Bcl-xL is required to protect endothelial cells latently infected with KSHV from virus induced intrinsic apoptosis.

Kaposi's Sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi's Sarcoma (KS), a highly vascularized tumor common in AIDS patients and many countries in Africa. KSHV is predominantly in the latent state in the main KS tumor cell, the spindle cell, a cell expressing endothelial cell markers. To identify host genes important for KSHV latent infection of endothelial cells we previously used a global CRISPR/Cas9 screen to identify genes necessary for the survival or proliferation of latently infected cells. In this study we rescreened top hits and found that the highest scoring gene necessary for infected cell survival is the anti-apoptotic Bcl-2 family member Bcl-xL. Knockout of Bcl-xL or treatment with a Bcl-xL inhibitor leads to high levels of cell death in latently infected endothelial cells but not their mock counterparts. Cell death occurs through apoptosis as shown by increased PARP cleavage and activation of caspase-3/7. Knockout of the pro-apoptotic protein, Bax, eliminates the requirement for Bcl-xL. Interestingly, neither Bcl-2 nor Mcl-1, related and often redundant anti-apoptotic proteins of the Bcl-2 protein family, are necessary for the survival of latently infected endothelial cells, likely due to their lack of expression in all the endothelial cell types we have examined. Bcl-xL is not required for the survival of latently infected primary effusion lymphoma (PEL) cells or other cell types tested. Expression of the KSHV major latent locus alone in the absence of KSHV infection led to sensitivity to the absence of Bcl-xL, indicating that viral gene expression from the latent locus induces intrinsic apoptosis leading to the requirement for Bcl-xL in endothelial cells. The critical requirement of Bcl-xL during KSHV latency makes it an intriguing therapeutic target for KS tumors.

Epigenetic Aging and Musculoskeletal Outcomes in a Cohort of Women Living With HIV.

BACKGROUND: The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. METHODS: We measured DNA methylation age using the Infinium MethylationEPIC BeadChip in a cohort from the Women's Interagency HIV Study (n = 190) with measures of bone mineral density (BMD) and physical function. We estimated 6 biomarkers of epigenetic aging-epigenetic age acceleration (EAA), extrinsic EAA, intrinsic EAA, GrimAge, PhenoAge, and DNA methylation-estimated telomere length-and evaluated associations of epigenetic aging measures with BMD and physical function. We also performed epigenome-wide association studies to examine associations of DNA methylation signatures with BMD and physical function. RESULTS: This study included 118 WWH (mean age, 49.7 years; 69% Black) and 72 without HIV (mean age, 48.9 years; 69% Black). WWH had higher EAA (mean ± SD, 1.44 ± 5.36 vs -1.88 ± 5.07; P < .001) and lower DNA methylation-estimated telomere length (7.13 ± 0.31 vs 7.34 ± 0.23, P < .001) than women without HIV. There were no significant associations between accelerated epigenetic aging and BMD. Rather, measures of accelerated epigenetic aging were associated with lower physical function. CONCLUSIONS: Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.

Subclinical Atherosclerosis Across the Menopausal Transition in Women With and Without HIV.

The menopausal transition is a pivotal time of cardiovascular risk, but knowledge is limited in HIV. We studied longitudinal carotid artery intima-media thickness (CIMT) in the Women's Interagency HIV Study (2004-2019; 979 women/3247 person-visits; 72% with HIV). Among women with HIV only, those who transitioned had greater age-related CIMT progression compared to those remaining premenopausal (difference in slope = 1.64 µm/year, P = .002); and CIMT increased over time in the pretransition (3.47 µm/year, P = .002) and during the menopausal transition (9.41 µm/year, P < .0001), but not posttransition (2.9 µm/year, P = .19). In women with HIV, menopause may accelerate subclinical atherosclerosis as measured by CIMT.

Single-cell transcriptomic and T cell antigen receptor analysis of human cytomegalovirus (hCMV)-specific memory T cells reveals effectors and pre-effectors of CD8+- and CD4+-cytotoxic T cells.

