtained; 35 required Intensive Care Unit (ICU) admission, and there were no deaths. APAP toxicity/100,000 admissions was similar between eras. DISCUSSION: APAP toxicity continues unabated after 20 years but with improved overall outcomes.

Epidemiology and risk factors for varicella zoster virus reactivation in heart transplant recipients.

Heart transplant (HT) recipients are at higher risk of varicella zoster virus (VZV) reactivation. Risk factors for VZV reactivation are currently not well defined, impeding the ability to design and implement strategies to minimize the burden of this illness in this population. Automated data extraction tools were used to retrieve data from the electronic health record (EHR) of all adult HT recipients at our center between 2010 and 2016. Information from the Organ Procurement and Transplantation Network Standard Analysis and Research Files was merged with the extracted data. Potential cases were manually reviewed and adjudicated using consensus definitions. Cumulative incidence and risk factors for VZV reactivation in HT recipients were assessed by the Kaplan-Meier method and Cox modeling, respectively. In 203 HT recipients, the cumulative incidence of VZV reactivation at 8-years post-transplantation was 26.4% (95% CI: 17.8-38.0). The median time to VZV reactivation was 2.1 years (IQR, 1.5-4.1). Half (14/28) of the cases experienced post-herpetic neuralgia (PHN). Post-transplant CMV infection (HR 9.05 [95% CI: 3.76-21.77) and post-transplant pulse-dose steroids (HR 3.19 [95% CI: 1.05-9.68]) were independently associated with a higher risk of VZV reactivation in multivariable modeling. Identification of risk factors will aid in the development of targeted preventive strategies.

Pathophysiology and Molecular Imaging of Diabetic Foot Infections.

Diabetic foot infection is the leading cause of non-traumatic lower limb amputations worldwide. In addition, diabetes mellitus and sequela of the disease are increasing in prevalence. In 2017, 9.4% of Americans were diagnosed with diabetes mellitus (DM). The growing pervasiveness and financial implications of diabetic foot infection (DFI) indicate an acute need for improved clinical assessment and treatment. Complex pathophysiology and suboptimal specificity of current non-invasive imaging modalities have made diagnosis and treatment response challenging. Current anatomical and molecular clinical imaging strategies have mainly targeted the host's immune responses rather than the unique metabolism of the invading microorganism. Advances in imaging have the potential to reduce the impact of these problems and improve the assessment of DFI, particularly in distinguishing infection of soft tissue alone from osteomyelitis (OM). This review presents a summary of the known pathophysiology of DFI, the molecular basis of current and emerging diagnostic imaging techniques, and the mechanistic links of these imaging techniques to the pathophysiology of diabetic foot infections.

Identification of biologically active δ-lactone eicosanoids as paraoxonase substrates.

The mammalian paraoxonases (PONs 1, 2 and 3) are a family of esterases that are highly conserved within and between species. They exhibit antioxidant and anti-inflammatory activities. However, their physiological function(s) and native substrates are uncertain. Previous structure-activity relationship studies demonstrate that PONs have a high specificity for lipophilic lactones, suggesting that such compounds may be representative of native substrates. This report describes the ability of PONs to hydrolyze two bioactive δ-lactones derived from arachidonic acid, 5,6-dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) and cyclo-epoxycyclopentenone (cyclo-EC). Both lactones were very efficiently hydrolyzed by purified PON3. PON1 efficiently hydrolyzed 5,6-DHTL, but with a specific activity about 15-fold lower than PON3. 5,6-DHTL was a poor substrate for PON2. Cyclo-EC was a poor substrate for PON1 and not hydrolyzed by PON2. Studies with the PON inhibitor EDTA and a serine esterase inhibitor indicated that the PONs are the main contributors to hydrolysis of the lactones in human and mouse liver homogenates. Studies with homogenates from PON3 knockout mouse livers indicated that >80% of the 5,6-DHTL and cyclo-EC lactonase activities were attributed to PON3. The findings provide further insight into the structural requirements for PONs substrates and support the hypothesis that PONs, particularly PON1 and PON3, evolved to hydrolyze and regulate a class of lactone lipid mediators derived from polyunsaturated fatty acids.

