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Novel Pfk13 and Pfubp1 genotypes in African Plasmodium falciparum isolates exhibiting reduced susceptibility to the antimalarials artemisinin and lumefantrine.
Get PDFUNLABELLED: Recent evidence indicates that the clinical efficacy of the antimalarial combination artemether-lumefantrine may be compromised by emerging Plasmodium falciparum populations with reduced susceptibility to both components in some parts of East Africa. In vitro studies of parasites of Ugandan origin collected in the field and from imported cases in European travelers suggest that partial resistance to the artemisinin component, mediated chiefly by genetic variants in the kelch propeller domain of the pfk13 locus, is arising in concert with increased tolerance of lumefantrine. Genetic determinants of this newly recognized phenotype are unknown. Previous phenotypic and genotypic characterization of six 2022 Ugandan isolates from UK travelers identified two lines, HL2208 and HL2210, with significantly reduced in vitro susceptibility to both artemisinin and lumefantrine and variant alleles of interest at resistance-associated loci. In this study, phenotype-genotype associations are evaluated among an extended panel of 50 P. falciparum isolates collected from UK travelers since 2012. Parasites with reduced ring-stage susceptibility to artemisinin in vitro carrying newly identified or previously established genetic variants in propeller and/or non-propeller domains of pfk13 came from Kenya, Uganda, Zambia, and Namibia. Variant alleles of pfap2μ, pfcoronin, or pfubp1 were also identified in some parasite lines. Among 39 evaluable P. falciparum isolates from 15 different countries tested since 2012, six of the ten least susceptible to lumefantrine were from individuals who had traveled to Uganda. Pfk13-dependent and -independent partial artemisinin resistance has arisen in multiple African settings, providing an opportunity for the development of reduced parasite susceptibility to the partner drug lumefantrine. IMPORTANCE: In our studies of UK travelers returning from Africa with malaria, we have encountered a small number of cases where standard combination drugs have failed to completely clear the infection. In this study, we present new assessments of the effectiveness of the major drugs in use against such parasites and link these findings to the genetic profiles of the parasites causing each infection. We identify new genetic types in some of these patient samples that may provide new markers for monitoring malaria drug resistance in African communities
Identification of multiple Acinetobacter baumannii protein antigens as targets for potential immunotherapies using a novel protein microarray screening approach.
Get PDFThe World Health Organisation has identified Acinetobacter baumannii as a critical priority antimicrobial resistant (AMR) pathogen for which new therapeutics are needed. Despite this, currently there are no antibody or vaccine candidates in advanced clinical development for A. baumannii. To help address this, we designed a protein microarray approach to identify multiple A. baumannii protein antigens for further investigation as potential targets for vaccination or an antibody therapy. An 868-protein microarray was constructed containing mainly highly conserved A. baumannii proteins, and was enriched for those predicted to be surface localised and for which the corresponding gene is highly expressed during culture in ex vivo human serum. Probing the protein microarray with sera obtained from mice after non-lethal infection with multiple different A. baumannii strains identified IgG responses to 66 proteins. Four proteins (three previously poorly described outer membrane proteins and BamA, a known protective vaccine antigen selected as a positive control) were selected for further investigation. Polyclonal rabbit IgG to all four protein antigens recognised multiple clinical AMR A. baumannii strains, and for selected strains promoted opsonisation with IgG and complement, improved neutrophil phagocytosis, and increased membrane attack complex formation. Passive immunisation with polyclonal IgG to each antigen partially protected mice against A. baumannii sepsis, and a combination of polyclonal to two antigens completely protected against A. baumannii murine sepsis. Repeating passive immunisation experiments in mice depleted of complement, neutrophils or tissue macrophages demonstrated protection against systemic infection was dependent on complement and neutrophils but not macrophages. Overall, the data demonstrate that our protein microarray is a novel approach that can rapidly identify multiple new protein antigens as potential antibody targets for preventing or treating AMR bacterial infections
Understanding the Role of 'Software' in Health System Capacity for Non-Communicable Disease Response: Hypertension Care in Rural Coastal Kenya.