Latent human cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune-compromised individuals. Although T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in hCMV immunity is lacking. Here, in an unbiased manner, we characterized over 8000 hCMV-reactive peripheral memory T cells isolated from seropositive human donors, at a single-cell resolution by analysing their single-cell transcriptomes paired with the T cell antigen receptor (TCR) repertoires. The hCMV-reactive T cells were highly heterogeneous and consisted of different developmental and functional memory T cell subsets such as, long-term memory precursors and effectors, T helper-17, T regulatory cells (TREGs) and cytotoxic T lymphocytes (CTLs) of both CD4 and CD8 origin. The hCMV-specific TREGs, in addition to being enriched for molecules known for their suppressive functions, showed enrichment for the interferon response signature gene sets. The hCMV-specific CTLs were of two types, the pre-effector- and effector-like. The co-clustering of hCMV-specific CD4-CTLs and CD8-CTLs in both pre-effector as well as effector clusters suggest shared transcriptomic signatures between them. The huge TCR clonal expansion of cytotoxic clusters suggests a dominant role in the protective immune response to CMV. The study uncovers the heterogeneity in the hCMV-specific memory T cells revealing many functional subsets with potential implications in better understanding of hCMV-specific T cell immunity. The data presented can serve as a knowledge base for designing vaccines and therapeutics.

Versatile and Remotely Controllable Light-Induced Coagulation of Particles Under Flow in a 2D Channel.

On-demand switch on/off blood clogging is of paramount importance for the survival of mammals, for example as a quick response to seal damage wounds to minimize their bleeding rate. This mechanism is a complex chain process from initiated red blood cell aggregation at the target location (open wound) that quickly seals on a macroscopic scale the damaged flash. Inspired by nature an on-demand switchable particle clogging mechanism is developed with high spatial resolution down to micrometer size using light as an external non-invasive stimulation. Particle clogging can be adjusted on demand strong enough to even withstand pressure-driven fluid flow, additionally building up walls of aggregated particles, which stop the momentum of big particles under shear. The principle relies on a photosensitive surfactant, which induces under light illumination a long-ranged lateral attractive phoretic-osmotic activity of silica microparticles forcing them to aggregate. The strength of aggregation and therefore motion reduction or even stop of the particles against the fluid flow depends on the ratio between the aggregation strength and the velocity of the particles. The aggregation strength can be precisely controlled by the applied light intensity and adjusted particle concentration. Increasing both parameters results in a stronger aggregation tendency.

Corrected and republished from: "VP4 Is a Determinant of Alpha-Defensin Modulation of Rotaviral Infection".

IMPORTANCE: Rotavirus is a leading cause of severe diarrhea in young children. Like other fecal-oral pathogens, rotaviruses encounter abundant, constitutively expressed defensins in the small intestine. These peptides are a vital part of the vertebrate innate immune system. By investigating the impact that defensins from multiple species have on the infectivity of different strains of rotavirus, we show that some rotaviral infections can be inhibited by defensins. We also found that rotaviruses may have evolved resistance to defensins in the intestine of their host species, and some even appropriate defensins to increase their infectivity. Because rotaviruses infect a broad range of animals and rotaviral infections are highly prevalent in children, identifying immune defenses against infection and how they vary across species and among viral genotypes is important for our understanding of the evolution, transmission, and zoonotic potential of these viruses as well as the improvement of vaccines.

A Single Surface-Exposed Amino Acid Determines Differential Neutralization of AAV1 and AAV6 by Human Alpha-Defensins.

