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Adolescents and young adults living with HIV (AYLHIV) in sub-Saharan Africa experience poorer HIV outcomes than adults, including lower ART adherence and virologic suppression. They also have high rates of unprotected sex, increasing the risk of adverse sexual health outcomes and onward transmission. This one-arm, pre–post study investigates a structured 14-session support group aiming to boost treatment adherence and sexual protective behavior for AYLHIV in South Africa. Logistic and Poisson regression analyses were performed on self-reported pre- and post-intervention survey data collected approximately 7.5 months apart from a cohort of 548 AYLHIV. Participants were significantly more likely to report at least 95% adherence at follow-up and rate their health as “good;” they also demonstrated greater treatment knowledge and had fewer absences from school overall and due to illness. Among sexually active AYLHIV, contraception use at last sex increased significantly, while condom use did not. Effects were small, and greater programmatic emphasis on adherence and multifaceted service packages is likely necessary to promote viral suppression. Nonetheless, the intervention addresses an important gap in service provision for AYLHIV in South Africa. Findings denote the potential for incorporating care and treatment components into sexual and reproductive health interventions tailored for AYLHIV.

Abstract Background Mental health and substance use disorders disproportionately affect people with HIV (PWH), and may have been exacerbated during COVID-19. The Promoting Access to Care Engagement (PACE) trial was designed to assess the effectiveness of electronic screening for mental health and substance use in HIV primary care and enrolled PWH from October 2018 to July 2020. Our objective here was to compare screening rates and results for PWH before (October 2018 – February 2020) and early in the COVID-19 pandemic (March-July 2020). Methods Adult (≥ 18 years) PWH from 3 large HIV primary care clinics in a US-based integrated healthcare system were offered electronic screening online or via in-clinic tablet computer every 6 months. Screening completion and results (for depression, suicidal ideation, anxiety, and substance use) were analyzed using logistic regression with generalized estimating equations to estimate prevalence ratios (PR) before and after the start of the regional COVID-19 shelter-in-place orders on March 17, 2020. Models adjusted for demographics (age, sex, race/ethnicity), HIV risk factors (men who have sex with men, injection drug use, heterosexual, other), medical center, and modality of screening completion (online or tablet). We conducted qualitative interviews with providers participating in the intervention to evaluate how the pandemic impacted patient care. Results Of 8,954 eligible visits, 3,904 completed screenings (420 during COVID, 3,484 pre-COVID), with lower overall completion rates during COVID (38% vs. 44%). Patients completing screening during COVID were more likely to be White (63% vs. 55%), male (94% vs. 90%), and MSM (80% vs., 75%). Adjusted PRs comparing COVID and pre-COVID (reference) were 0.70 (95% CI), 0.92 (95% CI), and 0.54 (95% CI) for tobacco use, any substance use, and suicidal ideation, respectively. No significant differences were found by era for depression, anxiety, alcohol, or cannabis use. These results were in contrast to provider-reported impressions of increases in substance use and mental health symptoms. Conclusion Findings suggest PWH had modest declines in screening rates early in the COVID-19 pandemic which may have been affected by the shift to telemedicine. There was no evidence that mental health problems and substance use increased for PWH in primary care. Trial registration NCT03217058 (First registration date: 7/13/2017); https://clinicaltrials.gov/ct2/show/NCT03217058

Despite the reported prevalence of micronutrient deficiencies in older adults, it is not yet established whether multivitamin/multimineral (MV/MM) supplements improve blood micronutrient status in individuals over the age of 65. Therefore, a cohort of 35 healthy men (>67 years) was recruited for an MV/MM supplementation trial. The primary endpoint was, as an indicator of micronutrient status, changes in blood micronutrient biomarkers from baseline to at least six months of supplementation with MV/MM or placebo. The secondary endpoint was basal O2 consumption in monocytes as an indicator of cellular metabolism. MV/MM supplementation improved blood concentrations of pyridoxal phosphate, calcifediol, α-tocopherol, and β-carotene concentrations throughout the cohort. By contrast, those in the placebo group generally showed declines in blood vitamin concentrations and an increased prevalence of suboptimal vitamin status during the study period. On the other hand, MV/MM supplementation did not significantly affect blood mineral concentrations, i.e., calcium, copper, iron, magnesium, and zinc. Interestingly, MV/MM supplementation prevented the decline in monocyte O2 consumption rate. Overall, MV/MM use improves or prevents declines in vitamin, but not mineral, status and limits declines in cellular O2 consumption, which may have important implications for metabolism and immune health in healthy older men.

