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HIV infections are growing the fastest amongst adolescents, especially in sub Saharan Africa. On reaching adolescence, perinatally-infected youth may have different needs to those who acquired infection behaviourally. Yet both have sub-optimal adherence with implications for their own health as well as onward transmission. This study uses the world's largest community-based study of HIV-positive adolescents from the Eastern Cape, South Africa. Clinic records at N = 53 district health facilities generated a log of all ART-initiated adolescents who were then interviewed in the community: N = 1058 (90%) were tracked and participated. Ethical approval, informed consent and data collector training preceded data gathering. Inventories comprised validated measures of mental health (depression, anxiety, suicidality and internalised stigma), substance use, ART adherence, and clinic attendance. Analyses were conducted using SPSS25 and STATA15. Perinatally-infected adolescents (n = 792, 77.3%) were significantly more likely to be ART adherent (OR = 1.54 95%CI: 1.14-2.07 p = 0.005), retained in healthcare (OR = 1.59 95%CI1.18-2.14 p = 0.002), and treated well by clinic staff (OR = 2.12 95%CI1.59-3.07 p ≤ 0.001). Behaviourally-infected adolescents were more likely to be depressed (B = 0.81 p ≤ 0.001), anxious (B = 1.36 p ≤ 0.001), report internalised stigma (B = 0.91 p ≤ 0.001), express suicidal ideation (OR = 3.65 95%CI: 1.96-6.82 p ≤ 0.001) and report excessive substance use in the past year (OR = 9.37 95%CI5.73-15.35 p ≤ 0.001). Being older explained most of these differences, with female adolescents living with HIV more likely to report suicidal ideation. However, behaviourally-infected adolescents were more likely to report substance use (OR = 2.69 95%CI: 1.48-4.91 p = 0.001), depression (B = 0.406, p = 0.022), anxiety (B = 1.359, p ≤ 0.001), and internalised stigma (B = 0.403, p = 0.007) in multivariate regression analyses, controlling for covariates. Moderation analyses (adjusting for multiple testing) suggest that behaviourally-infected HIV-positive adolescents who are also maternal orphans are more likely to report higher rates of depression (B = 1.075, p < 0.001). These notable differences by mode of infection suggest that studies which conflate HIV-positive adolescents may blur the clinical and psychological experiences of these two different sub-populations. Drivers of non-adherence, poor retention in care, and mental health problems may differ by mode of infection, requiring tailored interventions. Health and social service provision, if it is to be effective, needs to address these different youth profiles to ensure optimal adherence, development and wellbeing throughout the life course. [ABSTRACT FROM AUTHOR]

Background: Children born to adolescent mothers are more vulnerable to infant mortality and morbidity than those born to adult mothers. HIV-exposed children have lower antibody protection against vaccine-preventable diseases at birth compared to unexposed children. In South Africa, 17 % of adolescent girls aged 15-19 years are mothers, yet vaccination coverage and timeliness among their children is underreported., Methods: This study estimated age-appropriate vaccination coverage and timeliness among children (n = 1080) of adolescent mothers (n = 1015) in the Eastern Cape, South Africa. Mother-child dyads were recruited through healthcare and community-based sampling strategies. Vaccination data were abstracted from 1013 home-based child health records (2017-2019). Coverage is reported for Diphtheria-Tetanus-Pertussis 3rd dose (DTP3), under-1 vaccination among children over 12 months (n = 613) and measles 2nd dose (MCV2) among children over 24 months (n = 382) using proportions with 95 % confidence intervals (95 %CI). Timeliness is defined as receiving each vaccination within 4 weeks of recommended age. Findings are disaggregated by maternal HIV-status., Results: Overall, 27.3 % of adolescent mothers were living with HIV. Coverage of DTP3 was 85.6 % (95 %CI: 82.6-88.3 %), under-1 coverage was 53.2 % (95 %CI: 49.1-57.2 %), and MCV2 coverage was 62.3 % (95 %CI: 57.2-67.2 %). Vaccination coverage was lower among children of adolescent mothers living with HIV (AMLHIV) than unexposed children (DTP3 80.3 % vs 88.2 % p-value: 0.01; under-1 46.5 % vs 56.4 % p-value: 0.02; MCV2 55.4 % vs 67.1 % p-value: 0.02). Timeliness of vaccinations declined over time from 98.0 % at birth, 70.7 % at 14 weeks, 71.9 % at 9 months and 37.3 % at 18 months., Conclusion: Vaccination coverage among children of adolescent mothers in the Eastern Cape are below national targets. Children of AMLHIV had lower coverage than HIV-unexposed children. Further research is needed to identify risk factors associated with incomplete and delayed vaccinations among this group, particularly among HIV-exposed children. Enhanced vaccination campaigns may be required for children of adolescent mothers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Camille Wittesaele reports financial support was provided by Horowitz Foundation for Social Policy. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Seborrheic dermatitis (SD), a chronic inflammatory skin condition consisting of itchy, red patches with greasy scales, has been linked to numerous systemic conditions. This review evaluates comorbidities and lifestyle factors that are associated with seborrheic dermatitis. A literary search was conducted in August 2024 using EMBASE, PubMed, and Medline Industries, and evaluated according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following results were found from this search. Diet may play a role in seborrheic dermatitis as participants with a diet high in simple carbohydrates, high in vitamin D, and low in iron have a higher instance of disease. Femoral cartilage thickness (FCT), a potential indicator of early osteoarthritis, was greater in patients with SD than in controls and was positively correlated with increasing SD severity. SD has also been associated with chronic diseases. Nearly half of Parkinson's disease (PD) patients in one study also had SD. As the severity of Parkinson's disease symptoms increases, the development of SD was observed to occur at a much higher rate, with the burden of SD positively correlated to the severity of PD symptoms. In one cross-sectional study of patients with SD, the most common systemic comorbidities were hypertension and diabetes, however, this finding was not statistically significant. Another study found that obesity was common amongst patients with SD, but this finding was also not significant. Visceral protein levels and height, however, were positively associated with increased SD disease severity. Metabolic syndrome and lower high-density lipoprotein (HDL) and triglycerides have been shown to be associated with more severe SD. Osteoporosis had a higher prevalence and faster disease progression in individuals with comorbid SD than in controls. Around 16% of individuals with psychiatric disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, were found to have SD. HIV is a disease with higher incidence of SD, although the prevalence of comorbid SD may be decreasing as the use of antiretroviral therapy increases. These associations highlight the complex nature of seborrheic dermatitis and underscore the necessity for further research to better understand these relationships and improve disease management., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kluglein et al.)