Adeno-associated viruses (AAVs) are being developed as gene therapy vectors due to their low pathogenicity and tissue tropism properties. However, the efficacy of these vectors is impeded by interactions with the host immune system. One potential immune barrier to vector transduction is innate immune host defense peptides, such as alpha-defensins, which are potent antiviral agents against other nonenveloped viruses. To investigate the interaction between AAVs and alpha-defensins, we utilized two closely related AAV serotypes, AAV1 and AAV6. Although their capsids differ by only six residues, these two serotypes exhibit markedly different tissue tropisms and transduction efficiencies. Using two abundant human alpha-defensins, enteric human defensin 5 (HD5) and myeloid human neutrophil peptide 1 (HNP1), we found both serotype-specific and defensin-specific effects on AAV infection. AAV6 infection was uniformly neutralized by both defensins at low micromolar concentrations; however, inhibition of AAV1 infection was profoundly influenced by the timing of defensin exposure to the virus relative to viral attachment to the cell. Remarkably, these differences in the defensin-dependent infection phenotype between the viruses are completely dictated by the identity of a single, surface-exposed amino acid (position 531) that varies between the two serotypes. These findings reveal a determinant for defensin activity against a virus with unprecedented precision. Furthermore, they provide a rationale for the investigation of other AAV serotypes not only to understand the mechanism of neutralization of defensins against AAVs but also to design more efficient vectors. IMPORTANCE The ability of adeno-associated viruses (AAVs) to infect and deliver genetic material to a range of cell types makes them favorable gene therapy vectors. However, AAV vectors encounter a wide variety of host immune factors throughout the body, which can impede efficient gene delivery. One such group of factors is the alpha-defensins, which are a key component of the innate immune system that can directly block viral infection. By studying the impact that alpha-defensins have on AAV infection, we found that two similar AAV serotypes (AAV1 and AAV6) have different sensitivities to inhibition. We also identified a single amino acid (position 531) that differs between the two AAV serotypes and is responsible for mediating their defensin sensitivity. By investigating the effects that host immune factors have on AAV infection, more efficient vectors may be developed to evade intervention by the immune system prior to gene delivery.

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Competition between Self-Assembly and Phase Separation Governs High-Temperature Condensation of a DNA Liquid.

In many biopolymer solutions, attractive interactions that stabilize finite-sized clusters at low concentrations also promote phase separation at high concentrations. Here we study a model biopolymer system that exhibits the opposite behavior, whereby self-assembly of DNA oligonucleotides into finite-sized, stoichiometric clusters tends to inhibit phase separation. We first use microfluidics-based experiments to map a novel phase transition in which the oligonucleotides condense as the temperature increases at high concentrations of divalent cations. We then show that a theoretical model of competition between self-assembly and phase separation quantitatively predicts changes in experimental phase diagrams arising from DNA sequence perturbations. Our results point to a general mechanism by which self-assembly shapes phase boundaries in complex biopolymer solutions.

HealthCall: Smartphone Enhancement of Brief Interventions to Improve HIV Medication Adherence Among Patients in HIV Care.

Heavy drinking among people living with HIV (PLWH) reduces ART adherence and worsens health outcomes. Lengthy interventions are not feasible in most HIV care settings, and patients infrequently follow referrals to outside treatment. Utilizing visual and video features of smartphone technology, we developed HealthCall as an electronic means of increasing patient involvement in a brief intervention to reduce drinking and improve ART adherence. The objective of the current study is to evaluate the efficacy of HealthCall to improve ART adherence among PLWH who drink heavily when paired with two brief interventions: the National Institute on Alcoholism and Alcohol Abuse (NIAAA) Clinician's Guide (CG) or Motivational Interviewing (MI). Therefore, we conducted a 1:1:1 randomized trial among 114 participants with alcohol dependence at a large urban HIV clinic. Participants were randomized to one of three groups: (1) CG only (n = 37), (2) CG and HealthCall (n = 38), or (3) MI and HealthCall (n = 39). Baseline interventions targeting drinking reduction and ART adherence were ~ 25 min, with brief (10-15 min) booster sessions at 30 and 60 days. The outcome was ART adherence assessed using unannounced phone pill-count method (possible adherence scores: 0-100%) at 30-day, 60-day, 3, 6, and 12 months. Analyses were conducted using generalized linear mixed models with pre-planned contrasts. Of the 114 enrolled patients, 58% were male, 75% identified as Black/African American, 28% were Hispanic, and 62% had less than a high school education. The mean age was 47.5 years (standard deviation [SD] 10 years) and the mean number of years since they were diagnosed with HIV was 18.6 (SD 7.6). Participants assigned to HealthCall to extend the CG had increased levels of ART adherence at 60-day and 6-month follow-up (compared to CG only), although there was no statistically significant difference by 12-month follow-up. Participants who were assigned to HealthCall to extend the MI never had statistically significant higher levels of ART adherence. These results suggest that the use of a smartphone app can be used to initially extend the reach of a brief drinking intervention to improve ART adherence over a short period of time; however, sustained long-term improvements in ART adherence after intervention activity ends remains a challenge.