Get PDFResearch on health system capacity to manage non-communicable diseases (NCDs) has largely focused on 'system hardware' such as infrastructure, workforce, and commodities. However, this overlooks the critical role of 'system software' elements such as relationships, norms, and power, and the complex adaptive nature of health systems. This study aimed to explore how health system hardware and software elements interact to shape the capacity of the health system to deliver hypertension care in Kilifi County in the coastal region of Kenya. We conducted a cross-sectional qualitative study and collected data using document reviews (n=14) and in-depth interviews with purposively selected front-line health workers (FLHWs) at five health facilities and health managers at county and national levels (n=37). We applied a framework approach to data analysis, utilizing complex adaptive systems (CAS) theory as our analytic framework. Complex interactions of system hardware and software elements constrained the provision of hypertension care. Frequent medicines stockouts (hardware) stemmed from budgetary gaps, procurement delays, regulatory restrictions, and weak quantification practices (software). To mitigate medicines shortages, facilities employed adaptive responses such as inter-facility borrowing and sourcing from alternative suppliers (software). Access and continuity of care were enabled by organizational norms like dedicated hypertension clinic days (software) but undermined by inadequate consultation rooms, staff shortages (hardware) and limited training and support supervision (software). FLHWs' ideas to improve medication adherence were undermined by staff shortages (hardware) and inadequate support from facility managers (software), weakening service delivery. The application of CAS theory unpacked the hitherto underexplored aspects of health system capacity. System 'software' plays a central role in shaping health system capacity for hypertension care. Therefore, strengthening health system capacity for NCDs requires coordinated investment in both system hardware and software elements. Importantly, system strengthening interventions should consider the CAS nature of health systems to foster conditions for productive emergence
Conservative versus liberal oxygenation targets in critically ill children: the Oxy-PICU RCT.
Get PDFBACKGROUND: The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practised but is associated with harm in observational studies. OBJECTIVES: To evaluate the clinical and cost-effectiveness of a conservative oxygenation target of peripheral oxygen saturation 88-92% compared with peripheral oxygen saturation > 94% in critically ill children admitted to paediatric intensive care unit as an emergency. DESIGN AND SETTING: A pragmatic, open, multicentre, parallel-group, randomised clinical trial conducted in 15 National Health Service paediatric intensive care units and associated emergency transport services across England and Scotland. PARTICIPANTS: Children aged > 38 weeks corrected gestational age and 94% (liberal oxygenation) during invasive mechanical ventilation. MAIN OUTCOME MEASURES: Primary outcomes: duration of organ support at 30 days, with death by day 30 ranked as the worst outcome (clinical effectiveness) and incremental costs, quality-adjusted life-years and net monetary benefit at 12 months (cost-effectiveness). Secondary outcomes: incremental costs at 30 days; mortality at paediatric intensive care unit discharge, 30 days, 90 days and 12 months; time to liberation from ventilation; duration of organ support; length of paediatric intensive care unit and hospital stay; functional status at paediatric intensive care unit discharge; and health-related quality of life at 12 months. RESULTS: Two thousand and forty children were randomised between 1 September 2020 and 15 May 2022. Consent was obtained for 1872 (94%) - 939 to the conservative and 933 to the liberal oxygenation group - who were included in the primary analysis. Duration of organ support or death in the first 30 days was lower in the conservative oxygenation group [probabilistic index 0.53, 95% confidence interval 0.50 to 0.55; p = 0.04 Wilcoxon rank-sum test, adjusted odds ratio 0.84 (95% confidence interval 0.72 to 0.99)]. Both components of the composite primary outcome and secondary outcomes favoured conservative oxygenation. Average costs at 30 days strongly indicated lower costs with conservative oxygenation. Longer-term estimated incremental costs and quality-adjusted life-years were lower and net monetary benefit marginally favoured conservative oxygenation but with wide uncertainty [incremental costs -£879 (95% confidence interval -9036 to 7278); quality-adjusted life-years 0.001 (-0.010 to 0.011); net monetary benefit £894 (95% confidence interval -7290 to 9078)]. LIMITATIONS: Exclusion of two large paediatric intensive care unit populations, due to a lack of equipoise and the number of participants excluded because of not being able to obtain deferred consent. FUTURE WORK: Future work should focus on identification of the mechanisms underlying the observed benefit; trials of intermediate or lower peripheral oxygen saturation values in individuals at higher risk; and identification of individualised treatment effects in relation to oxygen therapy. CONCLUSIONS: A conservative oxygenation target resulted in a greater probability of a better outcome in terms of duration of organ support at 30 days or death. Longer-term survival and health-related quality of life were consistent with the primary outcome. While conservative oxygenation is likely to reduce costs in the short term, longer-term cost-effectiveness was surrounded with wide uncertainty. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR127547
Building Sustainable Long-Term Care Workforces in Africa and the Middle East: Evidence on Training, Wellbeing and Care Labour from the UK and Beyond
Get PDFA seminar at The American University in Cairo with research and government stakeholder
Implications for Newborn and Child Growth Classification Using INTERGROWTH-21st and WHO Child Growth Standards.
