Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Childhood cerebellar tumours mirror conserved fetal transcriptional programs.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.

Barriers to the quality delivery of seasonal malaria chemoprevention in Chad and Burkina Faso: a qualitative exploration of caregivers and community distributors' perspectives.

BACKGROUND: Recommended since 2012 by the World Health Organization (WHO), seasonal malaria chemoprevention (SMC) is a community-based intervention to prevent malaria in children in African regions where malaria transmission follows a seasonal pattern. Following the publication of consolidated WHO guidelines for malaria, SMC is expected to reach more children in new geographies in future years. Though SMC has been shown to reduce malaria-related morbidity and mortality, there is potential for quality improvement of the intervention implementation. Assisted by ten quality standards from a framework developed by Malaria Consortium, this paper aims to better understand the quality of SMC implementation and identify potential barriers to quality delivery of SMC. METHODS: A qualitative thematic analysis on data collected after the annual SMC rounds implemented in Burkina Faso and Chad in 2019 was conducted. Sixteen focus group discussions conducted with caregivers and community distributors were analysed. Three selected quality standards for SMC delivery; planning and enumeration; community engagement; and administration of SMC medicines provided overarching quality themes under which subthemes were identified. RESULTS: Eight subthemes relating to the three quality standards were identified. Although SMC was well accepted by communities in both settings, common barriers to the quality delivery of SMC were identified including difficulty ensuring adherence to the SMC administration protocol; difficulties reaching mobile populations; concerns around adverse drug reactions; rumours, and concerns about SMC safety; and community distributors' working conditions. Context-specific barriers included: the suboptimal timeliness of the SMC round in Burkina Faso, and the lack of involvement of female caregivers in mobilization activities in Chad. CONCLUSION: In the context of increased adoption of SMC, this paper provides relevant insights and recommendations for the improved implementation of SMC programmes. These include the integration of strategies addressing communities' concerns around adverse drug reactions, gender-specific mobilization strategies, and attention to community distributors' working conditions. It also highlights the importance and utility of further, robust research on the quality of SMC delivery.

RéSUMé EN FRANçAIS: BACKGROUND: Recommandée depuis 2012 par l'Organisation mondiale de la santé (OMS), la chimioprévention du paludisme saisonnier (CPS) est une intervention communautaire visant à prévenir le paludisme chez les enfants dans les régions d'Afrique où la transmission du paludisme suit un schéma saisonnier. Suite à la publication des lignes directrices consolidées de l'OMS sur le paludisme, la CPS devrait toucher davantage d'enfants dans de nouvelles zones géographiques dans les années à venir. Bien qu'il ait été démontré que la CPS réduisait la morbidité et la mortalité liées au paludisme, il y a du potentiel pour améliorer la qualité de l'implémentation l'intervention. En s'appuyant sur un cadre de normes de qualité de la CPS développé par le Malaria Consortium, cette publication vise à mieux comprendre la qualité de la mise en œuvre de la CPS et à identifier les obstacles potentiels à la qualité de la mise en œuvre de la CPS. METHODS: Une étude qualitative basée sur l'analyse secondaire des données collectées après les tournées annuelles du SMC mises en œuvre au Burkina Faso et au Tchad en 2019 a été menée. Une analyse thématique de 16 discussions de groupe menées avec des parents/tuteurs et des distributeurs communautaires a été faite. Trois des éléments clés du cadre des normes de qualité pour le déploiement de la CPS ont fourni les thèmes de qualité principaux sous lesquels les sous-thèmes identifiés ont été placés. RéSULTATS: Huit sous-thèmes relatifs aux normes de qualité ; la planification, la sensibilisation et l'engagement des communautés ainsi que l'administration des médicaments de la CPS ont été identifiés. Bien que la CPS ait été bien acceptée par les communautés dans les deux contextes, des obstacles communs à la qualité du déploiement de la CPS ont été identifiés, notamment : la difficulté d'assurer le respect du protocole d'administration de la CPS; atteindre les populations mobiles ; les préoccupations concernant les effets indésirables des médicaments ; les rumeurs et les préoccupations concernant le SMC; et les conditions de travail des distributeurs communautaires. D'autres barrières spécifiques au contexte de déploiement ont été identifiées, telles que le choix sous-optimal de la période de déploiement au Burkina Faso ou le manque d'implication des mères/tutrices dans les activités de mobilisation au Tchad. CONCLUSION: Dans le contexte de l'adoption croissante de la CPS, cette publication fournit des informations et des recommandations pertinentes pour l'amélioration de la mise en œuvre des programmes de CMS, telles que l'intégration de stratégies répondant aux préoccupations des communautés concernant les effets indésirables des médicaments, les stratégies de mobilisation spécifiques au genre, et/ou l'attention portée aux conditions de travail des distributeurs communautaires. Cette publication souligne également l'importance et l'utilité des recherches en cours sur la qualité du déploiement de la CPS.

