Evaluating the Impact of CenteringPregnancy Program Versus Individual Prenatal Care on Gestational Weight Gain.

Introduction: The CenteringPregnancy (CP) program-proven to reduce preterm births-was modified to achieve more optimal gestational weight gain (GWG) by an intentional incorporation of nutrition education. We compared the effect of the modified CP program versus individual prenatal care (IPNC) on GWG. Methods: This observational study used linked birth certificate data and hospital discharge records of women who received prenatal care (PNC) in South Carolina Midlands' obstetric clinics between 2015 and 2019. Linear and multinomial logistic regressions were used to compare participants in CP (n = 568) versus IPNC on weight gain, measured by total GWG (delivery weight minus prepregnancy weight), weekly rate of weight gain, and meeting the Institute of Medicine's recommendations (inadequate, adequate, and excessive GWG). Nonrandom assignment to program was controlled by propensity scoring. Results: CP participants differed from IPNC participants in race, nulliparous, education, and type of health insurance, but not in parity or month PNC began (p-Value <0.05). CP and IPNC participants had a similar GWG experience: total GWG (coef(ß) = -0.054; 95% confidence interval [CI] -0.78 to 0.6), total weekly weight gain (coef(ß) = -0.004; 95% CI -0.03 to 0.03), total GWG category (inadequate GWG: RRR = 0.85, 95% CI 0.64-1.21, and excessive GWG: relative risk ratio (RRR) = 0.92, 95% CI 0.71-1.20 vs. adequate), and weekly weight gain category (inadequate GWG: RRR = 0.73, 95% CI 0.53-1.01, and excessive GWG: RRR = 0.83, 95% CI 0.61-1.13 vs. adequate). Conclusion: The CP program with an enhanced nutritional knowledge component was not associated with achieving recommended GWG. Further investigation is needed to explain the lack of impact.

Impact of functional disability on health-care use and medical costs among cancer survivors.

BACKGROUND: Cancer survivors with a disability are among the most vulnerable in health status and financial hardship, but no prior research has systematically examined how disability modifies health-care use and costs. This study examined the association between functional disability among cancer survivors and their health-care utilization and medical costs. METHODS: We generated nationally representative estimates using the 2015-2019 Medical Expenditure Panel Survey. Outcomes included use of 6 service types (inpatient, outpatient, office-based physician, office-based nonphysician, emergency department, and prescription) and medical costs of aggregate services and by each of 6 service types. The primary independent variable was a categorical variable for the total number of functional disabilities. We employed multivariable generalized linear models and 2-part models, adjusting for sociodemographics and health conditions and accounting for survey design. RESULTS: Among cancer survivors (n = 9359; weighted n = 21 046 285), 38.8% reported at least 1 disability. Compared with individuals without a disability, cancer survivors with 4 or more disabilities experienced longer hospital stays (adjusted average marginal effect = 1.14 days, 95% confidence interval [CI] = 0.55 to 1.73), more visits to an office-based physician (average marginal effect = 1.43 visits, 95% CI = 0.51 to 2.35), and a greater number of prescriptions (average marginal effect = 12.1 prescriptions, 95% CI = 9.27 to 15.0). Their total (average marginal effect = $9537, 95% CI = $5713 to $13 361) and out-of-pocket (average marginal effect = $639, 95% CI = $79 to $1199) medical costs for aggregate services were statistically significantly higher. By type, disability in independent living was most strongly associated with greater costs for aggregate services. CONCLUSIONS: Cancer survivors with a disability experienced greater health-care use and higher costs. Cancer survivorship planning for health care and financial stability should consider the patients' disability profile.

Prediction of Pelvic Organ Prolapse Postsurgical Outcome Using Biomaterial-Induced Blood Cytokine Levels: Machine Learning Approach.

