Microbicides development programme: engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania.

BACKGROUND: HIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania. METHODS: A mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders' Advisory Group (SAG), which includes two CAC representatives. RESULTS: Key recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative. CONCLUSION: Participatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64716212

Walking in multiple sclerosis improves with tDCS: a randomized, double‐blind, sham‐controlled study

Objective: To evaluate whether multiple sessions of transcranial direct current stimulation (tDCS) applied to the primary motor (M1) cortex paired with aer- obic exercise can improve walking functions in multiple sclerosis (MS). Meth- ods: MS participants were recruited for a double-blind, parallel-arm, randomized, sham-controlled trial and assigned to 10 sessions (5 d/wk for 2 weeks) of either active or sham tDCS paired with unloaded cycling for 20 minutes. Stimulation was administered over the left M1 cortex (2.5 mA; anode over C3/cathode over FP2). Gait spatiotemporal parameters were assessed using a wearable inertial sensor (10-meter and 2-minute walking tests). Mea- surements were collected at baseline, end of tDCS intervention, and 4-week postintervention to test for duration of any benefits. Results: A total of 15 par- ticipants completed the study, nine in the active and six in the sham condition. The active and sham groups were matched according to gender (50% vs. 40% female), neurologic disability (median EDSS 5.5 vs. 5), and age (mean 52.1 ! 12.9 vs. 53.7 ! 9.8 years). The active group had a significantly greater increase in gait speed (0.87 vs. 1.20 m/s, p < 0.001) and distance covered dur- ing the 2-minute walking test (118.53 vs. 133.06 m, p < 0.001) at intervention end compared to baseline. At 4-week follow-up, these improvements were maintained (baseline vs. follow-up: gait speed 0.87 vs. 1.18 m/s, p < 0.001; dis- tance traveled 118.53 vs. 143.82 m, p < 0.001). Interpretation: Multiple ses- sions of tDCS paired with aerobic exercise lead to cumulative and persisting mprovements in walking and endurance in patients with MS

Demographic and pregnancy‐related predictors of postnatal contraception uptake: A cross‐sectional study

Objective: To examine the uptake of postnatal contraception (PNC) and experiences of PNC care across a geographical region of England. Design: Cross‐sectional online survey. Setting: The North East and North Cumbria Integrated Care System (ICS). Population: Women who had completed a pregnancy in the previous 3 years. Methods: The uptake of PNC by accessed method(s) and the availability of preferred method(s) is described, and adjusted odds ratios are reported for group differences in uptake by characteristics of interest. Main outcome measures: Uptake of medically prescribed/administered contraception and uptake of long‐acting reversible contraception (LARC) during the postnatal period, and access to preferred PNC methods. Results: Although almost half of respondents (47.1%; n = 1178) reinitiated some form of sexual activity during the postnatal period, only 38.7% (n = 969) of respondents accessed a medically prescribed/administered contraceptive method postnatally, and only 15.5% (n = 389) of respondents accessed a LARC. It is a matter of concern that 18.8% (n = 451) of respondents indicated that they were unable to access their preferred PNC. In multivariate analysis, younger age, lower household income, higher multiparity, operative delivery, unplanned pregnancy and not breastfeeding were significant predictors of higher PNC uptake. Conclusions: The uptake of PNC in this cohort was low, with almost a fifth of women unable to access their preferred method. However, there was some evidence that women belonging to groups perceived to be at risk of rapid repeat pregnancy were more likely to access reliable PNC methods

Strengthening integration of chronic care in Africa: protocol for the qualitative process evaluation of integrated HIV, diabetes and hypertension care in a cluster randomised controlled trial in Tanzania and Uganda

Introduction: In sub-Saharan Africa, the burden of non-communicable diseases (NCDs), particularly diabetes mellitus (DM) and hypertension, has increased rapidly in recent years, although HIV infection remains a leading cause of death among young-middle-aged adults. Health service coverage for NCDs remains very low in contrast to HIV, despite the increasing prevalence of comorbidity of NCDs with HIV. There is an urgent need to expand healthcare capacity to provide integrated services to address these chronic conditions. Methods and analysis: This protocol describes procedures for a qualitative process evaluation of INTE-AFRICA, a cluster randomised trial comparing integrated health service provision for HIV infection, DM and hypertension, to the current stand-alone vertical care. Interviews, focus group discussions and observations of consultations and other care processes in two clinics (in Tanzania, Uganda) will be used to explore the experiences of stakeholders. These stakeholders will include health service users, policy-makers, healthcare providers, community leaders and members, researchers, non-governmental and international organisations. The exploration will be carried out during the implementation of the project, alongside an understanding of the impact of broader structural and contextual factors. Ethics and dissemination: Ethical approval was granted by the Liverpool School of Tropical Medicine (UK), the National Institute of Medical Research (Tanzania) and TASO Research Ethics Committee (Uganda) in 2020. The evaluation will provide the opportunity to document the implementation of integration over several timepoints (6, 12 and 18 months) and refine integrated service provision prior to scale up. This synergistic approach to evaluate, understand and respond will support service integration and inform monitoring, policy and practice development efforts to involve and educate communities in Tanzania and Uganda. It will create a model of care and a platform of good practices and lessons learnt for other countries implementing integrated and decentralised community health services

HIV-1 Subtype C-Infected Individuals Maintaining High Viral Load as Potential Targets for the “Test-and-Treat” Approach to Reduce HIV Transmission

