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Introduction South Africa’s evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs.Methods and analysis Bukhali is the first individual randomised controlled trial in Africa to test the efficacy of a complex continuum of care intervention and forms part of the Healthy Life Trajectories Initiative (HeLTI) consortium implementing harmonised trials in Canada, China, India and SA. Starting preconception and continuing through pregnancy, infancy and childhood, the intervention is designed to improve nutrition, physical and mental health and health behaviours of South African women to offset obesity-risk (adiposity) in their offspring. Women aged 18–28 years (n=6800) will be recruited from Soweto, an urban-poor area of Johannesburg. The primary outcome is dual-energy X-ray absorptiometry derived fat mass index (fat mass divided by height2) in the offspring at age 5 years. Community health workers will deliver the intervention randomly to half the cohort by providing health literacy material, dispensing a multimicronutrient supplement, providing health services and feedback, and facilitating behaviour change support sessions to optimise: (1) nutrition, (2) physical and mental health and (3) lay the foundations for healthier pregnancies and early child development.Ethics and dissemination Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent.Trial registration This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871).Protocol version 20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries.

Background: The COVID-19 pandemic affected healthcare delivery globally, impacting care access and delivery of essential services., Objectives: We investigated the pandemic's impact on care for patients with type 2 diabetes and factors associated with care disruption in Kenya and Tanzania., Methods: A cross-sectional study was conducted among adults diagnosed with diabetes pre-COVID-19. Data were collected in February-April 2022 reflecting experiences at two time-points, three months before and the three months most affected by the COVID-19 pandemic. A questionnaire captured data on blood glucose testing, changes in medication prescription and access, and healthcare provider access., Results: We recruited 1000 participants (500/country). Diabetes care was disrupted in both countries, with 34.8% and 32.8% of the participants reporting change in place and frequency of testing in Kenya, respectively. In Tanzania, 12.4% and 17.8% reported changes in location and frequency of glucose testing, respectively. The number of health facility visits declined, 14.4% ( p  < 0.001) in Kenya and 5.6% ( p  = 0.001) in Tanzania. In Kenya, there was a higher likelihood of severe care disruption among insured patients (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI][1.05-2.34]; p  = 0.029) and a lower likelihood among patients residing in rural areas (aOR, 0.35[95%CI, 0.22-0.58]; p  < 0.001). Tanzania had a lower likelihood of severe disruption among insured patients (aOR, 0.51[95%CI, 0.33-0.79]; p  = 0.003) but higher likelihood among patients with low economic status (aOR, 1.81[95%CI, 1.14-2.88]; p  = 0.011)., Conclusions: COVID-19 disrupted diabetes care more in Kenya than Tanzania. Health systems and emergency preparedness should be strengthened to ensure continuity of service provision for patients with diabetes.

Aims: Renin-angiotensin-aldosterone system inhibitors (RAASi) are foundational in the management of heart failure (HF) and chronic kidney disease (CKD) but increase the risk of hyperkalaemia. To facilitate continuation of RAASi therapy, guidelines suggest managing hyperkalaemia using newer potassium binders such as sodium zirconium cyclosilicate (SZC). This observational study describes the likelihood of continued RAASi therapy by duration of SZC treatment., Methods: The study population included non-dialysis-dependent adults diagnosed with HF and/or CKD who initiated outpatient SZC treatment while receiving RAASi therapy. Patients were identified using healthcare registers and claims data from the United States, Japan and Spain. SZC treatment duration was described using the Kaplan-Meier method. Hernán's clone-censor-weight (CCW) approach, using principles of trial emulation, was applied to evaluate the likelihood of continued RAASi therapy at specific time points by distinct SZC treatment durations, using a weighted Kaplan-Meier method and Z-tests., Results: The study included 7980 patients, from the United States (n = 4849), Japan (n = 2759) and Spain (n = 372). Across the three countries, mean patient age was 73.1-75.0 years, 53.2%-66.4% of patients were male, 39.0%-75.0% had HF and 76.9%-95.3% had CKD. Between Days 30 and 120, the percentage of patients remaining on SZC treatment decreased from 36.5% to 12.8% in the United States, from 63.8% to 33.7% in Japan, and from 81.9% to 65.0% in Spain. In the United States, patients who continued SZC treatment beyond 30 days had a higher likelihood of continuing RAASi therapy for up to 90 days (P < 0.001), and continuing SZC treatment beyond 60 days was superior for continuing RAASi therapy for up to 6 months (P < 0.001), versus earlier SZC discontinuation. At 120 days, the likelihood of remaining on RAASi therapy was 69%-70% for SZC treatment durations exceeding 60 days, versus 59% for shorter durations (1-30 days) (P < 0.001). Similar patterns were observed in Japan. At 120 days, the likelihood of remaining on RAASi therapy was 86%-87% for SZC treatment durations exceeding 90 days, versus 82% for shorter SZC treatment durations (1-30 days) (P < 0.05). The CCW analyses were not deemed feasible in the Spanish dataset due to the smaller initial sample size and few patients having a relatively short SZC treatment duration., Conclusions: Patients with longer SZC treatment experience sustained protection against RAASi discontinuation, and the risk of RAASi discontinuation resumes once SZC is discontinued., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Tight junctions (TJs) serve as permeability filters between the internal and external cellular environment. A large number of proteins have been identified to be localized at the TJs. Due to limitations in tissue collection, TJs in the male genital tract have been understudied., Methods: We analysed the transcriptomics of 132 TJ genes in foreskin tissue of men requesting voluntary medical male circumcision (VMMC) and enrolled in the Combined HIV Adolescent Prevention Study (CHAPS) trial conducted in South Africa and Uganda (NCT03986970). The trial evaluated the dose requirements for event-driven HIV pre-exposure prophylaxis (PrEP) with emtricitabine-tenofovir (FTC-TDF) or emtricitabine-tenofovir alafenamide (FTC-TAF) during insertive sex. A total of 144 participants were randomized to either control arm or one of 8 PrEP arms (n=16/arm), receiving oral FTC-TDF or FTC-TAF over one or two days. Following in vivo oral PrEP dosing and VMMC, the expression level of three important TJ proteins (CLDN-1, OCN and ZO-1) was measured ex vivo in foreskin tissue by Western blot. The expression of cytokine genes implicated in TJ regulation was determined. Non-parametric Kruskal-Wallis tests were used to compare TJ gene expression and protein levels by type of PrEP received, and Spearman's correlation coefficients were calculated to assess whether TJ gene expression levels were related to cytokine gene levels or to PrEP drug concentrations and their active intracellularly phosphorylated metabolites., Results: A high level of expression in foreskin tissue was found for 118 (of 132) TJ genes analysed; this finding contributed to create a map of TJ components within the male genital tract. Importantly, PrEP regimens tested in the CHAPS trial did not affect the expression of TJ genes and the analysed proteins in the foreskin; thus, further supporting the safety of this prevention strategy against HIV-1 transmission during insertive sex. Additionally, we identified the level of several cytokines' genes to be correlated to TJ gene expression: among them, IL-18, IL-33 and VEGF., Discussion: TJs can limit viral entry into target cells; to affect this biological function viruses can reduce the expression of TJ proteins. Our study, on the expression and regulation of TJs in the foreskin, contribute important knowledge for PrEP safety and further design of HIV-1 prophylaxis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Webb, Petkov, Yun, Else, Lebina, Serwanga, Pillay, Seiphetlo, Mugaba, Namubiru, Odoch, Opoka, Ssemata, Kaleebu, Khoo, Martinson, Fox, Gray, Herrera and Chiodi.)

