Voluntary wheel running as a promising strategy to promote autonomic resilience to social stress in females: Vagal tone lies at the heart of the matter.

Social stress is a major risk factor for comorbid conditions including cardiovascular disease and depression. While women exhibit 2-3× the risk for these stress-related disorders compared to men, the mechanisms underlying heightened stress susceptibility among females remain largely unknown. Due to a lack in understanding of the pathophysiology underlying stress-induced comorbidities among women, there has been a significant challenge in developing effective therapeutics. Recently, a causal role for inflammation has been established in the onset and progression of comorbid cardiovascular disease/depression, with women exhibiting increased sensitivity to stress-induced immune signaling. Importantly, reduced vagal tone is also implicated in stress susceptibility, through a reduction in the vagus nerve's well-recognized anti-inflammatory properties. Thus, examining therapeutic strategies that stabilize vagal tone during stress may shed light on novel targets for promoting stress resilience among women. Recently, accumulating evidence has demonstrated that physical activity exerts cardio- and neuro-protective effects by enhancing vagal tone. Based on this evidence, this mini review provides an overview of comorbid cardiovascular and behavioral dysfunction in females, the role of inflammation in these disorders, how stress may impart its negative effects on the vagus nerve, and how exercise may act as a preventative. Further, we highlight a critical gap in the literature with regard to the study of females in this field. This review also presents novel data that are the first to demonstrate a protective role for voluntary wheel running over vagal tone and biomarkers of cardiac dysfunction in the face of social stress exposure in female rats.

The role of locus coeruleus neuroimmune signaling in the response to social stress in female rats.

Neuropsychiatric disorders that result from stress exposure, including post-traumatic stress disorder and substance abuse, are highly associated with central inflammation. Our previous work established that females selectively exhibit increased proinflammatory cytokine release within the noradrenergic locus coeruleus (LC) in response to witnessing social stress, which was associated with a hypervigilant phenotype. Thus, neuroimmune activation in the LC may be responsible for the heightened risk of developing mental health disorders following stress in females. Further, ablation of microglia using pharmacological techniques reduces the hypervigilant behavioral response exhibited by females during social stress. Therefore, these studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using DREADDs. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC. While the use of AAVs in preclinical research has been limited by observations regarding poor transfection efficiency in mice, recent data suggest that species specific differences in microglial genetics may render rats more receptive to chemogenetic targeting of microglia using a CD68 promoter. Therefore, clozapine-n-oxide (CNO) was used to activate the microglial expressed hM4Di to inhibit microglial activity during acute exposure to vicarious social defeat (witness stress, WS) in female rats. Neuroimmune activity within the LC, quantified by microglial morphology and cytokine release, was augmented by WS and prevented by chemogenetic microglial inhibition. Following confirmation of DREADD selectivity and efficacy, we utilized this technique to inhibit microglial activity during repeated WS. Subsequently, rats were tested in a marble burying paradigm and exposed to the WS cues and context to measure hypervigilant behaviors. Chemogenetic-mediated inhibition of microglial activity prior to each WS exposure prevented both acute and long-term hypervigilant responses induced by WS across multiple behavioral paradigms. Further, a history of microglial inactivation during WS prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit microglia within the female brain in vivo and establish LC inflammation as a key mechanism underlying the behavioral and neuronal responses to social stress in females.

Reflecting on Progress in and Establishing Benchmarks for Sex and Gender Health Education.

ABSTRACT: Sex and gender influence every aspect of human health; thus, sex- and gender-related topics should be incorporated in all aspects of health education curricula. Sex and gender health education (SGHE) is the rigorous, intersectional, data-driven integration of sex and gender into all elements of health education. A multisectoral group of thought leaders has collaborated to advance SGHE since 2012. This cross-sector collaboration to advance SGHE has been successful on several fronts, primarily developing robust interprofessional SGHE programs, hosting a series of international SGHE summits, developing sex- and gender-specific resources, and broadening the collaboration beyond medical education. However, other deeply entrenched challenges have proven more difficult to address, including accurate and consistent sex and gender reporting in research publications, broadening institutional support for SGHE, and the development and implementation of evaluation plans for assessing learner outcomes and the downstream effects of SGHE on patient care. This commentary reflects on progress made in SGHE over the first decade of the current collaboration (2012-2022), articulates a vision for next steps to advance SGHE, and proposes 4 benchmarks to guide the next decade of SGHE: (1) integrate sex, gender, and intersectionality across health curricula; (2) develop sex- and gender-specific resources for health professionals; (3) improve sex and gender reporting in research publications; and (4) develop evaluation plans to assess learner and patient outcomes.