BACKGROUND: Pelvic organ prolapse (POP) refers to symptomatic descent of the vaginal wall. To reduce surgical failure rates, surgical correction can be augmented with the insertion of polypropylene mesh. This benefit is offset by the risk of mesh complication, predominantly mesh exposure through the vaginal wall. If mesh placement is under consideration as part of prolapse repair, patient selection and counseling would benefit from the prediction of mesh exposure; yet, no such reliable preoperative method currently exists. Past studies indicate that inflammation and associated cytokine release is correlated with mesh complication. While some degree of mesh-induced cytokine response accompanies implantation, excessive or persistent cytokine responses may elicit inflammation and implant rejection. OBJECTIVE: Here, we explore the levels of biomaterial-induced blood cytokines from patients who have undergone POP repair surgery to (1) identify correlations among cytokine expression and (2) predict postsurgical mesh exposure through the vaginal wall. METHODS: Blood samples from 20 female patients who previously underwent surgical intervention with transvaginal placement of polypropylene mesh to correct POP were collected for the study. These included 10 who experienced postsurgical mesh exposure through the vaginal wall and 10 who did not. Blood samples incubated with inflammatory agent lipopolysaccharide, with sterile polypropylene mesh, or alone were analyzed for plasma levels of 13 proinflammatory and anti-inflammatory cytokines using multiplex assay. Data were analyzed by principal component analysis (PCA) to uncover associations among cytokines and identify cytokine patterns that correlate with postsurgical mesh exposure through the vaginal wall. Supervised machine learning models were created to predict the presence or absence of mesh exposure and probe the number of cytokine measurements required for effective predictions. RESULTS: PCA revealed that proinflammatory cytokines interferon gamma, interleukin 12p70, and interleukin 2 are the largest contributors to the variance explained in PC 1, while anti-inflammatory cytokines interleukins 10, 4, and 6 are the largest contributors to the variance explained in PC 2. Additionally, PCA distinguished cytokine correlations that implicate prospective therapies to improve postsurgical outcomes. Among machine learning models trained with all 13 cytokines, the artificial neural network, the highest performing model, predicted POP surgical outcomes with 83% (15/18) accuracy; the same model predicted POP surgical outcomes with 78% (14/18) accuracy when trained with just 7 cytokines, demonstrating retention of predictive capability using a smaller cytokine group. CONCLUSIONS: This preliminary study, incorporating a sample size of just 20 participants, identified correlations among cytokines and demonstrated the potential of this novel approach to predict mesh exposure through the vaginal wall following transvaginal POP repair surgery. Further study with a larger sample size will be pursued to confirm these results. If corroborated, this method could provide a personalized medicine approach to assist surgeons in their recommendation of POP repair surgeries with minimal potential for adverse outcomes.

Integrating maternal depression care at primary private clinics in low-income settings in Pakistan: A secondary analysis.

Introduction: The prevalence of depression among women in Pakistan ranges from 28% to 66%. There is a lack of structured mental healthcare provision at private primary care clinics in low-income urban settings in Pakistan. This study investigated the effectiveness and processes of a facility-based maternal depression intervention at private primary care clinics in low-income settings. Materials and methods: A mixed-methods study was conducted using secondary data from the intervention. Mothers were assessed for depression using the Patient Health Questionnaire-9 (PHQ-9). A total of 1,957 mothers (1,037 and 920 in the intervention and control arms, respectively) were retrieved for outcome measurements after 1 year of being registered. This study estimated the effectiveness of the depression intervention through cluster adjusted differences in the change in PHQ-9 scores between the baseline and the endpoint measurements for the intervention and control arms. Implementation was evaluated through emerging themes and codes from the framework analysis of 18 in-depth interview transcriptions of intervention participants. Results: Intervention mothers had a 3.06-point (95% CI: -3.46 to -2.67) reduction in their PHQ-9 score at the endpoint compared with their control counterparts. The process evaluation revealed that the integration of structured depression care was feasible at primary clinics in poor urban settings. It also revealed gaps in the public-private care linkage system and the need to improve referral systems. Conclusions: Intervening for depression care at primary care clinics can be effective in reducing maternal depression. Clinic assistants can be trained to identify and deliver key depression counseling messages. The study invites policymakers to seize an opportunity to implement a monitoring mechanism toward standard mental health care.

A National Perspective of Telemedicine Use and Direct Medical Costs: Who Uses It and How Much It Costs.