The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1–4.2 log10) and cART-initiating cohorts (5.1–5.3 log10) by about one log10. The proportion of individuals with high (≥50,000 (4.7 log10) copies/ml) HIV-1 RNA levels ranged from 24%–28% in the general HIV-positive population cohorts to 65%–83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%–50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load ≥50,000 (4.7 log10) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%–82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified “test-and-treat” strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities

Variability and Change in the West Antarctic Peninsula Marine System: Research Priorities and Opportunities

The west Antarctic Peninsula (WAP) region has undergone significant changes in temperature and seasonal ice dynamics since the mid-twentieth century, with strong impacts on the regional ecosystem, ocean chemistry and hydrographic properties. Changes to these long-term trends of warming and sea ice decline have been observed in the 21st century, but their consequences for ocean physics, chemistry and the ecology of the high-productivity shelf ecosystem are yet to be fully established. The WAP shelf is important for regional krill stocks and higher trophic levels, whilst the degree of variability and change in the physical environment and documented biological and biogeochemical responses make this a model system for how climate and sea ice changes might restructure high-latitude ecosystems. Although this region is arguably the best-measured and best-understood shelf region around Antarctica, significant gaps remain in spatial and temporal data capable of resolving the atmosphere-ice-ocean-ecosystem feedbacks that control the dynamics and evolution of this complex polar system. Here we summarise the current state of knowledge regarding the key mechanisms and interactions regulating the physical, biogeochemical and biological processes at work, the ways in which the shelf environment is changing, and the ecosystem response to the changes underway. We outline the overarching cross-disciplinary priorities for future research, as well as the most important discipline-specific objectives. Underpinning these priorities and objectives is the need to better define the causes, magnitude and timescales of variability and change at all levels of the system. A combination of traditional and innovative approaches will be critical to addressing these priorities and developing a co-ordinated observing system for the WAP shelf, which is required to detect and elucidate change into the future

Ethical issues in intervention studies on the prevention and management of diabetes and hypertension in sub-Saharan Africa

Conducting intervention studies in Africa, where medicines supply for chronic conditions is inequitable and patchy, raises major ethical issues. Here we discuss what should the ethical approach be for a research programme in terms of provision of a steady and sustainable supply of medicines for patients with diabetes and hypertension

Degradation of arouser by endosomal microautophagy is essential for adaptation to starvation in Drosophila

Hunger drives food-seeking behaviour and controls adaptation of organisms to nutrient availability and energy stores. Lipids constitute an essential source of energy in the cell that can be mobilised during fasting by autophagy. Selective degradation of proteins by autophagy is made possible essentially by the presence of LIR and KFERQ-like motifs. Using in silico screening of Drosophila proteins that contain KFERQ-like motifs, we identified and characterized the adaptor protein Arouser, which functions to regulate fat storage and mobilisation and is essential during periods of food deprivation. We show that hypomorphic arouser mutants are not satiated, are more sensitive to food deprivation, and are more aggressive, suggesting an essential role for Arouser in the coordination of metabolism and food-related behaviour. Our analysis shows that Arouser functions in the fat body through nutrient-related signalling pathways and is degraded by endosomal microautophagy. Arouser degradation occurs during feeding conditions, whereas its stabilisation during non-feeding periods is essential for resistance to starvation and survival. In summary, our data describe a novel role for endosomal microautophagy in energy homeostasis, by the degradation of the signalling regulatory protein Arouser

The orbit and stellar masses of the archetype colliding-wind binary WR 140

We present updated orbital elements for the Wolf-Rayet (WR) binary WR 140 (HD 193793; WC7pd + O5.5fc). The new orbital elements were derived using previously published measurements along with 160 new radial velocity measurements across the 2016 periastron passage of WR 140. Additionally, four new measurements of the orbital astrometry were collected with the CHARA Array. With these measurements, we derive stellar masses of $M_{\rm WR} = 10.31\pm0.45 M_\odot$ and $M_{\rm O} = 29.27\pm1.14 M_{\odot}$. We also include a discussion of the evolutionary history of this system from the Binary Population and Spectral Synthesis (BPASS) model grid to show that this WR star likely formed primarily through mass loss in the stellar winds, with only a moderate amount of mass lost or transferred through binary interactions.Comment: 10 pages, 5 figure

Rab27a and Rab27b control different steps of the exosome secretion pathway

Exosomes are secreted membrane vesicles that share structural and biochemical characteristics with intraluminal vesicles of multivesicular endosomes (MVEs). Exosomes could be involved in intercellular communication and in the pathogenesis of infectious and degenerative diseases. The molecular mechanisms of exosome biogenesis and secretion are, however, poorly understood. Using an RNA interference (RNAi) screen, we identified five Rab GTPases that promote exosome secretion in HeLa cells. Among these, Rab27a and Rab27b were found to function in MVE docking at the plasma membrane. The size of MVEs was strongly increased by Rab27a silencing, whereas MVEs were redistributed towards the perinuclear region upon Rab27b silencing. Thus, the two Rab27 isoforms have different roles in the exosomal pathway. In addition, silencing two known Rab27 effectors, Slp4 (also known as SYTL4, synaptotagmin-like 4) and Slac2b (also known as EXPH5, exophilin 5), inhibited exosome secretion and phenocopied silencing of Rab27a and Rab27b, respectively. Our results therefore strengthen the link between MVEs and exosomes, and introduce ways of manipulating exosome secretion in vivo