Reducing hospital admissions in patients with malignant pleural effusion: a quality improvement study.

BACKGROUND: Malignant pleural effusions (MPE) can cause severe dyspnoea leading to greater than 125 000 hospitalisations per year and cost greater than US$5 billion per year in the USA. Timely insertion of tunnelled pleural catheters (TPCs) is associated with fewer inpatient days and emergency department visits. We conducted a quality improvement study to reduce hospital admissions of patients with MPE. METHODS: Key stakeholders were surveyed, including thoracic and breast oncology teams, general pulmonary and interventional pulmonology (IP) to help identify the underlying causes and solutions. Our preintervention group consisted of 51 patients who underwent TPC placement by our IP service. In our first intervention, we reviewed referrals for MPE with the scheduling team and triaged them based on urgency. In the second intervention, we added a follow-up phone call 1 week after the initial thoracentesis performed by IP to assess for the recurrence of symptoms. RESULTS: Demographic and clinical characteristics were summarised across the three groups. We evaluated the rate ratio (RR) of admissions in the intervention groups with the multivariable Poisson regression and adjusted for race, gender and cancer. Compared with the preintervention group, intervention I showed trends towards a 41% lower hospital admission rate (RR 0.59 (0.33-1.07), p=0.11). Compared with the preintervention group, intervention II showed trends towards a 40% lower hospital admission rate (RR 0.6 (0.36-0.99), p=0.07). The results did not reach statistical significance. Exploratory comparisons in readmission rates between interventions I and II showed no difference (RR 0.89 (0.43-1.79), p=0.75). CONCLUSIONS: Both interventions showed trends toward fewer hospital readmissions although they were not statistically significant. Larger-size prospective studies would be needed to demonstrate the continued effectiveness of these interventions.

Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats.

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that ovarian hormones may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERß) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERß is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ERß activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following WS, rats exhibited stress-induced anxiety-like behaviors in the marble burying taskand brain analysis revealed increased ERß and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ERß antagonist, PHTPP, prior to each stress session. During WS, estrogen signaling through ERß was responsible for the behavioral sensitization to repeated social stress. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERß in the CeA during WS prevented the development of depressive-, anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated rats. These experiments indicate that ERß signaling in the CeA, likely through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.

Assuring TRICARE Coverage of Preventive Health Services for Women Beneficiaries of the Military Health System.

WHY DEFENSE HEALTH HORIZONS PERFORMED THIS STUDY: The primary role of the Military Health System is to assure readiness by protecting the health of the force by providing expert care to wounded, ill, and injured service members. In addition to this mission, the Military Health System (both directly through its own personnel and indirectly, through TRICARE) provides health services to millions of military family members, retirees, and their dependents. Women's preventive health services are an important part of comprehensive health care to reduce rates of disease and premature death and were included in the 2010 Patient Protection and Affordable Care Act's (ACA) expanded coverage of women's preventive health services, based on the best available evidence and guidelines. These guidelines were updated by the Health Resources and Services Administrations and the American College of Obstetrics and Gynecology in 2016. However, TRICARE is not subject to the ACA, and therefore, TRICARE's provisions or the access of TRICARE's female beneficiaries to women's preventive health services was not directly changed by the ACA. This report compares women's reproductive health care coverage under TRICARE with coverage available to women enrolled in civilian health insurance plans subject to the 2010 ACA. WHAT DEFENSE HEALTH HORIZONS RECOMMENDS: Three recommendations are proposed to ensure that women who are TRICARE beneficiaries have access to and receive preventive reproductive health services that are consistent with Health Resources and Services Administration recommendations as implemented in the ACA. Each recommendation has strengths and weaknesses that are described in detail in the body of this paper. WHAT DEFENSE HEALTH HORIZONS FOUND: In covering contraceptive drugs and devices, TRICARE appears to reflect the scope of coverage found in ACA-compliant plans but, by not incorporating the term "all FDA-approved methods" of contraception, TRICARE leaves open the possibility that a narrower definition could be adopted at a future date. There are important differences in how TRICARE and ACA-compliant plans address reproductive counseling and health screening, including TRICARE's more restrictive counseling benefit and some limits to preventive screening. By not aligning with policies related to the provision of clinical preventive services established under the ACA, TRICARE allows health care providers in purchased care to diverge from evidence-based guidelines. Although the ACA respects medical judgment when providing women's preventive services, standards restrict the extent to which health care systems and providers can depart from evidence-based screening and prevention guidelines essential to optimizing quality, cost, and patient outcomes.