We previously showed a link between maternal vascular malperfusion and pre-term birth (PTB) in pregnant people living with HIV (PPLH) initiating antiretroviral treatment (ART) before pregnancy, indicating poor placental vascularisation. After measuring antenatal plasma angiogenic factors to seek mechanistic insights, low levels of plasma Factor XIIIA1 (FXIIIA1) and vascular-endothelial-growth-factor (VEGF) was significantly associated with PTB at the time closest to delivery (median 34 weeks) in PPLH initiating ART before pregnancy. Knowing that FXIIIA1 is crucial for haemostasis, angiogenesis, implantation and pregnancy maintenance and that expression is found on placental macrophages (Hofbauer cells), we examined placentae at delivery from matching participants who either initiating ART before pregnancy or during gestation. Highest FXIIIA1 expression was on Hofbauer cells but was significantly lower in PTB regardless of HIV infection, but was significantly lower in PPLH in PTB from women who initiated ART before pregnancy. To test the hypothesis that antiretroviral drugs may disrupt vascularisation in the placenta, we used a human umbilical vein endothelial cell (HUVEC) matrigel angiogenesis assay. We identified that addition of pre-treated FXIIIA1-expressing MCSF- and IL-10-induced placenta-like macrophages with physiological concentrations of tenofovir, 3TC, and efavirenz resulted in significantly inhibited angiogenesis; akin to the inhibition observed with titratable concentrations of ZED1301, an inhibitor of FXIIIA1. Overall, an efavirenz-containing ART combination inhibits vasculogenesis without causing toxicity and likely does so through inhibition of a FXIIIA1-mediated-placental macrophage pathway., Competing Interests: Conflict of interest statement The authors have declared that no conflict of interest exists.

HIV exposed but uninfected infants (iHEU) display altered immunity and are at increased risk of infection. We previously reported that iHEU have decreased maternal microchimerism (MMc)-maternal cells transferred to the offspring in utero/during breastfeeding. We quantified MMc in T cell subpopulations in iHEU and unexposed infants (iHU) to determine whether a selective deficiency in MMc contributes to altered cellular immunity. Across all infants, MMc levels were highest in CD8+ T cells; however, the level of CD8+ T cell MMc was lower in iHEU versus iHU. In limited functional studies, we did not identify CMV-specific MMc during infant primary infection., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The European Fans in Training (EuroFIT) program integrated need-supportive motivational strategies from Self-Determination Theory (SDT) in the design of a healthy lifestyle program delivered to overweight or obese male football fans (n = 1113; mean age of 45.9 [SD = 9.0] years old and BMI of 33.2 kg/m2 [SD = 4.6]) in professional football club settings in the UK, Portugal, Norway and the Netherlands. With a critical realist approach, we developed a structured thematic framework analysis based on Self-Determination Theory (SDT) to investigate the process of change in men who participated in the EuroFIT randomized controlled trial (RCT). We examined whether men's experiences of the social context of EuroFIT, and whether their engagement with the program's motivational strategies supported or frustrated their basic psychological needs while attempting to change their lifestyle behaviours. We found that men in all countries perceived the social contexts of the EuroFIT program as mostly needs-supportive, and that they found engagement with most of the program components helpful in supporting their psychological needs when initiating health behaviour changes. However, some of the program elements in the EuroFIT program were perceived as needs-frustrating by some participants and need-supportive by others. Implications for the use of need-supportive motivational strategies in designing future lifestyle interventions in sport settings to promote health behaviour change among male football fans are discussed., Competing Interests: Declaration of competing interest 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.)

In this study, we compare the outcomes of two patients with similar spinal pathologies who chose different treatment options. The first case involves a 38-year-old female with significant lumbar disc herniation and associated degenerative spinal changes, including type I Modic changes. She presented with sciatica and, after conservative treatments failed, underwent an endoscopic discectomy. This intervention led to a marked improvement in her pain and functional status, along with a partial resolution of the Modic changes and a decrease in multifidus atrophy and fatty infiltration, on her follow-up MRI. In the second case, we discuss a 33-year-old patient with a large disc herniation. Despite three years of conservative management, she developed Modic changes and sclerosis in the adjacent vertebral endplates and a worsening of multifidus atrophy and fatty infiltration. This report supports the consideration of early minimally invasive discectomy for young patients who do not benefit from conservative treatment, as a means to prevent the progression of degenerative spinal changes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Toropchyn et al.)

Radiofrequency ablation (RFA) targeting the iliohypogastric and ilioinguinal (IH/IL) nerves is a recognized treatment for lower abdominal neuropathic pain. Despite its effectiveness, RFA typically offers only a temporary reprieve, necessitating repeated procedures. RFA procedures of the IH/IL nerves have been well described but often result in patient non-compliance and commonly necessitate the use of increased sedation. This case report details an RFA technique as a novel therapeutic technique for managing neuropathic pain associated with IH and IL pain. The technique described was conducted on a patient with complex pain and profound hyperalgesia with remarkable patient compliance and, more importantly, with reduced sedation. This case report delves into the progressive interventions employed by this novel technique in a patient being treated for IH/IL neuralgia. This case report describes increased patient compliance and potentially increased safety profile associated with this innovative RFA technique in comparison to traditional RFA and steroid injection. The patient, whose pain was unresponsive to standard treatments, was thoroughly assessed and underwent multiple failed interventions requiring sedation before the novel RFA technique was considered. We describe the patient's progression through various treatments, illustrating the benefits of this novel RFA method over the established ones. The discussion highlights the advantages of the new technique in terms of its effectiveness and the duration of its pain relief, offering valuable insights into the pain management field. This case contributes to the growing array of therapeutic strategies in pain medicine, potentially enhancing patient outcomes for those with IH/IL neuropathic pain., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Krogman et al.)

Although cognitive functions are hypothesized to be mediated by synchronous neuronal interactions in multiple frequency bands among widely distributed cortical areas, we still lack a basic understanding of the distribution and task dependence of oscillatory activity across the cortical map. Here, we ask how the spectral and temporal properties of the local field potential (LFP) vary across the primate cerebral cortex, and how they are modulated during visual short-term memory. We measured the LFP from 55 cortical areas in two macaque monkeys while they performed a visual delayed match to sample task. Analysis of peak frequencies in the LFP power spectra reveals multiple discrete frequency bands between 3 and 80 Hz that differ between the two monkeys. The LFP power in each band, as well as the sample entropy, a measure of signal complexity, display distinct spatial gradients across the cortex, some of which correlate with reported spine counts in cortical pyramidal neurons. Cortical areas can be robustly decoded using a small number of spectral and temporal parameters, and significant task-dependent increases and decreases in spectral power occur in all cortical areas. These findings reveal pronounced, widespread, and spatially organized gradients in the spectral and temporal activity of cortical areas. Task-dependent changes in cortical activity are globally distributed, even for a simple cognitive task. NEW & NOTEWORTHY We recorded extracellular electrophysiological signals from roughly the breadth and depth of a cortical hemisphere in nonhuman primates (NHPs) performing a visual memory task. Analyses of the band-limited local field potential (LFP) power displayed widespread, frequency-dependent cortical gradients in spectral power. Using a machine learning classifier, these features allowed robust cortical area decoding. Further task dependence in LFP power were found to be widespread, indicating large-scale gradients of LFP activity, and task-related activity.

Infants who are HIV exposed but uninfected (iHEU) have higher risk of viral infections compared to infants who are HIV unexposed (iHUU). We explored the effect of intrauterine HIV exposure on the infant antibody repertoire by quantifying plasma immunoglobulin (Ig) G against 206 eukaryote-infecting viruses using phage immunoprecipitation sequencing (PhiPSeq) in iHEU and iHUU at birth and 36 weeks of life. Maternal HIV infection altered the infant IgG repertoire against eukaryote-infecting viruses at birth, resulting in significantly lower antibody breadth and diversity among iHEU compared to iHUU. Neonatal anti-viral IgG repertoire was dominated by antibodies against viruses belonging to the Herpesviridae family, although, by 36 weeks, this had shifted toward antibodies against enteroviruses, likely due to waning of maternal-derived antibodies and polio vaccine-induced antibody responses as expected. The observed reduced anti-viral IgG repertoire breadth and diversity acquired at birth in iHEU might contribute to the increased rates of viral infections among iHEU during early life., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

While preventing vertical HIV transmission has been very successful, HIV-exposed uninfected infants (iHEU) experience an elevated risk to infections compared to HIV-unexposed and uninfected infants (iHUU). Here we present a longitudinal multimodal analysis of infant immune ontogeny that highlights the impact of HIV/ARV exposure. Using mass cytometry, we show alterations in T cell memory differentiation between iHEU and iHUU being significant from week 15 of life. The altered memory T cell differentiation in iHEU was preceded by lower TCR Vβ clonotypic diversity and linked to TCR clonal depletion within the naïve T cell compartment. Compared to iHUU, iHEU had elevated CD56 lo CD16 lo Perforin + CD38 + CD45RA + FcεRIγ + NK cells at 1 month postpartum and whose abundance pre-vaccination were predictive of vaccine-induced pertussis and rotavirus antibody responses post 3 months of life. Collectively, HIV/ARV exposure disrupted the trajectory of innate and adaptive immunity from birth which may underlie relative vulnerability to infections in iHEU., (© 2024. The Author(s).)