Examining associations between disordered eating and harmful substance use in a nationally representative sample of US veterans.

OBJECTIVE: The association between eating disorders (EDs) and harmful substance use (substance use that causes psychosocial impairment) is well recognized in the literature, and military veterans may be at heightened risk for both issues due to deployment-related stressors. However, little is known about which ED-related symptoms are associated with harmful substance use in veterans, and whether gender plays a differential role in this relationship. Our aims were to: (1) examine gender differences in ED-related symptoms; and (2) examine whether ED-related symptoms differentially predict harmful substance use in US veteran men and women who had recently separated from service. METHOD: This study was based on a nationally representative four-wave longitudinal sample of post-9/11 veterans (N = 835; 61.2% female). Longitudinal mixed modeling was used to test whether specific ED-related behaviors at baseline predicted harmful substance use at follow-ups. RESULTS: We replicated gendered patterns of ED-related symptoms observed in civilian populations, wherein men had higher weight-and-body-related concerns (including excessive exercise and muscle building) and negative attitude toward obesity, and women had higher bulimic and restricting symptoms. For women, alcohol, drug, and marijuana problems were predicted by higher bulimic symptoms, whereas for men, these problems were predicted by higher restricting symptoms. CONCLUSION: Gender played a differential role in the relationship between EDs and harmful substance use. Bulimic symptoms were the most robust predictor for harmful substance use among veteran women, whereas restricting was the most robust predictor for harmful substance use among veteran men. PUBLIC SIGNIFICANCE: The current study found that veteran women had higher bulimic symptoms (characterized by binge eating and purging) and restricting than veteran men. In women, bulimic symptoms predicted future harmful use of alcohol, marijuana, and other drugs. In contrast, veteran men had higher weight-and-body-related concerns (characterized by excessive exercise and muscle building) than veteran women. In men, restricting symptoms predicted future harmful use of alcohol, marijuana, and other drugs.

Understanding community provider practices in diagnosing and treating atypical anorexia nervosa: A mixed methods study.

OBJECTIVE: There is a lack of consensus in defining "significant weight loss" when diagnosing atypical anorexia nervosa (atypical AN) and no guidelines exist for setting target weight (TW). The current study aimed to identify community providers' practices related to the diagnosis of atypical AN and the determination of TW. A secondary aim was to evaluate whether professional discipline impacted "significant weight loss" definitions. METHOD: A variety of providers (N = 141; 96.4% female) completed an online survey pertaining to diagnostic and treatment practices with atypical AN. Descriptive statistics were computed to characterize provider-based practices and Fisher's exact tests were used to test for differences in diagnostic practices by professional discipline. Thematic analysis was used to examine open-ended questions. RESULTS: Most (63.97%) providers diagnosed atypical AN in the absence of any weight loss if other AN criteria were met, but doctoral-level psychologists and medical professionals were less likely to do so compared to nutritional or other mental health professionals. Most providers found weight gain was only sometimes necessary for atypical AN recovery. Qualitative responses revealed providers found atypical AN to be a stigmatizing label that was not taken seriously. Providers preferred to use an individualized approach focused on behaviors, rather than weight when diagnosing and treating atypical AN. DISCUSSION: Lack of diagnostic clarity and concrete treatment guidelines for atypical AN may result in substantial deviations from the DSM-5-TR criteria in real-world practice. Clinically useful diagnostic definitions for restrictive eating disorders and evidence-based treatment guidelines for TW and/or other relevant recovery metrics are needed. PUBLIC SIGNIFICANCE: The current study found variability in how community providers diagnose and determine target recovery weight for atypical anorexia nervosa (atypical AN). Many providers viewed the diagnosis of atypical AN as stigmatizing and preferred to focus on behaviors, rather than weight. This study underscores the importance of creating a clinically useful diagnostic definition and guidelines for recovery for atypical AN backed by empirical evidence that providers may implement in practice.

