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Simon Leedham has been one of this year's recepients of Cancer Research UK's "Future Leaders" prizes.
Safety and efficacy of single-dose primaquine to interrupt Plasmodium falciparum malaria transmission in children compared with adults: a systematic review and individual patient data meta-analysis.
BackgroundAdding a single dose of primaquine to artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria can reduce the transmission of Plasmodium falciparum and could limit the spread of artemisinin partial resistance, including in Africa, where the disease burden is greatest. We aimed to compare the safety and efficacy of single-dose primaquine plus ACT between young children (aged <5 years) and older children (aged 5 years to <15 years) and adults (aged ≥15 years), and between low and moderate-to-high transmission areas.MethodsFor this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, OpenGrey.eu, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform, from database inception to April 3, 2024, with no language restrictions. We included prospective studies on efficacy against falciparum malaria that enrolled at least one child younger than 15 years and involved a study group given a single dose of primaquine (≤0·75 mg/kg) plus ACT. Studies involving mass drug administration, healthy volunteers, or patients with severe malaria or mixed (with non-falciparum) infections were excluded. For inclusion in the efficacy analysis, data on transmission potential (as determined by gametocytaemia, infectivity, or both) at enrolment and follow-up (day 3, day 7, or day 14) were required; the safety analysis required data on haemoglobin concentrations or haematocrit values at enrolment and at one or more follow-up visits by day 7, any data on adverse events, or both. After independent screening of the search results by two reviewers, the investigators of eligible studies were invited to contribute individual patient data. We quantified day 7 gametocyte carriage, probability of infecting a mosquito, decreases (>25%) in haemoglobin concentration associated with anaemia, and adverse events until day 28 using regression analyses, with random study-site intercepts to account for clustered data. These analyses were registered with PROSPERO, CRD42021279363 (safety) and CRD42021279369 (efficacy).FindingsOf 5697 records identified by the search, 30 studies were eligible for analysis. Of these, individual patient data were shared for 23 studies, including 6056 patients from 16 countries: 1171 (19·3%) young children (aged <5 years), 2827 (46·7%) older children (aged 5 years to <15 years), and 2058 (34·0%) adults (aged ≥15 years). Adding a single low dose of primaquine (0·2-0·25 mg/kg) to ACTs reduced day 7 gametocyte positivity (adjusted odds ratio [aOR] 0·34, 95% CI 0·22-0·52; p<0·001) and infectivity to mosquitoes over time (aOR per day 0·02, 0·01-0·07, p<0·001). No difference was found in the effect of single low-dose primaquine both on gametocyte positivity in young children compared with older children (1·08, 0·52-2·23; p=0·84) and adults (0·50, 0·20-1·25; p=0·14) and between low-transmission and moderate-to-high transmission settings (1·07, 0·46-2·52; p=0·86), and on infectivity to mosquitoes in young children compared with older children (1·36, 0·07-27·71; p=0·84) and adults (0·31, 0·01-8·84; p=0·50) and between low-transmission and moderate-to-high transmission settings (0·18, 0·01-2·95; p=0·23). Gametocyte clearance was also similar for different ACTs (dihydroartemisinin-piperaquine vs artemether-lumefantrine) when combined with a primaquine target dose of 0·25 mg/kg (1·56, 0·65-3·79; p=0·32 at day 7). However, patients given a primaquine dose of less than 0·2 mg/kg with dihydroartemisinin-piperaquine were more likely to have gametocytaemia than those treated with artemether-lumefantrine (5·68, 1·38-23·48; p=0·016 at day 7). There was no increase in anaemia-associated declines in haemoglobin concentration (>25%) at a primaquine dose of 0·25 mg/kg, regardless of age group, transmission setting, and glucose-6-phosphate dehydrogenase status. The risks of adverse events of grade 2 or higher and of serious adverse events were similar between primaquine and no-primaquine groups, including in young children.InterpretationRegardless of malaria transmission intensity and age group, a single dose of 0·25 mg/kg primaquine is safe and efficacious for reducing P falciparum transmission. These findings underscore the need for primaquine formulations suitable for young children, and also provide supportive evidence to expand the use of single low-dose primaquine in regions with a moderate-to-high transmission rate that are threatened by artemisinin partial resistance.FundingThe EU and the Bill & Melinda Gates Foundation.
Putting health facilities on the map: a renewed call to create geolocated, comprehensive, updated, openly licensed dataset of health facilities in sub-Saharan African countries.
