Cholinergic signaling via the α7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation.

BACKGROUND: The involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the α7nAChR in the regulation of other aspects of the immune response, including the recruitment of monocytes/macrophages to the site of inflammation remained poorly understood. RESULTS: We observed an increased mortality in α7nAChR-deficient mice (compared with wild-type controls) in mice with endotoxemia, which was paralleled with a significant reduction in the number of monocyte-derived macrophages in the lungs. Corroborating these results, fluorescently labeled α7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. α7nAChR deficiency did not affect monocyte 2D transmigration across an endothelial monolayer, but it significantly decreased the migration of macrophages in a 3D fibrin matrix. In vitro analysis of major adhesive receptors (L-selectin, ß1 and ß2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin αM and αX on α7nAChR-deficient macrophages. Decreased expression of αMß2 was confirmed on fluorescently labeled, adoptively transferred α7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for α7nAChR-mediated migration. CONCLUSIONS: We demonstrate a novel role for the α7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation.

PrEP Uptake and Methamphetamine Use Patterns in a 4-Year U.S. National Prospective Cohort Study of Sexual and Gender Minority People, 2017-2022.

Methamphetamine use is on the rise among sexual and gender minority people who have sex with men (SGMSM), escalating their HIV risk. Despite pre-exposure prophylaxis (PrEP) being an effective biomedical HIV prevention tool, its uptake in relation to methamphetamine use patterns in SGMSM has not been studied. In a U.S. cohort study from 2017 to 2022, 6,253 HIV-negative SGMSM indicated for but not using PrEP were followed for four years. Methamphetamine use was categorized (i.e., newly initiated, persistently used, never used, used but quit), and PrEP uptake assessed using generalized estimating equation (GEE), adjusted for attrition. Participants had a median age of 29, with 51.9% White, 11.1% Black, 24.5% Latinx, and 12.5% other races/ethnicities. Over the four years, PrEP use increased from 16.3 to 27.2%. GEE models identified risk factors including housing instability and food insecurity. In contrast, older age, health insurance, clinical indications, and prior PrEP use increased uptake. Notably, Latinx participants were more likely to use PrEP than Whites. Regarding methamphetamine use, those who newly initiated it were more likely to use PrEP compared to non-users. However, those who quit methamphetamine and those who persistently used it had PrEP usage rates comparable to those of non-users. Though PrEP uptake increased, it remained low in SGMSM. Methamphetamine use was associated with PrEP uptake. Healthcare providers should assess methamphetamine use for harm reduction. Prioritizing younger, uninsured SGMSM and addressing basic needs can enhance PrEP uptake and reduce HIV vulnerabilities.

Coprevalence and associations of diabetes mellitus and hypertension among people living with HIV/AIDS in Cameroon.

BACKGROUND: The association between HIV infection and increased cardiometabolic risk, attributed to chronic inflammation in people living with HIV (PLWH) and/or antiretroviral therapy (ART) effects, has been inconsistent. In this study, we aimed to assess the associations of HIV-related factors with hypertension (HTN) and type-2 diabetes mellitus (T2DM), and the potential mediation effects of body mass index (BMI) in the associations between ART use and HTN or T2DM in PLWH in Cameroon. METHODS: A cross-sectional study was conducted with 14,119 adult PLWH from Cameroon enrolled in the International epidemiology Databases to Evaluate AIDS (IeDEA) between 2016 and 2021. HTN was defined as systolic/diastolic blood pressure ≥ 140/90 mmHg and/or current use of antihypertensive medication, while T2DM was defined as fasting blood sugar ≥ 126 mg/dL and/or use of antidiabetic medications. Univariable and multivariable multinomial logistic regression analyses examined the associations of factors with HTN alone, T2DM alone, and both (HTN + T2DM). Mediation analyses were conducted to assess the potential mediation roles of BMI, while controlling for age, sex, and smoking. RESULTS: Of the 14,119 participants, 9177 (65%) were women, with a median age of 42 (25th-75th percentiles: 35-51) years. Age > 50 years was associated with HTN alone, T2DM alone, and HTN + T2DM compared to the age group 19-29 years. Men had higher odds of having HTN + T2DM. Overweight and obesity were predictors of HTN alone compared to being underweight. WHO stages II and III HIV disease were inversely associated with HTN alone compared to stage I. The odds of diabetes alone were lower with ART use. BMI partially mediated the association between ART use and hypertension, with a proportion of mediation effect of 49.6% (all p < 0.02). However, BMI did not mediate the relationship between ART use and diabetes. CONCLUSIONS: Traditional cardiovascular risk factors were strongly associated with hypertension among PLWH, while HIV-related exposures had smaller associations. BMI partially mediated the association between ART use and hypertension. This study emphasizes the importance of screening, monitoring, and managing HTN and T2DM in older, male, and overweight/obese PLWH. Further research on the associations of HIV disease stage and ART use with HTN and T2DM is warranted.