Background: We conducted a systematic review and meta-analysis of comparative studies to analyze intra- and postoperative outcomes of robot-assisted radical prostatectomy (RARP) using either DaVinci (DV-RARP) or Hugo™RAS (H-RARP) platforms., Methods: The study was registered in PROSPERO (CRD42024562326) and followed PRISMA guidelines. Literature search was conducted in June 2024 using academic databases, focusing on articles from 2021 to 2024. Research question focused on men with PCa (P) undergoing H-RARP (I) versus DV-RARP (C) to evaluate surgical, pathology, and functional outcomes (O), across comparative studies. Continuous variables were summarized using mean difference (MD) and categorical variables using odds ratio with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran's Q test and I 2 statistics. Publication bias was evaluated with Egger's and Begg's tests. Statistical analysis was performed with Stata®17.0, with significance set at p < 0.05. Risk of bias was assessed using the ROBINS-I tool. Methodological quality was evaluated with AMSTAR 2., Results: Eight studies (three prospective, five retrospective) with 1114 patients (454 H-RARP vs. 660 DV-RARP) were included. Baseline characteristics were comparable between groups. No significant differences were found in overall operative time, console time, blood loss, nerve-sparing, or lymphadenectomy. Docking time was significantly longer for Hugo™RAS (MD:6 min,95% CI 4.2;7.8). Postoperative outcomes, including complications, length of stay, and catheterization time, were similar. Pathological outcomes showed no significant differences in positive surgical margins or staging, but lower node yield was observed with H-RARP (MD:-2,95% CI -3.3;-0.6). Urinary continence recovery was comparable. Risk of bias was moderate to serious., Conclusion: The meta-analysis suggests H-RARP and DV-RARP perform not statistically different across most of analyzed outcomes, except for docking time and lymph-node yield. The longer docking time associated with the Hugo™RAS suggests demanding setup but does not translate into significantly longer operative time. Although statistically significant, the observed difference in lymph-node yield might be clinically negligible., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Without effective, scalable interventions, we will fail to achieve the Global AIDS Targets of zero AIDS-related deaths, zero HIV transmission and zero discrimination. This study examines associations of social protection and food security among adolescents living with HIV (ALHIV), with three Global AIDS Targets aligned outcomes: antiretroviral treatment (ART) adherence and viral suppression, HIV transmission risk behaviour and enacted stigma., Methods: We conducted three study visits over 2014-2018 with 1046 ALHIV in South Africa's Eastern Cape province. Standardized surveys provided information on receipt of government-provided cash transfers and past-week food security, alongside self-reported ART adherence, sexual debut and condom use, and enacted HIV-related stigma. Viral load (VL) data was obtained through data extraction from patient files and linkage with National Health Laboratory Service test results (2014-2020). We used a multivariable random-effects regression model to estimate associations between receiving government cash transfers and food security and three outcomes: ART adherence and viral suppression, delayed sexual debut or consistent condom use and no enacted stigma. We tested moderation by sex and age and fitted disaggregated models for each outcome., Results: Among the 933 ALHIV completing all three study visits, 55% were female, and the mean age was 13.6 years at baseline. Household receipt of a government cash transfer was associated with improvements on all outcomes: ART adherence and viral suppression (aOR 2.03, 95% CI 1.29-3.19), delayed sexual debut or consistent condom use (aOR 1.62, 95% CI 1.16-2.27) and no enacted stigma (aOR 2.33, 95% CI 1.39-3.89). Food security was associated with improvements on all outcomes: ART adherence and viral suppression (aOR 1.73, 95% CI 1.30-2.30), delayed sexual debut or consistent condom use (aOR 1.30, 95% CI 1.03-1.64) and no enacted stigma (aOR 1.91, 95% CI 1.32-2.76). Receiving both cash transfers and food security increased the probability of ART adherence and VL suppression from 36% to 60%; delayed sexual debut or consistent condom use from 67% to 81%; and no enacted stigma from 84% to 96%., Conclusions: Government-provided cash transfers and food security, individually and in combination, are associated with improved outcomes for ALHIV aligned with Global AIDS Targets. They may be important, and underutilized, accelerators for achieving these targets., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Purpose: Adolescent mothers face heightened economic and social vulnerabilities, which can place them at increased risk of intimate partner violence (IPV), prepandemic, and during COVID-19. However, few studies examine this population, and even less disaggregate findings by HIV status., Methods: We analyzed data from 834 South African adolescent mothers, 35% living with HIV (LHIV), who reported on physical, psychological, and sexual IPV exposure at two interviews: 2018-2019 (prepandemic) and 2021-2022 (during COVID-19). We estimated lifetime prevalence of IPV, disaggregating by HIV status. We used inverse weighted probability multivariate mixed-effects logistic regression to examine changes in IPV between the two periods and if changes in IPV differed by HIV status., Results: A quarter of adolescent mothers had experienced any IPV during COVID-19, quadruple prepandemic levels (24.7% vs. 6.0%). The increase was driven by surges in physical (+15.7%) and psychological (+11.2%) IPV. In both periods, psychosocial and physical IPV were the most prevalent forms and the most common combination among those who had experienced multiple forms of IPV. Exposure to any IPV was significantly more prevalent among those LHIV compared to those without HIV, prepandemic (9.5% vs. 4.1%, p = .026) and during COVID-19 (31.8% vs. 20.6%, p < .001). Adjusted models revealed an 18.2% significant increase in the average predicted probability of reporting IPV during COVID-19 compared to prepandemic, with no differential effect by HIV status., Discussion: Adolescent mothers experienced a significantly higher burden of IPV during COVID-19 than prepandemic, with those LHIV experiencing the highest level. Initiatives to reduce IPV need to reach adolescent mothers, particularly those living with HIV., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR + )/human epidermal growth factor receptor 2-negative (HER2 - ) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR + BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC., Competing Interests: Declaration of Competing Interest S.A.W.: Consulting/Advisory Board: Foundation Medicine, Eli Lilly, Novartis, Astrazeneca, Biovica, Hologic, Pfizer, Puma Biotechnology; Education/Speaking: Guardant Health, Eli Lilly, 2ndMD; Institutional Research Support: Genentech, Eli Lilly, Pfizer, Pfizer, Nuvation Bio, Regor Therapeutics. A.B.: Consultant/Advisory board of: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/Astra Zeneca, Phillips, Eli Lilly, Foundation Medicine. Contracted Research/Grant (to institution): Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/Astra Zeneca, Eli Lilly. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adolescent girls and young women ages 15-24 experience high rates of gender-based violence (GBV), underpinned by gender and social norms that shape their transitions to adulthood. For interventions that seek to leverage and build on existing infrastructure for health service provision, it is important to understand how gender norms operate in the background and how they shape service engagement or non-engagement. In formative work for our project, Screen & Support, outside of Lusaka, Zambia, we engaged in community conversations with adolescent girls and young women to understand common types and experiences of violence, perceptions of what causes violence, and pathways to post-violence service access. This manuscript explores emerging findings surrounding social and gender norms. We engaged n = 12 adolescent girls and young women ages 15-24, including survivors of GBV, young women living with HIV, and young married women in separate conversations conducted in a mix of Nyanja, Bemba, and English. Arts-based activities accompanied guided focus group discussions. Translated transcripts were coded and thematically analysed by two authors using Dedoose software. Key themes emerged around two major themes-understanding the norms underpinning violence, and observing how these norms were activated in the aftermath of violence. Sub-themes focused on power differentials supporting violence, social expectations and community-enacted sanctions, and understanding dominant norms and assumptions. Considering what unfolded in the aftermath of violence, young women participants considered key reference groups upholding norms, explored the contexts where norms may be contested or become more complicated, and described how accepting silence was a common means of closure. We discuss the implications of these findings for programme design, delivery, and evaluation, as well as the potential, and roadmap, for shifting norms that negative affect adolescent girls and young women., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority., Methods: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations., Results: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1 st - (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05)., Conclusion: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents., (© 2024. The Author(s).)