BACKGROUND: Telemedicine has the potential to reduce medical costs among health systems. However, there is a limited understanding of the use of telemedicine and its association with direct medical costs. OBJECTIVES: Using nationally representative data, we investigated telemedicine use and the associated direct medical costs among respondents overall and stratified by medical provider type and patient insurance status. RESEARCH DESIGN, SUBJECTS, AND MEASURES: We used the 2020 Medical Expenditure Panel Survey full-year consolidated file, and outpatient department (OP) and office-based (OB) medical provider event files. Outcomes included total and out-of-pocket costs per visit for OP and OB. The primary independent variable was a binary variable indicating visits made through any telemedicine modality. We used multivariable generalized linear models and 2-part models, adjusting for types of providers and care, patient characteristics, and survey design. RESULTS: Among total OP (n = 2938) and OB (n = 20,204) visits, 47.6% and 24.7% of visits, respectively were made through telemedicine. For OP, telemedicine visits were associated with lower total costs (average marginal effect: -$228; 95% confidence interval -$362, -$95) and out-of-pocket costs for all visits and for visits to specialists and to nurse practitioners or physicians assistants. For OB, telemedicine visits were associated with lower total costs, but not with lower out-of-pocket costs, for visits to primary care physicians or nurse practitioners or physician assistants, and for visits by Medicare patients. CONCLUSION: Telemedicine was associated with lower direct medical costs. Its potential for cost curbing should be proactively identified and integrated into clinical practice and health policy design.

Participation in the CenteringPregnancy Program and Pregnancy-Induced Hypertension.

INTRODUCTION: CenteringPregnancy emphasizes nutrition, learning, and peer support through a group meeting format in contrast to the standard of prenatal care that maximizes a pregnant patient's time with their provider. It was hypothesized that the program may yield a reduced risk of pregnancy-induced hypertension. In this observational study, authors examined the impacts of the CenteringPregnancy program versus those of standard of prenatal care on pregnancy-induced hypertension. METHODS: In 2021, birth certificate data were linked to hospital discharge records of women who delivered in obstetric clinics in the Midlands of South Carolina between 2015 and 2019. Logistic regression models were used to estimate the association between CenteringPregnancy participation (n=547) and any pregnancy-induced hypertension and specific pregnancy-induced hypertension diagnoses (gestational hypertension/unspecified hypertension, mild pre-eclampsia, and severe pre-eclampsia/eclampsia). Propensity score techniques (e.g., inverse probability of treatment weighting) were used to adjust for self-selection into the program versus into standard of prenatal care. RESULTS: CenteringPregnancy participants had higher odds of developing any pregnancy-induced hypertension under all specifications (OR=1.48, 95% CI=1.15, 1.92) and specifically gestational hypertension/unspecified hypertension (OR=1.76, 95% CI=1.28, 2.42) than those in standard of prenatal care. However, CenteringPregnancy participants did not experience significantly higher odds of mild pre-eclampsia (OR=1.06, 95% CI=0.65, 1.78) and severe pre-eclampsia/eclampsia (OR=1.21, 95% CI=0.78, 1.89) compared with standard of prenatal care participants. CONCLUSIONS: Participation in CenteringPregnancy was associated with higher odds of pregnancy-induced hypertension, particularly gestational hypertension, than participation in standard of prenatal care. Additional research is warranted to definitely rule out selection bias and identify contributing factor(s) that increased pregnancy-induced hypertension despite efforts to improve pregnancy-related health outcomes among CenteringPregnancy participants.

Patient Goals for Living with Rheumatoid Arthritis: A Qualitative Study.

Rheumatoid arthritis is highly individualized in terms of its flare ups and periods of remission. Each patient's unique experience requires a high level of personalization in terms of treatment making it necessary to understand what their goals for living are. This study explores patient perceptions on how the burden of RA shapes patients' goals for living and their preferences for symptom and side-effect management within the United States. Fifteen patients diagnosed with RA with varying lengths of diagnosis were interviewed. A thematic analysis was conducted to construct a conceptual framework. Emerging themes identified disease burdens as: (1) inability to perform essential needs, (2) negative feelings about disease, and (3) its influence on relationships. These burdens shaped desired goals for living which guided the symptom and side-effect priorities the patient wanted managed. Practitioners should consider patient goals and preferences in conjunction with disease progression when engaging in treatment decisions.