Estimating the Health and Economic Impacts of Changes in Local Air Quality.

OBJECTIVES: To demonstrate the benefits-mapping software Environmental Benefits Mapping and Analysis Program-Community Edition (BenMAP-CE), which integrates local air quality data with previously published concentration-response and health-economic valuation functions to estimate the health effects of changes in air pollution levels and their economic consequences. METHODS: We illustrate a local health impact assessment of ozone changes in the 10-county nonattainment area of the Dallas-Fort Worth region of Texas, estimating the short-term effects on mortality predicted by 2 scenarios for 3 years (2008, 2011, and 2013): an incremental rollback of the daily 8-hour maximum ozone levels of all area monitors by 10 parts per billion and a rollback-to-a-standard ambient level of 65 parts per billion at only monitors above that level. RESULTS: Estimates of preventable premature deaths attributable to ozone air pollution obtained by the incremental rollback method varied little by year, whereas those obtained by the rollback-to-a-standard method varied by year and were sensitive to the choice of ordinality and the use of preloaded or imported data. CONCLUSIONS: BenMAP-CE allows local and regional public health analysts to generate timely, evidence-based estimates of the health impacts and economic consequences of potential policy options in their communities.

Self-Administered Outpatient Antimicrobial Infusion by Uninsured Patients Discharged from a Safety-Net Hospital: A Propensity-Score-Balanced Retrospective Cohort Study.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) is accepted as safe and effective for medically stable patients to complete intravenous (IV) antibiotics in an outpatient setting. Since, however, uninsured patients in the United States generally cannot afford OPAT, safety-net hospitals are often burdened with long hospitalizations purely to infuse antibiotics, occupying beds that could be used for patients requiring more intensive services. OPAT is generally delivered in one of four settings: infusion centers, nursing homes, at home with skilled nursing assistance, or at home with self-administered therapy. The first three-termed healthcare-administered OPAT (H-OPAT)--are most commonly used in the United States by patients with insurance funding. The fourth--self-administered OPAT (S-OPAT)--is relatively uncommon, with the few published studies having been conducted in the United Kingdom. With multidisciplinary planning, we established an S-OPAT clinic in 2009 to shift care of selected uninsured patients safely to self-administration of their IV antibiotics at home. We undertook this study to determine whether the low-income mostly non-English-speaking patients in our S-OPAT program could administer their own IV antimicrobials at home with outcomes as good as, or better than, those receiving H-OPAT. METHODS AND FINDINGS: Parkland Hospital is a safety-net hospital serving Dallas County, Texas. From 1 January 2009 to 14 October 2013, all uninsured patients meeting criteria were enrolled in S-OPAT, while insured patients were discharged to H-OPAT settings. The S-OPAT patients were trained through multilingual instruction to self-administer IV antimicrobials by gravity, tested for competency before discharge, and thereafter followed at designated intervals in the S-OPAT outpatient clinic for IV access care, laboratory monitoring, and physician follow-up. The primary outcome was 30-d all-cause readmission, and the secondary outcome was 1-y all-cause mortality. The study was adequately powered for readmission but not for mortality. Clinical, sociodemographic, and outcome data were collected from the Parkland Hospital electronic medical records and the US census, constituting a historical prospective cohort study. We used multivariable logistic regression to develop a propensity score predicting S-OPAT versus H-OPAT group membership from covariates. We then estimated the effect of S-OPAT versus H-OPAT on the two outcomes using multivariable proportional hazards regression, controlling for selection bias and confounding with the propensity score and covariates. Of the 1,168 patients discharged to receive OPAT, 944 (81%) were managed in the S-OPAT program and 224 (19%) by H-OPAT services. In multivariable proportional hazards regression models controlling for confounding and selection bias, the 30-d readmission rate was 47% lower in the S-OPAT group (adjusted hazard ratio [aHR], 0.53; 95% CI 0.35-0.81; p = 0.003), and the 1-y mortality rate did not differ significantly between the groups (aHR, 0.86; 95% CI 0.37-2.00; p = 0.73). The S-OPAT program shifted a median 26 d of inpatient infusion per patient to the outpatient setting, avoiding 27,666 inpatient days. The main limitation of this observational study-the potential bias from the difference in healthcare funding status of the groups-was addressed by propensity score modeling. CONCLUSIONS: S-OPAT was associated with similar or better clinical outcomes than H-OPAT. S-OPAT may be an acceptable model of treatment for uninsured, medically stable patients to complete extended courses of IV antimicrobials at home.

