Effectiveness of kangaroo mother care before clinical stabilisation versus standard care among neonates at five hospitals in Uganda (OMWaNA): a parallel-group, individually randomised controlled trial and economic evaluation.

BACKGROUND: Preterm birth is the leading cause of death in children younger than 5 years worldwide. WHO recommends kangaroo mother care (KMC); however, its effects on mortality in sub-Saharan Africa and its relative costs remain unclear. We aimed to compare the effectiveness, safety, costs, and cost-effectiveness of KMC initiated before clinical stabilisation versus standard care in neonates weighing up to 2000 g. METHODS: We conducted a parallel-group, individually randomised controlled trial in five hospitals across Uganda. Singleton or twin neonates aged younger than 48 h weighing 700-2000 g without life-threatening clinical instability were eligible for inclusion. We randomly assigned (1:1) neonates to either KMC initiated before stabilisation (intervention group) or standard care (control group) via a computer-generated random allocation sequence with permuted blocks of varying sizes, stratified by birthweight and recruitment site. Parents, caregivers, and health-care workers were unmasked to treatment allocation; however, the independent statistician who conducted the analyses was masked. After randomisation, neonates in the intervention group were placed prone and skin-to-skin on the caregiver's chest, secured with a KMC wrap. Neonates in the control group were cared for in an incubator or radiant heater, as per hospital practice; KMC was not initiated until stability criteria were met. The primary outcome was all-cause neonatal mortality at 7 days, analysed by intention to treat. The economic evaluation assessed incremental costs and cost-effectiveness from a disaggregated societal perspective. This trial is registered with ClinicalTrials.gov, NCT02811432. FINDINGS: Between Oct 9, 2019, and July 31, 2022, 2221 neonates were randomly assigned: 1110 (50·0%) neonates to the intervention group and 1111 (50·0%) neonates to the control group. From randomisation to age 7 days, 81 (7·5%) of 1083 neonates in the intervention group and 83 (7·5%) of 1102 neonates in the control group died (adjusted relative risk [RR] 0·97 [95% CI 0·74-1·28]; p=0·85). From randomisation to 28 days, 119 (11·3%) of 1051 neonates in the intervention group and 134 (12·8%) of 1049 neonates in the control group died (RR 0·88 [0·71-1·09]; p=0·23). Even if policy makers place no value on averting neonatal deaths, the intervention would have 97% probability from the provider perspective and 84% probability from the societal perspective of being more cost-effective than standard care. INTERPRETATION: KMC initiated before stabilisation did not reduce early neonatal mortality; however, it was cost-effective from the societal and provider perspectives compared with standard care. Additional investment in neonatal care is needed for increased impact, particularly in sub-Saharan Africa. FUNDING: Joint Global Health Trials scheme of the Department of Health and Social Care, Foreign, Commonwealth and Development Office, UKRI Medical Research Council, and Wellcome Trust; Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Did aid to the Ebola crisis divert aid for reproductive, maternal, and newborn health? An analysis of donor-reported data in Sierra Leone.

BACKGROUND: Infectious disease outbreaks like Ebola and Covid-19 are increasing in frequency. They may harm reproductive, maternal and newborn health (RMNH) directly and indirectly. Sierra Leone experienced a sharp deterioration of RMNH during the 2014-16 Ebola epidemic. One possible explanation is that donor funding may have been diverted away from RMNH to the Ebola response. METHODS: We analysed donor-reported data from the Organisation for Economic Cooperation and Development (OECD)'s Creditor Reported System (CRS) data for Sierra Leone before, during and after the 2014-16 Ebola epidemic to understand whether aid flows for Ebola displaced aid for RMNH. We estimated aid for Ebola using key term searches and manual review of CRS records. We estimated aid for RMNH by applying the Muskoka-2 algorithm to the CRS and analysing CRS purpose codes. RESULTS: We find substantial increases in aid to Sierra Leone (from $484 million in 2013 to $1 billion at the height of the epidemic in 2015), most of which was earmarked for the Ebola response. Overall, Ebola aid was additional to RMNH funding. RMNH aid was sustained during the epidemic (at $42 m per year) and peaked immediately after (at $77 m in 2016). There is some evidence of a small displacement of RMNH aid from the UK during the period when its Ebola funding increased. CONCLUSIONS: Modest changes to RMNH donor aid patterns are insufficient to explain the severe decline in RMNH indicators recorded during the outbreak. Our findings therefore suggest the need for substantial increases in routine aid to ensure that basic RMNH services and infrastructure are strong before an epidemic occurs, as well as increased aid for RMNH during epidemics like Ebola and Covid-19, if reproductive, maternal and newborn healthcare is to be maintained at pre-epidemic levels.