Microbial Nanotechnology for Precision Nanobiosynthesis: Innovations, Current Opportunities and Future Perspectives for Industrial Sustainability.

A new area of biotechnology is nanotechnology. Nanotechnology is an emerging field that aims to develope various substances with nano-dimensions that have utilization in the various sectors of pharmaceuticals, bio prospecting, human activities and biomedical applications. An essential stage in the development of nanotechnology is the creation of nanoparticles. To increase their biological uses, eco-friendly material synthesis processes are becoming increasingly important. Recent years have shown a lot of interest in nanostructured materials due to their beneficial and unique characteristics compared to their polycrystalline counterparts. The fascinating performance of nanomaterials in electronics, optics, and photonics has generated a lot of interest. An eco-friendly approach of creating nanoparticles has emerged in order to get around the drawbacks of conventional techniques. Today, a wide range of nanoparticles have been created by employing various microbes, and their potential in numerous cutting-edge technological fields have been investigated. These particles have well-defined chemical compositions, sizes, and morphologies. The green production of nanoparticles mostly uses plants and microbes. Hence, the use of microbial nanotechnology in agriculture and plant science is the main emphasis of this review. The present review highlights the methods of biological synthesis of nanoparticles available with a major focus on microbially synthesized nanoparticles, parameters and biochemistry involved. Further, it takes into account the genetic engineering and synthetic biology involved in microbial nanobiosynthesis to the construction of microbial nanofactories.

Pivoting from in-person to phone survey assessment of alcohol and substance use: effects on representativeness in a United States prospective cohort of women living with and without HIV.

Background: Many clinical and population-based research studies pivoted from in-person assessments to phone-based surveys due to the COVID-19 pandemic. The impact of these transitions on survey response remains understudied, especially for people living with HIV. Given that there are gender-specific trends in alcohol and substance use, it is particularly important to capture these data for women.Objective: Identify factors associated with responding to an alcohol and substance use phone survey administered during the COVID-19 pandemic in the Women's Interagency HIV Study, a multicenter US prospective cohort of women living with and without HIV.Methods: We used multivariable logistic regression to assess for associations of pre-pandemic (April-September 2019) sociodemographic factors, HIV status, housing status, depressive symptoms, alcohol use, and substance use with response to an early-pandemic (August-September 2020) phone survey.Results: Of 1,847 women who attended an in-person visit in 2019, 78% responded to a phone survey during the pandemic. The odds of responding were lower for women of Hispanic ethnicity (aOR 0.47 95% CI 0.33-0.66, ref=Black/African American) and those who reported substance use (aOR 0.63 95% CI 0.41-0.98). By contrast, the odds were higher for White women (aOR 1.64 95% CI 1.02-2.70, ref=Black/African American) and those with stable housing (aOR 1.74 95% CI 1.24-2.43).Conclusions: Pivoting from an in-person to phone-administered alcohol and substance use survey may lead to underrepresentation of key subpopulations of women who are often neglected in substance use and HIV research. As remote survey methods become more common, investigators need to ensure that the study population is representative of the target population.

Impact of enacted stigma on mental health, substance use, and HIV-related behaviors among sexual minority men in Zambia.