Site-Specific knockdown of microglia in the locus coeruleus regulates hypervigilant responses to social stress in female rats.

BACKGROUND: Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. METHODS: Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 µg/side, n = 5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 µg/side, n = 13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. RESULTS: Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1ß (IL-1ß). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1ß. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. CONCLUSIONS: These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

Reliability of functional outcome measures in adults with neurofibromatosis 2.

Objective: To determine inter- and intra-rater reliability of functional performance outcome measures in people with neurofibromatosis 2. To ascertain how closely objective and subjective measures align. Methods: Twenty-nine people with neurofibromatosis 2 were recorded performing the modified clinical test of sensory integration and balance, four square step test and modified nine-hole peg tests. Three raters scored each measure to determine inter-rater reliability. One rater scored the measures a second time to determine intra-rater reliability. Participants also completed a disease-specific quality of life questionnaire and dynamic visual acuity testing. Results: Inter-rater and intra-rater reliability scores (intra-class correlation coefficient) were excellent for all tests (intra-class correlation coefficient r ⩾ 0.9). The four square step test correlated with perceived walking challenges and modified clinical test of sensory integration and balance correlated with perceived balance challenges in a neurofibromatosis 2 quality of life patient report outcome measure. Conclusion: The modified clinical test of sensory integration and balance, four square step test and modified nine-hole peg tests are potentially useful measures for monitoring neurofibromatosis 2.

Stress- and drug-induced neuroimmune signaling as a therapeutic target for comorbid anxiety and substance use disorders.

Stress and substance use disorders remain two of the most highly prevalent psychiatric conditions and are often comorbid. While individually these conditions have a debilitating impact on the patient and a high cost to society, the symptomology and treatment outcomes are further exacerbated when they occur together. As such, there are few effective treatment options for these patients, and recent investigation has sought to determine the neural processes underlying the co-occurrence of these disorders to identify novel treatment targets. One such mechanism that has been linked to stress- and addiction-related conditions is neuroimmune signaling. Increases in inflammatory factors across the brain have been heavily implicated in the etiology of these disorders, and this review seeks to determine the nature of this relationship. According to the "dual-hit" hypothesis, also referred to as neuroimmune priming, prior exposure to either stress or drugs of abuse can sensitize the neuroimmune system to be hyperresponsive when exposed to these insults in the future. This review completes an examination of the literature surrounding stress-induced increases in inflammation across clinical and preclinical studies along with a summarization of the evidence regarding drug-induced alterations in inflammatory factors. These changes in neuroimmune profiles are also discussed within the context of their impact on the neural circuitry responsible for stress responsiveness and addictive behaviors. Further, this review explores the connection between neuroimmune signaling and susceptibility to these conditions and highlights the anti-inflammatory pharmacotherapies that may be used for the treatment of stress and substance use disorders.

Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression.

Major depressive disorder is a debilitating mental illness and a leading cause of global disease burden. While many etiological factors have been identified, social stress is a highly prevalent causative factor for the onset of depression. Unfortunately, rates of depression continue to increase around the world, and the recent COVID-19 pandemic has further exacerbated this mental health crisis. Though several therapeutic strategies are available, nearly 50% of patients who receive treatment never reach remission. The exact mechanisms by which social stress exposure promotes the development of depression are unclear, making it challenging to develop novel and more effective therapeutics. However, accumulating evidence points to a role for stress-induced neuroinflammation, particularly in treatment-resistant patients. Moreover, recent evidence has expanded the concept of the pathogenesis of depression to mitochondrial dysfunction, suggesting that the combined effects of social stress on mitochondria and inflammation may synergize to facilitate stress-related depression. In this chapter, we review evidence for neuroinflammation and mitochondrial dysfunction in the pathogenesis of social stress-induced depression and discuss these in the context of novel therapeutic targets for the treatment of depression.

Differentiating COPD and asthma using quantitative CT imaging and machine learning.