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.

Brown-Norway chromosome 1 mitigates the upregulation of proinflammatory pathways in mTAL cells and subsequent age-related CKD in Dahl SS/JrHsdMcwi rats.

Chronic kidney disease (CKD) has a strong genetic component; however, the underlying pathways are not well understood. Dahl salt-sensitive (SS)/Jr rats spontaneously develop CKD with age and are used to investigate the genetic determinants of CKD. However, there are currently several genetically diverse Dahl SS rats maintained at various institutions and the extent to which some exhibit age-related CKD is unclear. We assessed glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF) in 3- and 6-mo-old male and female SS/JrHsdMcwi, BN/NHsd/Mcwi [Brown-Norway (BN)], and consomic SS-Chr 1BN/Mcwi (SS.BN1) rats, in which chromosome 1 from the BN rat was introgressed into the genome of the SS/JrHsdMcwi rat. Rats were fed a 0.4% NaCl diet. GS (31 ± 3% vs. 7 ± 1%) and TIF (2.3 ± 0.2 vs. 0.5 ± 0.1) were significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi rats, and CKD was exacerbated in males. GS was minimal in 6- and 3-mo-old BN (3.9 ± 0.6% vs. 1.2 ± 0.4%) and SS.BN1 (2.4 ± 0.5% vs. 1.0 ± 0.3%) rats, and neither exhibited TIF. In SS/JrHsdMcwi and SS.BN1 rats, mean arterial blood pressure was significantly greater in 6-mo-old compared with 3-mo-old SS/JrHsdMcwi (162 ± 4 vs. 131 ± 2 mmHg) but not SS.BN1 (115 ± 2 vs. 116 ± 1 mmHg) rats. In 6-mo-old SS/JrHsdMcwi rats, blood pressure was significantly greater in females. RNA-sequencing analysis revealed that inflammatory pathways were upregulated in isolated medullary thick ascending tubules in 7-wk-old SS/JrHsdMcwi rats, before the development of tubule pathology, compared with SS.BN1 rats. In summary, SS/JrHsdMcwi rats exhibit robust age-related progression of medullary thick ascending limb abnormalities, CKD, and hypertension, and gene(s) on chromosome 1 have a major pathogenic role in such changes.NEW & NOTEWORTHY This study shows that the robust age-related progression of kidney disease in Dahl SS/JrHsdMcw rats maintained on a normal-salt diet is abolished in consomic SS.BN1 rats. Evidence that medullary thick ascending limb segments of SS/JrHsdMcw rats are structurally abnormal and enriched in proinflammatory pathways before the development of protein casts provides new insights into the pathogenesis of kidney disease in this model.

Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas.

[Figure: see text].

Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: Role of α7 nicotinic acetylcholine receptors.

The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn's disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.

Human Immunodeficiency Virus (HIV) and Menopause Are Independently Associated With Lower Bone Mineral Density: Results From the Women's Interagency HIV Study.

