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BackgroundAs people living with HIV (PWH) age, they face new challenges that can have a negative impact on their quality of life (QOL) and mental health.SettingThis study enrolled PWH at the end of life (EOL) who were actively engaged in cure-related research in Southern California, United States. EOL was defined as having a prognosis of 6 months or less to live. We examined the relationship between QOL, mental health, and research participation.MethodsStructured assessments were used to collect comprehensive data on QOL and mental health.ResultsFrom 2017 to 2023, 35 PWH in their final stages of life who were actively engaged in cure-related research were enrolled. Their median age was 62.7 years, and most were White or otherwise non-Hispanic/non-Latino (90.6%), and male (86.7%). Changes in QOL and the presence of neurologic and psychiatric conditions, with a focus on depression and anxiety, were the primary outcomes assessed in this study. Participants had stable QOL scores throughout the study. There was an inverse relationship between QOL and Beck Depression Inventory scores, with higher mean QOL scores being associated with lower mean Beck Depression Inventory scores ( P < 0.001).ConclusionsQOL remained stable among PWH who participate in cure-related research at EOL. The inverse relationship between QOL and depressive symptoms suggests that participation in cure-related research may improve QOL or reduce depressive symptoms in this population. Future interventions should look into ways to improve the well-being of PWH at EOL through research and customized mental health interventions.

Translation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation. Human genomes include both rare and more common mistranslating tRNA variants. We investigated three rare human tRNALeu variants that mis-incorporate Leu at phenylalanine or tryptophan codons. Expression of each tRNALeu anticodon variant in neuroblastoma cells caused defects in fluorescent protein production without significantly increased cytotoxicity under normal conditions or in the context of proteasome inhibition. Using tRNA sequencing and mass spectrometry we confirmed that each tRNALeu variant was expressed and generated mistranslation with Leu. To probe the flexibility of the entire genetic code towards Leu mis-incorporation, we created 64 yeast strains to express all possible tRNALeu anticodon variants in a doxycycline-inducible system. While some variants showed mild or no growth defects, many anticodon variants, enriched with G/C at positions 35 and 36, including those replacing Leu for proline, arginine, alanine, or glycine, caused dramatic reductions in growth. Differential phenotypic defects were observed for tRNALeu mutants with synonymous anticodons and for different tRNALeu isoacceptors with the same anticodon. A comparison to tRNAAla anticodon variants demonstrates that Ala mis-incorporation is more tolerable than Leu at nearly every codon. The data show that the nature of the amino acid substitution, the tRNA gene, and the anticodon are each important factors that influence the ability of cells to tolerate mistranslating tRNAs.

T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, we assessed samples for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered at high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4+ and CD8+ T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4+ T cell and CD8+ T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4+ and CD8+ T cells during acute COVID-19.

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is an effective and safe option to prevent HIV acquisition and vertical HIV transmission in pregnant and breastfeeding women. Understanding health system factors influencing the integration of PrEP into care for pregnant and breastfeeding women is key to increasing access. We explored managers and health care workers (HCWs) experiences with integrating PrEP into antenatal care and postnatal care services in primary health care clinics in Cape Town, South Africa. METHODS: This exploratory qualitative study used codebook thematic analysis, where HCWs were purposively, heterogeneously sampled from an implementation science study. Semistructured individual interviews were conducted with 9 managerial-level staff, and 3 focus group discussions were conducted with HCWs (nurses, midwives, and HIV counselors) providing PrEP (6-7 HCWs per group) between November 2022 and January 2023 (N=28). Interview guides covered health system facilitators, barriers, and recommendations. The Health Systems Dynamics framework guided data analysis and presentation of results. RESULTS: PrEP integration into antenatal care services was described as acceptable and feasible; however, changes to HIV testing policy and indicators in breastfeeding women are needed to integrate PrEP into postnatal clinics, together with identification of mother and baby as a dyad in visits. Results showed that supportive policies facilitated wider, simplified PrEP provision. The availability and accessibility of prescribing nurses and lay HIV counselors, PrEP (both within facilities and in communities), and information about PrEP for implementers and pregnant and breastfeeding women will be pivotal to facilitating integration. CONCLUSION: Facilitators for PrEP integration include task-shifting PrEP education and identification of women for PrEP initiation to HIV counselors, changes to national guidelines defining who can prescribe PrEP, revision and integration of PrEP training for HCWs, community-level interventions for PrEP demand creation and stigma reduction, and provision of differentiated PrEP delivery options.

IntroductionGlobalization has increased the importance of multicultural research to address health disparities and improve healthcare outcomes for underrepresented communities. The International Nursing Network for HIV Research (The Network) serves as a platform for researchers to collaborate on cross-cultural and cross-national HIV studies. This article discusses the Network's approach to overcoming barriers in multicultural and multinational research in a qualitative context.MethodsThe network created a protocol to guide decision-making throughout the translation process of qualitative data collected from participants in their native languages. The protocol includes aspects of why, when, what, who, how, where, and by what means the translation is completed.ResultsThe protocol has allowed researchers to enhance the validity, reliability, and cultural sensitivity of translation process, ensuring the clarity and impact of their research findings.DiscussionRigorous translation practices promote cross-cultural understanding and respect for participants' perspectives, fostering global collaborations and knowledge exchange.