RESUMO EM PORTUGUêS: INTRODUçãO: Recomendada desde 2012 pela Organização Mundial de Saúde (OMS), a quimioprevenção sazonal do paludismo (SMC) é uma intervenção de base comunitária para prevenir o paludismo em crianças em zonas da África onde a transmissão do paludismo segue um padrão sazonal. Após a publicação das diretrizes consolidadas da OMS sobre o paludismo, espera-se que a SMC chegue a mais crianças em novas zonas geográficas nos próximos anos. Embora se tenha demonstrado que a SMC reduz a morbilidade e a mortalidade causadas pelo paludismo, há potencial para melhorar a qualidade da implementação da intervenção. Com ajuda dum quadro de padrões de qualidade para a SMC desenvolvido pelo Malaria Consortium, a presente publicação visa compreender melhor a qualidade da implementação da SMC e identificar potenciais barreiras à qualidade da implementação da SMC. MéTODOS: Foi realizado um estudo qualitativo baseado na análise secundária dos dados recolhidos após as rondas anuais da SMC implementadas no Burkina Faso e no Chade em 2019. Foi efectuado uma análise temática de 16 discussões de grupos focais realizadas com cuidadores e distribuidores comunitários. Tres padrões do quadro de normas de qualidade para a implementação da SMC forneceu os principais temas de qualidade sob os quais os subtemas identificados foram colocados. RESULTADOS: Foram identificados oito sub-temas relacionados com padrões de qualidade; planeamento; sensibilização e envolvimento da comunidade; e administração de drogas da SMC. Embora a SMC tenha sido bem aceita pelas comunidades em ambos os contextos, foram identificadas barreiras comuns à implementação duma SMC de qualidade, incluindo: a dificuldade de assegurar o cumprimento do protocolo de administração da SMC; atingir populações móveis; preocupações com reacções adversas aos medicamentos; rumores e preocupações com a SMC; e as condições de trabalho dos distribuidores comunitários. Foram identificados outros obstáculos específicos ao contexto de implantação, tais como a escolha subaproveitada do período de implantação no Burkina Faso ou a falta de envolvimento das cuidadoras femininas nas actividades de mobilização no Chade. CONCLUSãO: No contexto do aumento da adopção da SMC, esta publicação fornece informações e recomendações relevantes para melhorar a implementação de programas de SMC, tais como estratégias integradoras que abordam as preocupações da comunidade sobre reacções adversas aos medicamentos, estratégias de mobilização específicas de género, e/ou atenção às condições de trabalho dos distribuidores comunitários. Salienta igualmente a importância e a utilidade das investigaçãos em curso sobre a qualidade da implementação da SMC.

Exploring existing malaria services and the feasibility of implementing community engagement approaches amongst conflict-affected communities in Cameroon: a qualitative study.