Word-finding impairment in veterans of the 1991 Persian Gulf War.

Approximately one quarter of 1991 Persian Gulf War Veterans experience cognitive and physiological sequelae that continue to be unexplained by known medical or psychological conditions. Difficulty coming up with words and names, familiar before the war, is a hallmark of the illness. Three Gulf War Syndrome subtypes have been identified and linked to specific war-time chemical exposures. The most functionally impaired veterans belong to the Gulf War Syndrome 2 (Syndrome 2) group, for which subcortical damage due to toxic nerve gas exposure is the suspected cause. Subcortical damage is often associated with specific complex language impairments, and Syndrome 2 veterans have demonstrated poorer vocabulary relative to controls. 11 Syndrome 1, 16 Syndrome 2, 9 Syndrome 3, and 14 age-matched veteran controls from the Seabees Naval Construction Battalion were compared across three measures of complex language. Additionally, functional magnetic resonance imaging (fMRI) was collected during a covert category generation task, and whole-brain functional activity was compared between groups. Results demonstrated that Syndrome 2 veterans performed significantly worse on letter and category fluency relative to Syndrome 1 veterans and controls. They also exhibited reduced activity in the thalamus, putamen, and amygdala, and increased activity in the right hippocampus relative to controls. Syndrome 1 and Syndrome 3 groups tended to show similar, although smaller, differences than the Syndrome 2 group. Hence, these results further demonstrate specific impairments in complex language as well as subcortical and hippocampal involvement in Syndrome 2 veterans. Further research is required to determine the extent of language impairments in this population and the significance of altered neurologic activity in the aforementioned brain regions with the purpose of better characterizing the Gulf War Syndromes.

Methods for measuring serum activity levels of the 192 Q and R isoenzymes of paraoxonase 1 in QR heterozygous individuals.

BACKGROUND: Paraoxonase 1 (PON1), an esterase that hydrolyzes toxic organophosphates and has antioxidative and antiatherogenic properties, contains a common polymorphism at position 192: glutamine (Q) or arginine (R). The Q and R isoenzymes exhibit different physical and protective properties. We describe 2 methods for quantifying their serum activity levels. METHODS: We measured serum hydrolytic activity with paraoxon [paraoxonase (PXN) activity], phenylacetate [arylesterase (AE) activity], and diazoxon [diazoxonase (DZN) activity] with standard automated assays. We determined PON1 Q192R genotypes with PCR and Q192R phenotypes using the PXN/AE and PXN/DZN ratios. Interpolation equations were empirically derived to predict the percentage of total PON1 hydrolytic activity due to the Q isoenzyme (%Q) from the PXN/AE and PXN/DZN ratios; %R is 100 - %Q. We estimated Q and R isoenzyme activity levels in sera from 2095 veterans by multiplying AE activity, a measure of total PON1 hydrolytic activity, by %Q and %R. RESULTS: In all 2095 samples, the PXN/AE and PXN/DZN ratios predicted Q192R phenotypes with nearly identical accuracy (κ = 0.997). In the 925 QR heterozygotes, the 2 interpolation methods predicted Q and R isoenzyme activity levels with excellent agreement (intraclass correlation 0.94). After excluding a few genotype/phenotype-discordant samples, the percentage of total PON1 activity due to the Q isoenzyme ranged from 22% to 70%. CONCLUSIONS: These new interpolation methods allow accurate estimation of PON1 192 Q and R isoenzyme activity levels, increasing specificity and power for studying susceptibility to disease.