Maxwell et al. show that ARID1A loss enhances antitumor immunity by triggering a type I IFN response through the cGAS-STING pathway, thereby promoting T cell infiltration and cytotoxicity. These findings highlight SWI/SNF inhibitors as a strategy to augment immunotherapy efficacy by potentially transforming non-responsive tumors into responders and advancing approaches to cancer treatment., Competing Interests: Declaration of interests E.T reports grants from AstraZeneca and consulting fees from Menarini. B.H.K. declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Persons with disabilities are disadvantaged in accessing sexual and reproductive health services, including condoms. In this study, we investigated whether condom access and use and their associated factors differed between persons with and without disabilities. We used data from adults in households receiving the Government of Zambia social cash transfers (SCT) in four districts of Luapula province. Condom access and use was the outcome. Disability, defined by the Washington Group Short Set Questions on Disability, was the main predictor. We performed logistic regression analyses to determine the associations between condom access and use and disability. In multivariable analyses, we controlled for covariates including age, sex, marital status, poverty status, HIV testing, and receiving the SCT. The sample comprised 1,143 people aged 16-49, with a median age of 21 years (interquartile range 18-28); 57.4% (n = 656) were female, 86.5% (n = 989) accessed and used condoms, and 17.9% (n = 205) were disabled, rating themselves with a 3 or a 4 on a scale of 1 = "not limited" to 4 = "cannot at all" in performing any of the six daily functions (seeing, hearing, walking, cognition, self-care, or communicating). Nearly sixty percent(58.5% (n = 120)) of persons with disabilities were female, 79.5% (n = 163) reported being very poor, 87.8% (n = 180) reported receiving SCT, and 86.3% (n = 177) reported accessing and using condoms. Condom access and use did not differ between persons with and without disabilities (adjusted odds ratio: 1.09; 95% confidence interval [CI]: 0.60-1.98]). We found no differences between persons with and without disabilities in condom access and use. We established that individual-level factors such as age, sex, marital status, and knowledge of being HIV positive might play a more important role in condom access and use than disability. Condom promotion interventions should account for these factors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chipanta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Lesotho's government has shown consistent efforts to implement social protection programmes. However, while recent evidence established a positive causal relationship between some of these programmes and food security there is little evidence on the extent to which these initiatives are associated with better educational and sexual and reproductive health outcomes among vulnerable adolescents in Lesotho., Methods and Findings: The study uses cross-sectional, nationally representative data from the 2018 Lesotho Violence Against Children and Youth Survey. Our research examined the association between social protection receipt and educational and sexual and reproductive health outcomes among adolescents and young people (13-24 years) living in poverty. We employed multivariate logistic regression controlling for age, orphanhood, HIV status and sex. Social protection receipt was defined as household receipt of financial support from a governmental, non-governmental, or community-based program that provides income. Additionally, we fitted a marginal effects model by sex. Among the 3,506 adolescent females and males living in the two lowest poverty quintiles, receipt of social protection was associated with improvements in multiple adolescent outcomes: higher odds of consistent condom use (aOR 1.64, 95% CI 1.17-2.29), educational attainment (aOR 1.79, 95% CI 1.36-2.36), and school enrolment (aOR 2.19, 95% CI 1.44-3.34). Stratified analyses by sex showed that social protection receipt was also associated with reduced likelihood of child marriage among females (aOR 0.59, 95% CI 0.42-0.83) and higher odds of educational attainment and school enrolment among males (aOR 2.53, 95% CI 1.59-4.03 and aOR 3.11, 95% CI 1.56-6.19, respectively)., Conclusions: Our study provides evidence that social protection programs are associated with improved educational, sexual and reproductive health and child marriage prevention outcomes among adolescents living in poverty. Implementing and expanding such social protection initiatives could prove instrumental in improving the well-being of vulnerable adolescents., Contributions: Social protection programs have been increasing in sub-Saharan African countries, playing a pivotal role in poverty reduction, with Lesotho being no exception. Despite the optimistic outlook brought about by the implementation of the National Social Protection Strategy Lesotho I (2014-19) and II (2021-2031), the impact of these programs on some specific outcomes that concern the lives of the most vulnerable adolescents in Lesotho remains to some extent unexplored. Additionally, Lesotho grapples with high rates of HIV, adolescent pregnancy, child marriage and early school dropout, which can further contribute to poor long-term health and social outcomes among adolescents. In this study, we used data from the 2018 Lesotho Violence Against Children and Youth Survey (VACS) to examine the association between receiving social protection and multiple adolescent outcomes: educational, sexual and reproductive. The findings revealed that social protection programs, particularly the existing government-provided cash transfers, are significantly associated with multiple better outcomes among adolescents living in the poorest households in Lesotho. Such cash transfer schemes in Lesotho are associated with improved sexual and reproductive health outcomes for adolescent females, including reduced child marriage rates, and improved educational outcomes for males. These findings indicate that government-led social protection programmes are positively associated with favourable outcomes that can improve the quality of life for adolescents in resource-limited settings., (© 2024. The Author(s).)