BACKGROUND: We previously reported lower bone mineral density (BMD) among premenopausal women with HIV (WWH) compared to women without HIV (HIV-). Rate of bone loss may be even greater for WWH during the menopausal transition. METHODS: Pre-, peri- and postmenopausal women in the Women\'s Interagency HIV Study (WIHS) underwent whole body DXA and central quantitative computed tomography to measure areal BMD (aBMD) and volumetric BMD (vBMD), respectively. Multivariable regression models with covariates associated with low aBMD (T score < -1.0) in univariate analyses (P≤.05) and known risk factors for low BMD assessed contributions of HIV and menopausal stage to the prediction of aBMD. RESULTS: Compared to HIV- women, in unadjusted analyses, WWH had 5-9% lower aBMD at the lumbar spine (P=.001), femoral neck (P=.04), total hip (P=.003) and the ultradistal radius (P=.004), and higher osteoporosis prevalence (T score<-2.5) at the ultradistal radius only (13.5% vs 0%, P=.0003). WWH also had lower vBMD at the spine and hip. In fully adjusted models, HIV independently predicted reduced aBMD at the lumbar spine, total hip, femoral neck, and ultradistal radius; menopausal stage remained a significant predictor of lumbar spine and ultradistal radius aBMD. CONCLUSIONS: HIV infection and menopausal stage were independent predictors of lower BMD, and had an additive effect on lumbar spine and total hip BMD. Additional research is needed to better understand underlying mechanisms by which HIV impacts BMD as women age and transition through menopause, and develop strategies to mitigate osteoporosis and fracture risk in this growing population.

Difference in HIV testing behavior by injection status, among users of illicit drugs.

Human Immunodeficiency Virus (HIV) infection remains prevalent among the marginalized and drug using population in the United States. Testing for HIV is an important and cost-effective way to reduce HIV prevalence. Our objective was to determine if there is a difference in the number of HIV testing by injection status among users of illicit drugs and if a person's social network characteristics is a contributing factor. Using a cross-sectional design and negative binomial regression models, we assessed HIV testing behavior of people who use non-injected drugs (PWND) compared to people who use injected drugs (PWID). In an analytic sample of 539 participants, PWND tested for HIV 19% less compared to PWID, PR (95% CI) = 0.81 (0.66, 0.98), p = 0.03. Other contributing factors of testing were education, condomless sex, STIs, heroin use, and participant's sex network. The interaction term between PWND and emotional support in relation to HIV testing was significant, 1.33 (1.03, 1.69), p=0.03. These findings suggest HIV testing behavior differed by injection status, and this relationship may be dependent on emotional support. To exert a greater impact on the HIV epidemic, interventions and policies encouraging HIV testing in PWND, an understudied at-risk sub-population, are warranted.

Retrospective Chart Review Examining Differences and Timelines in Recommended and Delivered Wheelchair Equipment in a Midwestern Dedicated Seating Department.

OBJECTIVE: To compare recommended wheeled mobility equipment with delivered equipment, excluding custom seats and backs, considering demographic factors, such as sex, age, and funding source, as well as the timeline of the procurement process. DESIGN: Retrospective chart review. SETTING: Dedicated wheelchair seating department within a Midwestern rehabilitation hospital and associated complex rehabilitation technology durable medical equipment suppliers. PARTICIPANTS: Wheelchair recommendations (N=546) made between January 1, 2017, and December 31, 2017, to physician-referred wheelchair users of all ages and diagnoses. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Recommended and delivered wheelchair equipment type and length of time between recommendation and delivery. RESULTS: Differences were found between the recommended and delivered equipment in manual wheelchairs, power mobility devices, seat backs, cushions, and power option equipment groups (P≤.001). Delivered manual wheelchairs were 7% more likely to be different than the recommendation for each year decrease in age (P≤.001), although the model lacked sufficient predictive accuracy for clinical application. The average length of time from equipment recommendation to delivery was about 6 months (mean, 176d). Standard and complex power mobility devices were associated with longer timelines (median, 137d and 173d, respectively; P=.001), although only complex power mobility device timelines were significantly associated with public funding sources (P=.02). CONCLUSIONS: Wheelchair bases, positioning accessories, and power options may be delivered differently than originally recommended, and the process for procuring complex power mobility devices with public funding sources should be studied further. Health care professionals should consistently follow up on delivered equipment to ensure that expectations and needs of the wheelchair user are met. Reducing systemic barriers to interdisciplinary communication postrecommendation may improve patient outcomes.