Get PDFOBJECTIVE: The aim of this study was to assess how the use of the WHO Child Growth Standards (WHO GS) and the INTERGROWTH-21st Standards (IG-21st) affect the classification and interpretation of growth trajectories. DESIGN: A secondary data analysis of an observational cohort study. SETTING: Five health facilities participating in the Low Birthweight Infant Feeding Exploration (LIFE) study in Malawi and Tanzania. POPULATION OR SAMPLE: 608 moderately low birthweight (1.5 to < 2.5 kg) infants. METHODS: Z-scores for weight-for-age (WAZ), length-for-age (LAZ), and head circumference-for-age (HCAZ) were calculated at birth using both the WHO GS and the IG-21st Newborn Size Standard (IG-21st NBS). Longitudinal trajectories were assessed over three periods (birth-6 months, 6-12 months and 12-24 months) using WHO GS and IG-21st Preterm Postnatal Standards (IG-21st PPS). Between 12 and 24 months, all infants were assessed using WHO GS. Conditional growth models were constructed to evaluate deviation from mean growth patterns within GA subgroups. MAIN OUTCOME MEASURES: WAZ, LAZ and HCAZ z-scores; prevalence of z-scores < -2, and absolute and conditional growth trajectory differences between WHO and IG-21st standards across three postnatal intervals. RESULTS: At birth, IG-21st NBS z-scores were higher than WHO GS values especially in lower GA subgroups, particularly for LAZ and HCAZ. The proportion of infants with < -2 z-scores was substantially lower with IG-21st PPS than WHO GS in preterm infants for weight (6.1% vs. 95.6%), length (14.4% vs. 89.2%) and head circumference (4.2% vs. 53.5%), respectively. From birth to 6 months, between-standard z-score differences (IG-21st PPS minus WHO GS) were largest in preterm infants (preterm overall: WAZ: +1.78, LAZ: +1.64, HCAZ: +1.80). From 6 to 12 months, differences persisted but were smaller (preterm overall: WAZ: +0.57, LAZ: +0.79, HCAZ: +0.54), while term infants showed minimal differences between the two standards. CONCLUSIONS: The application of the WHO GS alone may misclassify preterm and term infants' growth status, particularly at birth and during early infancy. The use of the IG-21st standards provides GA-specific classifications that may more closely align with expected growth patterns in term and preterm infants and could support more accurate monitoring during the first year of life. Based on these implications analyses, we recommend the use of the IG-21st NBS for cross-sectional assessment at birth, the IG-21st PPS from 27 to 64 weeks postmenstrual age, and the WHO GS for all babies thereafter
“I was given the card, but no one explained to me how to use it”: Challenges and facilitators of people with disabilities in Indonesia in accessing and using Jaminan Kesehatan Nasional (National Health Insurance)
Get PDFBackground: Jaminan Kesehatan Nasional (JKN), Indonesia’s National Health Insurance, is the world’s largest single-payer scheme. However, an estimated 35 % of people with disabilities remain not-enrolled, and many enrolled individuals continue to face high out-of-pocket spending and catastrophic health expenditure. This study aims to explore barriers and facilitators to accessing and using JKN amongst people with disabilities, with a focus on Yogyakarta Province.
Methods: We conducted a qualitative study using phenomenology approach. We interviewed 22 people with disabilities and 14 key informants (i.e., national and subnational government, organisation of people with disabilities (OPDs), and national disability representatives). Data collection and analysis were guided by the Universal Health Coverage framework.
Findings: Enrolment was facilitated by formal employment, government subsidies, outreach by social workers and support from OPDs. Key enrolment barriers included lack of identity documents, restrictive poverty criteria for subsidies, and accessibility constraints. Service use was supported by improved referral mechanisms but limited by inadequate coverage of assistive technology (AT) and rehabilitation, uneven distribution and quality of health facilities, perceived negative attitude from health workers, and physical and informational inaccessibility. Financial protection under JKN was limited by high out-of-pocket payments driven by gaps in benefit coverage, indirect costs, and underutilisation of services.