Background: Compared with other age groups, adolescents living with HIV (ALHIV) are estimated to have lower levels of adherence to antiretroviral treatment. Despite this, we lack evidence on adolescents' adherence patterns over time to inform the customization of intervention strategies., Setting: Eastern Cape province, South Africa., Methods: We analyzed data from a cohort of ALHIV (N = 1046, aged 10-19 years at baseline) recruited from 53 public health facilities. The cohort comprised 3 waves of data collected between 2014 and 2018 and routine viral load data from the National Institute for Communicable Disease data warehouse (2014-2019). Durable viral suppression was defined as having suppressed viral load (<1000 copies/mL) at ≥2 consecutive study waves. Group-based multitrajectory model was used to identify adherence trajectories using 5 indicators of self-reported adherence. Logistic regression modeling evaluated the associations between adherence trajectories and durable viral suppression., Results: Overall, 933 ALHIV (89.2%) completed all 3 study waves (55.1% female, mean age: 13.6 years at baseline). Four adherence trajectories were identified, namely, "consistent adherence" (49.8%), "low start and increasing" (20.8%), "gradually decreasing" (23.5%), and "low and decreasing" (5.9%). Adolescents experiencing inconsistent adherence trajectories were more likely to be older, live in rural areas, and have sexually acquired HIV. Compared with the consistent adherence trajectory, the odds of durable viral suppression were lower among adolescents in the low start and increasing (adjusted odds ratio [aOR]: 0.62, 95% CI: 0.41 to 0.95), gradually decreasing (aOR: 0.40, 95% CI: 0.27 to 0.59), and the low and decreasing adherence (aOR: 0.25, 95% CI: 0.10 to 0.62) trajectories., Conclusions: Adherence to antiretroviral treatment remains a challenge among ALHIV in South Africa. Identifying adolescents at risk of nonadherence, based on their adherence trajectories may inform the tailoring of adolescent-friendly support strategies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer., Competing Interests: Declaration of interests M. Sallaku is an employee of Loxo Oncology. M. Scaltriti has ownership interest (including patents) in Medendi.org, reports other support from AstraZeneca, and is an employee of AstraZeneca. H.M.C. and T.C. are employees of AstraZeneca. P.C. reports personal fees from Venthera outside the submitted work. P.R. has received institutional grants/funding from Grail, Novartis, AstraZeneca, EpicSciences, Invitae/ArcherDx, Biothernostics, Tempus, Neogenomics, Biovica, Guardant, Personalis, and Myriad and has shares/ownership interest in Odyssey Biosciences as well as consultation/ad-board/honoraria from Novartis, AstraZeneca, Pfizer, Lilly/Loxo, Prelude Therapeutics, Epic Sciences, Daiichi-Sankyo, Foundation Medicine, Inivata, Tempus, SAGA Diagnostics, Paige.ai, Guardant, and Myriad. E.T. reports grants and personal fees from AstraZeneca and consulting from Menarini., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Estrogen receptor-positive (ER+) breast cancer is the most frequent breast cancer subtype. Agents targeting the ER signaling pathway have been successful in reducing mortality from breast cancer for decades. However, mechanisms of resistance to these treatments arise, especially in the metastatic setting. Recently, it has been recognized that epigenetic dysregulation is a common feature that facilitates the acquisition of cancer hallmarks across cancer types, including ER+ breast cancer. Alterations in epigenetic regulators and transcription factors (TF) coupled with changes to the chromatin landscape have been found to orchestrate breast oncogenesis, metastasis, and the development of a resistant phenotype. Here, we review recent advances in our understanding of how the epigenome dictates breast cancer tumorigenesis and resistance to targeted therapies and discuss novel therapeutic interventions for overcoming resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eneda Toska reports financial support was provided by AstraZeneca Pharmaceuticals LP. Eneda Toska reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory and funding grants. Eneda Toska reports a relationship with Menarini Research that includes: consulting or advisory., (Copyright © 2024. Published by Elsevier B.V.)

Although digital health promotion (DHP) technologies for young people are increasingly available in low- and middle-income countries (LMICs), there has been insufficient research investigating whether existing ethical and policy frameworks are adequate to address the challenges and promote the technological opportunities in these settings. In an effort to fill this gap and as part of a larger research project, in November 2022, we conducted a workshop in Cape Town, South Africa, entitled 'Unlocking the Potential of Digital Health Promotion for Young People in Low- and Middle-Income Countries'. The workshop brought together 25 experts from the areas of digital health ethics, youth health and engagement, health policy and promotion and technology development, predominantly from sub-Saharan Africa (SSA), to explore their views on the ethics and governance and potential policy pathways of DHP for young people in LMICs. Using the World Café method, participants contributed their views on (i) the advantages and barriers associated with DHP for youth in LMICs, (ii) the availability and relevance of ethical and regulatory frameworks for DHP and (iii) the translation of ethical principles into policies and implementation practices required by these policies, within the context of SSA. Our thematic analysis of the ensuing discussion revealed a willingness to foster such technologies if they prove safe, do not exacerbate inequalities, put youth at the center and are subject to appropriate oversight. In addition, our work has led to the potential translation of fundamental ethical principles into the form of a policy roadmap for ethically aligned DHP for youth in SSA., (© The Author(s) 2024. Published by Oxford University Press.)

