Cortical Transcriptomic Alterations in Association With Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder.

BACKGROUND: The molecular pathology underlying posttraumatic stress disorder (PTSD) remains unclear mainly due to a lack of human PTSD postmortem brain tissue. The orexigenic neuropeptides ghrelin, neuropeptide Y, and hypocretin were recently implicated in modulating negative affect. Drawing from the largest functional genomics study of human PTSD postmortem tissue, we investigated whether there were molecular changes of these and other appetitive molecules. Further, we explored the interaction between PTSD and body mass index (BMI) on gene expression. METHODS: We analyzed previously reported transcriptomic data from 4 prefrontal cortex regions from 52 individuals with PTSD and 46 matched neurotypical controls. We employed gene co-expression network analysis across the transcriptomes of these regions to uncover PTSD-specific networks containing orexigenic genes. We utilized Ingenuity Pathway Analysis software for pathway annotation. We identified differentially expressed genes (DEGs) among individuals with and without PTSD, stratified by sex and BMI. RESULTS: Three PTSD-associated networks (P < .01) contained genes in signaling families of appetitive molecules: 2 in females and 1 in all subjects. We uncovered DEGs (P < .05) between PTSD and control subjects stratified by sex and BMI with especially robust changes in males with PTSD with elevated vs normal BMI. Further, we identified putative upstream regulators (P < .05) driving these changes, many of which were enriched for involvement in inflammation. CONCLUSIONS: PTSD-associated cortical transcriptomic modules contain transcripts of appetitive genes, and BMI further interacts with PTSD to impact expression. DEGs and inferred upstream regulators of these modules could represent targets for future pharmacotherapies for obesity in PTSD.

Immune Correlates of Diffuse Myocardial Fibrosis and Diastolic Dysfunction Among Aging Women With Human Immunodeficiency Virus.

Human immunodeficiency virus (HIV) imparts increased heart failure risk to women. Among women with HIV (WHIV), immune pathways relating to heart failure precursors may intimate targets for heart failure prevention strategies. Twenty asymptomatic, antiretroviral-treated WHIV and 14 non-HIV-infected women matched on age and body mass index underwent cardiac magnetic resonance imaging and immune phenotyping. WHIV (vs non-HIV-infected women) exhibited increased myocardial fibrosis (extracellular volume fraction, 0.34 ± 0.06 vs 0.29 ± 0.04; P = .002), reduced diastolic function (diastolic strain rate, 1.10 ± 0.23 s-1 vs 1.39 ± 0.27 s-1; P = .003), and heightened systemic monocyte activation. Among WHIV, soluble CD163 levels correlated with myocardial fibrosis (r = 0.53; P = .02), while circulating inflammatory CD14+CD16+ monocyte CCR2 expression related directly to myocardial fibrosis (r = 0.48; P = .04) and inversely to diastolic function (r = -0.49; P = .03). Clinical Trials Registration. NCT02874703.

Barriers to Identifying Learning Disabilities: A Qualitative Study of Clinicians and Educators.

OBJECTIVE: The estimated prevalence of learning disabilities (LDs) is nearly 8% of all children. Fewer than 5% of all children are diagnosed in public schools, jeopardizing remediation. We aimed to identify barriers affecting front-line child-facing professionals in detecting LDs in school-aged children. METHODS: We conducted a qualitative study with individual interviews of 40 professionals from different areas of the United States identified through theoretical sampling (20 educators, 10 pediatricians, and 10 child mental health clinicians). Clinicians represented academic and community settings, and educators represented public, private, and charter schools. Twenty had expertise in assessing LDs; 20 were generalists without specific training. We also endeavored to maximize representation across age, gender, race and ethnicity, and location. We analyzed transcripts utilizing grounded theory and identified themes reflecting barriers to detection. RESULTS: Themes and sub-themes included: 1) areas requiring improved professional education (misconceptions that may hinder detection, confounding factors that may mask LDs, and need for increasing engagement of parents or guardians in identifying LDs) and 2) systemic barriers (time constraints that limited professionals' ability to advocate for children and to delve into their emotional experiences, inconsistent guidelines across institutions and inconsistent perceptions of professional responsibility for detection, and confusion surrounding screening tools and lack of screening by some professionals in the absence of overt problems). CONCLUSIONS: Clinicians and other child-facing professionals may benefit from augmented training in screening and identification and enhanced evidence-based and institutional guidance. These efforts could increase efficiency and perceived responsibility for recognition and improve earlier detection.