Abstract Background Child and youth care workers (CYCWs) are a crucial and growing component of South Africa’s national response to HIV and AIDS and other issues affecting children and families. CYCWs use the community-centred Isibindi model of care to reach the most vulnerable with key services including psychosocial, health, economic and education support. Like others in similar professions, they may be at risk for occupational challenges affecting retention. Methods This study uses data from the first nationally representative survey of CYCWs in South Africa to identify factors associated with workers’ retention intentions. Data were collected in 2015 as part of a formative evaluation conducted around the mid-point of a nationwide Isibindi programme expansion. A total of 1158 CYCWs from 78 sites participated. The response rate for the sample was 87%. Questions addressed demographics, work history, retention intentions, training, mentorship and supervision experiences, workload and remuneration. Mixed effects regression models with random intercepts for project site and mentor were used to estimate factors associated with retention intentions. Results High-quality mentorship and frequent supervision support retention intentions among CYCWs. Respondents who indicated that wanting to help children or the community was their primary motivator for seeking work as a CYCW were also more likely to report intending to continue working as a CYCW. High perceived workloads and feeling threatened or unsafe on the job were negatively associated with retention intentions. As CYCWs gained experience, they were also less likely to intend to stay. Conclusions Understanding the factors affecting retention in the CYCW workforce is vital to helping vulnerable children and families across South Africa access key social and health services. Findings highlight the importance of mentoring and supervision as part of the Isibindi model and the value of support for manageable workloads, workplace safety, and career advancement opportunities for promoting worker retention.

Isolated hepatocytes from young (4–6 mo) and old (24–26 mo) F344 rats were exposed to increasing concentrations of menadione, a vitamin K derivative and redox cycling agent, to determine whether the age-related decline in Nrf2-mediated detoxification defenses resulted in heightened susceptibility to xenobiotic insult. An LC50 for each age group was established, which showed that aging resulted in a nearly 2-fold increase in susceptibility to menadione (LC50 for young: 405 μM; LC50 for old: 275 μM). Examination of the known Nrf2-regulated pathways associated with menadione detoxification revealed, surprisingly, that NAD(P)H: quinone oxido-reductase 1 (NQO1) protein levels and activity were induced 9-fold and 4-fold with age, respectively (p=0.0019 and p=0.018; N=3), but glutathione peroxidase 4 (GPX4) declined by 70% (p=0.0043; N=3). These results indicate toxicity may stem from vulnerability to lipid peroxidation instead of inadequate reduction of menadione semi-quinone. Lipid peroxidation was 2-fold higher, and GSH declined by a 3-fold greater margin in old versus young rat cells given 300 µM menadione (p2-fold reduction in cell death, suggesting that the age-related increase in menadione susceptibility likely stems from attenuated GSH-dependent defenses. This data identifies cellular targets for intervention in order to limit age-related toxicological insults to menadione and potentially other redox cycling compounds.

The mitochondrial oxidative stress theory of aging posits that membrane susceptibility to peroxidation and the organization of the electron transport system (ETS) linked with reactive oxygen species (ROS) generation are two main drivers of lifespan. While a clear correlation has been established from species comparative studies, the significance of these characteristics as potential modulators of lifespan divergences among populations of individual species is still to be tested. The bivalve Arctica islandica, the longest-lived non-colonial animal with a record lifespan of 507 years, possesses a lower mitochondrial peroxidation index (PI) and reduced H2O2 efflux linked to complexes I and III activities than related species. Taking advantage of the wide variation in maximum reported longevities (MRL) among 6 European populations (36–507 years), we examined whether these two mitochondrial properties could explain differences in longevity. We report no relationship between membrane PI and MRL in populations of A. islandica, as well as a lack of intraspecific relationship between ETS complex activities and MRL. Individuals from brackish sites characterized by wide temperature and salinity windows had, however, markedly lower ETS enzyme activities relative to citrate synthase activity. Our results highlight environment-dependent remodeling of mitochondrial phenotypes.