BACKGROUND: Cameroon is one of the countries with the highest burden of malaria. Since 2018, there has been an ongoing conflict in the country, which has reduced access to healthcare for populations in affected regions, and little is known about the impact on access to malaria services. The objective of this study was to understand the current situation regarding access to malaria services in Cameroon to inform the design of interventions to remove barriers and encourage the use of available services. METHODS: A qualitative research study was carried out to understand the barriers preventing communities accessing care, the uptake of community health worker (CHW) services, and to gather perceptions on community engagement approaches, to assess whether these could be an appropriate mechanism to encourage uptake of community health worker (CHW) services. Twenty-nine focus group discussions and 11 in-depth interviews were carried out between May and July 2021 in two regions of Cameroon, Southwest and Littoral. Focus group discussions were held with CHWs and community members and semi-structured, in-depth interviews were conducted with key stakeholders including regional government staff, council staff, community leaders and community-based organisations. The data were analysed thematically; open, descriptive coding was combined with exploration of pre-determined investigative areas. RESULTS: The study confirmed that access to healthcare has become increasingly challenging in conflict-affected areas. Although the Ministry of Health are providing CHWs to improve access, several barriers remain that limit uptake of these services including awareness, availability, cost, trust in competency, and supply of testing and treatment. This study found that communities were supportive of community engagement approaches, particularly the community dialogue approach. CONCLUSION: Communities in conflict-affected regions of Cameroon continue to have limited access to healthcare services, in part due to poor use of CHW services provided. Community engagement approaches can be an effective way to improve the awareness and use of CHWs. However, these approaches alone will not be sufficient to resolve all the challenges faced by conflict-affected communities when accessing health and malaria services. Additional interventions are needed to increase the availability of CHWs, improve the supply of diagnostic tests and treatments and to reduce the cost of treatment for all.

Using the role model approach to optimise caregiver administration of sulfadoxine-pyrimethamine amodiaquine to children aged 3-59 months in Burkina Faso, Chad and Togo: findings from an evaluation.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a World Health Organization-recommended intervention for the prevention of malaria among children at high risk in areas with seasonal transmission. During the coronavirus disease 2019 (COVID-19) pandemic, SMC drug distribution was rapidly adapted to reduce contact and mitigate the risk of transmission between communities and community distributors, with caregivers administering doses. To address the challenges and find local solutions to improve administration and adherence, the role model approach was designed, implemented and evaluated in selected communities of Burkina Faso, Chad and Togo. This paper describes the results of this evaluation. METHODS: Focus group discussions were held with primary caregivers in all three countries to understand their perceptions of the approach's acceptability and feasibility. In Burkina Faso and Togo, household surveys assessed the characteristics of caregivers reached by role model activities. Key indicators on SMC coverage and adherence allowed for an assessment of caregiver engagement outcomes related to participation in activities. Statistical associations between participation in study's activities and caregiver beliefs related to SMC had been tested. RESULTS: The majority of caregivers believed the approach to have a positive effect on drug administration, with most adopting the promoted strategies. Greater involvement of fathers in drug administration and acknowledgement of their joint responsibility was a notable positive outcome. However, several barriers to participation were noted and there was criticism of the group approach. In Burkina Faso and Togo, end-of-round survey results revealed that 98.4% of respondents agreed the approach improved their knowledge and skills in malaria prevention, while 100% expressed a desire to continue practicing the behaviours learned. However, there was a relatively low level of awareness of the approach among communities. Participation was strongly associated with participants' self-reported belief in ease of remembering to administer, and ease of administering, SMC medicines. CONCLUSION: Caregivers perceived the role model approach to be beneficial in aiding drug administration, with other positive impacts also reported. Replication and scale-up should utilize the most popular communication channels and existing community structures to ensure activities are promoted effectively. A mixture of group and one-on-one approaches should be used where appropriate and feasible.

A formative cross-sectional study to assess caregiver's health-seeking behaviour and knowledge surrounding malaria, and understand the burden of malaria among children under-five in conflict-affected communities of Cameroon.