Sexual minority men (SMM) in Zambia face significant challenges including stigma, discrimination, and mental health issues, which further impact their HIV-related risk behaviors. This study aimed to investigate the associations between enacted stigma, substance abuse, HIV-related behaviors, and mental health (i.e., depression, anxiety, and post-traumatic stress disorder [PTSD] symptoms) among SMM in Zambia. SMM aged 18-35 years who reported having multiple and/or concurrent sexual partners or low and/or inconsistent condom use in the past three months were recruited from four districts in Zambia between February and November 2021. Participants completed an anonymous interviewer-administered survey. Key variables of interest were compared between participants with higher vs. lower levels of enacted stigma. Independent samples t-tests were used for continuous variables, and chi-squared tests were used for categorical variables. A total of 197 eligible SMM participated in the study (mean age = 24.41 years). Participants with a higher level of enacted stigma showed a higher level of anxiety symptoms (χ2 = 12.91, p ≤ .001), PTSD symptoms (χ2 = 7.13, p < .01), tobacco use (χ2 = 10.47, p < .01), cannabis use (χ2 = 5.90, p < .05), and a higher number of sexual partners (t = 1.99, p < .05) in the past three months. Stigma reduction interventions may help mitigate substance abuse, HIV-related behaviors, and adverse mental health outcomes among SMM in Zambia. Health care providers, especially psychiatric-mental health nurses, can incorporate strategies for recognizing and addressing stigma into their practice through training and integrate multiple resources to create an inclusive and non-judgmental environment for SMM to improve their well-being.

Association of Gut Microbiota With Objective Sleep Measures in Women With and Without Human Immunodeficiency Virus Infection: The IDOze Study.

BACKGROUND: Poor sleep health is an underrecognized health challenge, especially for people with human immunodeficiency virus (HIV). Gut microbiota related to sleep are underinvestigated. METHODS: The IDOze microbiota substudy included 190 women (114 with HIV and 76 without HIV). Wrist actigraphy measured total sleep duration, sleep efficiency, number of wake bouts, wake after sleep onset, fragmentation index, and sleep timing. 16S rRNA gene sequencing identified gut microbial genera. Analysis of compositions of microbiomes with bias correction was used to investigate cross-sectional associations between gut microbiota and sleep. Abundances of sleep-related gut microbial genera were compared between women with and without HIV. RESULTS: Enrichment of 7 short-chain fatty acid-producing genera (eg, Butyricimonas, Roseburia, and Blautia) was associated with lower fragmentation index. Enrichment of 9 genera (eg, Dorea) was associated with lower sleep efficiency and/or more wake after sleep onset. Enrichment of proinflammatory Acidaminococcus was associated with late sleep midpoint and offset time. These associations were largely consistent regardless of HIV status. The abundance of Butyricimonas was lower among women with HIV compared to those without HIV. CONCLUSIONS: Seventeen genera were identified to be associated with sleep continuity or timing. Butyricimonas, a potentially beneficial genus associated with sleep continuity, was less abundant among women with HIV.

Body Composition Changes Over the Menopausal Transition in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Women are at risk for weight gain during the transition to menopause, but few have examined the contribution of menopause to weight gain in women with human immunodeficiency virus (WWH). METHODS: From 2000 to 2013, participants (621 WWH; 218 without HIV [WWOH]) from the Women's Interagency HIV Study were categorized by menopausal phase using serial measures of anti-Müllerian hormone (AMH). Multivariable linear mixed models examined the association of menopausal phase with body mass index (BMI) and waist circumference (WC) trajectory, stratified by HIV status. RESULTS: In models controlled for chronologic age, the estimated effects (95% confidence interval) of menopausal phase on annual rate of BMI change across early perimenopause, late perimenopause, and menopause, respectively, compared to premenopause were -0.55% (-.80 to -.30), -0.29% (-.61 to .03), and -0.67% (-1.12 to -.20) in WWH, whereas estimated effects were 0.43% (-.01 to .87) and 0.15% (-.42 to .71) across early and late perimenopause, respectively, and -0.40% (-1.24 to .45) across menopause in WWOH. The estimated effects on rate of WC change were negative across early perimenopause (-0.21% [-.44 to .03]) and menopause (-0.12% [-.5 to .26]) and positive across late perimenopause (0.18% [-.10 to .45]) in WWH, and positive across all 3 menopausal phases in WWOH, but these effects were not statistically significant. CONCLUSIONS: In WWH, the menopausal transition was associated with BMI and WC trajectories that were mostly in a negative direction and opposite from WWOH after adjusting for age, suggesting that HIV blunts weight gain during the menopausal transition.