Objective: To synthesise current evidence on knowledge, perceptions and practices towards type 2 diabetes risk in sub-Saharan Africa., Design: Mixed-methods scoping review, which included 101 studies (seventy-three quantitative, twenty qualitative and eight mixed methods) from seven electronic databases., Setting: Sub-Saharan Africa, 2000-2023., Participants: Men and women without diabetes with mean ages ranging from 20 to 63 years., Results: The majority of participants in most studies knew the three main diabetes modifiable risk factors - excess weight, unhealthy diet and physical inactivity. However, most people with excess weight in almost all studies underestimated their weight. Further, the self-described ideal body weight was between midpoint of normal weight and the upper limits of overweight in most quantitative studies and was described as not too skinny but not too fat in qualitative studies. In the majority of studies, participants reported low engagement in weight control, high regular sugar intake, and low regular fruit and vegetable intake but moderate to high engagement in physical activity. Barriers to reducing diabetes risk were social (e.g. societal perceptions promoting weight gain) and environmental (e.g. limited affordability of healthy foods, high accessibility of Western diets and lack of physical activity facilities)., Conclusion: There is a need for multicomponent type 2 diabetes prevention interventions that increase knowledge of identifying diabetes risk (e.g. what constitutes excess weight) and create social and physical environments that support healthy lifestyles (e.g. societal perceptions that promote healthy living, increased availability and affordability of healthy foods and physical activity facilities).

Background: Postpartum weight (PPW) contributes to long-term obesity, a growing concern in persons with HIV (PWH). We investigated whether inflammatory markers in pregnancy may be involved in postpartum (PP) obesity in PWH., Setting: A total of 57 pregnant PWH enrolled at ≤14 weeks gestation (T1) in Gugulethu antenatal care clinic in Cape Town and followed through 48 weeks PP were included., Methods: Plasma soluble (s) CD14, sCD163, leptin, tumour necrosis factor receptor 1 (TNFR-1), resistin, adiponectin, and interleukin-6 (IL-6) were assayed in duplicate using the Luminex platform. We considered each inflammatory marker at T1 (n=57) and T3 (29-36 weeks gestation, n=31) as a separate exposure of interest. Linear mixed effects models were fit to examine whether each exposure was associated with average PPW and PPW trajectories; linear regression was used for associations with PPW change between T1 and 48 weeks., Results: Median age was 32 years (IQR, 29-35), 98% were multigravida, and 49% had a BMI≥30 kg/m2. Higher T1 sCD14 levels were associated with higher average weight through 48 weeks PP (ß = 0.002, p=0.04), and T3 sCD14 with higher PPW gain (ß = 0.007, p=0.04). Leptin (ß = 0.414, p<0.01), TNFR-1 (ß = 11.048, p<0.01) and resistin (ß = 0.714, p=0.01) at T3 were associated with higher average PPW, and IL-6 (ß = 2.266, p=0.02) with PPW gain., Conclusion: These findings suggest that low-grade inflammation in pregnancy may play a role in postpartum obesity, pointing to potential mechanisms with implications for long-term cardiometabolic health in PWH., Competing Interests: Conflicts of Interest and Source of Funding: The authors declare that they have no competing interests. The study was funded by the Fogarty International Center of the National Institutes of Health under Award Number D43TW010543-05. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Type 2 diabetes is increasing in Kenya, especially in urban settings, and prevention interventions based on local evidence and context are urgently needed. Therefore, this study aimed to explore diabetes risk and co-create a diabetes prevention theory of change in two socioeconomically distinct communities to inform future diabetes prevention interventions., Methods: In-depth interviews were conducted with middle-aged residents in two communities in Nairobi (one low-income (n = 15), one middle-income (n = 14)), and thematically analysed. The theory of change for diabetes prevention was informed by analysis of the in-depth interviews and the Behaviour Change Wheel framework, and reviewed by a sub-set (n = 13) of interviewees., Results: The key factors that influenced diabetes preventive practices in both communities included knowledge and skills for diabetes prevention, understanding of the benefits/consequences of (un)healthy lifestyle, social influences (e.g., upbringing, societal perceptions), and environmental contexts (e.g., access to (un)healthy foods and physical activity facilities). The proposed strategies for diabetes prevention included: increasing knowledge and understanding about diabetes risk and preventive measures particularly in the low-income community; supporting lifestyle modification (e.g., upskilling, goal setting, action planning) in both communities; identifying people at high risk of diabetes through screening in both communities; and creating social and physical environments for lifestyle modification (e.g., positive social influences on healthy living, access to healthy foods and physical activity infrastructure) particularly in the low-income community. Residents from both communities agreed that the strategies were broadly feasible for diabetes prevention but proposed the addition of door-to-door campaigns and community theatre for health education. However, residents from the low-income community were concerned about the lack of government prioritisation for implementing population-level interventions, e.g., improving access to healthy foods and physical activity facilities/infrastructure., Conclusion: Diabetes prevention initiatives in Kenya should involve multicomponent interventions for lifestyle modification including increasing education and upskilling at individual level; promoting social and physical environments that support healthy living at population level; and are particularly needed in low-income communities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Manyara 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.)

Infants who are exposed to HIV but uninfected (iHEU) have higher risk of infectious morbidity than infants who are HIV-unexposed and uninfected (iHUU), possibly due to altered immunity. As infant gut microbiota may influence immune development, we evaluated the effects of HIV exposure on infant gut microbiota and its association with tetanus toxoid vaccine responses. We evaluated the gut microbiota of 82 South African (61 iHEU and 21 iHUU) and 196 Nigerian (141 iHEU and 55 iHUU) infants at <1 and 15 weeks of life by 16S rRNA gene sequencing. Anti-tetanus antibodies were measured by enzyme-linked immunosorbent assay at matched time points. Gut microbiota in the 278 included infants and its succession were more strongly influenced by geographical location and age than by HIV exposure. Microbiota of Nigerian infants, who were exclusively breastfed, drastically changed over 15 weeks, becoming dominated by Bifidobacterium longum subspecies infantis . This change was not observed among South African infants, even when limiting the analysis to exclusively breastfed infants. The Least Absolute Shrinkage and Selection Operator regression suggested that HIV exposure and gut microbiota were independently associated with tetanus titers at week 15, and that high passively transferred antibody levels, as seen in the Nigerian cohort, may mitigate these effects. In conclusion, in two African cohorts, HIV exposure minimally altered the infant gut microbiota compared to age and setting, but both specific gut microbes and HIV exposure independently predicted humoral tetanus vaccine responses.IMPORTANCEGut microbiota plays an essential role in immune system development. Since infants HIV-exposed and uninfected (iHEU) are more vulnerable to infectious diseases than unexposed infants, we explored the impact of HIV exposure on gut microbiota and its association with vaccine responses. This study was conducted in two African countries with rapidly increasing numbers of iHEU. Infant HIV exposure did not substantially affect gut microbial succession, but geographic location had a strong effect. However, both the relative abundance of specific gut microbes and HIV exposure were independently associated with tetanus titers, which were also influenced by baseline tetanus titers (maternal transfer). Our findings provide insight into the effect of HIV exposure, passive maternal antibody, and gut microbiota on infant humoral vaccine responses., Competing Interests: The authors declare no conflict of interest.