BACKGROUND: Malaria remains a major global health problem often worsened by political instability and armed conflict. The purpose of the study was to explore community knowledge, attitudes and practices on malaria prevention, and to understand the burden of malaria and health-seeking behaviours of caregivers of children under-five in conflict-affected communities of the South West and Littoral Regions of Cameroon. METHODS: A cross-sectional survey involving internally displaced persons (IDPS), host population, and their children under-five was conducted across 80 communities. The survey was conducted from May to June 2021. Participants were interviewed using a structured questionnaire. Malaria prevalence for children under-five was determined using rapid diagnostic tests (RDT) on blood samples. Association between variables and displacement status was measured using chi square test and multivariate logistic regression model was fitted to identify factors associated with adequate knowledge on malaria prevention. RESULTS: A total of 2386 adults participated in the study and 1543 RDTs were conducted for children under-five. Adequate levels of knowledge and attitudes on malaria prevention was recorded among 1258 (52.9%) of the participants, with very strong evidence to suggest the level to be higher among the host (59.5%) compared to the IDPs (49.5%) and returnees (39.7%) (p < 0.001). Good practices towards malaria prevention was 43.3%, with very strong evidence indicating lower levels among IDPs (42.8%) and returnees (28.5%) compared to the host (49.4%) (p < 0.001). Malaria prevalence for children under-five was 54.0% and adequate health-seeking for suspected episodes of malaria was 53.0%, without any difference among IDPs (51.78%) and returnees (48.7%) compared to host populations (55.4%) (p = 0.154). Multivariate logistic regression model showed that there was quite strong evidence to suggest primary and secondary levels of education have higher odds of having correct knowledge of malaria prevention (adjusted odds ratio (AOR) 1.71, 95% confidence interval (CI): 1.11-2.64, p = 0.015 and AOR 1.80, 95% CI 1.15-2.82, p = 0.010 respectively). There was very strong evidence to suggest that owning a radio or a television was associated with greater odds of having a higher knowledge on malaria prevention (AOR 1.49, 95% CI 1.233-1.81, p = 0.000 and AOR 1.47, 95% CI 1.18-1.84, p = 0.001). CONCLUSION: Over half of the population have correct knowledge and attitudes towards malaria prevention but gaps in complete knowledge remained. Some of the caregivers know the correct malaria preventive practices coupled with largely unsatisfactory treatment approaches and reflected by the high prevalence of malaria among their children. In order to effectively treat malaria, innovative strategies should target community participation.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells.

BACKGROUND AIMS: The targeting of solid cancers with chimeric antigen receptor (CAR) T cells faces many technological hurdles, including selection of optimal target antigens. Promising pre-clinical and clinical data of CAR T-cell activity have emerged from targeting surface antigens such as GD2 and B7H3 in childhood cancer neuroblastoma. Anaplastic lymphoma kinase (ALK) is expressed in a majority of neuroblastomas at low antigen density but is largely absent from healthy tissues. METHODS: To explore an alternate target antigen for neuroblastoma CAR T-cell therapy, the authors generated and screened a single-chain variable fragment library targeting ALK extracellular domain to make a panel of new anti-ALK CAR T-cell constructs. RESULTS: A lead novel CAR T-cell construct was capable of specific cytotoxicity against neuroblastoma cells expressing low levels of ALK, but with only weak cytokine and proliferative T-cell responses. To explore strategies for amplifying ALK CAR T cells, the authors generated a co-CAR approach in which T cells received signal 1 from a first-generation ALK construct and signal 2 from anti-B7H3 or GD2 chimeric co-stimulatory receptors. The co-CAR approach successfully demonstrated the ability to avoid targeting single-antigen-positive targets as a strategy for mitigating on-target off-tumor toxicity. CONCLUSIONS: These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target.

Optimizing the role of 'lead mothers' in seasonal malaria chemoprevention (SMC) campaigns: formative research in Kano State, northern Nigeria.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a safe and effective intervention for preventing malaria in children under 5 years of age. Lead mothers are community health volunteers that help caregivers comply with monthly administration of anti-malarial drugs during SMC campaigns. The lead mother approach is used in several SMC implementing states across Nigeria, but there is lack of evidence about their roles and how effective they are. This study sought to better understand the current role of lead mothers, identify areas for improvement and ways to optimize the role of lead mothers during SMC campaigns. METHODS: This paper reports the formative phase of a three-phased intervention development study. The formative phase involved semi-structured interviews with stakeholders from national, state, local government and community levels (n = 20). Thematic analysis was used to identify key themes, forming the basis of a subsequent co-design workshop with stakeholders routinely involved in SMC campaigns. RESULTS: The findings of the formative phase converged around four overarching themes: skills and attributes required of lead mothers; factors that affect lead mother's roles; how lead mothers interact with Community Health Influencers Promoters Services (CHIPS) agents and re-imagining the role of lead mothers during SMC campaigns. CONCLUSION: This formative work in Kano state indicates that through their strong connection to communities and unique relationship with caregivers, lead mothers can and do influence caregivers to adopt healthy behaviours during SMC campaigns. However, there is room for improvement in how they are recruited, trained and supervised. There is need to improve lead mothers' knowledge and skills through adequate training and supporting materials, so they can deliver targeted health messages to caregivers. Sustainability of the lead mother approach is at risk if policymakers do not find a way of transitioning their role into the existing community health worker infrastructure, for example by using CHIPs agents, and ensuring less reliance on external donor support.

