Wellcome Trust

Abstract Background Health system responsiveness is regarded as a core goal of health systems, both for its intrinsic value and its potential to contribute to inclusive, participatory, and accountable health systems. Although responsiveness is frequently mentioned in health policy documents, the public experience challenges in engaging with and eliciting responses from health systems. There is also limited receptivity to public concerns by policymakers and health providers. We analysed national policy documents for responsiveness content and framing with the aim of identifying how to strengthen policy proposals towards more responsive health systems. Methods We conducted a three-stage qualitative analysis of Kenyan and South African policy documents: (1) policy document retrieval; (2) data extraction and coding; and (3) content and framing analysis. We analysed purposively selected public sector plans, legislative instruments and health-sector specific plans and policies released between 1994 and 2024 (n = 28 [Kenya]; n = 26 [South Africa]). Documents were identified from government and Ministry of Health websites. Results Responsiveness was framed differently across the analysed texts. Public sector and legislative instruments primarily adopted public participation frames, while health sector documents predominantly framed responsiveness as ‘health service feedback’. Within health sector policy documents, the measurement of responsiveness was underdeveloped, with no clear overarching strategy to support the achievement of system responsiveness. There was also little evidence of intention to integrate feedback from multiple channels and limited description of monitoring and evaluation of feedback mechanisms. There was almost no attention to how public feedback could be used to shape a responsive health system. Conclusion In Kenya and South Africa, while legislative and public policy documents had a broad and inclusive remit for responsiveness, health policy documents had a narrow focus with a dominant ‘health service feedback’ framing. This framing undermines a systemic approach to responsiveness by inadequately addressing equity challenges and power and knowledge differentials between the public and health system actors. Integrating the broader frames identified in public sector and legislative instruments (public participation, accountability) into health policy documents can re-define health system responsiveness to include a focus beyond service delivery, attention to the wider public, including varied population segments and vulnerable groups.

Abstract Introduction and aims Dominant dystrophic epidermolysis bullosa (DDEB) is a congenital blistering skin disease caused by mutant collagen VII (C7) chains interfering with the folding of wildtype (WT) C7, which weakens dermoepidermal junctions. Base editors (BEs) offer unique advantage in precisely correcting the mutant COL7A1 allele while preserving the WT allele. While our group has previously demonstrated the use of adenine base editor 8e (ABE8e) to correct recessive dystrophic epidermolysis bullosa (RDEB), this is the first report of ABE8e being applied to DDEB. Methods Primary fibroblasts from patients with DDEB carrying the COL7A1 exon 73 c.6127G>A mutation were electroporated with ABE8e mRNA and single guide (sg)RNA. Base editing efficiency was evaluated by semiquantitative analysis of Sanger sequencing chromatographs in EditR. Protein-level correction was assessed using a C7 Western blot. In preparation for future in vivo base editing, we validated a DDEB mouse model carrying the Col7a1 exon 73 c.6085C>G mutation using Sanger sequencing. Results Sanger sequencing analysis revealed that ABE8e achieved 19–41% editing efficiency in correcting the c.6127G>A mutation, with a 2 : 1 sgRNA-to-ABE8e ratio yielding higher efficiency than a 1 : 2 ratio. However, Western blot analysis did not show consistent protein-level correction. Sanger sequencing confirmed that our DDEB mouse model is heterozygous for the Col7a1 c.6085G>C mutation. Conclusions This study demonstrated partial DNA-level correction of the COL7A1 c.6127 G>A allele in ABE8e-electroporated primary DDEB fibroblasts ex vivo. However, this editing did not result in increased C7 protein levels. Notably, Western blots assess differences in C7 quantity, but not stability – a key factor in DDEB pathology. Further replication of DNA-level correction and evaluation of C7 stability using a trypsin digestion assay will be essential. These efforts will lay the foundation for transitioning from ex vivo experiments to in vivo correction of the Col7a1 c.6085C>G mutation in our DDEB mouse model.

Background Chronic malaria exposure has been proposed to modulate immune function, but its long-term effects on antibody-mediated responses to unrelated pathogens remain poorly defined. Whether these effects persist beyond periods of active infection, and how early-life exposure shapes humoral immunity over time, is not well understood. Methods We leveraged a natural experiment in coastal Kenya - where two regions (Junju and Ngerenya) diverged sharply in malaria transmission from around 2004 - to evaluate the long-term immunological consequences of malaria exposure in childhood. Using a protein microarray platform, we measured IgG responses to vaccine and pathogen antigens in 123 children sampled longitudinally over a 15-year period. Active weekly malaria surveillance enabled precise reconstruction of individual exposure histories. Results IgG responses to Plasmodium falciparum apical membrane antigen 1 (AMA1) tracked closely with clinical malaria episodes, confirming the ability of the microarray platform to detect biologically meaningful variation in antigen-specific immunity. Despite comparable vaccination histories, children from the high malaria transmission setting (Junju) exhibited persistently lower measles-specific IgG levels than children from the low-transmission setting (Ngerenya), a pattern validated by ELISA. At 10 years of age, Junju children showed significantly reduced antibody levels to a wide range of unrelated pathogens, including Bordetella pertussis, CMV, rubella, and measles. Within the Ngerenya cohort, children with documented early-life malaria had broadly lower IgG responses at age 10 compared to malaria-naïve peers, despite identical geography, vaccines, and follow-up duration. Conclusions These findings suggest that malaria exposure during early childhood is linked with durable suppression of antibody responses to unrelated pathogens and vaccines. This effect persists long after infection and may partially explain the overall diminished long-term vaccine effectiveness in malaria-endemic settings.