Development of an integrated and decentralised skin health strategy to improve experiences of skin neglected tropical diseases and other skin conditions in Atwima Mponua District, Ghana.

Integrated strategies are recommended to tackle neglected tropical diseases of the skin (skin NTDs), which pose a substantial health and economic burden in many countries, including Ghana. We describe the development of an integrated and decentralised skin health strategy designed to improve experiences of skin NTDs in Atwima Mponua district in Ashanti Region. A multidisciplinary research team led an iterative process to develop an overall strategy and specific interventions, based on a theory of change informed by formative research conducted in Atwima Mponua district. The process involved preparatory work, four co-development workshops (August 2021 to November 2022), collaborative working groups to operationalise intervention components, and obtaining ethical approval. Stakeholders including affected individuals, caregivers, other community members and actors from different levels of the health system participated in co-development activities. We consulted these stakeholders at each stage of the research process, including discussion of study findings, development of our theory of change, identifying implementable solutions to identified challenges, and protocol development. Participants determined that the intervention should broadly address wounds and other skin conditions, rather than only skin NTDs, and should avoid reliance on non-governmental organisations and research teams to ensure sustainable implementation by district health teams and transferability elsewhere. The overall strategy was designed to focus on a decentralised model of care for skin conditions, while including other interventions to support a self-care delivery pathway, community engagement, and referral. Our theory of change describes the pathways through which these interventions are expected to achieve the strategy's aim, the assumptions, and problems addressed. This complex intervention strategy has been designed to respond to the local context, while maximising transferability to ensure wider relevance. Implementation is expected to begin in 2023.

Assessing equity and efficiency of health financing towards universal health coverage between regions in Tanzania.

Equity and efficiency in health financing are intermediate universal health coverage (UHC) objectives. While there is growing attention to monitoring these goals at the national level, subnational assessment is also needed to uncover potential divergences across subnational units. We assessed whether health funds were allocated or contributed equitably and spent efficiently across 26 regions in Tanzania in 2017/18 for four sources of funding. Government and donor health basket fund (HBF) expenditure data were obtained from government authorities. Household contributions to health insurance and out-of-pocket payments were obtained from the national household budget survey. We used the Kakwani index (KI) to measure regional funding equity, whereby regional GDP per capita measured regional economic status. Efficiency analysis included four financing inputs and two UHC outputs (maternal health service coverage and financial protection indices). Data envelopment analysis estimated efficiency scores. There was substantial variation in per capita regional funding, especially in insurance contributions (TZS 473-13,520), and service coverage performance (49-86.3%). There was less variation in per capita HBF spending (TZS 1294-2394) and financial protection (93.5-99.4%). Government spending (KI: -0.047, p = 0.348) was proportional to regional economic status; but HBF spending (KI: -0.195, p < 0.001) was significantly progressive (equitably distributed), being targeted to regions with high economic need (poor). The burden of contributing to social health insurance (NHIF) was proportional (KI: 0.058, p = 0.613), while the burden of paying for community-based insurance (CHF, KI: -0.152, p=0.012) and out-of-pocket payments (KI: -0.187, p=0.005) was higher among the poor (regressive). The average efficiency score across regions was 90%, indicating that 90% of financial resources were used optimally, while 10% were wasted or underutilised. Tanzania should continue mobilising domestic resources for health towards UHC, and reduce reliance on inequitable out-of-pocket payments and community-based health insurance. Policymakers must enhance resource allocation formulas, public financial management, and sub-national resource tracking to improve equity and efficiency in resource use.