BackgroundHealthcare service provision, planning, and management depend on the availability of a geolocated, up-to-date, comprehensive health facility database (HFDB) to adequately meet a population's healthcare needs. HFDBs are an integral component of national health system infrastructure forming the basis of efficient health service delivery, planning, surveillance, and ensuring equitable resource distribution, response to epidemics and outbreaks, as well as for research. Despite the value of HFDBs, their availability remains a challenge in sub-Saharan Africa (SSA). Many SSA countries face challenges in creating a HFDB; existing facility lists are incomplete, lack geographical coordinates, or contain outdated information on facility designation, service availability, or capacity. Even in countries with a HFDB, it is often not available open-access to health system stakeholders. Consequently, multiple national and subnational parallel efforts attempt to construct HFDBs, resulting in duplication and lack of governmental input, use, and validation.Main bodyIn this paper, we advocate for a harmonized SSA-wide HFDB. To achieve this, we elaborate on the steps required and challenges to overcome. We provide an overview of the minimum attributes of a HFDB and discuss past and current efforts to collate HFDBs at the country and regional (SSA) levels. We contend that a complete HFDB should include administrative units, geographic coordinates of facilities, attributes of service availability and capacity, facilities from both public and private sectors, be updated regularly, and be available to health system stakeholders through an open access policy. We provide historical and recent examples while looking at key issues and challenges, such as privacy, legitimacy, resources, and leadership, which must be considered to achieve such HFDBs.ConclusionA harmonized HFDB for all SSA countries will facilitate efficient healthcare planning and service provision. A continental, cross-border effort will further support planning during natural disasters, conflicts, and migration. This is only achievable if there is a regional commitment from countries and health system stakeholders to open data sharing. This SSA-wide HFDB should be a government-led initiative with contributions from all stakeholders, ensuring no one is left behind in the pursuit of improved health service provision and universal health coverage.
Pediatric Outcomes Data Collection Instrument is a Useful Patient-Reported Outcome Measure for Physical Function in Children with Osteogenesis Imperfecta.
PurposePatient-reported outcome measures (PROMs) are increasingly recognized as valuable endpoints in clinical trials. The Pediatric Outcomes Data Collection Instrument (PODCI) is a PROM utilized in children with musculoskeletal disorders. We evaluated the validity and reliability of PODCI in children with osteogenesis imperfecta (OI).MethodsPhysical functioning and psychological well-being were assessed using PODCI in a large cohort of children enrolled in a multicenter study conducted by the Brittle Bone Disorders Consortium. Physical function scores were correlated with a validated, observer-rated scale, Brief Assessment of Motor Function (BAMF), and with psychological well-being scores. We calculated sample sizes required to detect clinically meaningful differences in physical function.ResultsFour hundred seventeen children with OI types I, III, and IV were enrolled. Physical function scores in OI type III were significantly lower than those in OI types I and IV. There were no significant differences in psychological well-being. PODCI physical function scores showed moderate-to-strong correlation with BAMF. The Global Functioning Scale, a composite of physical function, did not consistently correlate with psychological well-being.ConclusionPODCI can be a reliable measure of physical functioning in children with OI and offers valuable information about patient-reported health status and new ways to examine the utility of interventions in this population.
Disease-specific B cell clones are shared between patients with Crohn's disease.
B cells have important functions in gut homeostasis, and dysregulated B cell populations are frequently observed in patients with inflammatory bowel diseases, including both ulcerative colitis (UC) and Crohn's disease (CD). How these B cell perturbations contribute to disease remains largely unknown. Here, we perform deep sequencing of the B cell receptor (BCR) repertoire in four cohorts of patients with CD, together with healthy controls and patients with UC. We identify BCR clones that are shared between patients with CD but not found in healthy individuals nor in patients with UC, indicating CD-associated B cell immune responses. Shared clones are present in the inflamed gut mucosa, draining intestinal lymph nodes and blood, suggesting the presence of common CD-associated antigens that drive B cell responses in CD patients.
Infant-level and child-level predictors of mortality in low-resource settings: the WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort
Background: Despite impressive reductions in overall global child mortality, the rate of decline has slowed during the past decade. Current guidelines for the care of paediatric patients in low-resource settings mostly focus on broad clinical syndromes or undernutrition rather than children's individual contextualised risk. We aimed to identify readily assessable child-level characteristics that can predict mortality risk in a range of community and health-care settings in high-burden settings. Methods: The WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort (WHO-CMRS) included pooled data from individual children enrolled in observational or randomised controlled trials in low-income and middle-income countries. The criteria for inclusion of a dataset were documentation of age, weight, vital status, and date of death, and at least two observations per participant younger than 60 months. To calculate odds ratios, we built generalised linear mixed effects regression (glmer) models with each child and each study as random intercepts and time interval as the offset. In all analyses, the outcome was defined as death within the respective observation period of the child. From the glmer models, we predicted absolute risk of death per child-month associated with risk exposures separately and combined with anthropometry according to the following age groups: 0–5 months, 6–11 months, 12–23 months, and 24–59 months. Studies were grouped according to population types studied: the general population, populations selected based on anthropometric criteria, and populations selected based on the presence of illness. Findings: We analysed pooled data from WHO-CMRS, including 75 287 children from 33 studies done in 17 countries between Jan 1, 2001, and Dec 31, 2021. During a total of 69 085 child-years of follow-up, 2805 (3·7%) children died. Age younger than 24 months, low anthropometry, preterm birth, low birthweight, and absence of breastfeeding (either was breastfeeding not offered or an underlying illness interfered with breastfeeding practices) were each associated with increased mortality: risks declined with increasing age. The highest absolute mortality risk was among the youngest children (age 0−5 months), with a weight-for-age Z score of less than −3 (ie, a predicted absolute risk of 11·0 [95% CI 6·2−19·5] per 1000 child-months in general population studies). Risks were additive: underlying risk exposures such as low birthweight and preterm birth added to the mortality risks in children with anthropometric deficit. For example, children aged 0−5 months with a weight-for-age Z score of less than −3 and a history of preterm birth had a predicted absolute mortality risk of 40·1 (95% CI 22·0−72·1). However, overall mortality and the association between child-level characteristics and mortality differed according to the type of study population and child age. Interpretation: Risk assessments combining individual child-level characteristics including anthropometry can enable programmes to identify children at high and lower risk of mortality and, thereafter, differentiate care accordingly. Such a strategy could reduce mortality and optimise health system efficiency and effectiveness. Funding: US Agency for International Development. Translations: For the Spanish and French translations of the abstract see Supplementary Materials section.
