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.

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 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.

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.

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.

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.

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.

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.

Effects, equity, and cost of school-based and community-wide treatment strategies for soil-transmitted helminths in Kenya: a cluster-randomised controlled trial.

BACKGROUND: School-based deworming programmes can reduce morbidity attributable to soil-transmitted helminths in children but do not interrupt transmission in the wider community. We assessed the effects of alternative mass treatment strategies on community soil-transmitted helminth infection. METHODS: In this cluster-randomised controlled trial, 120 community units (clusters) serving 150 000 households in Kenya were randomly assigned (1:1:1) to receive albendazole through annual school-based treatment targeting 2-14 year olds or annual or biannual community-wide treatment targeting all ages. The primary outcome was community hookworm prevalence, assessed at 12 and 24 months through repeat cross-sectional surveys. Secondary outcomes were Ascaris lumbricoides and Trichuris trichiura prevalence, infection intensity of each soil-transmitted helminth species, and treatment coverage and costs. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02397772. FINDINGS: After 24 months, prevalence of hookworm changed from 18·6% (95% CI 13·9-23·2) to 13·8% (10·5-17·0) in the annual school-based treatment group, 17·9% (13·7-22·1) to 8·0% (6·0-10·1) in the annual community-wide treatment group, and 20·6% (15·8-25·5) to 6·2% (4·9-7·5) in the biannual community-wide treatment group. Relative to annual school-based treatment, the risk ratio for annual community-wide treatment was 0·59 (95% CI 0·42-0·83; p<0·001) and for biannual community-wide treatment was 0·46 (0·33-0·63; p<0·001). More modest reductions in risk were observed after 12 months. Risk ratios were similar across demographic and socioeconomic subgroups after 24 months. No adverse events related to albendazole were reported. INTERPRETATION: Community-wide treatment was more effective in reducing hookworm prevalence and intensity than school-based treatment, with little additional benefit of treating every 6 months, and was shown to be remarkably equitable in coverage and effects. FUNDING: Bill & Melinda Gates Foundation, the Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, the Wellcome Trust, and the Children's Investment Fund Foundation.

BAFF, IL-4 and IL-21 separably program germinal center-like phenotype acquisition, BCL6 expression, proliferation and survival of CD40L-activated B cells in vitro.

A B cell culture system using BAFF, IL-4 and IL-21 was recently developed that generates B cells with phenotypic and functional characteristics of in vivo-generated germinal center (GC) B cells. Here, we observe discrete influences of each exogenous signal on the expansion and differentiation of a CD40L-activated B cell pool. IL-4 was expressly necessary, but neither BAFF nor IL-21 was required for B cell acquisition of the GC B cell phenotypes of peanut agglutinin binding and loss of CD38 and IgD expression. Both IL-4 and IL-21 enhanced cell cycle entry upon initial activation dose-dependently, and did so additively. Importantly, while both cytokines acted in concert to increase overall BCL6 expression amounts, IL-21 exposure uniquely caused a small proportion of cells to attain a higher level of BCL6 expression, reminiscent of in vivo GC B cells. In contrast, BAFF supported survival of a fraction of memory-like B cells in extended cultures after removal of surrogate T cell-help signals. Thus, by separably programming proliferation, survival and GC phenotype acquisition, IL-4, BAFF and IL-21 drive distinct components of activated B cell fate.

Stillbirths: progress and unfinished business.

This first paper of the Lancet Series on ending preventable stillbirths reviews progress in essential areas, identified in the 2011 call to action for stillbirth prevention, to inform the integrated post-2015 agenda for maternal and newborn health. Worldwide attention to babies who die in stillbirth is rapidly increasing, from integration within the new Global Strategy for Women's, Children's and Adolescents' Health, to country policies inspired by the Every Newborn Action Plan. Supportive new guidance and metrics including stillbirth as a core health indicator and measure of quality of care are emerging. Prenatal health is a crucial biological foundation to life-long health. A key priority is to integrate action for prenatal health within the continuum of care for maternal and newborn health. Still, specific actions for stillbirths are needed for advocacy, policy formulation, monitoring, and research, including improvement in the dearth of data for effective coverage of proven interventions for prenatal survival. Strong leadership is needed worldwide and in countries. Institutions with a mandate to lead global efforts for mothers and their babies must assert their leadership to reduce stillbirths by promoting healthy and safe pregnancies.