Ghrelin as a Stress Hormone: Implications for Psychiatric Illness.

The stress response is an adaptive means of maintaining physiological homeostasis in the face of changing environmental conditions. However, protracted recruitment of stress systems can precipitate wear and tear on the body and may lead to many forms of disease. The mechanisms underlying the connection between chronic stress and disease are not fully understood and are likely multifactorial. In this review, we evaluate the possibility that the hormone ghrelin may contribute to the pathophysiology that follows chronic stress. Since ghrelin was discovered as a pro-hunger hormone, many additional roles for it have been identified, including in learning, memory, reward, and stress. We describe the beneficial effects that ghrelin exerts in healthy mammals and discuss that prolonged exposure to ghrelin has been linked to maladaptive responses and behaviors in the realm of psychiatric disease. In addition, we consider whether chronic stress-associated altered ghrelin signaling may enhance susceptibility to posttraumatic stress disorder and comorbid conditions such as major depressive disorder and alcohol use disorder. Finally, we explore the possibility that ghrelin-based therapeutics could eventually form the basis of a treatment strategy for illnesses that are linked to chronic stress and potentially also ghrelin dysregulation, and we identify critical avenues for future research in this regard.

Intramyocardial Triglycerides Among Women With vs Without HIV: Hormonal Correlates and Functional Consequences.

CONTEXT: Women with HIV (WHIV) on anti-retroviral therapy (ART) are living longer but facing heightened vulnerability to heart failure. OBJECTIVE: We investigated metabolic/hormonal/immune parameters relating to diastolic dysfunction-a precursor to heart failure-among WHIV without known cardiovascular disease (CVD). DESIGN AND OUTCOME MEASURES: Nineteen ART-treated WHIV and 11 non-HIV-infected women without known CVD enrolled and successfully completed relevant study procedures [cardiac magnetic resonance spectroscopy (MRS) and cardiac MRI]. Groups were matched on age and body mass index. Primary outcome measures included intramyocardial triglyceride content (cardiac MRS) and diastolic function (cardiac MRI). Relationships between intramyocardial triglyceride content and clinical parameters were also assessed. RESULTS: Among WHIV (vs non-HIV-infected women), intramyocardial triglyceride content was threefold higher [1.2 (0.4, 3.1) vs 0.4 (0.1, 0.5)%, P = 0.01], and diastolic function was reduced (left atrial passive ejection fraction: 27.2 ± 9.6 vs 35.9 ± 6.4%, P = 0.007). There was a strong inverse relationship between intramyocardial triglyceride content and diastolic function (ρ = -0.62, P = 0.004). Among the whole group, intramyocardial triglyceride content did not relate to chronologic age but did increase across the reproductive aging spectrum (P = 0.02). HIV status and reproductive aging status remained independent predictors of intramyocardial triglyceride content after adjusting for relevant cardiometabolic parameters (overall model R2 = 0.56, P = 0.003; HIV status P = 0.01, reproductive aging status P = 0.02). CONCLUSIONS: For asymptomatic WHIV, increased intramyocardial triglyceride content is associated with diastolic dysfunction. Moreover, relationships between intramyocardial triglyceride accumulation and women's reproductive aging are noted.

Epicardial adipose tissue volume and cardiovascular risk indices among asymptomatic women with and without HIV.