Donor aid mentioning newborns and stillbirths, 2002-19: an analysis of levels, trends, and equity.

BACKGROUND: Global aid for reproductive, maternal, newborn, and child health has stagnated in recent years, and aid mentioning newborns or stillbirths has previously represented a very small proportion of aid for reproductive, maternal, newborn, and child health. Neonatal survival targets have been set by 78 countries, and stillbirth prevention targets have been set by 30 countries, to address the 4·4 million newborn deaths and stillbirths globally. We aimed to generate novel estimates of current levels of, and trends in, aid mentioning newborns and stillbirths over 2002-19, and to assess whether the amount of aid disbursed aligns with the associated mortality burden. METHODS: For this analysis, we did a manual review and coding of the Organisation for Economic Co-operation and Development (OECD)'s Creditor Reporting System database from 2002 to 2019 using key search terms for aid mentioning newborns and stillbirths. We compared these findings with estimates of aid for reproductive, maternal, newborn, and child health for 2002-19 based on the Muskoka2 method. Findings are presented in 2019 US$ according to the OECD's Development Assistance Committee deflators, which account for variation in exchange rates and inflation in donor countries. FINDINGS: We identified 21 957 unique records in the 2002-19 period. Aid mentioning newborns and stillbirths comprised approximately 10% ($1·6 billion) of reproductive, maternal, newborn, and child health funding overall in 2019 ($15·9 billion), with a small decrease in value between 2015 and 2019. 1284 (6%) of 21 957 records and 3·4% ($535 million) of their total value mentioned aid focused only on newborn health. Ten donors contributed 87% ($13·7 billion) of the total value of aid mentioning newborns and stillbirths during 2002-19. Aid mentioning newborns and stillbirths was inequitably allocated in the least developed countries (as defined by the UN), ranging from $18 per death in Angola to $1389 per death in Timor-Leste. Stillbirths were not mentioned in any funding in 2002-09, and they were only mentioned in 46 of 21 957 records in 2010-19, comprising $44·4 million of aid disbursed during this period. INTERPRETATION: Aid mentioning newborns and stillbirths is poorly matched to their corresponding mortality burden (representing 10% of aid for reproductive, maternal, newborn, and child health overall, yet accounting for approximately 50% of mortality in children <5 years) and across recipient countries (with substantial variation in the amount of aid received per newborn death and stillbirth between countries with similar health and economic needs). Our findings indicate that aid needs to be better targeted to populations with the highest mortality burdens, creating greater potential for impact. FUNDING: John D and Catherine T MacArthur Foundation, Bill & Melinda Gates Foundation, ELMA Philanthropies, Children's Investment Fund Foundation UK, Lemelson Foundation, and Ting Tsung and Wei Fong Chao Foundation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Process and costs for readiness to safely implement immediate kangaroo mother care: a mixed methods evaluation from the OMWaNA trial at five hospitals in Uganda.

BACKGROUND: Preterm birth complications result in > 1 million child deaths annually, mostly in low- and middle-income countries. A World Health Organisation (WHO)-led trial in hospitals with intensive care reported reduced mortality within 28 days among newborns weighing 1000-1799 g who received immediate kangaroo mother care (iKMC) compared to those who received standard care. Evidence is needed regarding the process and costs of implementing iKMC, particularly in non-intensive care settings. METHODS: We describe actions undertaken to implement iKMC, estimate financial and economic costs of essential resources and infrastructure improvements, and assess readiness for newborn care after these improvements at five Ugandan hospitals participating in the OMWaNA trial. We estimated costs from a health service provider perspective and explored cost drivers and cost variation across hospitals. We assessed readiness to deliver small and sick newborn care (WHO level-2) using a tool developed by Newborn Essential Solutions and Technologies and the United Nations Children's Fund. RESULTS: Following the addition of space to accommodate beds for iKMC, floor space in the neonatal units ranged from 58 m2 to 212 m2. Costs of improvements were lowest at the national referral hospital (financial: $31,354; economic: $45,051; 2020 USD) and varied across the four smaller hospitals (financial: $68,330-$95,796; economic: $99,430-$113,881). In a standardised 20-bed neonatal unit offering a level of care comparable to the four smaller hospitals, the total financial cost could be in the range of $70,000 to $80,000 if an existing space could be repurposed or remodelled, or $95,000 if a new unit needed to be constructed. Even after improvements, the facility assessments demonstrated broad variability in laboratory and pharmacy capacity as well as the availability of essential equipment and supplies. CONCLUSIONS: These five Ugandan hospitals required substantial resource inputs to allow safe implementation of iKMC. Before widespread scale-up of iKMC, the affordability and efficiency of this investment must be assessed, considering variation in costs across hospitals and levels of care. These findings should help inform planning and budgeting as well as decisions about if, where, and how to implement iKMC, particularly in settings where space, devices, and specialised staff for newborn care are unavailable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02811432 . Registered: 23 June 2016.

Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan.

Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60 days. ASC longevity past 60 days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying "long-lived" ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement.

Why cost-effectiveness thresholds for global health donors should differ from thresholds for Ministries of Health (and why it matters).

Healthcare cost-effectiveness analysis is increasingly used to inform priority-setting in low- and middle-income countries and by global health donors. As part of such analyses, cost-effectiveness thresholds are commonly used to determine what is, or is not, cost-effective. Recent years have seen a shift in best practice from a rule-of-thumb 1x or 3x per capita GDP threshold towards using thresholds that, in theory, reflect the opportunity cost of new investments within a given country. In this paper, we observe that international donors face both different resource constraints and opportunity costs compared to national decision-makers. Hence, their perspective on cost-effectiveness thresholds must be different. We discuss the potential implications of distinguishing between national and donor thresholds and outline broad options for how to approach setting a donor-perspective threshold. Further work is needed to clarify healthcare cost-effectiveness threshold theory in the context of international aid and to develop practical policy frameworks for implementation.

Long-lived plasma cells accumulate in the bone marrow at a constant rate from early in an immune response.

Vaccines work largely by generating long-lived plasma cells (LLPCs), but knowledge of how such cells are recruited is sparse. Although it is clear that LLPCs preferentially originate in germinal centers (GCs) and relocate to survival niches in bone marrow where they can persist for decades, the issues of the timing of LLPC recruitment and the basis of their retention remain uncertain. Here, using a genetic timestamping system in mice, we show that persistent PCs accrue in bone marrow at an approximately constant rate of one cell per hour over a period spanning several weeks after a single immunization with a model antigen. Affinity-based selection was evident in persisting PCs, reflecting a relative and dynamic rather than absolute affinity threshold as evidenced by the changing pattern of VH gene somatic mutations conveying increased affinity for antigen. We conclude that the life span of persistent, antigen-specific PCs is in part intrinsic, preprogrammed, and varied and that their final number is related to the duration of the response in a predictable way. This implies that modulating vaccines to extend the duration of the GC reaction will enhance antibody-mediated protective immunity.

CD137L and CD4 T cells limit BCL6-expressing pre-germinal center B cell expansion and BCL6-driven B cell malignancy.

Aberrant expression of the proto-oncogene BCL6 is a driver of tumorigenesis in diffuse large B cell lymphoma (DLBCL). Mice overexpressing BCL6 from the B cell-specific immunoglobulin heavy chain µ intron promoter (Iµ-Bcl6Tg/+ ) develop B cell lymphomas with features typical of human DLBCL. While the development of B cell lymphoma in these mice is tightly controlled by T cells, the mechanisms of this immune surveillance are poorly understood. Here we show that CD4 T cells contribute to the control of lymphoproliferative disease in lymphoma-prone Iµ-Bcl6Tg/+ mice. We reveal that this CD4 T cell immuno-surveillance requires signaling by the co-stimulatory molecule CD137 ligand (CD137L; also known as 4-1BBL), which may promote the transition of pre-malignant B cells with an activated phenotype into the germinal center stage via reverse signaling, preventing their hazardous accumulation. Thus, CD137L-mediated CD4 T cell immuno-surveillance adds another layer of protection against B cell malignancy to that provided by CD8 T cell cytotoxicity.

IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation.