Anteroposterior perfusion heterogeneity in human hippocampus measured by arterial spin labeling MRI.

Measurements of blood flow in the human hippocampus are complicated by its relatively small size, unusual anatomy and patterns of blood supply. Only a handful of arterial spin labeling (ASL) MRI articles have reported regional cerebral blood flow (rCBF) values for the human hippocampus. Numerous reports have found heterogeneity in a number of other physiological and biochemical parameters along the longitudinal hippocampal axis. There is, however, only one ASL study of perfusion properties as a function of anteroposterior location in the hippocampus, reporting that rCBF is lower and the arterial transit time (ATT) is longer in the anterior hippocampus than in the posterior hippocampus of the rat brain. The purpose of this article was to measure ATT and rCBF in anterior, middle and posterior normal adult human hippocampus. To better distinguish anteroposterior perfusion heterogeneity in the hippocampus, a modified ASL method, called Orthogonally Positioned Tagging Imaging Method for Arterial Labeling with Flow-sensitive Alternating Inversion Recovery (OPTIMAL FAIR), was developed that provides high in-plane resolution with oblique coronal imaging slices perpendicular to the long axis of the hippocampus to minimize partial volume effects. Perfusion studies performed with this modified FAIR method at 3 T indicated that anterior, middle and posterior human hippocampus segments have unique transit time and rCBF values. Of these three longitudinal hippocampal regions, the middle hippocampus has the highest perfusion and the shortest transit time and the anterior hippocampus has the lowest perfusion and the longest transit time. Copyright © 2013 John Wiley & Sons, Ltd.

Meteorological and intelligence evidence of long-distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War.

BACKGROUND: Coalition bombings on the night of 18-19 January 1991, early in the Gulf War, targeted the Iraqi chemical weapons infrastructure. On 19 January 1991, nerve agent alarms sounded within Coalition positions hundreds of kilometers to the south, and the trace presence of sarin vapor was identified by multiple technologies. Considering only surface dispersion of plumes from explosions, officials concluded that the absence of casualties around bombed sites precluded long-distance transit of debris to US troop positions to explain the alarms and detections. Consequently, they were discounted as false positives, and low-level nerve agent exposure early in the air war was disregarded in epidemiologic investigations of chronic illnesses. INTELLIGENCE DATA: Newly assembled evidence indicates that plumes from those nighttime bombings of Iraqi chemical facilities would have traversed the stable nocturnal boundary layer and penetrated the residual layer where they would be susceptible to rapid transit by supergeostrophic winds. This explanation is supported by plume height predictions, available weather charts, weather satellite images showing transit of a hot air mass, effects of solar mixing of atmospheric layers, and observations of a stationary weather front and thermal inversion in the region. CONCLUSIONS: Current evidence supports long-distance transit. Epidemiologic studies of chronic postwar illness should be reassessed using veterans' reports of hearing nerve agent alarms as the measure of exposure.

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.

Memory impairment exhibited by veterans with Gulf War Illness.

Roughly 26-32% of US veterans, who served in the first Gulf War, report suffering from chronic health problems ( Golomb, 2008 , Proceedings of the National Academies of Science, 105, 4295). The present study investigated the memory deficits reported by these ill Gulf War veterans (GWV) using a face-name associative memory paradigm administered during functional magnetic resonance imaging (fMRI). The fMRI data confirmed memory performance on the memory task to be related to the amount of activation in the left hippocampus observed during the study. In addition, ill-GWV demonstrated decreased memory performance relative to unaffected GWV on this memory test, providing evidence of memory deficits using an objective measure of memory.