The role of mitochondrial GSH (mGSH) in the enhanced age-related susceptibility to xenobiotic toxicity is not well defined. We determined mGSH status and indices of mitochondrial bioenergetics in hepatocytes from young and old F344 rats treated with 300 μM menadione, a concentration that causes 50% cell death in old. At this concentration, mGSH was significantly lost only in hepatocytes from old rats, and with near total depletion due to lower basal mGSH in aged cells. In old hepatocytes, menadione caused mitochondrial membrane potential to collapse, as well as significant deficits in maximal O2 consumption and respiratory reserve capacity, indicators of cellular bioenergetic resiliency. Further examination revealed that the menadione-mediated loss of respiratory reserve capacity in aged hepatocytes was from significant inhibition of Complex I activity and increased proton leak, for which an increase in Complex II activity was not able to compensate. These data demonstrate an age-related increase in mitochondrial susceptibility to a redox-cycling challenge, particularly in regards to Complex I activity, and provide a plausible mechanism to link this vulnerability to mGSH perturbations. Keywords: Aging, Redox cyclers, Mitochondria, Glutathione, Respiratory reserve capacity

We engineered a concatenated fluorescent biosensor and dual-wavelength fluorescence lifetime (FLT) detection, to perform high-throughput screening (HTS) in living cells for discovery of potential heart-failure drugs. Heart failure is correlated with insufficient activity of the sarcoplasmic reticulum Ca-pump (SERCA2a), often due to excessive inhibition by phospholamban (PLB), a small transmembrane protein. We sought to discover small molecules that restore SERCA2a activity by disrupting this inhibitory interaction between PLB and SERCA2a. Our approach was to fluorescently tag the two proteins and measure fluorescence resonance energy transfer (FRET) to detect changes in binding or structure of the complex. To optimize sensitivity to these changes, we engineered a biosensor that concatenates the two fluorescently labeled proteins on a single polypeptide chain. This SERCA2a-PLB FRET biosensor construct is functionally active and effective for HTS. By implementing 2-wavelength FLT detection at extremely high speed during primary HTS, we culled fluorescent compounds as false-positive Hits. In pilot screens, we identified Hits that alter the SERCA2a-PLB interaction, and a newly developed secondary calcium uptake assay revealed both activators and inhibitors of Ca-transport. We are implementing this approach for large-scale screens to discover new drug-like modulators of SERCA2a-PLB interactions for heart failure therapeutic development.