BACKGROUND: Mechanisms underlying the heightened myocardial infarction risk among HIV-infected women (versus non-HIV-infected women) remain unclear. Our objectives were to assess epicardial adipose tissue (EAT) volume and its associations among asymptomatic women with and without HIV. METHODS: A total of 55 HIV-infected and 27 non-HIV-infected women without known cardiovascular disease who underwent cardiac CT and metabolic/immune phenotyping were included. EAT volume derived from CT was compared among women with and without HIV, and within-group EAT associations were assessed. Next, immune and atherosclerotic plaque parameters were compared among groups stratified by HIV serostatus and high/low EAT (defined in reference to median EAT for each serostatus group). RESULTS: Asymptomatic HIV-infected women and age-matched non-HIV-infected women with comparable mean body mass index (28 ±1 versus 29 ±1 kg/m2) had similar median (IQR) volumes of EAT (54 [41-79] versus 65 [41-78] cm3; P>0.05); however, different within-group associations were noted. Markers of monocyte activation/arterial inflammation differed by HIV serostatus/EAT volume subgroup (CXCL10 [P=0.02], sCD163 [P=0.004], sCD14 [P=0.03], Lp-PLA2 [P=0.04]; P for overall ANOVA) and were highest among HIV-infected women with excess EAT (versus HIV-infected women without excess EAT, non-HIV-infected women with excess EAT and non-HIV-infected women without excess EAT). The percentage of segments with non-calcified coronary plaque also differed by HIV serostatus/EAT volume subgroup and was highest among HIV-infected women with excess EAT. CONCLUSIONS: Asymptomatic women with and without HIV have similar volumes of EAT, but drivers of EAT may differ between groups. HIV-infected women with excess EAT have highest-level immune activation and the highest percentage of non-calcified plaque. Future studies are needed to determine whether EAT contributes pathogenetically to HIV-associated cardiovascular disease in women.

Sex Differences in Subclinical Coronary Atherosclerotic Plaque Among Individuals With HIV on Antiretroviral Therapy.

BACKGROUND: In high-resource settings, the HIV-attributable risk of myocardial infarction (MI) is higher among women than among men. The extent to which unique mechanisms contribute to MI risk among women vs. men with HIV remains unclear. METHODS: Subclinical coronary atherosclerotic plaque characteristics-including high-risk morphology plaque features-were compared among 48 HIV-infected women [48 (41, 54) years] and 97 HIV-infected men [48 (42, 52) years] on stable antiretroviral therapy (ART) without known cardiovascular disease. These individuals had previously completed coronary computed tomography angiography and metabolic/immune phenotyping as part of a prospective study. RESULTS: Extending previous analyses, now focusing exclusively on ART-treated participants, we found that HIV-infected women had a lower prevalence of any subclinical coronary atherosclerotic plaque (35% vs. 62%, P = 0.003) and a lower number of segments with plaque (P = 0.01), compared with HIV-infected men. We also report for the first time that ART-treated HIV-infected women had a lower prevalence of high-risk positively remodeled plaque (25% vs. 51%, P = 0.003) and a lower number of positively remodeled plaque segments (P = 0.002). In models adjusting for cardiovascular risk factors, we further showed that male sex remained associated with any coronary plaque [odds ratio 3.8, 95% confidence interval: (1.4 to 11.4)] and with positively remodeled plaque [odds ratio 3.7, 95% confidence interval: (1.4, 10.9)]. CONCLUSIONS: ART-treated HIV-infected women (vs. HIV-infected men) had a lower prevalence and burden of subclinical coronary plaque and high-risk morphology plaque. Thus, unique sex-specific mechanisms beyond subclinical plaque may drive the higher HIV-attributable risk of MI among women vs. men.

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV.

BACKGROUND: Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis. METHODS: We compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque. RESULTS: PCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters. CONCLUSIONS: Among HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden. CLINICAL TRIAL REGISTRATION: NCT00455793.