Investing in adolescents in Africa holds great promise for the development of the continent. The steps involved in identifying factors linked to interventions that may accelerate the attainment of multiple SDGs for adolescents in Nigeria are described. Data from a survey to investigate the well-being of 1800 adolescents aged 10-19 years in Southwest Nigeria was analysed. A four-step process was employed: 1) Mapping of variables deemed as suitable proxies for SDG targets; 2) Mapping hypothesised protective factors (accelerators) from the study instruments. Consequently, SDG targets related to elimination of hunger, good health, gender equality and peace; and seven accelerators (safe schools, parenting support, good mental health, no survival work, food security, stable childhood, and regular physical activity) were identified; 3) evaluating associations using bivariate analysis and multivariable logistic regression, 4) calculating adjusted probabilities. The mean age of the adolescents was 15.02 ± 2.27 years (48.6% female). Good mental health, not doing survival work, safe schools, stable childhood and parental support were significantly associated with at least two SDG targets. For example, food security was significantly associated with the highest number of SDG outcomes: one SDG target related to child survival (no substance use: x 2  = 3.39, p = <0.001); three SDG targets related to educational outcomes (school progression: x 2  = 5.68, p  = 0.017, ability to concentrate in school: x 2  = 26.92, p = <0.001, and school attendance: x 2  = 25.89, p = <0.001); and four SDG targets related to child protection (no risky sexual behaviours: x 2  = 16.14, p = <0.001, no perpetration of violence: x 2  = 15.74, p = <0.001, no community violence: x 2  = 39.06, p =<0.001, and no sexual abuse: x 2  = 7.66, p  = 0.006). Interventions centred around good mental health, not doing survival work, safe schools, small family size, stable childhood and parental support are potential accelerators for the attainment of SDG outcomes by adolescents living in Nigeria.

Adolescent girls and young women (AGYW) in South Africa are at a three times higher risk of acquiring HIV than their male counterparts. The HIV prevention cascade is a tool which can be used to measure coverage of HIV prevention services, although there is limited empirical evidence to demonstrate its application in low-resourced settings. The unifying framework is a conceptualisation of the HIV prevention cascade which theorises that both motivation and access are required for an individual to effectively use an HIV prevention method. We applied this framework to data from a random sample of 127,951 beneficiaries of a combination HIV prevention programme for AGYW aged 15-24 in South Africa to measure the steps to, and identify key barriers to, effective use of male condoms and oral pre-exposure prophylaxis (PrEP) among this vulnerable population. Barriers to each step were analysed using univariate and multivariable logistic regression. Among self-reported HIV-negative AGYW who had sex in the past 6 months, effective use of condoms (15.2%), access to PrEP (39.1%) and use of PrEP (3.8%) were low. AGYW were: less likely to be motivated to use condoms if they believed that they had a faithful partner (aOR 0.44, 95% CI 0.22-0.90) or disliked condoms (aOR 0.26, 95% CI 0.11-0.57), less likely to access condoms if the place where AGYW accessed them was far away (aOR 0.25, 95% CI 0.10-0.64), more likely to effectively use condoms if they received counselling on how to use them (aOR 2.24, 95% CI 1.05-4.76), less likely to be motivated to use PrEP if they did not believe PrEP was efficacious (aOR 0.35, 95% CI 0.17-0.72), more likely to be motivated if they felt confident that they could use PrEP, and more likely to have access to PrEP if they had ever been offered PrEP (aOR 2.94, 95% CI 1.19-7.22). This combination HIV prevention programme and similar programmes should focus on risk-reduction counselling interventions for AGYW and their male partners to improve effective use of condoms and ensure easy access to condoms and PrEP by making them available in youth-friendly spaces. Our findings demonstrate that the application of HIV prevention cascades can inform AGYW HIV prevention programming in low-resourced settings., (© 2023. The Author(s).)

Introduction: Adolescent girls and young women (AGYW) living with HIV experience poor HIV outcomes and high rates of unintended pregnancy. Little is known about which healthcare provisions can optimize their HIV-related outcomes, particularly among AGYW mothers., Methods: Eligible 12- to 24-year-old AGYW living with HIV from 61 health facilities in a South African district completed a survey in 2018-2019 (90% recruited). Analysing surveys and medical records from n = 774 participants, we investigated associations of multiple HIV-related outcomes (past-week adherence, consistent clinic attendance, uninterrupted treatment, no tuberculosis [TB] and viral suppression) with seven healthcare provisions: no antiretroviral therapy (ART) stockouts, kind and respectful providers, support groups, short travel time, short waiting time, confidentiality, and safe and affordable facilities. Further, we compared HIV-related outcomes and healthcare provisions between mothers (n = 336) and nulliparous participants (n = 438). Analyses used multivariable regression models, accounting for multiple outcomes., Results: HIV-related outcomes were poor, especially among mothers. In multivariable analyses, two healthcare provisions were "accelerators," associated with multiple improved outcomes, with similar results among mothers. Safe and affordable facilities, and kind and respectful staff were associated with higher predicted probabilities of HIV-related outcomes (p<0.001): past-week adherence (62% when neither accelerator was reported to 87% with both accelerators reported), clinic attendance (71%-89%), uninterrupted ART treatment (57%-85%), no TB symptoms (49%-70%) and viral suppression (60%-77%)., Conclusions: Accessible and adolescent-responsive healthcare is critical to improving HIV-related outcomes, reducing morbidity, mortality and onward HIV transmission among AGYW. Combining these provisions can maximize benefits, especially for AGYW mothers., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression serve as a mechanism of intrinsic early/adaptive CDK4i/6i resistance. ALM cells that have acquired CDK4i/6i resistance following chronic treatment exposure also exhibit hyperactivation of the MAPK pathway. MEK and/or ERK inhibition increases CDK4i/6i efficacy against therapy naïve and CDK4i/6i-resistant AM cells in xenograft and patient-derived xenograft (PDX) models and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach for patients with metastatic ALM to improve outcomes., (© 2023. The Author(s).)

Brief tools are necessary to identify adolescents at greatest risk for ART non-adherence. From the WHO's HEADSS/HEADSS+ adolescent wellbeing checklists, we identify constructs strongly associated with non-adherence (validated with viral load). We conducted interviews and collected clinical records from a 3-year cohort of 1046 adolescents living with HIV from 52 South African government facilities. We used least absolute shrinkage and selection operator variable selection approach with a generalized linear mixed model. HEADSS constructs most predictive were: violence exposure (aOR 1.97, CI 1.61; 2.42, p < 0.001), depression (aOR 1.71, CI 1.42; 2.07, p < 0.001) and being sexually active (aOR 1.80, CI 1.41; 2.28, p < 0.001). Risk of non-adherence rose from 20.4% with none, to 55.6% with all three. HEADSS+ constructs were: medication side effects (aOR 2.27, CI 1.82; 2.81, p < 0.001), low social support (aOR 1.97, CI 1.60; 2.43, p < 0.001) and non-disclosure to parents (aOR 2.53, CI 1.91; 3.53, p < 0.001). Risk of non-adherence rose from 21.6% with none, to 71.8% with all three. Screening within established checklists can improve identification of adolescents needing increased support. Adolescent HIV services need to include side-effect management, violence prevention, mental health and sexual and reproductive health., (© 2023. The Author(s).)