Family type and cognitive function in older Chinese Americans: acculturation as a moderator.

OBJECTIVES: Acculturation to the mainstream culture and the settlement contexts could shape cognitive function of older immigrants. Guided by ecological theory, this study examines the interaction effect between individual acculturation and ecology of family on cognitive function among older Chinese Americans. METHODS: Data were derived from the Population Study of Chinese Elderly in Chicago (n = 3,019). Family types included tight-knit (high solidarity and low conflicts), unobligated-ambivalent (high solidarity and conflicts), commanding-conflicted (low solidarity and high conflicts), and detached (low solidarity and low conflicts). Acculturation was measured via language ability, media use, and ethnic social relations. Cognitive function was evaluated by global cognition, episodic memory, working memory, processing speed, and mini-mental state examination. Multiple regression analyses and interaction terms were used. RESULTS: Older adults in the commanding-conflicted type had the lowest cognitive function. After controlling confounding variables, higher levels of acculturation (b = 0.009, SE = 0.003, p < .01) were associated with higher levels of global cognition. Acculturation buffered the negative impact of having a commanding-conflicted relationship with children on global cognition (b = 0.070, SE = 0.016, p < .001). Language ability, media use, and ethnic social relations played a unique role in the relationships between family types and cognitive domains. CONCLUSION: Acculturation to the dominant culture is identified as a cultural asset for cognitive function in older Chinese Americans. Social services could protect cognitive function of older immigrants in the commanding-conflicted type through enhancing cultural participation. Future research could test how affective and cognitive aspects of acculturation affect health.

Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice.

Donepezil is a centrally acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central versus peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg sc), neostigmine methyl sulfate (80 or 240 µg/kg ip), atropine sulfate (5 mg/kg ip), atropine methyl bromide (5 mg/kg ip), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36 ± 4% and 44 ± 3% compared with saline (n = 10, P < 0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13 ± 2% and 22 ± 2% compared with saline (n = 6, P < 0.001). Modest (P < 0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice coadministered atropine sulfate; however, coadministration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature, but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high-frequency HR variability. We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via the activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.

Comparative poisson clinical trials of multiple experimental treatments vs a single control using the negative multinomial distribution.

This paper introduces a method which conditions on the number of events that occur in the control group to determine rejection regions and power for comparative Poisson trials with multiple experimental treatment arms that are each compared to one control arm. This leads to the negative multinomial as the statistical distribution used for testing. For one experimental treatment and one control with curtailed sampling, this is equivalent to Gail's (1974) approach. We provide formulas to calculate exact one-sided overall Type I error and pointwise power for tests of treatment superiority and inferiority (vs the control). Tables of trial design parameters for combinations of one-sided overall Type I error = 0.05, 0.01 and pointwise power = 0.90, 0.80 are provided. Curtailment approaches are presented to stop follow-up of experimental treatment arms or to stop the study entirely once the final outcomes for each arm are known.

TRUST: Assessing the Efficacy of an Intervention to Increase HIV Self-Testing Among Young Black Men Who have Sex with Men (MSM) and Transwomen.