Effectiveness of Seasonal Malaria Chemoprevention in Children under Ten Years of Age in Senegal: A Stepped-Wedge Cluster-Randomised Trial.

BACKGROUND: Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age. METHODS AND FINDINGS: SMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3-59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68-1.2, p = 0.496). A reduction of 60% (95% CI 54%-64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%-72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%-33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%-35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%-68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%-85%) p = 0.002 in 2008, 84% (95% CI 58%-94%, p < 0.001) in 2009, and 30% (95% CI -130%-79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint. CONCLUSIONS: SMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT00712374.

Economic Evaluation in Global Perspective: A Bibliometric Analysis of the Recent Literature.

We present a bibliometric analysis of recently published full economic evaluations of health interventions and reflect critically on the implications of our findings for this growing field. We created a database drawing on 14 health, economic, and/or general literature databases for articles published between 1 January 2012 and 3 May 2014 and identified 2844 economic evaluations meeting our criteria. We present findings regarding the sensitivity, specificity, and added value of searches in the different databases. We examine the distribution of publications between countries, regions, and health areas studied and compare the relative volume of research with disease burden. We analyse authors' country and institutional affiliations, journals and journal type, language, and type of economic evaluation conducted. More than 1200 economic evaluations were published annually, of which 4% addressed low-income countries, 4% lower-middle-income countries, 14% upper-middle-income countries, and 83% high-income countries. Across country income levels, 53, 54, 86, and 100% of articles, respectively, included an author based in a country within the income level studied. Biomedical journals published 74% of economic evaluations. The volume of research across health areas correlates more closely with disease burden in high-income than in low-income and middle-income countries. Our findings provide an empirical basis for further study on methods, research prioritization, and capacity development in health economic evaluation.

Comparison of Economic Evaluation Methods Across Low-income, Middle-income and High-income Countries: What are the Differences and Why?

There are marked differences in methods used for undertaking economic evaluations across low-income, middle-income, and high-income countries. We outline the most apparent dissimilarities and reflect on their underlying reasons. We randomly sampled 50 studies from each of three country income groups from a comprehensive database of 2844 economic evaluations published between January 2012 and May 2014. Data were extracted on ten methodological areas: (i) availability of guidelines; (ii) research questions; (iii) perspective; (iv) cost data collection methods; (v) cost data analysis; (vi) outcome measures; (vii) modelling techniques; (viii) cost-effectiveness thresholds; (ix) uncertainty analysis; and (x) applicability. Comparisons were made across income groups and odds ratios calculated. Contextual heterogeneity rightly drives some of the differences identified. Other differences appear less warranted and may be attributed to variation in government health sector capacity, in health economics research capacity and in expectations of funders, journals and peer reviewers. By highlighting these differences, we seek to start a debate about the underlying reasons why they have occurred and to what extent the differences are conducive for methodological advancements. We suggest a number of specific areas in which researchers working in countries of differing environments could learn from one another.

Incorporating Demand and Supply Constraints into Economic Evaluations in Low-Income and Middle-Income Countries.

Global guidelines for new technologies are based on cost and efficacy data from a limited number of trial locations. Country-level decision makers need to consider whether cost-effectiveness analysis used to inform global guidelines are sufficient for their situation or whether to use models that adjust cost-effectiveness results taking into account setting-specific epidemiological and cost heterogeneity. However, demand and supply constraints will also impact cost-effectiveness by influencing the standard of care and the use and implementation of any new technology. These constraints may also vary substantially by setting. We present two case studies of economic evaluations of the introduction of new diagnostics for malaria and tuberculosis control. These case studies are used to analyse how the scope of economic evaluations of each technology expanded to account for and then address demand and supply constraints over time. We use these case studies to inform a conceptual framework that can be used to explore the characteristics of intervention complexity and the influence of demand and supply constraints. Finally, we describe a number of feasible steps that researchers who wish to apply our framework in cost-effectiveness analyses.

Cost-effectiveness of strategies to improve the utilization and provision of maternal and newborn health care in low-income and lower-middle-income countries: a systematic review.