Objective: We aimed to understand how, why and in what context upskilling programmes for unregulated care providers (UCPs) to provide foot screening for systematically marginalised groups living with diabetes were implemented., Design: We used realist synthesis based on Realist And Meta-narrative Evidence Syntheses: Evolving Standards guidance., Data Sources: We searched the Medline, Embase, PsycINFO, CINAHL, ERIC, Web of Science Core Collection, and Scopus databases and the grey literature (Google Scholar, ProQuest Dissertations and Theses) up to November 2022., Eligibility Criteria: We included experimental and non-experimental articles in English that either described mechanisms or discussed expected outcomes for educational interventions for patients and family caregivers or healthcare providers, both regulated and unregulated. We also included articles that evaluated the impact of foot care programmes if the UCPs' training was described., Data Extraction and Synthesis: The lead author extracted, annotated and coded uploaded relevant data to identify contexts, mechanisms and outcome configurations using MAXQDA (a qualitative data analysis software). We used deductive and inductive coding to structure the process. Our team members double-reviewed and appraised a random sample of 20% of articles at all stages to ensure consistency., Results: Our search identified 52 articles. Evidence suggested the necessity of developing upskilling foot screening programmes within the context of preventive care programmes that also provide education in diabetes, and early referrals for appropriate interventions. Multidisciplinary programmes created an ideal context facilitating coordination between UCPs and their regulated counterparts. Engaging patients and community partners, using a competency-based model, and incorporating cultural competencies were determinants of success for these programmes., Conclusion: This review provides a realistic programme theory for the mechanisms used, the context in which these programmes were developed, and the expected outcomes to train UCPs to provide preventive foot care for systematically marginalised populations., Prospero Registration Number: CRD42022369208., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In the vast and diverse continent of Africa, the field of immunology holds immense significance as it navigates the complex landscape of infectious diseases and public health challenges. In this article, we speak with Professor Clive Gray, who provides powerful and valuable insights into the unique research opportunities and immunological advancements supported by Africa's unique blend of social, economic and environmental factors and also discusses the societal and cultural challenges that need to be overcome for equitable research to be achieved across the continent., (© 2023 the Australian and New Zealand Society for Immunology, Inc.)

Bacille Calmette-Guerin (BCG) vaccine can elicit good T H 1 responses in neonates. We hypothesized that the pioneer gut microbiota affects vaccine T cell responses. Infants who are HIV exposed but uninfected (iHEU) display an altered immunity to vaccination. BCG-specific immune responses were analyzed at 7 weeks of age in iHEU, and responses were categorized as high or low. Bifidobacterium longum subsp. infantis was enriched in the stools of high responders, while Bacteroides thetaiotaomicron was enriched in low responders at time of BCG vaccination. Neonatal germ-free or SPF mice orally gavaged with live B. infantis exhibited significantly higher BCG-specific T cells compared with pups gavaged with B. thetaiotaomicron. B. infantis and B. thetaiotaomicron differentially affected stool metabolome and colonic transcriptome. Human colonic epithelial cells stimulated with B. infantis induced a unique gene expression profile versus B. thetaiotaomicron . We thus identified a causal role of B. infantis in early-life antigen-specific immunity.

Background: People with type 2 diabetes (T2D) are at increased risk of poor outcomes from COVID-19. Vaccination can improve outcomes, but vaccine hesitancy remains a major challenge. We examined factors influencing COVID-19 vaccine uptake among people with T2D in two sub-Saharan Africa countries that adopted different national approaches to combat COVID-19, Kenya and Tanzania., Methods: A mixed-methods study was conducted in February-March 2022, involving a survey of 1000 adults with T2D (500 Kenya; 500 Tanzania) and 51 in-depth interviews (21 Kenya; 30 Tanzania). Determinants of COVID-19 vaccine uptake were identified using a multivariate logistic regression model, while thematic content analysis explored barriers and facilitators., Results: COVID-19 vaccine uptake was lower in Tanzania (26%) than in Kenya (75%), which may reflect an initial political hesitancy about vaccines in Tanzania. People with college/university education were four times more likely to be vaccinated than those with no education (Kenya AOR=4.25 (95% CI 1.00 to 18.03), Tanzania AOR=4.07 (1.03 to 16.12)); and people with health insurance were almost twice as likely to be vaccinated than those without health insurance (Kenya AOR=1.70 (1.07 to 2.70), Tanzania AOR=1.81 (1.04 to 3.13)). Vaccine uptake was higher in older people in Kenya, and among those with more comorbidities and higher socioeconomic status in Tanzania. Interviewees reported that wanting protection from severe illness promoted vaccine uptake, while conflicting information, misinformation and fear of side-effects limited uptake., Conclusion: COVID-19 vaccine uptake among people with T2D was suboptimal, particularly in Tanzania, where initial political hesitancy had a negative impact. Policy-makers must develop strategies to reduce fear and misconceptions, especially among those who are less educated, uninsured and younger., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

The penile epithelial microbiome remains underexplored. We sequenced human RNA and a segment of the bacterial 16S rRNA gene from the foreskin tissue of 144 adolescents from South Africa and Uganda collected during penile circumcision after receipt of 1-2 doses of placebo, emtricitabine + tenofovir disoproxil fumarate, or emtricitabine + tenofovir alafenamide to investigate the microbiome of foreskin tissue and its potential changes with antiretroviral use. We identified a large number of anaerobic species, including Corynebacterium acnes, which was detected more frequently in participants from South Africa than Uganda. Bacterial populations did not differ by treatment received, and no differentially abundant taxa were identified between placebo versus active drug recipients. The relative abundance of specific bacterial taxa was negatively correlated with expression of genes downstream of the innate immune response to bacteria and regulation of inflammation. Our results show no difference in the tissue microbiome of the foreskin with short-course antiretroviral use but that bacterial taxa were largely inversely correlated with inflammatory gene expression, consistent with commensal colonization., 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., (© 2023 The Authors.)

Background Transforaminal epidural steroid injections (TFESIs) are widely used as a minimally invasive treatment for lumbar radicular pain. This study presents an alternative approach for lumbar TFESI, the Kumar Technique, which utilizes a more lateral and inferior needle starting point to better align the trajectory of the needle with the neural foramen. We hypothesize the Kumar Technique will result in safer and more effective outcomes than the traditional approach to TFESI. This article was previously presented as a poster at the 2023 University of Florida College of Medicine Celebration of Research on February 27-28, 2023, and as an abstract and poster at the 2023 University of Florida Department of Anesthesiology Celebration of Research on March 29, 2023. Methods The charts for 1,424 patients who received lumbar TFESIs were retrospectively reviewed, and patients were stratified into groups receiving either the traditional approach or the Kumar Technique. Outcomes measures included numerical pain scores, measures of functional status and activity limitations, duration of pain relief, and procedural complications. Results Compared to the group undergoing the traditional approach, patients receiving the Kumar Technique reported a significantly greater decrease in average pain (-2.3 (95% CI: -3.0 to -1.6) vs -1.1 (95% CI: -1.4 to -0.7)) and maximum pain (-2.4 (95% CI: -3.2 to -1.6) vs -1.3 (95% CI: -1.8 to -0.9)). Patients receiving the Kumar Technique had a significantly greater likelihood of reporting any pain relief (OR: 2.10, 95% CI:1.59 to 2.79) compared to those undergoing the traditional approach. In addition, a greater percentage of patients receiving the Kumar Technique experienced at least one month of pain relief compared to the traditional approach (54% vs 40%; z = 3.85, p < 0.001). The occurrence of complications did not significantly vary between the modified (4.1%) and the traditional (3.0%) approaches. Conclusions The Kumar Technique is a modified TFESI approach that allows for improved access to the nerve roots through a more lateral and inferior needle entry point. The analysis supports the benefits of the Kumar Technique with patients experiencing a greater reduction in pain and longer durations of pain relief without increasing the risk of complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gray et al.)