HIV testing among young Black MSM and transwomen (YBMSM/TW) is the gateway to biomedical HIV prevention or treatment. HIV self-testing (HST) is a method that may increase consistent HIV testing. TRUST, a brief, peer-based behavioral intervention, was designed to increase uptake of consistent (every three months) HST among YBMSM/TW in New York City. To test the efficacy of the intervention, we randomized 200 friend pairs into either the intervention condition (TRUST) or a time and attention control condition. A modified intent-to-treat analysis found that self-reported HST at 3-month follow-up was statistically significantly higher (uOR 2.29; 95% CI 1.15, 4.58) and at 6-month follow-up was marginally statistically significantly higher (uOR 1.94; 95% CI 1.00, 3.75) in the intervention arm as compared with the control arm. There were no statistically significant differences by arm at 9- or 12-month follow-up. TRUST, a culturally-congruent intervention to increase HST among YBMSM/TW, had short-term impact on past-three month HST.Clinical Trials Registration ClinicalTrial.gov NCT04210271.

Validity of the 6-Minute Walk Test and YMCA Submaximal Cycle Test During Midpregnancy.

ABSTRACT: Tinius, RA, Blankenship, M, Maples, JM, Pitts, BC, Furgal, K, Norris, ES, Hoover, DL, Olenick, A, Lambert, J, and Cade, WT. Validity of the 6-minute walk test and Young Men's Christian Association (YMCA) submaximal cycle test during midpregnancy. J Strength Cond Res 35(11): 3236-3242, 2021-Submaximal exercise testing can be a feasible alternative to maximal testing within special populations to safely predict fitness levels; however, submaximal exercise testing has not been well-validated for use during pregnancy. The purpose of this study was to determine the concurrent validity of the 6-minute walk test (6MWT) and the YMCA submaximal cycle test (YMCAT) to predict V̇o2max in physically active women during midpregnancy. Thirty-seven (n = 37) pregnant women (22.1 ± 1.4 weeks' gestation) and 10 (n = 10) nonpregnant women participated in the study. Subjects completed a graded maximal treadmill test at 1 visit to measure maximal oxygen consumption (V̇o2max), and then subjects completed the 6MWT and YMCAT in randomized order during a separate visit. The predicted V̇o2max from each submaximal test were compared with the measured V̇o2max from the treadmill test to assess the validity of these tests during pregnancy. Among pregnant women, predicted V̇o2max from the YMCAT was not correlated to the measured V̇o2max (r = 0.14, p = 0.42), and the predicted V̇o2max from the 6MWT was only moderately correlated (r = 0.40, p = 0.016) to the measured V̇o2max. Among nonpregnant women, the predicted V̇o2max values from both the YMCAT and the 6MWT had strong correlations with the measured V̇o2max values (YMCAT: r = 0.71, p = 0.02; 6MWT: r = 0.80, p = 0.006). Neither test demonstrated concurrent validity among the pregnant sample. The main finding is that the YMCAT is not a valid method to estimate V̇o2max during midpregnancy (likely due to physiological changes in heart rate [HR] during pregnancy). The 6MWT has potential to be used clinically for estimating fitness as actual and predicted values did positively correlate, and it is not dependent on HR responses to exercise. However, if a precise measure of fitness is needed, then neither test appears to have strong validity for use during midpregnancy.

Estimates of the Time From Seroconversion to Antiretroviral Therapy Initiation Among People Newly Diagnosed With Human Immunodeficiency Virus From 2006 to 2015, New York City.

BACKGROUND: We estimated the time from human immunodeficiency virus (HIV) seroconversion to antiretroviral therapy (ART) initiation during an era of expanding HIV testing and treatment efforts. METHODS: Applying CD4 depletion parameters from seroconverter cohort data to our population-based sample, we related the square root of the first pretreatment CD4 count to time of seroconversion through a linear mixed model and estimated the time from seroconversion. RESULTS: Among 28 162 people diagnosed with HIV during 2006-2015, 89% initiated ART by June 2017. The median CD4 count at diagnosis increased from 326 (interquartile range [IQR], 132-504) cells/µL to 390 (IQR, 216-571) cells/µL from 2006 to 2015. The median time from estimated seroconversion to ART initiation decreased by 42% from 6.4 (IQR, 3.3-11.4) years in 2006 to 3.7 (IQR, 0.5-8.3) years in 2015. The time from estimated seroconversion to diagnosis decreased by 28%, from a median of 4.6 (IQR, 0.5-10.5) years to 3.3 (IQR, 0-8.1) years from 2006 to 2015, and the time from diagnosis to ART initiation reduced by 60%, from a median of 0.5 (IQR, 0.2-2.1) years to 0.2 (IQR, 0.1-0.3) years from 2006 to 2015. CONCLUSIONS: The estimated time from seroconversion to ART initiation was reduced in tandem with expanded HIV testing and treatment efforts. While the time from diagnosis to ART initiation decreased to 0.2 years, the time from seroconversion to diagnosis was 3.3 years among people diagnosed in 2015, highlighting the need for more effective strategies for earlier HIV diagnosis.