Mepolizumab to Prevent Exacerbations of COPD with an Eosinophilic Phenotype.
BackgroundMepolizumab is a humanized monoclonal antibody that targets interleukin-5, a cytokine that plays a central role in eosinophilic inflammation, which is present in 20 to 40% of patients with chronic obstructive pulmonary disease (COPD).MethodsIn a phase 3, double-blind, randomized, placebo-controlled trial, patients with COPD, a history of exacerbations, and a blood eosinophil count of at least 300 cells per microliter who were receiving triple inhaled therapy were assigned, in a 1:1 ratio, to receive mepolizumab (at a dose of 100 mg) or placebo subcutaneously every 4 weeks for 52 to 104 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Secondary end points, tested hierarchically to control for multiplicity, were moderate or severe exacerbation as assessed in a time-to-first-event analysis, measures of health-related quality of life and symptoms, and the annualized rate of exacerbations leading to an emergency department visit, hospitalization, or both.ResultsOf the 804 patients who underwent randomization, 403 were assigned to receive mepolizumab and 401 to receive placebo. The annualized rate of moderate or severe exacerbations was significantly lower with mepolizumab than with placebo (0.80 vs. 1.01 events per year; rate ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.01). The time to the first moderate or severe exacerbation was longer with mepolizumab than with placebo (Kaplan-Meier median time to the first moderate or severe exacerbation, 419 vs. 321 days; hazard ratio, 0.77; 95% CI, 0.64 to 0.93; P = 0.009). Between-group differences in measures of health-related quality of life and symptoms were not significant; thus, no statistical inferences regarding subsequent secondary end points in the statistical testing hierarchy were made. The incidence of adverse events was similar in the mepolizumab and placebo groups.ConclusionsTreatment with mepolizumab led to a lower annualized rate of moderate or severe exacerbations when added to background triple inhaled therapy among patients with COPD and an eosinophilic phenotype. (Funded by GSK; MATINEE ClinicalTrials.gov number, NCT04133909.).
Wrangling Real-World Data: Optimizing Clinical Research Through Factor Selection with LASSO Regression.
Data-driven approaches to clinical research are necessary for understanding and effectively treating infectious diseases. However, challenges such as issues with data validity, lack of collaboration, and difficult-to-treat infectious diseases (e.g., those that are rare or newly emerging) hinder research. Prioritizing innovative methods to facilitate the continued use of data generated during routine clinical care for research, but in an organized, accelerated, and shared manner, is crucial. This study investigates the potential of CURE ID, an open-source platform to accelerate drug-repurposing research for difficult-to-treat diseases, with COVID-19 as a use case. Data from eight US health systems were analyzed using least absolute shrinkage and selection operator (LASSO) regression to identify key predictors of 28-day all-cause mortality in COVID-19 patients, including demographics, comorbidities, treatments, and laboratory measurements captured during the first two days of hospitalization. Key findings indicate that age, laboratory measures, severity of illness indicators, oxygen support administration, and comorbidities significantly influenced all-cause 28-day mortality, aligning with previous studies. This work underscores the value of collaborative repositories like CURE ID in providing robust datasets for prognostic research and the importance of factor selection in identifying key variables, helping to streamline future research and drug-repurposing efforts.
Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.
Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.
ERS Congress 2024: highlights from the Thoracic Oncology Assembly.
#ERSCongress 2024: highlights from the Thoracic Oncology Assembly (@oncology_ERS) https://bit.ly/42vNDmp.
Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK
ObjectiveThe UK government’s response to the COVID-19 pandemic included a ‘test, trace and isolate’ strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services.DesignScoping review.Search strategyPubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA).Data extraction and synthesisData were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme.ResultsThis study included 40 sources, including 17 from projects that informed UKHSA’s decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing.ConclusionsUniversal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.
Risk analysis for outpatient experimental infection as a pathway for affordable RSV vaccine development.
Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae, rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.