Health related quality of life trajectories after stereotactic radiosurgery for brain metastases: a systematic review.

PURPOSE: Health related quality of life (HRQoL) is often used as an outcome measure of cancer treatment. Stereotactic radiosurgery (SRS) is a mainstay treatment of brain metastases (BMs) with constantly improving treatment envelope. The goal of this systematic review was to evaluated HRQoL trajectories after SRS, identify important predictors of HRQoL after SRS, and to evaluate clinical importance of post-SRS HRQoL trajectories of BM patients treated with SRS. METHODS: A systematic literature review according to the PRISMA guidelines analyzing HRQoL trajectories after SRS for BM published in the Pubmed/MEDLINE database before January, 2022. RESULTS: We identified 18 studies that evaluated HRQoL before and at least once after SRS for BMs. The majority of studies were single-institution retrospective series and included patients with different cancer types. Different instruments were used to assess HRQoL. In the majority of studies (n = 10) at group level, there was no significant change in global HRQoL after SRS. Stability, improvement, and deterioration of HRQoL global and subscale scores at individual patient level were common. Post-SRS HRQoL deterioration was predicted by worse functional status, greater number of BMs, delayed SRS, symptomatic BMs, and presence of seizures and cognitive impairment. Shorter post-SRS survival and adverse radiation effects (AREs) were associated with worse HRQoL. CONCLUSIONS: SRS for BMs is often associated with sustained preservation of HRQoL. Individual variation of HRQoL domains after SRS is common. Shorter survival and AREs are associated with worse HRQoL. Worse functional status and greater disease burden predict unfavorable HRQoL trajectories after SRS for BMs.

Delivery of seasonal malaria chemoprevention with enhanced infection prevention and control measures during the COVID-19 pandemic in Nigeria, Burkina Faso and Chad: a cross-sectional study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a WHO-recommended intervention for children aged 3-59 months living in areas of high malaria transmission to provide protection against malaria during the rainy season. Operational guidelines were developed, based on WHO guidance, to support countries to mitigate the risk of coronavirus disease 2019 (COVID-19) transmission within communities and among community distributors when delivering SMC. METHODS: A cross-sectional study to determine adherence to infection prevention and control (IPC) measures during two distribution cycles of SMC in Nigeria, Chad and Burkina Faso. Community distributors were observed receiving equipment and delivering SMC. Adherence across six domains was calculated as the proportion of indications in which the community distributor performed the correct action. Focus group discussions were conducted with community distributors to understand their perceptions of the IPC measures and barriers and facilitators to adherence. RESULTS: Data collectors observed community distributors in Nigeria (n = 259), Burkina Faso (n = 252) and Chad (n = 266) receiving IPC equipment and delivering SMC. Adherence to IPC indications varied. In all three countries, adherence to mask use was the highest (ranging from 73.3% in Nigeria to 86.9% in Burkina Faso). Adherence to hand hygiene for at least 30 s was low (ranging from 3.6% in Nigeria to 10.3% in Burkina Faso) but increased substantially when excluding the length of time spent hand washing (ranging from 36.7% in Nigeria to 61.4% in Burkina Faso). Adherence to safe distancing in the compound ranged from 5.4% in Chad to 16.4% in Nigeria. In Burkina Faso and Chad, where disinfection wipes widely available compliance with disinfection of blister packs for SMC was low (17.4% in Burkina Faso and 16.9% in Chad). Community distributors generally found the IPC measures acceptable, however there were barriers to optimal hand hygiene practices, cultural norms made social distancing difficult to adhere to and caregivers needed assistance to administer the first dose of SMC. CONCLUSION: Adherence to IPC measures for SMC delivery during the COVID-19 pandemic varied across domains of IPC, but was largely insufficient, particularly for hand hygiene and safe distancing. Improvements in provision of protective equipment, early community engagement and adaptations to make IPC measures more feasible to implement could increase adherence.