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

BackgroundThere are few data on tenofovir-diphosphate (TFV-DP) concentrations in pregnant and postpartum women on Tenofovir Disoproxil Fumarate-Emtricitabine (TDF-FTC) or Tenofovir Alafenamide-Emtricitabine (TAF-FTC).MethodsEligible pregnant women were randomized to TDF-FTC or TAF-FTC and followed for 16 weeks (8-weeks pregnant, 8-weeks postpartum) with weekly collection of dried blood spot (DBS) and 4-weekly peripheral blood mononuclear cells (PBMC). PrEP dosing was observed daily via asynchronous videos sent via cell phone. We report geometric means (GM) and their ratios (GMR) with 95% confidence intervals (CIs) for TFV-DP in PBMC and DBS from pregnancy and postpartum.ResultsWe enrolled N = 39 participants (n = 19 TDF-FTC, n = 20 TAF-FTC): median age was 28 years (IQR:25-34); median gestational age was 24-weeks (IQR:21-28). For TDF-FTC, TFV-DP DBS concentrations at 8-weeks did not differ significantly between pregnancy (GM: 675; 95%CI:537-849) and postpartum (GM: 583; 95%CI:471-722; GMR-TDF = 1.16; 95%CI:0.74-1.80). For TAF-FTC, TFV-DP DBS concentrations at 8-weeks were 44% higher in postpartum (GM: 1199; 95%CI:929-1549) versus pregnancy (GM: 832; 95%CI:751-922; GMR-TAF = 1.44; 95% CI: 1.01-2.06). In PBMC analysis of TDF-FTC, 8-week median TFV-DP (pmol/10^6 cell) was 71 (IQR 44-112) in pregnancy and 73 (IQR 50-102) in postpartum (GMR = 1.04; 95%CI:0.44-2.44). In TAF-FTC, median PBMC at 8-weeks was 580 (IQR:341-985) in pregnancy and 666 (IQR:396-1123) in postpartum (GMR = 1.15; 95%CI:0.30-2.49).ConclusionTFV-DP concentrations were overall lower during pregnancy than postpartum for TAF-FTC. We found high concentrations of TFV-DP in PBMC in pregnancy and postpartum on TAF-FTC, suggesting PrEP efficacy is maintained. Efficacy and safety studies are warranted to evaluate TAF-FTC for PrEP in pregnant and postpartum women.

BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

In South Africa, alcohol use during pregnancy is prevalent and associated with increased HIV risk. Developing locally sensitive and contextually appropriate evidence-based interventions to address alcohol use among pregnant and breastfeeding women in South Africa requires comprehensive understanding of the context of perinatal alcohol use and how relationships and lived environments may serve as barriers or supports for alcohol reduction. We conducted twenty in-depth qualitative interviews with isiXhosa speaking women who reported alcohol use during their recent pregnancy and/or recent intimate partner violence in Cape Town, South Africa between September and November 2022. We describe patterns and drivers of ongoing alcohol use during pregnancy and map them onto levels of the socioecological model. Data were analyzed utilizing the interpretivist paradigm and interpretive thematic analysis. Eight women reported alcohol use during pregnancy, sixteen reported experiencing recent IPV, and four women reported both alcohol use during pregnancy and recent IPV. In interviews, commonly cited reasons for continued alcohol use in pregnancy included stress (e.g., due to financial concerns), peer pressure, the central role of alcohol use in socialization and the persistence of misconceptions regarding the safety of alcohol use in pregnancy. Still, despite women reporting social norms that supported continued alcohol use in pregnancy, many altered who they drank with due to fear of judgement from close friends and family, leaving them isolated from their social support system. Interventions aimed at increasing interpersonal support, such as the use of peer mentors, could prove beneficial. Although the clinic provides messaging around the harms of alcohol use in pregnancy, these messages conflict with messaging received from their peers, limiting their impact on behavior. Locally sensitive tailored, relevant programming that intervenes on barriers to reducing alcohol use in pregnancy at multiple levels of the socioeconomic model are vital to effectively addressing this public health issue.

Research at the intersection of social science and genomics, 'sociogenomics', is transforming our understanding of the interplay between genomics, individual outcomes and society. It has interesting and maybe unexpected implications for education research and policy. Here we review the growing sociogenomics literature and discuss its implications for educational researchers and policymakers. We cover key concepts and methods in genomic research into educational outcomes, how genomic data can be used to investigate social or environmental effects, the methodological strengths and limitations of genomic data relative to other observational social data, the role of intergenerational transmission and potential policy implications. The increasing availability of genomic data in studies can produce a wealth of new evidence for education research. This may provide opportunities for disentangling the environmental and genomic factors that influence educational outcomes and identifying potential mechanisms for intervention.