Infants who are human immunodeficiency virus (HIV)-exposed uninfected (iHEU) experience higher risk of infectious morbidity than infants HIV-unexposed uninfected (iHUU). We compared tuberculosis (TB) infection prevalence in 418 Bacillus Calmette-Guérin vaccinated sub-Saharan African iHEU and iHUU aged 9-18 months using T-SPOT.TB. Prevalence of TB infection was low and did not differ by HIV exposure status., Competing Interests: Potential conflicts of interest. All authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Although COVID-19 booster vaccination is widely recommended, there is limited long-term, population-level, real-world evidence on the magnitude of improved protection against severe COVID-19 conferred by boosting with monovalent COVID-19 vaccines developed against ancestral SARS-CoV-2, especially in low- or middle-income countries. We present interim results from the first large-scale assessment of the relative vaccine effectiveness (rVE) of first and second booster doses against severe COVID-19 in a low-/middle-income country., Methods: REFORCO-Brazil is an ongoing, test-negative case-control study (NCT05697705) utilizing Brazil national severe acute respiratory syndrome (SARS) surveillance and vaccination data. In SARS hospitalizations from August 1, 2021 to July 31, 2022, we matched test-positive (via SARS-CoV-2 antigen/reverse transcription polymerase chain reaction [RT-PCR]) cases and test-negative case-controls (via RT-PCR) based on admission date, preceding vaccinations, and age. We evaluated the rVEs of four monovalent COVID-19 vaccines (AZD1222, Ad26.COV2.S, CoronaVac, and BNT162b2) as second boosters compared with any first boosters received ≥4 months previously, and as first boosters compared with primary-series vaccinations completed ≥4 months previously., Results: The overall rVE of second boosters, from 5668 (2238 test-positive) evaluated hospitalizations, was 24.7 % (95 % confidence interval [CI]: 12.6-35.1); the overall rVE of first boosters, from 30,272 (12,063 test-positive) hospitalizations, was 46.8 % (95 % CI: 43.3-50.0). The rVEs of AZD1222 and BNT162b2 were similar: 29.4 % (95 % CI: 8.6-45.5) and 25.5 % (95 % CI: 4.2-42.2), respectively, for second boosters; and 42.5 % (95 % CI: 28.0-54.0) and 50.8 % (95 % CI: 47.5-54.0), respectively, for first boosters. In general, rVEs were higher in elderly (≥80 years) and immunocompromised/high-risk individuals., Conclusions: Our results support the use of AZD1222 and other adenoviral/mRNA vaccine boosters to maintain protection against COVID-19 hospitalization from Omicron subvariants, including in elderly and immunocompromised individuals at increased risk of accelerated waning or severe outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support, administrative support, article publishing charges, statistical analysis, and writing assistance were provided by AstraZeneca. André Santa Maria, Bárbara Emoingt Furtado, Christen M. Gray, Mario Ouwens, Hugo Gomes da Silva, Sylvia Taylor, and Wilhelmine Meeraus report relationships with AstraZeneca that include: employment and equity or stocks. Anke L. Stuurman and Eduardo Conde-Sousa report relationships with P95 that includes: employment; Ilgaz Durukal reports a relationship with ZS Associates that includes: employment; Andrew Lee reports a relationship with Source Group International that includes: employment. All worked on behalf of AstraZeneca. Douglas Andreas Valverde reports a relationship with Techtrials Healthcare Data Science that includes: employment., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is large potential to increase cycling participation worldwide. Participation in cycling is associated with lower risk of mortality from any cause, and incidence of cardiovascular disease and type 2 diabetes, as well as positive mental health and well-being. The largest potential for health gains likely to come from increasing participation amongst those who do not currently cycle regularly, rather than encouraging those who already cycle regularly to cycle more. Replacing car journeys with cycling can lead to reductions in air pollution emissions and lower pollutant exposure to the general population. Important gaps and uncertainties in the existing evidence base include: the extent to which the health benefits associated with cycling participation are fully causal due to the observational nature of much of the existing evidence base; the real-world economic cost-benefits of pragmatic interventions to increase cycling participation; and the most effective (combination of) approaches to increase cycling participation. To address these uncertainties, large-scale, long-term randomised controlled trials are needed to: evaluate the effectiveness, and cost-effectiveness, of (combinations of) intervention approaches to induce sustained long-term increases in cycling participation in terms of increases in numbers of people cycling regularly and number of cycling journeys undertaken, across a range of population demographic groups; establish the effects of such interventions on relevant outcomes related to health and wellbeing, economic productivity and wider societal impacts; and provide more robust quantification of potential harms of increasing cycling participation, such as collision risks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The nature of the Cycle Nation Project meant that the funders, British Cycling and HSBC UK, were intimately involved as representatives in this review. All analysis was performed by the authors without input from British Cycling or HSBC UK., (© 2023 Logan, Somers, Baker, Connell, Gray, Kelly, McIntosh, Welsh, Gray and Gill.)