Background: Bereavement increases children's risk for psychological disorders, highlighting the need for effective interventions, especially in areas where orphanhood is common. We aimed to assess the effects of an eight-session support group intervention on the psychological health of bereaved female adolescents in South Africa. Methods: This randomised controlled trial enrolled female adolescents at 11 schools in three peri-urban towns of Free State province, South Africa. 453 bereaved ninth-grade students aged 13–17 years who had expressed interest in taking part in the group were randomly assigned (1:1) to receive the intervention or to be waitlisted for programme enrolment after the study period and serve as the control group. The intervention, Abangane (“friends” in isiZulu), is a locally derived, curriculum-based support group focused on coping with loss incorporating indigenous stories and cognitive behavioural therapy components. Weekly group sessions were facilitated by trained social workers or social auxiliary workers from a local non-profit organisation. The primary outcomes included indicators of grief and depression as reported by adolescents and behavioural problems reported by their caregivers. Grief was measured with three scales: the grief subscale of the Core Bereavement Items to assess normative grief; and the Intrusive Grief Thoughts Scale and the Inventory of Complicated Grief–Revised for Children to assess maladaptive grief symptoms in the past 4 weeks. Depression symptoms in the past 7 days were measured with the Center for Epidemiological Studies–Depression Scale for Children. Caregivers completed the Brief Problem Monitor-Parent Form to report on adolescent's behaviour in the previous 4 weeks. Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT02368808. Findings: Between Sept 30, 2014, and Feb 5, 2015, eligible female participants were identified, of whom 226 were assigned to the intervention, Abangane, and 227 were assigned to the waitlisted control group. Analysis included 382 adolescents who completed both surveys (193 participants assigned to Abangane and 189 assigned to waitlist). At follow up, the intervention group had significantly lower scores for primary outcomes, including intrusive grief (p=0·000, Cohen's d=–0·21), complicated grief (p=0·015, d=–0·14), and depression (p=0·009, d=–0·21) relative to the waitlisted group, while core bereavement scores were similar between groups (p=0·269). Caregivers in the intervention group reported lower levels of behavioural problems among adolescents (p=0·017, d=–0·31). Interpretation: Short-term, structured, theory-based support groups with contextually relevant content show promise in mitigating psychological and behavioural problems among bereaved adolescents. Abangane is replicable in resource limited settings, using freely available curriculum materials, existing programme structures, and appropriately trained personnel to implement it. Funding: US Agency for International Development Southern Africa.

We have developed fluorescence resonance energy transfer (FRET) biosensors with red-shifted fluorescent proteins (FP), yielding improved characteristics for time-resolved (lifetime) fluorescence measurements. In comparison to biosensors with green and red FRET pairs (GFP/RFP), FPs that emit at longer wavelengths (orange and maroon, OFP/MFP) increased the FRET efficiency, dynamic range, and signal-to-background of high-throughput screening (HTS). OFP and MFP were fused to specific sites on the human cardiac calcium pump (SERCA2a) for detection of structural changes due to small-molecule effectors. When coupled with a recently improved HTS fluorescence lifetime microplate reader, this red-shifted FRET biosensor enabled high-precision nanosecond-resolved fluorescence decay measurements from microliter sample volumes at three minute read times per 1536-well-plate. Pilot screens with a library of small-molecules demonstrate that the OFP/MFP FRET sensor substantially improves HTS assay quality. These high-content FRET methods detect minute FRET changes with high precision, as needed to elucidate novel structural mechanisms from small-molecule or peptide regulators discovered through our ongoing HTS efforts. FRET sensors that emit at longer wavelengths are highly attractive to the FRET biosensor community for drug discovery and structural interrogation of new therapeutic targets.

Identifying factors associated with condom use can help inform the design of sexual reproductive health interventions for young people living with HIV. Data were collected from 294 sexually active youth in South Africa aged 14–24 years, living with HIV and aware of their status. Logistic regression found condom use was associated with partner status, disclosure, treatment adherence, knowledge, alcohol use, enacted stigma, and age at known status. Seventy-seven percent reported condom use at last sex, with higher odds among those who: disclosed their status to their last partner (OR = 2.13, 95% CI = 1.09–4.15), had not missed any ART doses in the previous week (OR = 2.67, 95% CI = 1.35–5.27), knew to use condoms when both partners have HIV (OR = 2.65, 95% CI = 1.34–5.25) and learned their status by age 12 (OR = 2.89, 95% CI = 1.30–6.43). Lower odds of condom use were among participants with an HIV-positive partner (OR = 0.36, 95% CI = 0.18–0.73), those who experienced recent stigma (OR = 0.55, 95% CI = 0.31–1.00), who drank at least 1 day per month (OR = 0.43, 95% CI = 0.22–0.84) and females (OR = 0.41, 95% CI = 0.20–0.84). Condom education and services promoting stigma management and safe disclosure could increase condom use among young people living with HIV. Lower condom use among adolescents reporting non-adherence to treatment underscores the critical need for effective interventions. [ABSTRACT FROM AUTHOR]