Health Insurance and Initiation of Direct-Acting Antivirals for Hepatitis C in US Women With Human Immunodeficiency Virus.

BACKGROUND: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) is well tolerated, cost-effective, and yields high sustained virologic response rates, yet it has remained financially inaccessible to many patients. METHODS: Participants of the Women's Interagency HIV Study (an observational US cohort) with human immunodeficiency virus (HIV) and HCV (RNA+) reporting no prior hepatitis C treatment were followed for DAA initiation (2015-2019). We estimated risk ratios (RRs) of the relationship between time-varying health insurance status and DAA initiation, adjusting for confounders with stabilized inverse probability weights. We also estimated weighted cumulative incidences of DAA initiation by health insurance status. RESULTS: A total of 139 women (74% Black) were included; at baseline, the median age was 55 years and 86% were insured. Most had annual household incomes ≤$18 000 (85%); advanced liver fibrosis (21%), alcohol use (45%), and recreational drug use (35%) were common. Across 439 subsequent semiannual visits, 88 women (63%) reported DAA initiation. Compared with no health insurance, health insurance increased the likelihood of reporting DAA initiation at a given visit (RR, 4.94; 95% confidence limit [CL], 1.92 to 12.8). At 2 years, the weighted cumulative incidence of DAA initiation was higher among the insured (51.2%; 95% CL, 43.3% to 60.6%) than the uninsured (3.5%; 95% CL, 0.8% to 14.6%). CONCLUSIONS: Accounting for clinical, behavioral, and sociodemographic factors over time, health insurance had a substantial positive effect on DAA initiation. Interventions to increase insurance coverage should be prioritized to increase HCV curative therapy uptake for persons with HIV.

Menopausal Hormone Therapy and Subclinical Cardiovascular Disease in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Estrogen-based hormone therapy (HT) may have beneficial cardiovascular effects when initiated in early menopause. This has not been examined in women with human immunodeficiency virus (HIV), who have heightened immune activation and cardiovascular risks. METHODS: Among 609 postmenopausal women (1234 person-visits) in the Women's Interagency HIV Study, we examined the relationship of ever HT use (oral, patch, or vaginal) with subclinical atherosclerosis: carotid artery intima-media thickness (CIMT), distensibility, and plaque assessed via repeated B-mode ultrasound imaging (2004-2013). We also examined associations of HT with cross-sectional biomarkers of immune activation and D-dimer. Statistical models were adjusted for sociodemographic, behavioral, and cardiometabolic factors. RESULTS: Women (mean age, 51 years; 80% HIV positive) who ever used HT at baseline were older, and more likely to be non-Hispanic White and report higher income, than never-users. Women who ever used HT had 43% lower prevalence of plaque (prevalence ratio, 0.57 [95% confidence interval {CI}, .40-.80]; P < .01), 2.51 µm less progression of CIMT per year (95% CI, -4.60, to -.41; P = .02), and marginally lower incidence of plaque over approximately 7 years (risk ratio, 0.38 [95% CI, .14-1.03; P = .06), compared with never-users, adjusting for covariates; ever HT use was not associated with distensibility. These findings were similar for women with and without HIV. Ever HT use was associated with lower serum D-dimer, but not with biomarkers of immune activation after covariate adjustment. CONCLUSIONS: HT may confer a subclinical cardiovascular benefit in women with HIV. These results begin to fill a knowledge gap in menopausal care for women with HIV, in whom uptake of HT is very low.

Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.