Objectives: As topical pre-exposure prophylaxis (PrEP) has been shown to cause immune modulation in rectal or cervical tissue, our aim was to examine the impact of oral PrEP on lymphoid and myeloid changes in the foreskin in response to dosing and timing of drug administration., Design: HIV-negative male individuals ( n  = 144) were recruited in South Africa and Uganda into an open-label randomized controlled trial in a 1 : 1 : 1 : 1 : 1 : 1 : 1 : 1 : 1 ratio to control arm (with no PrEP) or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) at one of two different doses, 5 or 21 h before undergoing voluntary medical male circumcision (VMMC)., Methods: After dorsal-slit circumcision, foreskin tissue sections were embedded into Optimal Cutting Temperature media and analysed, blinded to trial allocation, to determine numbers of CD4 + CCR5 + , CD1a + cells and claudin-1 expression. Cell densities were correlated with tissue-bound drug metabolites and p24 production after ex-vivo foreskin challenge with HIV-1 bal ., Results: There was no significant difference in CD4 + CCR5 + or CD1a + cell numbers in foreskins between treatment arms compared with the control arm. Claudin-1 expression was 34% higher ( P  = 0.003) in foreskin tissue from participants receiving PrEP relative to controls, but was no longer statistically significant after controlling for multiple comparisons. There was neither correlation of CD4 + CCR5 + , CD1a + cell numbers, or claudin-1 expression with tissue-bound drug metabolites, nor with p24 production after ex-vivo viral challenge., Conclusion: Oral doses and timing of on-demand PrEP and in-situ drug metabolite levels in tissue have no effect on numbers or anatomical location of lymphoid or myeloid HIV target cells in foreskin tissue., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In sub-Saharan Africa, the origins of asthma and high prevalence of abnormal lung function remain unclear. In high-income countries (HICs), associations between birth measurements and childhood asthma and lung function highlight the importance of antenatal and early life factors in the aetiology of asthma and abnormal lung function in children. We present here the first study in sub-Saharan Africa to relate birth characteristics to both childhood respiratory symptoms and lung function., Methods: Children attending schools in two socioeconomically contrasting but geographically close areas of Nairobi, Kenya, were recruited to a cross-sectional study of childhood asthma and lung function. Questionnaires quantified respiratory symptoms and preterm birth; lung function was measured by spirometry; and parents were invited to bring the child's immunisation booklet containing records of birth weight and serial weights in the first year., Results: 2373 children participated, 52% girls, median age (IQR), 10 years (8-13). Spirometry data were available for 1622. Child immunisation booklets were available for 500 and birth weight and infant weight gain data were available for 323 and 494 children, respectively. In multivariable analyses, preterm birth was associated with the childhood symptoms 'wheeze in the last 12 months'; OR 1.64, (95% CI 1.03 to 2.62), p=0.038; and 'trouble breathing' 3.18 (95% CI 2.27 to 4.45), p<0.001. Birth weight (kg) was associated with forced expiratory volume in 1 s z-score, regression coefficient (β) 0.30 (0.08, 0.52), p=0.008, FVC z-score 0.29 (95% CI 0.08 to 0.51); p=0.008 and restricted spirometry, OR 0.11 (95% CI 0.02 to 0.78), p=0.027., Conclusion: These associations are in keeping with those in HICs and highlight antenatal factors in the aetiology of asthma and lung function abnormalities in sub-Saharan Africa., Competing Interests: Competing interests: RD has declared employment by the University of Stirling for the duration of the study. JKQ has declared personal funding from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Chiesi, Teva, Insmed, Bayer and institutional funding from UKRI MRC, Health Data Research UK, GlaxoSmithKline, Bayer, Boehringer Ingelheim, Chiesi, Astra Zeneca and Asthma and Lung UK., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Characterised by the onset of hypertension and proteinuria in the second half of pregnancy, it can lead to maternal end-organ injury such as cerebral ischemia and oedema, pulmonary oedema and renal failure, and potentially fatal outcomes for both mother and fetus. The causes of the different maternal end-organ phenotypes of pre-eclampsia and why some women develop pre-eclampsia condition early in pregnancy have yet to be elucidated. Omics methods include proteomics, genomics, metabolomics, transcriptomics. These omics techniques, previously mostly used on bulk tissue and individually, are increasingly available at a single cellular level and can be combined with each other. Multi-omics techniques on a single-cell or spatial level provide us with a powerful tool to understand the pathophysiology of pre-eclampsia. This review will explore the status of omics methods and how they can and could contribute to understanding the pathophysiology of pre-eclampsia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Foot ulcers are one of the most devastating complications of diabetes mellitus leading to leg amputations. In Canada, systematically marginalised and racialised populations are more prone to developing foot ulcers and at higher risk of limb amputations. Shortages of regulated healthcare have hindered efforts to provide foot care. Upskilling unregulated care providers (UCPs) to deliver foot screening seems a reasonable solution to reduce limb loss. UCPs can advocate for health equity and deliver appropriate care. There is a need, however, to understand how and why an educational intervention for UCPs providing foot screening for these high-risk groups may or may not work., Methods and Analysis: This realist review will follow the Realist And Meta-narrative Evidence Syntheses: Evolving Standards standards. First, we will develop an initial programme theory (PrT) based on exploratory searches and discussions with experts and stakeholders. Then, we will search MEDLINE, Embase, PsycINFO, ERIC, CINAHL and Scopus databases along with relevant sources of grey literature. The retrieved articles will be screened for studies focusing on planned educational interventions for UCPs related to diabetic foot assessment. Data regarding contexts, mechanisms and outcomes will be extracted and analysed using a realist analysis through an iterative process that includes data reviewing and consultation with our team. Finally, we will use these results to modify the initial PrT., Ethics and Dissemination: Ethical approval is not required for this review. The main output of this research will be an evidence-based PrT for upskilling programmes for UCPs. We will share our final PrT using text, tables and infographics to summarise our results and draw insights across papers/reports. For academic, clinical, social care and educational audiences, we will produce peer-reviewed journal articles, including those detailing the process and findings of the realist review and establishing our suggestions for effective upskilling programmes., Prospero Registration Number: CRD42022369208., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The efficacy of on-demand HIV pre-exposure prophylaxis (PrEP) for men in sub-Saharan Africa has not been evaluated, and the on-demand PrEP dosing requirement for insertive sex remains unknown., Methods: HIV-negative males 13-24 years, requesting voluntary medical male circumcision (VMMC), were enrolled into an open-label randomised controlled trial (NCT03986970), and randomised 1:1:1:1:1:1:1:1:1 to control arm or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) over one or two days, and circumcised 5 or 21 h thereafter. The primary outcome was foreskin p24 concentrations following ex vivo HIV-1 BaL challenge. Secondary outcomes included peripheral blood mononuclear cell (PBMC) p24 concentration, and drug concentrations in foreskin tissue, PBMCs, plasma and foreskin CD4+/CD4-cells. In the control arm, post-exposure prophylaxis (PEP) activity of non-formulated tenofovir-emtricitabine (TFV-FTC) or TAF-FTC was assessed with ex vivo dosing 1, 24, 48 or 72 h post-HIV-1 challenge., Findings: 144 participants were analysed. PrEP with F/TDF or F/TAF prevented ex vivo infection of foreskins and PBMCs both 5 and 21 h after PrEP dosing. There was no difference between F/TDF and F/TAF (p24 day15 geometric mean ratio 1.06, 95% confidence interval: 0.65-1.74). Additional ex vivo dosing did not further increase inhibition. In the control arm, PEP ex vivo dosing was effective up to 48 post-exposure diminishing thereafter, with TAF-FTC showing prolonged protection compared to TFV-FTC. Participants receiving F/TAF had higher TFV-DP concentrations in foreskin tissue and PBMCs compared with F/TDF, irrespective of dose and sampling interval; but F/TAF did not confer preferential TFV-DP distribution into foreskin HIV target cells. FTC-TP concentrations with both drug regimens were equivalent and ∼1 log higher than TFV-DP in foreskin., Interpretation: A double dose of either F/TDF or F/TAF given once either 5 or 21 h before ex vivo HIV-challenge provided protection across foreskin tissue. Further clinical evaluation of pre-coital PrEP for insertive sex is warranted., Funding: EDCTP2, Gilead Sciences, Vetenskapsrådet., Competing Interests: Declaration of interests CH has received research grants from EDCTP, Vetenskapsrådet and Gilead Sciences. LE has received research grants from EDCTP, and Gilead Sciences. LL has received research grants from EDCTP, Gilead Sciences, Roche Diagnostic, DO has received research grants from EDCTP, AS has received research grants from EDCTP, AP has received research grants from EDCTP, PN has received research grants from EDCTP, PS has received research grants from EDCTP, DS has received research grants from EDCTP, RM has received research grants from EDCTP, BA has received research grants from EDCTP, SP has received research grants from EDCTP, CC is an employee of Gilead Sciences, JS has received research grants from EDCTP, HW has received research grants from EDCTP, SK has received research funding, speaker honoraria and consulting fees from EDCTP, Gilead Sciences, ViiV, Merck, GSK, and Ridgeback. FC has received research grants from EDCTP and Vetenskapsrådet. ELW has received grants from EDCTP, MRC, and NIH. CG has received research grants from EDCTP. PK has received research grants from EDCTP. EW has received research grants from EDCTP, NIH and MRC. NM has received research grants from EDCTP, and Gilead Sciences and provided unpaid advice and leadership in the DSMB and Setshaba boards. CC is a full-time employee of Gilead Sciences. All other authors declare no competing interests aside from the research grant received for this study by EDCTP., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vaccine effectiveness (VE) studies with long-term follow-up are needed to understand durability of protection against severe COVID-19 outcomes conferred by primary-series vaccination in individuals not receiving boosters. COVIDRIVE is a European public-private partnership evaluating brand-specific vaccine effectiveness (VE). We report a prespecified interim analysis of primary-series AZD1222 (ChAdOx1 nCoV-19) VE., Methods: Seven Study Contributors in Europe collected data on individuals aged ≥18 years who were hospitalised with severe acute respiratory infection (June 1st, 2021-September 5th, 2022) and eligible for COVID-19 vaccination prior to hospitalisation. In this test-negative case-control study, individuals were defined as test-positive cases or test-negative controls (SARS-CoV-2 RT-PCR) and were either fully vaccinated (two AZD1222 doses, 4-12 weeks apart, completed ≥14 days prior to symptom onset; no booster doses) or unvaccinated (no COVID-19 vaccine prior to hospitalisation). The primary objective was to estimate AZD1222 VE against COVID-19 hospitalisation. A literature review and meta-regression were conducted to contextualise findings on durability of protection., Findings: 761 individuals were included during the 15-month analysis period. Overall AZD1222 VE estimate was 72.8% (95% CI, 53.4-84.1). VE was 93.8% (48.6-99.3) in participants who received second AZD1222 doses ≤8 weeks prior to hospitalisation, with spline-based VE estimates demonstrating protection (VE ≥ 50%) 30 weeks post-second dose. Meta-regression analysis (data from seven publications) showed consistent results, with ≥80% protection against COVID-19 hospitalisation through ∼43 weeks post-second dose, with some degree of waning., Interpretation: Primary-series AZD1222 vaccination confers protection against COVID-19 hospitalisation with enduring levels of VE through ≥6 months., Funding: AstraZeneca., Competing Interests: WM, CMG, MO, and ST declare employment by AstraZeneca and ownership of AstraZeneca stocks/shares. LdM, AD, CW-T, WH-M, LD, GR, ALS, TYCN, and KB declare employment by P95. ALS and TYCN were contracted to AstraZeneca at the time of this work. P95 received consulting fees from several COVID-19 vaccine manufacturers, including AstraZeneca, for the COVIDRIVE study. AC declares funding from COVIDRIVE industry partners (AstraZeneca, Janssen, Moderna, Novavax, CureVac, Sanofi, Valneva, GlaxoSmithKline, Bavarian Nordic) for the COVIDRIVE consortium, of which FISABIO is the coordinator, and honoraria for lectures and educational events from GlaxoSmithKline and for presentations from MSD and HIPRA. GM declares no conflicts of interest related to this analysis, and honoraria from GlaxoSmithKline associated with herpes virus vaccine. AM-I declares funding from COVIDRIVE industry partners (AstraZeneca, Janssen, Moderna, Novavax, CureVac, Sanofi, Valneva, GlaxoSmithKline, Bavarian Nordic) for the COVIDRIVE consortium, of which FISABIO is the coordinator, and honoraria for educational events from MSD and for presentations from Sanofi Pasteur. GI declares no conflicts of interest. SO-R declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from EXCEMED and Sanofi. SB declares speaker honorarium from GlaxoSmithKline. CM declares advisory board participation for AstraZeneca in 2021., (© 2023 The Author(s).)