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation, and competitiveness in the response, largely through determining access to T cell help. However, how T cell-derived signals contribute to these outcomes is incompletely understood. Here, we report how the signature cytokine of follicular helper T cells, IL-21, acts as a key regulator of the initial B cell response by accelerating cell cycle progression and the rate of cycle entry, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and correlates with elevated AKT and S6 phosphorylation. Moreover, the resultant increased proliferation can explain the IL-21-mediated promotion of plasma cell differentiation. Collectively, our data establish that IL-21 acts from the outset of a T cell-dependent immune response to increase cell cycle progression and fuel cyclic re-entry of B cells, thereby regulating the initial GC size and early plasma cell output.

Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest.

Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.

Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells.

Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity.

Effectiveness and cost-effectiveness against malaria of three types of dual-active-ingredient long-lasting insecticidal nets (LLINs) compared with pyrethroid-only LLINs in Tanzania: a four-arm, cluster-randomised trial.

BACKGROUND: Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread resistance to insecticides among vectors. We evaluated new classes of LLINs with two active ingredients with differing modes of action against resistant malaria vectors. METHODS: We did a four-arm, cluster-randomised trial in Misungwi, Tanzania. Clusters were villages, or groups of hamlets, with at least 119 households containing children aged 6 months to 14 years living in the cluster's core area. Constrained randomisation was used to allocate clusters (1:1:1:1) to receive one of four types of LLIN treated with the following: α-cypermethrin only (pyrethroid-only [reference] group); pyriproxyfen and α-cypermethrin (pyriproxyfen group); chlorfenapyr and α-cypermethrin (chlorfenapyr group); or the synergist piperonyl butoxide and permethrin (piperonyl butoxide group). At least one LLIN was distributed for every two people. Community members and the field team were masked to group allocation. Malaria prevalence data were collected through cross-sectional surveys of randomly selected households from each cluster, in which children aged 6 months to 14 years were assessed for Plasmodium falciparum malaria infection by rapid diagnostic tests. The primary outcome was malaria infection prevalence at 24 months after LLIN distribution, comparing each of the dual-active-ingredient LLINs to the standard pyrethroid-only LLINs in the intention-to-treat population. The primary economic outcome was cost-effectiveness of dual-active-ingredient LLINs, based on incremental cost per disability-adjusted life-year (DALY) averted compared with pyrethroid-only LLINs, modelled over a 2-year period; we included costs of net procurement and malaria diagnosis and treatment, and estimated DALYs in all age groups. This study is registered with ClinicalTrials.gov (NCT03554616), and is ongoing but no longer recruiting. FINDINGS: 84 clusters comprising 39 307 households were included in the study between May 11 and July 2, 2018. 147 230 LLINs were distributed among households between Jan 26 and Jan 28, 2019. Use of study LLINs was reported in 3155 (72·1%) of 4378 participants surveyed at 3 months post-distribution and decreased to 8694 (40·9%) of 21 246 at 24 months, with varying rates of decline between groups. Malaria infection prevalence at 24 months was 549 (45·8%) of 1199 children in the pyrethroid-only reference group, 472 (37·5%) of 1258 in the pyriproxyfen group (adjusted odds ratio 0·79 [95% CI 0·54-1·17], p=0·2354), 512 (40·7%) of 1259 in the piperonyl butoxide group (0·99 [0·67-1·45], p=0·9607), and 326 [25·6%] of 1272 in the chlorfenapyr group (0·45 [0·30-0·67], p=0·0001). Skin irritation or paraesthesia was the most commonly reported side-effect in all groups. Chlorfenapyr LLINs were the most cost-effective LLINs, costing only US$19 (95% uncertainty interval 1-105) more to public providers or $28 (11-120) more to donors per DALY averted over a 2-year period compared with pyrethroid-only LLINs, and saving costs from societal and household perspectives. INTERPRETATION: After 2 years, chlorfenapyr LLINs provided significantly better protection than pyrethroid-only LLINs against malaria in an area with pyrethroid-resistant mosquitoes, and the additional cost of these nets would be considerably below plausible cost-effectiveness thresholds ($292-393 per DALY averted). Before scale-up of chlorfenapyr LLINs, resistance management strategies are needed to preserve their effectiveness. Poor textile and active ingredient durability in the piperonyl butoxide and pyriproxyfen LLINs might have contributed to their relative lack of effectiveness compared with standard LLINs. FUNDING: Joint Global Health Trials scheme (UK Foreign, Commonwealth and Development Office; UK Medical Research Council; Wellcome; UK Department of Health and Social Care), US Agency for International Development, President's Malaria Initiative.