BACKGROUND: There are similarities and differences between chronic obstructive pulmonary disease (COPD) and asthma patients in terms of computed tomography (CT) disease-related features. Our objective was to determine the optimal subset of CT imaging features for differentiating COPD and asthma using machine learning. METHODS: COPD and asthma patients were recruited from Heidelberg University Hospital (Heidelberg, Germany). CT was acquired and 93 features were extracted: percentage of low-attenuating area below -950 HU (LAA950), low-attenuation cluster (LAC) total hole count, estimated airway wall thickness for an idealised airway with an internal perimeter of 10 mm (Pi10), total airway count (TAC), as well as airway inner/outer perimeters/areas and wall thickness for each of five segmental airways, and the average of those five airways. Hybrid feature selection was used to select the optimum number of features, and support vector machine learning was used to classify COPD and asthma. RESULTS: 95 participants were included (n=48 COPD and n=47 asthma); there were no differences between COPD and asthma for age (p=0.25) or forced expiratory volume in 1 s (p=0.31). In a model including all CT features, the accuracy and F1 score were 80% and 81%, respectively. The top features were: LAA950, outer airway perimeter, inner airway perimeter, TAC, outer airway area RB1, inner airway area RB1 and LAC total hole count. In the model with only CT airway features, the accuracy and F1 score were 66% and 68%, respectively. The top features were: inner airway area RB1, outer airway area LB1, outer airway perimeter, inner airway perimeter, Pi10, TAC, airway wall thickness RB1 and TAC LB10. CONCLUSION: COPD and asthma can be differentiated using machine learning with moderate-to-high accuracy by a subset of only seven CT features.

To Address Women's Health Inequity, It Must First Be Measured.

Research and data collection related to what is historically known as "women's health" is consistently underfunded and marginalizes the health risks and experiences of women of color and transgender people. In the wake of the pandemic, the United States has an opportunity to redesign and reimagine a modern public health data infrastructure that centers equity and elevates the health and well-being of under-represented communities, including the full spectrum of gender identities. This piece offers a blueprint for transformational change in how the United States collects, interprets, and shares critical data to deliver greater health justice for all.

International Recommendations for the Management of Adults Treated With Ketogenic Diet Therapies.

OBJECTIVE: To evaluate current clinical practices and evidence-based literature to establish preliminary recommendations for the management of adults using ketogenic diet therapies (KDTs). METHODS: A 12-topic survey was distributed to international experts on KDTs in adults consisting of neurologists and dietitians at medical institutions providing KDTs to adults with epilepsy and other neurologic disorders. Panel survey responses were tabulated by the authors to determine the common and disparate practices between institutions and to compare these practices in adults with KDT recommendations in children and the medical literature. Recommendations are based on a combination of clinical evidence and expert opinion regarding management of KDTs. RESULTS: Surveys were obtained from 20 medical institutions with >2,000 adult patients treated with KDTs for epilepsy or other neurologic disorders. Common side effects reported are similar to those observed in children, and recommendations for management are comparable with important distinctions, which are emphasized. Institutions differ with regard to recommended biochemical assessment, screening, monitoring, and concern for long-term side effects, and further investigation is warranted to determine the optimal clinical management. Differences also exist between screening and monitoring practices among adult and pediatric providers. CONCLUSIONS: KDTs may be safe and effective in treating adults with drug-resistant epilepsy, and there is emerging evidence supporting the use in other adult neurologic disorders and general medical conditions as well. Therefore, expert recommendations to guide optimal care are critical as well as further evidence-based investigation.

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions.

BACKGROUND: Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound-particularly for interleukin 6 (IL-6)-possibly due to differences in sex, species/strain, and/or the brain regions studied. METHODS: As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. RESULTS: In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1ß in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1ß. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. CONCLUSIONS: Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

Community Health Centers' Practices, Barriers, and Facilitators for Providing a 1-Year Supply of Oral Contraception on Site.

INTRODUCTION: High-quality family planning services help women to achieve their preferred family size and birth spacing, which in turn leads to improved health outcomes and better quality of life. This study investigates whether women have access to a 1-year supply of oral contraceptives (OCs) on site when they receive care at community health centers and whether states require coverage for a 1-year supply. METHODS: This study used a concurrent, mixed-methods approach, with a single phase of quantitative research (survey of health centers) and two phases of qualitative research (50-state policy environment scan and in-depth interviews). RESULTS: Only three states require coverage for a 1-year supply of OCs under all Medicaid and private insurance coverage mechanisms; the majority of states limit it through at least one mechanism. The survey found that 50.9% of health centers provided OCs on site, and of these, only 29.9% offered up to a 1-year supply at a time. An analysis of interviews revealed that clinician and pharmacist preferences and the organization's overall approach to family planning played a role in these practices. CONCLUSION: This study finds that that only a minority of health centers provide a 1-year supply on site and that a minority of states have rules requiring coverage for a 1-year supply of OCs. To remedy these gaps, change is needed at multiple levels, including health center practices, clinician knowledge and beliefs, federal agency guidance, and state-level insurance policy.

Both CRF1 and CRF2 receptors in the bed nucleus of stria terminalis are involved in baroreflex impairment evoked by chronic stress in rats.