Decidual leukocytes play key roles in maternal-fetal tolerance and immunity. Here, we present detailed methods to purify, culture, and functionally analyze human placental dNK, dTreg, dTem, and dMɸ from decidua parietalis, the maternal part of the placental membranes; decidua basalis, the maternal part of the placenta; and placental villi. These sites have high clinical relevance in the development of villitis and chorioamnionitis. This allows in-depth phenotypic and functional investigation of placental immune populations and their interactions with extravillous trophoblasts. For complete details on the use and execution of this protocol, please refer to Ikumi et al., 1 Tilburgs et al., 2 Salvany-Celades et al., 3 Crespo et al., 4 van der Zwan et al. 5 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This paper investigated facilitators and barriers to implementing the European Football Fans in Training program (EuroFIT) in professional sports clubs in England, the Netherlands, Norway, and Portugal. We analyzed qualitative data collected at clubs that delivered EuroFIT, based on semi-structured interviews with coordinating staff (n = 15), coaches (n = 16), and focus group interviews with participants (n = 108), as well as data from clubs that considered delivering EuroFIT in the future, based on interviews with staff (n = 7) and stakeholders (n = 8). Facilitators for implementation related to the content and structure of the program, its evidence-base, and the context for delivery in the football stadia. Financial and human resources were both facilitators and barriers. Further barriers were mostly practical, relating to human resources and infrastructure. Major differences between countries related to experience and commitment to running community projects, and differences in infrastructure, financing, and human resources. Professional football clubs' ability to support health promotion efforts depended on their ethos and the financial and human resources available to them. Overall, the EuroFIT program was well received by clubs, coaches, participants, and stakeholders, which was reflected by the many facilitators supporting sustained implementation. For sustainable implementation, it is crucial that clubs and their stakeholders engage fully with the EuroFIT program and understand that for an adequate program delivery their views (ethos) and ways of working influence the implementation and thereby the effectiveness of EuroFIT. An important prerequisite for future roll out of EuroFIT would be a strong EuroFIT delivery partner organization to ensure financial and human resources while overseeing and guiding the quality of delivery in clubs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Background: A healthy lifestyle program that appeals to, and supports, overweight and obese New Zealand (NZ) European, Māori (indigenous) and Pasifika men to achieve weight loss is urgently needed. A pilot program inspired by the successful Football Fans in Training program but delivered via professional rugby clubs in NZ (n = 96) was shown to be effective in weight loss, adherence to healthy lifestyle behaviors, and cardiorespiratory fitness in overweight and obese men. A full effectiveness trial is now needed., Aims: To determine the effectiveness and cost effectiveness of Rugby Fans In Training-NZ (RUFIT-NZ) on weight loss, fitness, blood pressure, lifestyle change, and health related quality of life (HRQoL) at 12- and 52-weeks., Methods: We conducted a pragmatic, two-arm, multi-center, randomized controlled trial in NZ with 378 (target 308) overweight and obese men aged 30-65 years, randomized to an intervention group or wait-list control group. The 12-week RUFIT-NZ program was a gender-sensitised, healthy lifestyle intervention delivered through professional rugby clubs. Each intervention session included: i) a 1-h workshop-based education component focused on nutrition, physical activity, sleep, sedentary behavior, and learning evidence-based behavior change strategies for sustaining a healthier lifestyle; and 2) a 1-h group-based, but individually tailored, exercise training session. The control group were offered RUFIT-NZ after 52-weeks. The primary outcome was change in body weight from baseline to 52-weeks. Secondary outcomes included change in body weight at 12-weeks, waist circumference, blood pressure, fitness (cardiorespiratory and musculoskeletal), lifestyle behaviors (leisure-time physical activity, sleep, smoking status, and alcohol and dietary quality), and health-related quality of life at 12- and 52-weeks., Results: Our final analysis included 200 participants (intervention n = 103; control n = 97) who were able to complete the RUFIT-NZ intervention prior to COVID-19 restrictions. At 52-weeks, the adjusted mean group difference in weight change (primary outcome) was -2.77 kg (95% CI -4.92 to -0.61), which favored the intervention group. The intervention also resulted in favorable significant differences in weight change and fruit and vegetable consumption at 12-weeks; and waist circumference, fitness outcomes, physical activity levels, and health-related quality of life at both 12 and 52 weeks. No significant intervention effects were observed for blood pressure, or sleep. Incremental cost-effective ratios estimated were $259 per kg lost, or $40,269 per quality adjusted life year (QALY) gained., Conclusion: RUFIT-NZ resulted in sustained positive changes in weight, waist circumference, physical fitness, self-reported physical activity, selected dietary outcomes, and health-related quality of life in overweight/obese men. As such, the program should be recommended for sustained delivery beyond this trial, involving other rugby clubs across NZ., Trial Registration: Australia New Zealand Clinical Trials Registry, ACTRN12619000069156. Registered 18 January 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376740 Universal Trial Number, U1111-1245-0645., (© 2023. The Author(s).)

In 1989, one in four (25%) infants born to women living with HIV were infected; by the age of 2 years, there was 25% mortality among them due to HIV. These and other pieces of data prompted the development of interventions to offset vertical transmission, including the landmark Pediatric AIDS Clinical Trial Group Study (PACTG 076) in 1994. This study reported a 67.5% reduction in perinatal HIV transmission with prophylactic antenatal, intrapartum, and postnatal zidovudine. Numerous studies since then have provided compelling evidence to further optimize interventions, such that annual transmission rates of 0% are now reported by many health departments in the US and elimination has been validated in several countries around the world. Despite this success, the elimination of HIV's vertical transmission on the global scale remains a work in progress, limited by socioeconomic factors such as the prohibitive cost of antiretrovirals. Here, we review some of the key trials underpinning the development of guidelines in the US as well as globally, and discuss the evidence through a historic lens.

Background: A randomised trial of European Fans in Training (EuroFIT), a 12-week healthy lifestyle program delivered in 15 professional football clubs in the Netherlands, Norway, Portugal, and the United Kingdom, successfully increased physical activity and improved diet but did not reduce sedentary time. To guide future implementation, this paper investigates how those effects were achieved. We ask: 1) how was EuroFIT implemented? 2) what were the processes through which outcomes were achieved?, Methods: We analysed qualitative data implementation notes, observations of 29 of 180 weekly EuroFIT deliveries, semi-structured interviews with 16 coaches and 15 club representatives, and 30 focus group discussions with participants (15 post-program and 15 after 12 months). We descriptively analysed quantitative data on recruitment, attendance at sessions and logs of use of the technologies and survey data on the views of participants at baseline, post program and after 12 months. We used a triangulation protocol to investigate agreement between data from difference sources, organised around meeting 15 objectives within the two research questions., Results: We successfully recruited clubs, coaches and men to EuroFIT though the draw of the football club seemed stronger in the UK and Portugal. Advertising that emphasized getting fitter, club-based deliveries, and not 'standing out' worked and attendance and fidelity were good, so that coaches in all countries were able to deliver EuroFIT flexibly as intended. Coaches in all 15 clubs facilitated the use of behaviour change techniques and interaction between men, which together enhanced motivation. Participants found it harder to change sedentary time than physical activity and diet. Fitting changes into daily routines, planning for setbacks and recognising the personal benefit of behaviour change were important to maintain changes. Bespoke technologies were valued, but technological hitches frustrated participants., Conclusion: EuroFIT was delivered as planned by trained club coaches working flexibly in all countries. It worked as expected to attract men and support initiation and maintenance of changes in physical activity and diet but the use of bespoke, unstable, technologies was frustrating. Future deliveries should eliminate the focus on sedentary time and should use only proven technologies to support self-monitoring and social interaction., Trial Registration: ISRCTN81935608, registered 16/06/2015., (© 2023. The Author(s).)