The 2012 West Nile encephalitis epidemic in Dallas, Texas.

IMPORTANCE: After progressive declines over recent years, in 2012 West Nile virus epidemics resurged nationwide, with the greatest number of cases centered in Dallas County, Texas. OBJECTIVE: To analyze the epidemiologic, meteorologic, and geospatial features of the 2012 Dallas West Nile virus epidemic to guide future prevention efforts. DESIGN, SETTING, AND PATIENTS: Public health surveillance of Dallas County, an area of 2257 km2 and population of 2.4 million. Surveillance data included numbers of residents diagnosed with West Nile virus infection between May 30, 2012, and December 3, 2012; mosquito trap results; weather data; and syndromic surveillance from area emergency departments. MAIN OUTCOMES AND MEASURES: Incidence and age-adjusted incidence rates of West Nile neuroinvasive disease (WNND), daily prevalence of emergency department visits for asthma and skin rash, and Culex quinquefasciatus species-specific vector index (an estimate of the average number of West Nile virus-infected mosquitoes per trap-night). RESULTS: The investigation identified 173 cases of WNND, 225 of West Nile fever, 17 West Nile virus-positive blood donors, and 19 deaths in 2012. The incidence rate for WNND was 7.30 per 100,000 residents in 2012, compared with 2.91 per 100,000 in 2006, the largest previous Dallas County outbreak. An unusually rapid and early escalation of large numbers of human cases closely followed increasing infection trends in mosquitoes. The Cx quinquefasciatus species-specific vector index predicted the onset of symptoms among WNND cases 1 to 2 weeks later (count regression ß = 2.97 [95% CI, 2.34 to 3.60]; P < .001). Although initially widely distributed, WNND cases soon clustered in neighborhoods with high housing density in the north central area of the county, reflecting higher vector indices and following geospatial patterns of West Nile virus in prior years. During the 11 years since West Nile virus was first identified in Dallas, the log-transformed annual prevalence of WNND was inversely associated with the number of days with low temperatures below 28°F (-2.2°C) in December through February (ß = -0.29 [95% CI, -0.36 to -0.21]; P < .001). Aerial insecticide spraying was not associated with increases in emergency department visits for respiratory symptoms (ß = -4.03 [95% CI, -13.76 to 5.70]; P = .42) or skin rash (ß = -1.00 [95% CI, -6.92 to 4.92]; P = .74). CONCLUSIONS AND RELEVANCE: Large West Nile virus epidemics in Dallas County begin early after unusually warm winters, revisit similar geographical distributions, and are strongly predicted by the mosquito vector index. Consideration of weather patterns and historical geographical hot spots and acting on the vector index may help prevent West Nile virus-associated illness.

Dynamic physostigmine effects on hippocampus perfusion.

PURPOSE: To characterize the dynamic response of hippocampus blood flow to physostigmine infusion and to determine an infusion duration sufficiently long for robust detection of effects with arterial spin labeling (ASL) and sufficiently short to avoid peripheral side effects of physostigmine. MATERIALS AND METHODS: Two female (49 ± 15 years) and nine male (53 ± 13 years) subjects were studied to determine the time course of the physostigmine effect on hippocampus blood flow with ASL perfusion imaging during 20 minutes of baseline, 30 minutes of physostigmine infusion at 1.0 mg/hr, and 70 minutes of recovery. RESULTS: Hippocampus perfusion decreased steadily over the course of the infusion, with the reduction in flow becoming significant after 20 minutes of infusion, reaching lowest levels near the end of infusion, and remaining significantly low and stable in the 70-minute recovery period. Percentage changes of hippocampus perfusion were -13.3%, -13.4%, and -13.4% for left, right, and bilateral hippocampus, respectively, at the end of infusion. CONCLUSION: At a dose rate of 1.0 mg/hr it is feasible to use an infusion time as short as 20 minutes, performing perfusion imaging up to an hour after physostigmine infusion is discontinued, to minimize chances for adverse side effects.