Divergent clonal selection dominates medulloblastoma at recurrence.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Extending seasonal malaria chemoprevention to five cycles: a pilot study of feasibility and acceptability in Mangodara district, Burkina Faso.

BACKGROUND: Seasonal malaria chemoprevention (SMC) involves administering antimalarial drugs at monthly intervals during the high malaria transmission period to children aged 3 to 59 months as recommended by the World Health Organization. Typically, a full SMC course is administered over four monthly cycles from July to October, coinciding with the rainy season. However, an analysis of rainfall patterns suggest that the malaria transmission season is longer and starting as early as June in the south of Burkina Faso, leading to a rise in cases prior to the first cycle. This study assessed the acceptability and feasibility of extending SMC from four to five cycles to coincide with the earlier rainy season in Mangodara health district. METHODS: The mixed-methods study was conducted between July and November 2019. Quantitative data were collected through end-of-cycle and end-of-round household surveys to determine the effect of the additional cycle on the coverage of SMC in Mangodara. The data were then compared with 22 other districts where SMC was implemented by Malaria Consortium. Eight focus group discussions were conducted with caregivers and community distributors and 11 key informant interviews with community, programme and national-level stakeholders. These aimed to determine perceptions of the acceptability and feasibility of extending SMC to five cycles. RESULTS: The extension was perceived as acceptable by caregivers, community distributors and stakeholders due to the positive impact on the health of children under five. However, many community distributors expressed concern over the feasibility, mainly due to the clash with farming activities in June. Stakeholders highlighted the need for more evidence on the impact of the additional cycle on parasite resistance prior to scale-up. End-of-cycle survey data showed no difference in coverage between five SMC cycles in Mangodara and four cycles in the 22 comparison districts. CONCLUSIONS: The additional cycle should begin early in the day in order to not coincide with the agricultural activities of community distributors. Continuous sensitisation at community level is critical for the sustainability of SMC and acceptance of an additional cycle, which should actively engage male caregivers. Providing additional support in proportion to the increased workload from a fifth cycle, including timely remuneration, is critical to avoid the demotivation of community distributors. Further studies are required to understand the effectiveness, including cost-effectiveness, of tailoring SMC according to the rainy season. Understanding the impact of an additional cycle on parasite resistance to SPAQ is critical to address key informants' concerns around the deviation from the current four-cycle policy recommendation.

Presumed Dissent? Opt-out Organ Donation and the Exclusion of Organs and Tissues.

It is often claimed that a legitimate approach to organ donation is an opt-out system, also known as 'presumed consent', 'deemed consent', or 'deemed authorisation', whereby individuals are presumed or deemed willing to donate at least some of their organs and tissues after death unless they have explicitly refused permission. While sharing a default in favour of donation, such systems differ in several key respects, such as the role and importance assigned to the family members of prospective donors and their preferences, and exclusions and safeguards which often specify the demographic groups, purposes, or organs and tissues that will remain outside the scope of the opt-out system. Using the recent shift to opt-out in England, Scotland, and Northern Ireland as case studies, and by reference to the key goals motivating this shift across the UK, this article asks whether and, if so, why, and how, opt-out systems for post-mortem organ donation should restrict the types of organs and tissues for which consent is deemed. In other words, ought opt-out systems for PMOD presume dissent regarding the donation of certain organs and tissues?

Health management information system (HMIS) data quality and associated factors in Massaguet district, Chad.