Aim: This study aims to investigate associations of formal childcare with maternal and child outcomes in a large sample of adolescent mothers., Background: Forty percent of adolescent girls in Africa are mothers. Increasing evidence shows positive impacts of formal childcare use for adult women, but no known studies in the Global South examine associations for adolescent mothers and their children., Methods: We interviewed 1046 adolescent mothers and completed developmental assessments with their children (n = 1139) in South Africa's Eastern Cape between 2017 and 2019. Questionnaires measured childcare use, maternal and child outcomes and socio-demographic background variables. Using cross-sectional data, associations between formal childcare use and outcomes were estimated in multivariate multi-level analyses that accounted for individual-level and family-level clustering., Results: Childcare use was associated with higher odds of being in education or employment (AOR: 4.01, 95% CIs: 2.59-6.21, p < .001), grade promotion (AOR: 2.08, 95% CIs: 1.42-3.05, p < .001) and positive future ideation (AOR: 1.58, 95% CIs: 1.01-2.49, p = .047) but no differences in mental health. Childcare use was also associated with better parenting on all measures: positive parenting (AOR: 1.66, 95% CIs: 1.16-2.38, p = .006), better parental limit-setting (AOR: 2.00, 95% CIs: 1.37-2.93, p < .001) and better positive discipline (AOR: 1.77, 95% CIs: 1.21-2.59, p = .003). For the children, there were no differences in temperament or illness, but a significant interaction showed stronger associations between childcare use and better cognitive, language and motor scores with increasing child age (AOR: 5.04, 95% CIs: 1.59-15.96, p = .006)., Conclusions: Adolescent mothers might benefit substantially from formal childcare, but causal links need to be explored further. Childcare use was also associated with improved parenting and better child development over time, suggesting positive pathways for children. At an average of $9 per month, childcare provisions for adolescent mothers may offer low-cost opportunities to achieve high returns on health and human capital outcomes in Sub-Saharan African contexts., (© 2023 The Authors. Child: Care, Health and Development published by John Wiley & Sons Ltd.)

Increasing rates of mobile phone access present potential new opportunities and risks for adolescents' sexual and reproductive health in resource-poor settings. We investigated associations between mobile phone access/use and sexual risks in a cohort of 10-24-year-olds in South Africa. 1563 adolescents (69% living with HIV) were interviewed in three waves between 2014 and 2018. We assessed mobile phone access and use to search for health content and social media. Self-reported sexual risks included: sex after substance use, unprotected sex, multiple sexual partnerships and inequitable sexual partnerships in the past 12 months. We examined associations between mobile phone access/use and sexual risks using covariate-adjusted mixed-effects logistic regression models. Mobile phone access alone was not associated with any sexual risks. Social media use alone (vs. no mobile phone access) was associated with a significantly increased probability of unprotected sex (adjusted average marginal effects [AMEs] + 4.7 percentage points [ppts], 95% CI 1.6-7.8). However, health content use (vs. no mobile phone access) was associated with significantly decreased probabilities of sex after substance use (AMEs -5.3 ppts, 95% CI -7.4 to -3.2) and unprotected sex (AMEs -7.5 ppts, 95% CI -10.6 to -4.4). Moreover, mobile phone access and health content use were associated with increased risks of multiple sexual partnerships in boys. Health content use was associated with increased risks of inequitable sexual partnerships in adolescents not living with HIV. Results suggest an urgent need for strategies to harness mobile phone use for protection from growing risks due to social media exposure.

Rates of adolescent pregnancy within sub-Saharan Africa are increasing. Adolescent mothers ages 10-19 years face a distinct set of risks to their own and their children's health, compounded by many economic, social, and epidemiological challenges, such as living with HIV. In navigating this complex developmental period, many adolescent mothers face structural barriers impeding safe transitions to adulthood and motherhood. Drawing on existing literature and emerging data, we outline three normative, legal, and policy issues - violence and gender inequity, access to sexual and reproductive health services, and access to social and structural supports - which affect the health, wellbeing and development of adolescent mothers and their children. We also highlight emergent evidence about programming and policy changes that can better support adolescent mothers and their children. These key proposed responses include removing barriers to SRH and HIV service integration; ensuring implementation of return-to-school policies; and extending social protection systems to cater for adolescent mothers. Despite ongoing global crises and shifts in funding priorities, these normative, legal, and policy considerations remain critical to safeguard the health and wellbeing of adolescent mothers and their children.

The timely identification of ART non-adherence among adolescents living with HIV presents a significant challenge, particularly in resource-limited settings where virologic monitoring is suboptimal. Using South African adolescent cohort data (N = 933, mean age 13.6 ± 2.89 years, 55.1% female, follow-up = 2014-2018), we examined the association between elevated viral load (VL ≥ 1000 copies/mL) and seven self-reported adherence measures on missed doses, and clinic appointments -with varying recall timeframes. The best performing measures, which were significantly associated with elevated viral load in covariate-adjusted models are: any missed dose -past 3 days (sensitivity = 91.6% [95%CI: 90.3-92.8], positive predictive value (PPV) = 78.8% [95%CI: 77.2-80.4]), -past week (sensitivity = 87% [95%CI: 85.4-88.6], PPV = 78.2% [95%CI: 76.5-79.9]), -past month (sensitivity = 79.5% [95%CI: 77.5-81.4], PPV = 78.2% [95%CI: 76.4-79.9]), any past-month days missed (sensitivity = 86.7% [95%CI: 85.1-88.3], PPV = 77.9% [95%CI:76.2-79.6]), and any missed clinic appointment (sensitivity = 88.3% [95%CI: 86.8-89.8], PPV = 78.4% [95%CI: 76.8-79.9]). Combining the three best performing measures missed dose -past 3 days, -past week, and any past-year missed clinic appointment increased sensitivity to 96.4% while maintaining a PPV of about 78%. The discriminatory power of simple and easy-to-administer self-reported adherence measures in detecting elevated viral load warrants consideration in resource-limited settings and may contribute to the aims of the new Global Alliance to End AIDS in children and adolescents by 2030., (© 2023. The Author(s).)