BACKGROUND: Each year almost 3 million newborns die within the first 28 days of life, 2.6 million babies are stillborn, and 287,000 women die from complications of pregnancy and childbirth worldwide. Effective and cost-effective interventions and behaviours for mothers and newborns exist, but their coverage remains inadequate in low- and middle-income countries, where the vast majority of deaths occur. Cost-effective strategies are needed to increase the coverage of life-saving maternal and newborn interventions and behaviours in resource-constrained settings. METHODS: A systematic review was undertaken on the cost-effectiveness of strategies to improve the demand and supply of maternal and newborn health care in low-income and lower-middle-income countries. Peer-reviewed and grey literature published since 1990 was searched using bibliographic databases, websites of selected organizations, and reference lists of relevant studies and reviews. Publications were eligible for inclusion if they report on a behavioural or health systems strategy that sought to improve the utilization or provision of care during pregnancy, childbirth or the neonatal period; report on its cost-effectiveness; and were set in one or more low-income or lower-middle-income countries. The quality of the publications was assessed using the Consolidated Health Economic Evaluation Reporting Standards statement. Incremental cost per life-year saved and per disability-adjusted life-year averted were compared to gross domestic product per capita. RESULTS: Forty-eight publications were identified, which reported on 43 separate studies. Sixteen were judged to be of high quality. Common themes were identified and the strategies were presented in relation to the continuum of care and the level of the health system. There was reasonably strong evidence for the cost-effectiveness of the use of women's groups, home-based newborn care using community health workers and traditional birth attendants, adding services to routine antenatal care, a facility-based quality improvement initiative to enhance compliance with care standards, and the promotion of breastfeeding in maternity hospitals. Other strategies reported cost-effectiveness measures that had limited comparability. CONCLUSION: Demand and supply-side strategies to improve maternal and newborn health care can be cost-effective, though the evidence is limited by the paucity of high quality studies and the use of disparate cost-effectiveness measures. TRIAL REGISTRATION: PROSPERO_ CRD42012003255.

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.

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.

The role of economic factors in shaping and constituting the household burden of neglected tropical diseases of the skin: Qualitative findings from Ghana and Ethiopia.

Tracers of health system equity, neglected tropical diseases (NTDs) disproportionately affect marginalized populations. NTDs that manifest on the skin - "skin NTDs" - are associated with scarring, disfigurement, physical disability, social exclusion, psychological distress, and economic hardship. To support development and evaluation of appropriate intervention strategies, we aimed to improve understanding of the role of economic factors in shaping and constituting the burden that skin NTDs place on households. We collected data in 2021 in two predominantly rural districts: Atwima Mponua in Ghana (where Buruli ulcer, yaws, and leprosy are endemic) and Kalu in Ethiopia (where cutaneous leishmaniasis and leprosy are endemic). We conducted interviews (n = 50) and focus group discussions (n = 14) that explored economic themes with affected individuals, caregivers, and community members and analysed the data thematically using a pre-defined framework. We found remarkable commonalities across countries and diseases. We developed a conceptual framework which illustrates skin NTDs' negative economic impact, including financial costs of care-seeking and reductions in work and schooling; categorises coping strategies by their degree of risk-pooling; and clarifies the mechanisms through which skin NTDs disproportionately affect the poorest. Despite health insurance schemes in both countries, wide-ranging, often harmful coping strategies were reported. Traditional healers were often described as more accessible, affordable and offering more flexible payment terms than formal health services, except for Ethiopia's well-established leprosy programme. Our findings are important in informing strategies to mitigate the skin NTD burden and identifying key drivers of household costs to measure in future evaluations. To reduce skin NTDs' impact on households' physical, mental, and economic wellbeing, intervention strategies should address economic constraints to prompt and effective care-seeking. While financial support and incentives for referrals and promotion of insurance enrolment may mitigate some constraints, structural interventions that decentralise care may offer more equitable and sustainable access to skin NTD care.

Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement.

The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen-receptor gene rearrangements occurred. We identified that Ki67 was required for normal global chromatin accessibility involving regulatory regions of genes critical for checkpoint stages in B cell lymphopoiesis. In line with this, mRNA expression of Rag1 was diminished and gene rearrangement was less efficient in the absence of Ki67. Transgenes encoding productively rearranged immunoglobulin heavy and light chains complemented Ki67 deficiency, completely rescuing early B cell development. Collectively, these results identify a unique contribution from Ki67 to somatic antigen-receptor gene rearrangement during lymphopoiesis.