Buruli-RifDACC: Evaluation of the efficacy and cost-effectiveness of high-dose versus standard-dose rifampicin on outcomes in Mycobacteriumulcerans disease, a protocol for a randomised controlled trial in Ghana.

Background: Buruli ulcer (BU) can lead to disfiguring ulcers and permanent disability. The 2030 World Health Organization (WHO) road map for Neglected Tropical Diseases (NTDs) calls for major scaling up in diagnosis and management to eliminate disability due to the disease. Current treatment for BU is with daily oral rifampicin (10mg/kg dose) and clarithromycin (15mg/kg dose) for eight weeks, combined with standard gauze wound dressings. Dialkylcarbamoyl chloride (DACC)-coated dressings have been shown to irreversibly bind bacteria on wound surfaces resulting in their removal when dressings are changed. This trial aims to determine whether combining a high-dose oral rifampicin regimen with DACC dressings can improve the rate of wound healing relative to standard-dose oral rifampicin combined with DACC dressings. Methods: This is an individual, multi-centre Phase 3 randomised controlled trial, which will be conducted in three clinical sites in Ghana. The primary outcome measure will be the mean time to clearance of viable mycobacteria. Cost and health-related quality of life data will be collected, and a cost-effectiveness analysis will be performed. Discussion: The findings from this trial could lead to a change in how BU is treated. A shorter but more efficacious regimen would lead to improved treatment outcomes and potentially substantial financial and economic savings. Trial registration: Pan African Clinical Trials Repository (registration number; PACTR202011867644311). Registered on 30 th November 2020.

Buruli ulcer (BU), caused by Mycobacterium ulcerans, manifests clinically as a wound or swelling. There are several approaches for managing this condition. One is the availability of two antibiotics, usually rifampicin in combination with clarithromycin, that can be used to treat the disease. Rifampicin is thought to be the most important of these two drugs. Scientists have found out that a higher dose of rifampicin is safe and may help improve healing outcome and shorten the duration of treatment. Individuals with BU wounds also go through wound dressing procedures at their hospitals and health centres. Commonly, wounds are dressed using Vaseline gauze and bandages. However, it has been observed that some affected individuals heal faster than others even with the antibiotic treatment. Some still have living organisms in their wounds many weeks after the antibiotic treatment. There is a new dressing material called DACC which is believed to permanently bind bacteria on the wound surface leading to their removal when the dressings are changed. This may be a good way to treat and prevent infection without the use of more drugs. This study aims to determine whether combining a high-dose oral rifampicin regimen with DACC dressings can improve the rate of wound healing relative to standard-dose oral rifampicin combined with DACC dressings. Furthermore, cost and health-related quality of life data will be collected and a cost-effectiveness analysis will be performed. The findings from this trial could lead to a change in how BU is treated. A shorter but more efficacious regimen would lead to improved treatment outcomes and potentially substantial financial and economic savings.

Protocol for a four parallel-arm, single-blind, cluster-randomised trial to assess the effectiveness of three types of dual active ingredient treated nets compared to pyrethroid-only long-lasting insecticidal nets to prevent malaria transmitted by pyrethroid insecticide-resistant vector mosquitoes in Tanzania.