Adolescent girls and young women in sub-Saharan Africa are at high risk of HIV, unintended pregnancy, and early motherhood. These intersecting risks can adversely affect their developmental trajectories and lifelong well-being. Because young mothers living with HIV in these settings experience high levels of stigma, shame, and isolation, tailored psychosocial intervention approaches for this group are critical yet unavailable. Enlisting young peer supporters may be a promising way to expand the reach of health services and enhance psychosocial well-being. To date, few peer-based interventions have targeted young mothers living with HIV. In 2019-2021, we codeveloped a peer-based, facility-embedded intervention package, Ask-Boost-Connect-Discuss (ABCD), with young peer supporters to address the psychosocial needs of young mothers living with HIV in Malawi, Tanzania, Uganda, and Zambia. We then analyzed programmatic data from ABCD to assess the feasibility of using young peers to deliver psychosocial support. Data sources included post-intervention interviews, focus groups, and written feedback from multiple stakeholders (participants, peer supporters, their supervisors, and clinic-based mentors), which were analyzed thematically. We organized our findings according to Bowen et al.'s feasibility framework. Findings spoke to the acceptability, practicality, and integration of the ABCD program. We found that young peer supporters were seen as acceptable program implementers; able to adopt responsive, engaging, and nonjudgmental approaches; and supported through training, technical skills development, and supervision, alongside purposeful facility integration. Importantly, we also found evidence reflecting the roles of demand and adaptation in program delivery (i.e., how peers responded to emerging participant needs or pivoted in their approach based on shifting circumstances). We conclude that considerations of intervention feasibility and/or program fidelity should be attuned to the dynamic qualities of young peer supporters as implementers and should extend beyond standard modes of assessment to consider intervention codevelopment and implementation as an iterative and adaptive process., (© Laurenzi et al.)

The prevalence of opioid use in the current opioid epidemic era has led to a public health emergency due to the ties to mortality and morbidity. Studies have investigated opioids' impacts on different aspects of cardiovascular health, although there seems to be a lack of a current concise review. Therefore, the aim of this literature review is to provide a summary of the most recent studies from the past decade that postulate a connection between opioids and their impact on cardiovascular health while highlighting conflicting areas among published research. For this literature review, three databases, PubMed (NLM), EMBASE, and Web of Science (Core Collection), were searched for full peer-reviewed articles written in English about human subjects and published between 2013 and 2023 inclusive. The following initial approach was to search for terms in the title of articles: "opioid AND ("vascular" OR "artery" OR "vein" OR "heart rate" OR "infarct" OR "stroke" OR "aortic" OR "cardiovascular disease"). After assessing for duplicate articles from the three databases, the remaining articles were assessed for inclusion eligibility. In the present review, a brief description of the overall role of opioid receptors is provided followed by the literature findings. These findings indicate potentially important negative impacts of opioid use on cardiovascular health in a number of areas. These include opioid-associated increases in the following: (1) vascular aging based on demonstrated increases in arterial stiffness, (2) opioid-related reductions in heart rate variability (HRV) and its implications on morbidity and mortality, (3) opioid's impacts on coronary artery and coronary heart disease (CHD), (4) opioids as a risk factor for atrial fibrillation (AF) and (5) opioid use as a risk factor for vascular occlusion processes. In addition to these broad cardiovascular effects, other aspects of concern are related to the potential impacts of withdrawal from opioid use, which, when done rapidly, are associated with increases in blood pressure and a decrease in HRV., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Toska et al.)

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Estimates on sexual violence (SV) among adolescents are rarely disaggregated by key indicators., Objective: We examine the independent effects of sex, age, HIV status and mode of HIV acquisition on the exposure to SV using generalised estimating equations models and proportional hazard model., Participant and Setting: Data from a 4-year prospective cohort study of 1447 adolescents (ages 10-19, 57% girls, 76% living with HIV) in South Africa., Methods: We describe the lifetime prevalence of three forms of SV: non-contact (unwanted showing of private parts), contact (coerced sexual debut, attempted and completed forced penetrative or oral sex,) and exploitative (sex in exchange for goods/money)., Results: Overall, 23.9% (95%CI = 21.7%-26.1%) reported exposure to SV at some point in their lives: non-contact = 5.7%, contact = 9.0% and exploitative = 15.8%. While girls reported higher rates of exploitative (18.4% vs 12.3%; p < 0.001) and contact SV (12.3% vs 4.6%; p < 0.001), there were no differences in levels of non-contact SV by sex (6.5% vs 4.6%; p = 0.086). Exposure to any SV doubled in late adolescence (10-14 years = 7.0% vs ≥15 years = 31.7%; aIRR = 2.07; 95%CI = 1.82-2.37). Though level of SV were comparable between those living with HIV and those HIV-uninfected (22.9% vs 26.2%; p = 0.182), adolescents who recently acquired HIV were twice as likely to experience SV compared to adolescents who perinatally acquired HIV (42.3% vs 15.7%; aIRR = 2.03; 95%CI = 1.73-2.39). This association persisted when analysis was restricted to incidence SV during follow-up (aIRR = 1.53; 95%CI = 1.23-2.10)., Conclusion: Exposure to SV was high for both sexes, increased with age and more prevalent among adolescents who recently acquired HIV. SV prevention and response services must also be offered to boys and strengthened in HIV care services., Competing Interests: Declaration of competing interest The authors have no conflict of interests to report., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Structural interventions are endorsed to enhance biomedical and behavioural HIV prevention programmes for adolescents. Aiming to inform future interventions, we evaluated longitudinal associations between six protective factors that link closely to existing structural HIV prevention interventions, and five sexual risk behaviours for HIV transmission in a cohort of adolescents in South Africa., Methods: We used three rounds of data between 2014-2018 on 1046 adolescents living with HIV and 473 age-matched community peers in South Africa's Eastern Cape (Observations = 4402). We estimated sex-specific associations between six time-varying protective factors - number of social grants, education enrolment, days with enough food, caregiver supervision, positive caregiving, and adolescent-caregiver communication; and five HIV risk behaviours - multiple sexual partners, transactional sex, age-disparate sex, condomless sex, and sex on substances. HIV risk behaviours were analysed separately in multivariable random effects within-between logistic regression models that accounted for correlation of repeated observations on the same individual. We calculated prevalence ratios (PR), contrasting adjusted probabilities of HIV risk behaviours at 'No' and 'Yes' for education enrolment, and average and maximum values for the other five protective factors., Results: The sample mean age was 15.29 (SD: 3.23) years and 58% were girls. Among girls, within-individuals, increases from mean to maximum scores in positive caregiving were associated with lower probability of transactional sex (PR = 0.79; 95%CI = 0.67-0.91); in caregiver supervision were associated with lower probability of transactional sex (PR = 0.75; 95%CI = 0.66-0.84), and age-disparate sex (PR = 0.84; 95%CI = 0.73-0.95); in adolescent-caregiver communication were associated with higher probability of transactional sex (PR = 1.70; 95%CI = 1.08-2.32); and in days with enough food at home were associated with lower probability of multiple sexual partners (PR = 0.89; 95%CI = 0.81-0.97), and transactional sex (PR = 0.82; 95%CI = 0.72-0.92). Change from non-enrolment in education to enrolment was associated with lower probability of age-disparate sex (PR = 0.49; 95%CI = 0.26-0.73). Between-individuals, relative to mean caregiver supervision scores, maximum scores were associated with lower probability of multiple sexual partners (PR = 0.59; 95%CI = 0.46-0.72), condomless sex (PR = 0.80; 95%CI = 0.69-0.91), and sex on substances (PR = 0.42; 95%CI = 0.26-0.59); and relative to non-enrolment, education enrolment was associated with lower probability of condomless sex (PR = 0.59; 95%CI = 0.39-0.78). Among boys, within-individuals, increases from mean to maximum scores in positive caregiving were associated with lower probability of transactional sex (PR = 0.77; 95%CI = 0.59-0.96), and higher probability of condomless sex (PR = 1.26; 95%CI = 1.08-1.43); in caregiver supervision were associated with lower probability of multiple sexual partners (PR = 0.73; 95%CI = 0.64-0.82), transactional sex (PR = 0.63; 95%CI = 0.50-0.76), age-disparate sex (PR = 0.67; 95%CI = 0.49-0.85), and sex on substances (PR = 0.61; 95%CI = 0.45-0.78), and in days with enough food at home were associated with lower probability of transactional sex (PR = 0.91; 95%CI = 0.84-0.98)., Conclusion: Effective structural interventions to improve food security and education enrolment among adolescent girls, and positive and supervisory caregiving among adolescent girls and boys are likely to translate into crucial reductions in sexual risk behaviours linked to HIV transmission in this population., (© 2023. The Author(s).)