Mobile Health Apps for Patient-Centered Care: Review of United States Rheumatoid Arthritis Apps for Engagement and Activation.

BACKGROUND: Rheumatoid arthritis (RA) is a highly dynamic and individualized disease in terms of its patterns of symptomatic flare-ups and periods of remission. Patient-centered care (PCC) aligns patients' lifestyle goals with their preferences for managing symptoms and side effects through the selection of therapies appropriate for disease management. Mobile health (mHealth) apps have the potential to engage and activate patients in PCC. mHealth apps can provide features that increase disease knowledge, collect patient-generated health indicators and behavioral metrics, and highlight goals for disease management. However, little evidence-based guidance exists as to which apps contain functionality essential for supporting the delivery of PCC. OBJECTIVE: The objective of this study was to evaluate the patient-centeredness of United States-based rheumatoid arthritis mobile apps in terms of patient engagement and activation. METHODS: A search of mobile apps on 2 major United States app stores (Apple App Store and Google Play) was conducted from June 2020 to July 2021 to identify apps designed for use by patients with RA by adapting the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for mobile health app screening based on the literature. Reviewers conducted a content analysis of mobile app features to evaluate their functionality for patient engagement and activation. Engagement and activation were assessed using the Mobile Application Rating Scale (MARS) and social cognitive theory, respectively. Apps were ranked by their ability to facilitate PCC care along 2 dimensions: engagement and activation. RESULTS: A total of 202 mobile apps were initially identified, and 20 remained after screening. Two apps emerged with the greatest ability to facilitate PCC. Both apps were scored as having acceptable or good patient engagement according to the MARS. These 2 apps also had high patient activation according to social cognitive theory, with many features within those apps representing theoretical constructs such as knowledge, perceived self-efficacy, and expectations about outcomes that support behavioral management of RA. CONCLUSIONS: We found very few mobile apps available within the United States that have functionality that both engages and activates the patient to facilitate PCC. As the prevalence of mobile apps expands, the design of mobile apps needs to integrate patients to ensure that their functionality promotes engagement and activation. More research is needed to understand how mobile app use impacts patient engagement and activation, and ultimately, treatment decisions and disease trajectory.

Generalized anxiety disorder symptoms during COVID-19 pandemic in Jazan, Saudi Arabia.

The aim of this study was to measure anxiety levels and many co-factors that might influence the levels of anxiety during the COVID-19 outbreak in southern Saudi Arabia (KSA). A cross-sectional self-reporting survey was conducted to determine the level of generalized anxiety disorder (GAD) symptoms related to COVID-19 and quarantining. We selected a convenience sample of eligible participants who had been invited online through social media apps. The survey instrument was distributed, and 981 participants responded. Of the total sample, almost 90% were under the age of 40, 75% were women, and 77% had an educational level beyond high school. Just over half were single, with nearly all participants Saudi nationals. The overall prevalence of anxiety related to COVID-19 was 27%. Factors most strongly related to reporting anxiety included having a diagnosis of COVID-19, spending 1- ≥ 3 h focused on COVID-19, having a previous mental illness history, being a current or former smoker, being female, having a previous diagnosis of chronic or respiratory illness, being below age 40, having a limited standard of living, and being a student. Our study reveals how critical it is to emphasize preventive mental health care during pandemics and what factors may make some individuals most vulnerable to anxiety. Further research is recommended to examine GAD levels pre, during and post pandemic. Additional research to explore the long-term impact of the pandemic on mental health is also needed. being a student, and a limited standard of living.

Needlestick and sharps injuries among secondary and tertiary healthcare workers, Saudi Arabia.

AIM: The study aimed to assess the incidence of needlestick and sharps injuries among healthcare workers (HCWs) in the Jazan region of Saudi Arabia, as well as to determine whether there exists an association between hospital level and needlestick and sharps injuries rate. DESIGN: A cross-sectional survey was conducted among 609 randomly selected HCWs from nine general hospitals. METHODS: A self-administered questionnaire, which covered the structure and process of injection safety, was used for data collection. RESULTS: The overall needlestick and sharps injuries incidence rate was 24%. The needlestick and sharps injuries rates were 30% and 14% in secondary and tertiary hospitals, respectively. HCWs working in tertiary hospitals were 61% less likely to have needlestick and sharps injuries than those employed in secondary hospitals. This was mainly the impact of better and continuous training. High safety level maintenance and health education provision are vital in such settings.