Key properties of D-optimal designs for event-related functional MRI experiments with application to nonlinear models.

To properly formulate functional magnetic resonance imaging (fMRI) experiments with complex mental activity, it is advantageous to permit great flexibility in the statistical components of the design of these studies. The length of an experiment, the placement of various stimuli and the modeling approach used all affect the ability to detect mental activity. Major advances in understanding the implications of various designs of fMRI experiments have taken place over the last decade. Nevertheless, new and increasingly difficult issues relating to the modeling of hemodynamic responses and the detection of activated brain regions continue to arise because of the increasing complexity of the experiments. In this article, the D-optimality criterion is used in conjunction with a genetic algorithm to create probability-based design generators for the selection of designs in event-related fMRI experiments where the hemodynamic response function is modeled with a function that is nonlinear in the parameters. The designs produced by these generators are shown to perform well compared with locally D-optimal designs and provide insight into optimal design characteristics that investigators can utilize in the selection of interstimulus intervals. Designs with these characteristics are shown to be applicable to fMRI studies involving one or two stimulus types. The designs are also shown to be robust with respect to misspecification of an AR(1) error autocorrelation and compare favorably with a maximin procedure.

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.

Striatal functional connectivity networks are modulated by fMRI resting state conditions.

Resting state fluctuations in blood oxygenation level dependent functional connectivity magnetic resonance imaging (BOLD fcMRI) time-series have been increasingly employed to study functional connectivity networks in healthy and diseased brain. FcMRI studies have been conducted under a number of different conditions, including resting eyes open, visual fixation and finger tapping. BOLD fcMRI networks are believed to reflect both anatomically constrained spontaneous fluctuations and state-dependent activity. In this study, state-dependence of functional connectivity to dorsal and ventral striatum was assessed with fcMRI during an eyes open resting state condition (REST) and during continuous 3 Hz transcutaneous electrical nerve stimulation (TENS), with the a priori hypotheses: (1) dorsal striatum connectivity with sensorimotor/attention networks will be stronger during TENS compared to REST, (2) ventral striatum connectivity with limbic system emotion-processing network will be weaker during TENS compared to REST and (3) ventral striatum connectivity with sensorimotor/attention networks will be stronger during TENS compared to REST. These hypotheses were confirmed by the results obtained, indicating that resting state BOLD fMRI networks reflect, in substantial measure, state-dependent activity.

Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge.

PURPOSE: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. MATERIALS AND METHODS: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. RESULTS: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. CONCLUSION: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.

Improved quantification of brain perfusion using FAIR with active suppression of superior tagging (FAIR ASST).

PURPOSE: To address two problems for perfusion studies in the middle or inferior brain regions: (1) to reduce venous artifacts due to the intrinsic superior labeling of FAIR; (2) to alleviate the discrepancy of the existence of both superior and inferior boluses, but with only the inferior bolus having a temporally defined bolus width with Q2TIPs or QUIPSS. MATERIALS AND METHODS: Superior tagging suppression methods for FAIR with different combinations of pre- and postinversion superior saturation pulses were evaluated and compared with FAIR with Q2TIPS for producing perfusion maps of superior, middle, and inferior brain regions. RESULTS: One preinversion plus two postinversion superior saturation radio frequency pulses effectively suppressed the superior tagging of FAIR and sufficiently eliminated venous artifacts without negative effects, avoiding the overestimations of cerebral blood flow that can occur in FAIR. CONCLUSION: FAIR ASST improves FAIR with Q2TIPS and provides more reliable and accurate blood flow estimations for perfusion studies of middle and lower brain regions. FAIR ASST confers the advantages of asymmetric PASL techniques, such as PICORE, in which only the inferiorly labeled blood is used for perfusion quantification, to the symmetric PASL technique FAIR, while preserving the robustness of FAIR against MT effects.