Chronic exposure to adverse events has been proposed as a prominent factor involved in etiology and progression of cardiovascular dysfunctions in humans and animals. However, the neurobiological mechanisms involved are still poorly understood. In this sense, chronic stress has been reported to evoke neuroplasticity in corticotropin-releasing factor (CRF) neurotransmission in several limbic structures, including the bed nucleus of the stria terminalis. However, a possible involvement of BNST CRF neurotransmission in cardiovascular dysfunctions evoked by chronic stress has never been reported. Thus, this study investigated the involvement of CRF1 and CRF2 receptors within the BNST in cardiovascular changes evoked by chronic stress in rats. We identified that exposure to a 10-day chronic variable stress (CVS) protocol decreased expression of both CRF1 and CRF2 receptors within the BNST. These effects were followed by increased arterial pressure and impairment of baroreflex function, but without changes on heart rate. Bilateral microinjection of either the selective CRF1 receptor antagonist CP376395 or the selective CRF2 receptor antagonist antisauvagine-30 into the BNST did not affect CVS-evoked arterial pressure increase. Nevertheless, BNST treatment with CP376395 decreased both tachycardic and bradycardic responses of the baroreflex in non-stressed rats; but these effects were not identified in chronically stressed animals. BNST pharmacological treatment with antisauvagine-30 decreased the reflex tachycardia in control animals, whereas reflex bradycardic response was increased in CVS animals. Altogether, the results reported in the present study indicate that down regulation of both CRF1 and CRF2 receptors within the BNST is involved in baroreflex impairment evoked by chronic stress.

Demographic and exposure characteristics as predictors of serum per- and polyfluoroalkyl substances (PFASs) levels - A community-level biomonitoring project in Pennsylvania.

Per- and polyfluoroalkyl substances (PFASs) are widely used in industrial and consumer products and have been linked to various adverse health effects. Communities near two former military bases in Pennsylvania were exposed to PFAS through contaminated drinking water for several decades. The Pennsylvania Department of Health (DOH) conducted biomonitoring of 235 randomly selected community members living in four public water system (PWS) service areas to evaluate a toolkit developed by the Centers for Disease Control and Prevention (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR). DOH also collected data on participants' demographics, exposure history and self-reported health conditions. Serum PFAS levels were compared with the national averages for 2013-2014 and their relationships with demographic and exposure characteristics were analyzed. Of the 11 PFASs analyzed for, only perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were consistently detected in the serum samples. The average levels of PFOA, PFOS, PFHxS and PFNA among the study participants were 3.13, 10.24, 6.64 and 0.74 µg per liter (µg/L), respectively. Overall, 75, 81, 94 and 59 percent of the study participants had levels exceeding the national average for PFOA (1.94 µg/L), PFOS (4.99 µg/L), PFHxS (1.35 µg/L) and PFNA (0.66 µg/L), respectively. Results indicated associations between serum levels of some PFAS compounds and sex, age, employment in the study area, PWS area, quantity of daily tap water consumption, and length of residence in the study area.

Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy.

Women are at significantly greater risk of developing stress-related disorders such as depression. The increased risk begins during puberty and continues throughout life until menopause, suggesting a role for ovarian hormones in this increased susceptibility. Importantly, inflammation has been gaining momentum in its role in the pathogenesis of depression. Herein, clinical and preclinical studies have been reviewed to better understand how sex differences within the immune system may contribute to exaggerated risk of depression in females. First, studies that investigate the ability of psychologic stress episodes to engage the inflammatory systems both in the brain and periphery are reviewed with a special focus on sex-specific effects. Moreover, studies are discussed that identify whether imbalanced inflammatory milieu contributes to the development of depression in males versus females and whether these effects are regulated by estradiol. Importantly, we propose a locus coeruleus-norepinephrine-cytokine circuit as a conduit through which stress could increase stress susceptibly in females. Finally, the anti-inflammatory capacity of traditional and nontraditional antidepressants is investigated, with the goal of providing a better understanding of pharmacotherapeutics to enhance strategies to personalize antidepressant treatments between the sexes. The studies reviewed herein strongly support the need for further studies to elucidate whether females are especially sensitive to anti-inflammatory compounds as adjuvants to traditional therapies. SIGNIFICANCE STATEMENT: Women have hve an increased risk of developing stress-related disorders such as depression. In this review, literature from clinical and preclinical studies are integrated to define sex differences in stress-induced inflammatory responses as a potential source for the etiology of sex differences in depressive disorders. Moreover, the anti-inflammatory capacity of traditional and nontraditional antidepressants is reviewed to inform on potential pharmacotherapeutic strategies to personalize antidepressant therapy in a sex-dependent manner.