People living with mental health issues use a range of self-management strategies. Most strategy recommendations have been developed by clinicians and researchers, so they may not reflect the full range of approaches used in practice. A citizen mental health science methodology can address this bias in strategy identification. We co-created a list of 77 pre-defined self-management strategies, and 1116 public contributors (n = 468 mental health service users, n = 497 lived experience not using services, n = 151 no lived experience) living in the United Kingdom completed an online survey identifying their use of each strategy, and identifying extra strategies. A wide range of pre-defined strategies were used by contributors, with differences in usage patterns identified between the three groups. 401 distinct extra strategies were identified. The active use of avoidance as a self-management strategy was more common than anticipated, including avoiding alcohol, social media, thinking about problems, other people, and mental health services.

Abstract Background Vaccine uptake in Uganda remains below target, especially in hard-to-reach places such as Koome Island, a fishing community in Lake Victoria’s Mukono District. Although national immunization efforts have made progress, social and structural barriers limit access to and trust in vaccines. As part of the NIHR Global Health Research Group on Vaccines for Vulnerable People in Africa (VAnguard), we conducted a situational analysis to understand the local factors influencing vaccination attitudes and practices on Koome Island. Methods Using the socioecological model as a framework, we employed qualitative methods, including community dialogues, stakeholder consultations, transect walks, informal conversations, and field observations, from November 2022 to October 2023. The participants included community members, health workers, local leaders, and district officials. The data were thematically analysed to capture influences on vaccine uptake across multiple social and structural levels. Findings: Despite longstanding Ministry of Health efforts, vaccine uptake remains limited in remote areas such as Koome Island. Structural challenges such as long distances to health centres, poor infrastructure, and frequent vaccine stockouts restrict access. These are worsened by high transport costs, gendered caregiving roles, limited awareness of the full immunization schedule, and persistent myths and misinformation, for example, fears that vaccines cause infertility or goitre. These findings shaped the stakeholder mapping and community engagement approaches for VAnguard and guided the design of a follow-up survey in three districts to further explore the complex social, biological, and structural factors affecting vaccine equity. Conclusion The analysis underscores the need to ground vaccine research and interventions in local realities. It informs culturally sensitive, systems-aware strategies and supports participatory approaches aimed at strengthening vaccine uptake in underserved communities.

Summary Background Reducing perinatal deaths is a priority, but data on maternal infectious causes are sparse in low- and middle-income countries where the burden is highest. We aimed to describe maternal infections at delivery and their association with perinatal death in Kilifi County Hospital (KCH), Kenya and Hiwot Fana Comprehensive Specialised Hospital (HFCSH), Ethiopia. Methods We investigated 642 mothers delivering stillbirths/newborns dying in the first 24h after birth (cases) and 855 mothers with newborns surviving > 24h (controls), from well-characterised pregnancy cohorts in a nested case-control design in KCH (2011-17) retrospectively and HFCSH (2019-20) prospectively. We tested maternal blood for infection at delivery using molecular methods with 60 PCR targets (TaqMan Array Cards, TAC). In HFCSH, vagino-rectal swabs (VRS) and oropharyngeal swabs (OPS) were also tested, with 28 and 42 PCR targets respectively, along with conventional microbiological testing. We tested associations between maternal infection and perinatal death for each site, separately, and combined, and adjusted for potential confounders. We did a sensitivity analysis using only controls with good pregnancy outcomes in KCH. Where appropriate, we calculated the population attributable fraction (PAF). Results In HFCSH, maternal bacteraemia was associated with perinatal death (adjusted odds ratio aOR3.7 [1.5-9.2]). In KCH, bacterial detection in maternal blood was associated with perinatal death (aOR2.7 [1.2-6.0]), but only in sensitivity analysis. Escherichia coli /Shigella was associated with perinatal death when cultured/detected in blood (aOR2.6 [1.1-6.3]) across sites. Though infrequent, Bordetella sp . was associated with perinatal death (OR4.9[1.1-23.0]) on OPS in HFCSH. No other individual infections were associated with perinatal death. The PAF for perinatal deaths among hospital deliveries was 6.1% (4.0%-8.2%) for maternal bacteraemia in HFCSH and 4.9% (2.6%-7.2%) for bacterial detection in KCH. Conclusions Maternal bacterial infection is associated with perinatal death in high-burden settings, and in our study accounted for around 5% of perinatal deaths in hospital deliveries. The study was underpowered to detect species-specific infections associated with perinatal death. Funding Wellcome (205184)