INTRODUCTION: The massive scale-up of long-lasting insecticidal nets (LLINs) has led to major reductions in malaria burden in many sub-Saharan African countries. This progress is threatened by widespread insecticide resistance among malaria vectors. This cluster-randomised controlled trial (c-RCT) compares three of the most promising dual active ingredients LLINs (dual-AI LLINs), which incorporate mixtures of insecticides or insecticide synergists to standard LLINs in an area of pyrethroid insecticide resistance. METHODS: A four-arm, single-blinded, c-RCT will evaluate the effectiveness of three types of dual-AI LLINs (1) Royal Guard, combining two insecticides, pyriproxyfen and the pyrethroid alpha-cypermethrin; (2) Interceptor G2, combining chlorfenapyr and alpha-cypermethrin; (3) Olyset Plus, an LLIN combining a synergist, piperonyl butoxide and the pyrethroid permethrin, compared with; (4) Interceptor LN, a standard LLIN containing the pyrethroid alpha-cypermethrin as the sole AI. The primary outcomes are malaria infection prevalence in children aged 6 months-14 years and entomological inoculation rate (EIR), as a standard measure of malaria transmission at 24 months postintervention and cost-effectiveness. ETHICS AND DISSEMINATION: Ethical approval was received from the institutional review boards of the Tanzanian National Institute for Medical Research, Kilimanjaro Christian Medical University College, London School of Hygiene and Tropical Medicine, and University of Ottawa. Study findings will be actively disseminated via reports and presentations to stakeholders, local community leaders, and relevant national and international policy makers as well as through conferences, and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03554616.

Effectiveness and cost-effectiveness of reactive, targeted indoor residual spraying for malaria control in low-transmission settings: a cluster-randomised, non-inferiority trial in South Africa.

BACKGROUND: Increasing insecticide costs and constrained malaria budgets could make universal vector control strategies, such as indoor residual spraying (IRS), unsustainable in low-transmission settings. We investigated the effectiveness and cost-effectiveness of a reactive, targeted IRS strategy. METHODS: This cluster-randomised, open-label, non-inferiority trial compared reactive, targeted IRS with standard IRS practice in northeastern South Africa over two malaria seasons (2015-17). In standard IRS clusters, programme managers conducted annual mass spray campaigns prioritising areas using historical data, expert opinion, and other factors. In targeted IRS clusters, only houses of index cases (identified through passive surveillance) and their immediate neighbours were sprayed. The non-inferiority margin was 1 case per 1000 person-years. Health service costs of real-world implementation were modelled from primary and secondary data. Incremental costs per disability-adjusted life-year (DALY) were estimated and deterministic and probabilistic sensitivity analyses conducted. This study is registered with ClinicalTrials.gov, NCT02556242. FINDINGS: Malaria incidence was 0·95 per 1000 person-years (95% CI 0·58 to 1·32) in the standard IRS group and 1·05 per 1000 person-years (0·72 to 1·38) in the targeted IRS group, corresponding to a rate difference of 0·10 per 1000 person-years (-0·38 to 0·59), demonstrating non-inferiority for targeted IRS (p<0·0001). Per additional DALY incurred, targeted IRS saved US$7845 (2902 to 64 907), giving a 94-98% probability that switching to targeted IRS would be cost-effective relative to plausible cost-effectiveness thresholds for South Africa ($2637 to $3557 per DALY averted). Depending on the threshold used, targeted IRS would remain cost-effective at incidences of less than 2·0-2·7 per 1000 person-years. Findings were robust to plausible variation in other parameters. INTERPRETATION: Targeted IRS was non-inferior, safe, less costly, and cost-effective compared with standard IRS in this very-low-transmission setting. Saved resources could be reallocated to other malaria control and elimination activities. FUNDING: Joint Global Health Trials.

Energy Landscape for the Membrane Fusion Pathway in Influenza A Hemagglutinin From Discrete Path Sampling.

The conformational change associated with membrane fusion for Influenza A Hemagglutinin is investigated with a model based upon pre- and post-fusion structures of the HA2 component. We employ computational methods based on the potential energy landscape framework to obtain an initial path connecting these two end points, which provides the starting point for refinement of a kinetic transition network. Here we employ discrete path sampling, which provides access to the experimental time and length scales via geometry optimization techniques to identify local minima and the transition states that connect them. We then analyse the distinct phases of the predicted pathway in terms of structure and energetics, and compare with available experimental data and previous simulations. Our results provide the foundations for future work, which will address the effect of mutations, changes in pH, and incorporation of additional components, especially the HA1 chain and the fusion peptide.