Long-acting injectable anti-retroviral therapy (LAART) may overcome barriers to long-term adherence and improve the survival of adolescents and young people living with HIV (AYLHIV). Research on the acceptability of LAART for this age-group is limited. We asked 953 AYLHIV about their preferred (theoretical) ART mode of delivery (pill, injectable, or other) in 2017-2018, before LAART was available or known to AYLHIV in South Africa. One in eight (12%) AYLHIV preferred LAART over single or multiple pill regimens. In multivariate analyses, six factors were associated with LAART preference: medication stock-outs (aOR = 2.56, 95% CI 1.40-4.68, p = 0.002), experiencing side-effects (aOR = 1.84, 95% CI 1.15-2.97, p = 0.012), pill-burden (aOR = 1.88, 95% CI 1.20-2.94, p = 0.006), past-year treatment changes (aOR = 1.63, 95% CI 1.06-2.51, p = 0.025), any HIV stigma (aOR = 2.22, 95% CI 1.39-3.53, p ≤ 0.001) and recent ART initiation (aOR = 2.02, 95% CI 1.09-3.74, p = 0.025). In marginal effects modelling, 66% of adolescents who experienced all factors were likely to prefer LAART, highlighting the potential high acceptability of LAART among adolescents and young people living with HIV struggling to adhere and have good HIV treatment outcomes. Adolescent boys who reported high ART pill burden were more likely to prefer LAART than their female peers in moderation analyses, suggesting that LAART may be particularly important to improve treatment outcomes among male AYLHIV as they become older. Adding LAART to existing treatment options for AYLHIV, particularly higher risk groups, would support AYLHIV to attain and sustain viral suppression-the third 95, and reduce their risk of AIDS-related mortality., (© 2023. The Author(s).)

We have shown that KRAS-TP53 genomic coalteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating KRAS-TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry. Silencing of cell-intrinsic Cxcl1 in LSL-KrasG12D/+;Trp53R172H/+;Pdx-1Cre/+(KPC) cells reprograms the trafficking and functional dynamics of neutrophils to overcome T-cell exclusion and controls tumor growth in a T cell-dependent manner. Mechanistically, neutrophil-derived TNF is a central regulator of this immunologic rewiring, instigating feed-forward Cxcl1 overproduction from tumor cells and cancer-associated fibroblasts (CAF), T-cell dysfunction, and inflammatory CAF polarization via transmembrane TNF-TNFR2 interactions. TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell-neutrophil cross-talk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC., Significance: By decoding connections between high-risk tumor genotypes, cell-autonomous inflammatory programs, and myeloid-enriched/T cell-excluded contexts, we identify a novel role for neutrophil-derived TNF in sustaining immunosuppression and stromal inflammation in pancreatic tumor microenvironments. This work offers a conceptual framework by which targeting context-dependent TNF signaling may overcome hallmarks of chemoresistance in pancreatic cancer. This article is highlighted in the In This Issue feature, p. 1275., (©2023 American Association for Cancer Research.)

This study explores the cognitive development of children born to adolescent mothers within South Africa compared to existing reference data, and explores development by child age bands to examine relative levels of development. Cross-sectional analyses present data from 954 adolescents (10-19 years) and their first-born children (0-68 months). All adolescents completed questionnaires relating to themselves and their children, and standardized child cognitive assessments (Mullen Scales of Early Learning) were undertaken. Cognitive development scores of the sample were lower than USA reference population scores and relative performance compared to the reference population was found to decline with increasing child age. When compared to children born to adult mothers in the sub-Saharan African region, children born to adolescent mothers (human immunodeficiency virus [HIV] unexposed; n  = 724) were found to have lower cognitive development scores. Findings identify critical periods of development where intervention may be required to bolster outcomes for children born to adolescent mothers., Highlights: An exploration of the cognitive development of children born to adolescent mothers within South Africa utilizing the Mullen Scales of Early Learning.Cognitive development scores of children born to adolescent mothers within South Africa were lower compared to USA norm reference data and declined with child age.Previous studies utilizing the Mullen Scales of Early Learning within sub-Saharan Africa were summarized, and comparisons were made with the current sample.Findings highlight a potential risk of developmental delay among children born to adolescent mothers compared to children of adult mothers in the sub-Saharan African region., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Infant and Child Development published by John Wiley & Sons Ltd.)