BACKGROUND: Quality data from Health Management Information Systems (HMIS) are important for tracking the effectiveness of malaria control interventions. However, HMIS data in many resource-limited settings do not currently meet standards set by the World Health Organization (WHO). We aimed to assess HMIS data quality and associated factors in Chad. METHODS: A cross-sectional study was conducted in 14 health facilities in Massaguet district. Data on children under 15 years were obtained from the HMIS and from the external patient register covering the period January-December 2018. An additional questionnaire was administered to 16 health centre managers to collect data on contextual variables. Patient registry data were aggregated and compared with the HMIS database at district and health centre level. Completeness and accuracy indicators were calculated as per WHO guidelines. Multivariate logistic regressions were performed on the Verification Factor for attendance, suspected and confirmed malaria cases for three age groups (1 to < 12 months, 1 to < 5 years and 5 to < 15 years) to identify associations between health centre characteristics and data accuracy. RESULTS: Health centres achieved a high level of data completeness in HMIS. Malaria data were over-reported in HMIS for children aged under 15 years. There was an association between workload and higher odds of inaccuracy in reporting of attendance among children aged 1 to < 5 years (Odds ratio [OR]: 10.57, 95% CI 2.32-48.19) and 5- < 15 years (OR: 6.64, 95% CI 1.38-32.04). Similar association was found between workload and stock-outs in register books, and inaccuracy in reporting of malaria confirmed cases. Meanwhile, we found that presence of a health technician, and of dedicated staff for data management, were associated with lower inaccuracy in reporting of clinic attendance in children aged under five years. CONCLUSION: Data completeness was high while the accuracy was low. Factors associated with data inaccuracy included high workload and the unavailability of required data collection tools. The results suggest that improvement in working conditions for clinic personnel may improve HMIS data quality. Upgrading from paper-based forms to a web-based HMIS may provide a solution for improving data accuracy and its utility for future evaluations of health interventions. Results from this study can inform the Ministry of Health and it partners on the precautions to be taken in the use of HMIS data and inform initiatives for improving its quality.

Ethical and policy issues raised by uterus transplants.

INTRODUCTION: In 2014, Brännström and colleagues reported the first human live birth following uterine transplantation (UTx). Research into this treatment for absolute uterine factor infertility has since grown with clinical trials currently taking place across centers in at least thirteen countries worldwide. SOURCES OF DATA: This review summarizes and critiques the academic literature on ethical and policy issues raised by UTx. AREAS OF AGREEMENT: There is general agreement on the importance of risk reduction and, in principle, to the sharing and maintenance of patient data on an international registry. AREAS OF CONTROVERSY: There are numerous areas of controversy ranging from whether it is ethically justified to carry out uterus transplants at all (considering the associated health risks) to how deceased donor organs for transplant should be allocated. This review focuses on three key issues: the choice between deceased and living donors, ensuring valid consent to the procedure and access to treatment. GROWING POINTS: UTx is presently a novel and rare procedure but is likely to become more commonplace in the foreseeable future, given the large number of surgical teams working on it worldwide. AREAS TIMELY FOR DEVELOPING RESEARCH: Uterus transplantation requires us to re-examine fundamental questions about the ethical and social value of gestation. If eventually extended to transgender women or even to men, it may also require us to reconceptualize what it is to be a 'father' or to be a 'mother', and the definition of these terms in law.

Headaches in Patients with Pituitary Tumors: a Clinical Conundrum.

PURPOSE OF REVIEW: Pituitary tumors account for approximately 17% of all intracranial neoplasms, with the majority being pituitary adenomas. Often, these are found incidentally during a workup for headache; however, the relationship between symptom and pathology remains unclear. The purpose of this article is to review the most recent literature on the epidemiology, pathophysiology, and management of headaches in patients with pituitary tumors. RECENT FINDINGS: The current literature is limited, with few prospective trials focusing on this question. With the exception of pituitary apoplexy, the relationship between headaches and pituitary masses remains unclear. Intervention does not always improve headache and can lead to development of new headache syndromes. Further research is needed to better elucidate the relationship between pituitary tumors and headaches. Headache alone is rarely an indication for surgical management of a pituitary adenoma.

Pushing the boundaries: Uterine transplantation and the limits of reproductive autonomy.

Over the course of recent years, various scientific advances in the realm of reproduction have changed the reproductive landscape, enhancing women's procreative rights and the choices available to them. Uterus transplants (UTx) are the latest of such medical innovations aimed at restoring fertility in women suffering from absolute uterine factor infertility, providing them with the possibility not only of conceiving a genetically related child but also of gestating their own pregnancies. This paper critically examines the primacy of reproductive liberty in the context of uterus transplantation. It questions whether and to what extent we should respect the reproductive autonomy of a woman who chooses UTx, given the significant risks that attach to the procedure and existing concerns that UTx may perpetuate potentially troubling gendered norms surrounding pregnancy and the role of women's bodies in reproduction, which may place undue reproductive pressures on women.