Objectives: Given the decline in physical activity levels in Malawi, like other sub-Saharan African countries, and its implication for non-communicable disease (NCD) prevention, this study aimed to compare and contrast accounts of practices and attitudes towards physical activity among Malawian men and women (previously identified as having pre-diabetes) in urban and rural settings., Setting: Two communities: one urban (Lilongwe) and one rural (Karonga)., Participants: 14 men (urban N=6, rural N=8) and 18 women (urban N=9, rural N=9) classified as prediabetic during their participation in an NCD survey 3-5 years previously., Design: A qualitative focus group study (N=4) and thematic analysis, with the ecological model used as a framework to characterise the types of physical activity people engaged in and potential ways to support them to exercise more., Results: Participants reported undertaking different types of physical activity across all ecological model domains (household, occupational, transport, recreational). Rural participants reported more vigorous physical activities than urban participants, and women reported more household activities than men. Many participants recognised a need to promote physical activity in Malawi, and the health benefits of doing so, including the importance of physical activity in helping them stay strong to maintain physical functioning. Barriers to physical activity included competing priorities (especially urban men), societal expectations around wealth, use of motorised transport, lack of accessible facilities for women, ageing and ill health., Conclusions: Physical activity is declining in Malawi as working and transport practices change in response to economic development, making promotion of alternative forms of physical activity a public health priority. Multilevel interventions emphasising the personal benefits/value of physical activity for all ages, and routine and group-based exercising, as well as investment in accessible recreational facilities (including for women) and active travel infrastructure should be considered to improve physical activity levels in Malawi., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Transdisciplinary research (TDR) approaches have been cited as essential for overcoming the intractable sustainability challenges that the world is currently facing, including air pollution, water management and climate change. However, such approaches can be difficult to undertake in practice and can consequently fail to add value. Therefore, examples of what works in practice (and what does not) are helpful to guide future research. In this study, we used a conceptual TDR framework as the basis to examine and evaluate the strengths and weaknesses of our approach in a project exploring air pollution in an informal settlement in Nairobi, Kenya. Reflection diaries exploring experiences of participation in the project were undertaken by the project team (comprising academic and community partners) at multiple time points throughout the project. These reflection diaries played an important role in evaluation and for providing space for team learning. Diaries were thematically coded according to the TDR framework to explore aspects of the project that worked well, and areas which presented challenges. We draw upon our reflections, and the extant literature, to make practical recommendations for researchers undertaking TDR projects in future. Recommendations focus on three key project stages (pre-funding, funded period, post-funding) and include; building the team in a way that includes all key stakeholders in relevant and appropriate roles, giving everyone sufficient time to work on the project, and ensuring regular and open communication. Building these recommendations into the design and delivery of transdisciplinary sustainability science projects will support progress towards achieving the Sustainable Development Goals (SDGs)., Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-023-01317-0., (© The Author(s) 2023.)

The burden of noncommunicable diseases (NCDs) including hypertension, diabetes, and cancer, is rising in Sub-Saharan African countries like Tanzania and Malawi. This increase reflects complex interactions between diverse social, environmental, biological, and political factors. To intervene successfully, new approaches are therefore needed to understand how local knowledges and attitudes towards common NCDs influence health behaviours. This study compares the utility of using a novel arts-based participatory method and more traditional focus groups to generate new understandings of local knowledges, attitudes, and behaviours towards NCDs and their risk factors. Single-gender arts-based participatory workshops and focus group discussions were conducted with local communities in Tanzania and Malawi. Thematic analysis compared workshop and focus group transcripts for depth of content and researcher-participant hierarchies. In addition, semiotic analysis examined the contribution of photographs of workshop activities to understanding participants' experiences and beliefs about NCD risk factors. The arts-based participatory workshops produced in-depth, vivid, emotive narratives of participants' beliefs about NCDs and their impact (e.g., "… it spreads all over your body and kills you-snake's poison is similar to diabetes poison"), while the focus groups provided more basic accounts (e.g., "diabetes is a fast killer"). The workshops also empowered participants to navigate activities with autonomy, revealing their almost overwhelmingly negative beliefs about NCDs. However, enabling participants to direct the focus of workshop activities led to challenges, including the perpetuation of stigma (e.g., comparing smells associated with diabetes symptoms with sewage). Semiotic analysis of workshop photographs provided little additional insight beyond that gained from the transcripts. Arts-based participatory workshops are promising as a novel method to inform development of culturally relevant approaches to NCD prevention in Tanzania and Malawi. Future research should incorporate more structured opportunities for participant reflection during the workshops to minimise harm from any emerging stigma., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Bissett 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.)

Whilst short-term oral pre-exposure prophylaxis (PrEP) with antiretroviral drugs in men who have sex with men has shown protection against HIV-1 infection, the impact of this regimen on the in vivo foreskin transcriptome is unknown. We collected foreskin tissue after voluntary medical male circumcision from 144 young men (72 from Uganda and 72 from South Africa) randomized to one to two doses of either oral tenofovir (TFV) disoproxil fumarate (FTC-TDF) or tenofovir alafenamide (FTC-TAF) or no drug (untreated controls). This novel approach allowed us to examine the impact of short-term oral PrEP on transcriptome of the male genital tract. A single dose of FTC-TDF did not affect the foreskin transcriptome in relation to control arm, however one dose of FTC-TAF induced upregulation of four genes AKAP8 , KIAA0141 , HSCB and METTL17 . Following two doses of either FTC-TDF or FTC-TAF, there was an increase in 34 differentially expressed genes for FTC-TDF and 15 for FTC-TAF, with nine DEGs in common: KIAA0141 , SAFB2 , CACTIN , FXR2 , AKAP8 , HSCB , CLNS1A , DDX27 and DCAF15 . Functional analysis of differentially expressed genes revealed modulation of biological processes related to mitochondrial stress (KIAA0141, HSCB and METTL17) , anti-viral and anti-inflammatory pathways ( CACTIN and AKAP8) . Our results show that short-course on-demand oral PrEP in men modulates genes in foreskin tissue which are likely unfavorable to HIV acquisition and replication. We also describe an upregulated expression of genes involved in diverse mitochondria biology which may potentially result in worsened mitochondria-related. These results warrant further studies to assess the role of short-course and prolonged oral PrEP on biological processes of the foreskin mucosa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Petkov, Herrera, Else, Lebina, Opoka, Seiphetlo, Pillay, Mugaba, Namubiru, Odoch, Ssemata, Serwanga, Kaleebu, Webb, Khoo, Martinson, Gray, Fox and Chiodi.)

The Cycle Nation Project (CNP) aimed to develop, test the feasibility of and optimize a multi-component individual-/social-level workplace-based intervention to increase cycling among office staff at a multinational bank (HSBC UK). To do this, we first explored barriers to cycling in a nationally-representative survey of UK adults, then undertook focus groups with bank employees to understand any context-specific barriers and ways in which these might be overcome. These activities led to identification of 10 individual-level, two social-level, and five organizational-level modifiable factors, which were mapped to candidate intervention components previously identified in a scoping review of cycling initiatives. Interviews with HSBC UK managers then explored the practicality of implementing the candidate intervention components in bank offices. The resultant pilot CNP intervention included 32 core components across six intervention functions (education, persuasion, incentivisation, training, environmental restructuring, enablement). Participants received a loan bike for 12-weeks (or their own bike serviced), and a 9-week cycle training course (condensed to 6 weeks for those already confident in basic cycling skills), including interactive information sharing activities, behavior change techniques (e.g., weekly goal setting), bike maintenance training, practical off-road cycling skill games and on-road group rides. Sessions were delivered by trained bank staff members who were experienced cyclists. The CNP pilot intervention was delivered across three sites with 68 participants. It was completed in two sites (the third site was stopped due to COVID-19) and was feasible and acceptable to both women and men and across different ethnicities. In addition, the CNP intervention was successful (at least in the short term) in increasing cycling by 3 rides/week on average, and improving perceptions of safety, vitality, confidence, and motivation to cycle. Following minor modifications, the long-term effectiveness and cost-effectiveness of the CNP intervention should be tested in a full-scale randomized controlled trial., Competing Interests: The nature of the co-design of the Cycle Nation Project intervention meant that the funders, British Cycling and HSBC UK, were intimately involved in the design and delivery of the intervention, and representatives from both organizations are authors on the paper. All data analysis was performed by researchers at the University of Glasgow without input from British Cycling or HSBC UK. Authors SB and JP were employed by British Cycling, and authors SR and LH are employees of HSBC UK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Connell, Logan, Somers, Baker, Broadfield, Bunn, Harper, Kelly, McIntosh, Pell, Puttnam, Robson, Gill and Gray.)