Multilevel predictors of guideline concordant needle biopsy use for non-metastatic breast cancer.

PURPOSE: Persistent breast cancer disparities, particularly geographic disparities, may be explained by diagnostic practice patterns such as utilization of needle biopsy, a National Quality Forum-endorsed quality metric for breast cancer diagnosis. Our objective was to assess the relationship between patient- and facility-level factors and needle biopsy receipt among women with non-metastatic breast cancer in the United States. METHODS: We examined characteristics of women diagnosed with breast cancer between 2004 and 2015 in the National Cancer Database. We assessed the relationship between patient- (e.g., race/ethnicity, stage, age, rurality) and facility-level (e.g., facility type, breast cancer case volume) factors with needle biopsy utilization via a mixed effects logistic regression model controlling for clustering by facility. RESULTS: In our cohort of 992,209 patients, 82.96% received needle biopsy. In adjusted models, the odds of needle biopsy receipt were higher for Hispanic (OR 1.04, Confidence Interval 1.01-1.08) and Medicaid patients (OR 1.04, CI 1.02-1.08), and for patients receiving care at Integrated Network Cancer Programs (OR 1.21, CI 1.02-1.43). Odds of needle biopsy receipt were lower for non-metropolitan patients (OR 0.93, CI 0.90-0.96), patients with cancer stage 0 or I (at least OR 0.89, CI 0.86-0.91), patients with comorbidities (OR 0.93, CI 0.91-0.94), and for patients receiving care at Community Cancer Programs (OR 0.84, CI 0.74-0.96). CONCLUSION: This study suggests a need to account for sociodemographic factors including rurality as predictors of utilization of evidence-based diagnostic testing, such as needle biopsy. Addressing inequities in breast cancer diagnosis quality may help improve breast cancer outcomes in underserved patients.

Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk.

Gulf War Illness (GWI) is a chronic multi-symptomatic illness that is associated with fatigue, pain, cognitive deficits, and gastrointestinal disturbances and presents a significant challenge to treat in clinics. Our previous studies show a role of an altered Gut-Brain axis pathology in disease development and symptom persistence in GWI. The present study utilizes a mouse model of GWI to study the role of a labdane diterpenoid andrographolide (AG) to attenuate the Gut-Brain axis-linked pathology. Results showed that AG treatment in mice (100 mg/kg) via oral gavage restored bacteriome alterations, significantly increased probiotic bacteria Akkermansia, Lachnospiraceae, and Bifidobacterium, the genera that are known to aid in preserving gut and immune health. AG also corrected an altered virome with significant decreases in virome families Siphoviridae and Myoviridae known to be associated with gastrointestinal pathology. AG treatment significantly restored tight junction proteins that correlated well with decreased intestinal proinflammatory mediators IL-1ß and IL-6 release. AG treatment could restore Claudin-5 levels, crucial for maintaining the BBB integrity. Notably, AG could decrease microglial activation and increase neurotrophic factor BDNF, the key to neurogenesis. Mechanistically, microglial conditioned medium generated from IL-6 stimulation with or without AG in a concentration similar to circulating levels found in the GWI mouse model and co-incubated with neuronal cells in vitro, decreased Tau phosphorylation and neuronal apoptosis. In conclusion, we show that AG treatment mitigated the Gut-Brain-Axis associated pathology in GWI and may be considered as a potential therapeutic avenue for the much-needed bench to bedside strategies in GWI.

Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model.

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1ß in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1ß, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.

TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model.

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive. Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1ß and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro. Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.

Host Akkermansia muciniphila Abundance Correlates With Gulf War Illness Symptom Persistence via NLRP3-Mediated Neuroinflammation and Decreased Brain-Derived Neurotrophic Factor.