Safety and continued use of the levonorgestrel intrauterine system as compared with the copper intrauterine device among women living with HIV in South Africa: A randomized controlled trial.

BACKGROUND: Women living with HIV (WLHIV) have lower rates of contraceptive use than noninfected peers, yet concerns regarding contraceptive efficacy and interaction with antiretroviral therapy (ART) complicate counseling. Hormonal contraceptives may increase genital tract HIV viral load (gVL) and sexual transmission risk to male partners. We compared gVL, plasma VL (pVL), and intrauterine contraceptive (IUC) continuation between the levonorgestrel intrauterine system (LNG-IUS) and copper intrauterine device (C-IUD) in Cape Town, South Africa. METHODS AND FINDINGS: In this double-masked, randomized controlled noninferiority trial, eligible WLHIV were ages 18-40, not pregnant or desiring pregnancy within 30 months, screened and treated (as indicated) for reproductive tract infections (RTIs) within 1 month of enrollment, and virologically suppressed using ART or above treatment threshold at enrollment (non-ART). Between October 2013, and December 2016, we randomized consenting women within ART groups, using 1:1 permuted block randomization stratified by ART use, age (18-23, 24-31, 32-40), and recent injectable progestin contraceptive (IPC) exposure, and provided the allocated IUC. At all visits, participants provided specimens for gVL (primary outcome), pVL, RTI, and pregnancy testing. We assessed gVL and pVL across 6 and 24 months controlling for enrollment measures, ART group, age, and RTI using generalized estimating equation and generalized linear models (non-ART group pVL and hemoglobin) in as-treated analyses. We measured IUC discontinuation rates with Kaplan-Meier estimates and Cox proportional hazards models. We enrolled 71 non-ART (36 LNG-IUS, 31 C-IUD; 2 declined and 2 were ineligible) and 134 ART-using (65 LNG-IUS, 67 C-IUD; 1 declined and 1 could not complete IUC insertion) women. Participant median age was 31 years, and 95% had 1 or more prior pregnancies. Proportions of women with detectable gVL were not significantly different comparing LNG-IUS to C-IUD across 6 (adjusted odds ratio [AOR]: 0.78, 95% confidence interval [CI] 0.44-1.38, p = 0.39) and 24 months (AOR: 1.03, 95% CI: 0.68-1.57, p = 0.88). Among ART users, proportions with detectable pVL were not significantly different at 6 (AOR = 0.83, 95% CI 0.37-1.86, p = 0.65) and 24 months (AOR = 0.94, 95% CI 0.49-1.81, p = 0.85), whereas among non-ART women, mean pVL was not significantly different at 6 months (-0.10 log10 copies/mL, 95% CI -0.29 to 0.10, p = 0.50) between LNG-IUS and C-IUD users. IUC continuation was 78% overall; C-IUD users experienced significantly higher expulsion (8% versus 1%, p = 0.02) and elective discontinuation (adjusted hazard ratio: 8.75, 95% CI 3.08-24.8, p < 0.001) rates. Sensitivity analysis adjusted for differential IUC discontinuation found similar gVL results. There were 39 serious adverse events (SAEs); SAEs believed to be directly related to IUC use (n = 7) comprised 3 pelvic inflammatory disease (PID) cases and 4 pregnancies with IUC in place with no discernible trend by IUC arm. Mean hemoglobin change was significantly higher among LNG-IUS users across 6 (0.57 g/dL, 95% CI 0.24-0.90; p < 0.001) and 24 months (0.71 g/dL, 95% CI 0.47-0.95; p < 0.001). Limitations included not achieving non-ART group sample size following change in ART treatment guidelines and truncated 24 months' outcome data, as 17 women were not yet eligible for their 24-month visit at study closure. Also, a change in VL assay during the study may have caused some discrepancy in VL values because of different limits of detection. CONCLUSIONS: In this study, we found that the LNG-IUS did not increase gVL or pVL and had low levels of contraceptive failure and associated PID compared with the C-IUD among WLHIV. LNG-IUS users were significantly more likely to continue IUC use and had higher hemoglobin levels over time. The LNG-IUS appears to be a safe contraceptive with regard to HIV disease and may be a highly acceptable option for WLHIV. TRIAL REGISTRATION: ClinicalTrials.gov NCT01721798.

Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection.

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by preexisting cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin-converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang-(1-7) but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.

Association of the Affordable Care Act Medicaid Expansion with Dilated Eye Examinations among the United States Population with Diabetes.

PURPOSE: To evaluate the association between Medicaid expansion and diabetic dilated eye examinations. DESIGN: A retrospective difference in differences (DiD) analysis using individual-level survey response data from January 1, 2009, to December 31, 2017. PARTICIPANTS: A total of 52 392 survey responses from 50 states and the District of Columbia between 2009 and 2017. Responders were adults aged 18 to 64 years reporting a previous diagnosis of diabetes and a household income below 138% of the US federal poverty line (FPL). METHODS: The Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System data were used to identify survey responders who were asked about the presence of dilated eye examinations from years before and after Medicaid expansion implementation. MAIN OUTCOME MEASURES: The DiD in proportion of dilated eye examinations among diabetic persons aged 18 to 64 years with household incomes below 138% of the FPL between states that did and did not implement Medicaid expansion. RESULTS: Implementation of Medicaid expansion policies was associated with a 1.3% (95% confidence interval [CI], -3.8 to 6.4; P = 0.61), 6.3% (95% CI, 1.3-11.3; P = 0.016), 4.1% (95% CI, -0.8 to 9.0; P = 0.11), and 2.3% (95% CI, -1.6 to 6.2; P = 0.23) increase in the proportion of diabetic persons aged 18 to 64 years with incomes below 138% of the FPL receiving a dilated eye examination within the past year due to Medicaid expansion 1, 2, 3, and 4 cumulative years after expansion, respectively. CONCLUSIONS: Medicaid expansion policies were significantly associated with an increase in dilated eye examination rates within the first 2 years after implementation. However, this increase did not persist beyond this period, with nonsignificant increases 3 and 4 cumulative years after implementation. Healthcare policymakers should be aware that additional measures beyond expanding insurance coverage may be necessary to increase and sustain the rate of dilated eye examinations among diabetic populations.

Correlates of HIV Transmission Behaviors and HIV Testing in Predominately African American/Black Women with High-Risk Male Sex Partners.

This study was conducted among predominately African American/Black women, aged 18-29, in Northeast cities with high HIV prevalence. Demographic, behavioral, and partner characteristics associated with condomless vaginal and anal sex acts with high-risk partners (CVS-HRP and CAS-HRP) and with HIV testing were explored. The high-risk sample was largely recruited online. Of 4972 women screened, 2254 (45.3%) were high-risk for HIV acquisition; 2214 were included. Bivariate and stepwise multivariate logistic regression models were fit. After adjusting for other factors, sex risk behavior did not differ by race and ethnicity. CAS-HRP was associated with believing condoms don't reduce HIV risk and with several high-risk behaviors, including; alcohol use, multiple partners, and sex with men who had sex with men, but, not with HIV testing. Half the sample had condomless sex with partners who never HIV tested and were themselves three times as likely to have never tested. These results point to the ongoing need for effective prevention strategies among at-risk heterosexual women.