Neurological disorders are commonly reported among veterans who returned from the Gulf war. Veterans who suffer from Gulf War illness (GWI) complain of continued symptom persistence that includes neurological disorders, muscle weakness, headaches, and memory loss, that developed during or shortly after the war. Our recent research showed that chemical exposure associated microbial dysbiosis accompanied by a leaky gut connected the pathologies in the intestine, liver, and brain. However, the mechanisms that caused the symptoms to persist even 30 years after the war remained elusive to investigators. In this study, we used a rodent model of GWI to investigate the persistence of microbiome alterations, resultant chronic inflammation, and its effect on neurotrophic and synaptic plasticity marker BDNF. The results showed that exposure to GW chemicals (the pesticide permethrin and prophylactic drug pyridostigmine bromide) resulted in persistent pathology characterized by the low relative abundance of the probiotic bacteria Akkermansia muciniphila in the gut, which correlated with high circulatory HMGB1 levels, blood-brain barrier dysfunction, neuroinflammation and lowered neurotrophin BDNF levels. Mechanistically, we used mice lacking the NLRP3 gene to investigate this inflammasome's role in observed pathology. These mice had significantly decreased inflammation and a subsequent increase in BDNF in the frontal cortex. This suggests that a persistently low species abundance of Akkermansia muciniphila and associated chronic inflammation due to inflammasome activation might be playing a significant role in contributing to chronic neurological problems in GWI. A therapeutic approach with various small molecules that can target both the restoration of a healthy microbiome and decreasing inflammasome activation might have better outcomes in treating GWI symptom persistence.

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology.

About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100ß/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence.

Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness.

Gulf War illness (GWI) is characterized by the persistence of inflammatory bowel disease, chronic fatigue, neuroinflammation, headache, cognitive impairment, and other medically unexplained conditions. Results using a murine model show that enteric viral populations especially bacteriophages were altered in GWI. The increased viral richness and alpha diversity correlated positively with gut bacterial dysbiosis and proinflammatory cytokines. Altered virome signature in GWI mice also had a concomitant weakening of intestinal epithelial tight junctions with a significant increase in Claudin-2 protein expression and decrease in ZO1 and Occludin mRNA expression. The altered virome signature in GWI, decreased tight junction protein level was followed by the presence an activation of innate immune responses such as increased Toll-like receptor (TLR) signaling pathways. The altered virome diversity had a positive correlation with serum IL-6, IL-1ß, and IFN-γ, intestinal inflammation (IFN-γ), and decreased Brain-Derived Neurotrophic Factor (BDNF), a neurogenesis marker. The co-exposure of Gulf War chemical and antibiotic (for gut sterility) or Gulf War chemical and Ribavirin, an antiviral compound to suppress virus alteration in the gut showed significant improvement in epithelial tight junction protein, decreased intestinal-, systemic-, and neuroinflammation. These results showed that the observed enteric viral dysbiosis could activate enteric viral particle-induced innate immune response in GWI and could be a novel therapeutic target in GWI.

The Gut-Microbiome in Gulf War Veterans: A Preliminary Report.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting the central nervous system (CNS), immune and gastrointestinal (GI) systems of Gulf War veterans (GWV). We assessed the relationships between GWI, GI symptoms, gut microbiome and inflammatory markers in GWV from the Boston Gulf War Illness Consortium (GWIC). Three groups of GWIC veterans were recruited in this pilot study; GWV without GWI and no gastrointestinal symptoms (controls), GWV with GWI and no gastrointestinal symptoms (GWI-GI), GWV with GWI who reported gastrointestinal symptoms (GW+GI). Here we report on a subset of the first thirteen stool samples analyzed. Results showed significantly different gut microbiome patterns among the three groups and within the GWI +/-GI groups. Specifically, GW controls had a greater abundance of firmicutes and the GWI+GI group had a greater abundance of the phyla bacteroidetes, actinobacteria, euryarchaeota, and proteobacteria as well as higher abundances of the families Bacteroidaceae, Erysipelotrichaceae, and Bifidobacteriaceae. The GWI+GI group also showed greater plasma levels of the inflammatory cytokine TNF-RI and they endorsed significantly more chemical weapons exposure during the war and reported significantly greater chronic pain, fatigue and sleep difficulties than the other groups. Studies with larger samples sizes are needed to confirm these initial findings.