Interpretation: Improving equity for people with disabilities under JKN requires reforms that account for disability-related costs, expand benefit coverage for AT and rehabilitation, strengthen accessibility standards in health facilities, and pilot disability-inclusive reforms at sub-national level leveraging regional autonomy
Beyond diet and health: scoping umbrella review of the wider impact and influence of ultra-processed foods.
Get PDFBACKGROUND: Research on Ultra-Processed Foods (UPF) chiefly focuses on their direct health impacts, with less attention to their wider harms and benefits. This review aimed to synthesise existing evidence on the potential wider impacts of UPF and the mechanisms through which these might operate and to identify evidence gaps to inform research, policy and practice. METHODS: Comprehensive searches on PubMed, Scopus, and Web of Science were done in May 2025. All publication years and languages were considered. Eligible reviews were those that applied a systematic or structured review process. Findings were categorised by domain, level (mechanism, proximal outcome, distal impact), and type of exposure. A narrative synthesis was used to summarise patterns and identify evidence gaps. RESULTS: Of the 386 identified reviews, only six were eligible. Three broad thematic impact areas were identified: commercial, environmental, and social. Commercial mechanisms included foreign direct investment, glocalization, industry-led research, marketing, corporate playbook, and policy influence. These led to proximal impacts: improved productive capacity, increase in UPF sales, market capitalization and consolidation, income redistribution, reduced government revenue, and shifts in policymaking, ultimately reinforcing corporate power. Environmental mechanisms were relatively limited, covering energy, land, water, and pesticide/herbicide use, with proximal impacts including packaging waste, land degradation, rising greenhouse emissions, biodiversity loss, and food loss and waste. Social mechanisms and impacts were less frequently reported and mainly proximal, such as changes to culinary practices, disruption of food culture, and greater food access. None of the reviews discussed fast-food or the wider out-of-home sector. Distal impacts for all three thematic areas were rarely reported; and no review assessed effects on food system resilience. CONCLUSIONS: This review of reviews found that the production, distribution and sale of UPF potentially exert wide-ranging impacts on food systems that go beyond health. However, current reviews provide limited evidence on the environmental and social impacts of UPF. Whilst policies which reduce UPF distribution and consumption are likely to have net population benefits, further research may be needed to understand the interactions between such policies and the multi-faceted impacts of UPF. Consolidation of developing evidence in primary studies, particularly on environmental and social domains, will be essential to fill these gaps and better support robust policymaking
Feasibility and reproducibility of handheld and table-mounted optical coherence tomography in children with craniosynostosis.
Get PDFBACKGROUND: Optical coherence tomography (OCT) can be a valuable tool for non-invasively monitoring the optic nerve status in children with craniosynostosis. However, it is currently unknown whether optic nerve parameters derived from handheld OCT are comparable to those derived from table-mounted OCT, which is more widely used. This study aims to assess the feasibility and reproducibility of handheld and table-mounted OCT in craniosynostosis. METHODS: This was a cross-sectional study conducted at Great Ormond Street Hospital (GOSH), London. Twenty children aged 4-18 years with a clinical/genetic diagnosis of craniosynostosis were included. Bilateral optic nerve head OCT imaging was performed using the Spectralis (Heidelberg Engineering), followed by the handheld Envisu C2300 (Leica Microsystems). Primary outcome measures were quantitative cup, disc, rim and peripapillary parameters. Intraclass correlation coefficients (ICC) and coefficient of variation (CoV) were calculated for each quantitative OCT parameter. RESULTS: 20 children (100%) were successfully recruited. Median age at the time of OCT examination was 6 years (range: 4-16; IQR: 5-8). Ten participants (50%) were female. Seven participants (35%) had syndromic craniosynostosis and 13 participants (65%) had non-syndromic craniosynostosis. Bilateral imaging success was 100% for both machines. ICCs were good-to-excellent for all parameters, ranging from 0.81 to 1.00. The coefficient of variation was low for all parameters. CONCLUSIONS: OCT imaging of the optic nerve is feasible in school-aged children with craniosynostosis and comparable between the Spectralis and handheld Envisu OCT. This could allow comparison and pooling of data between the two machines, greatly enhancing patient care and future research
Maternal immunity drives age-related patterns of RSV disease.
Get PDFRespiratory Syncytial Virus (RSV) is a leading cause of respiratory illness in young children. While maternal antibodies offer temporary protection in early infancy, their interaction with age-dependent disease risk remains poorly quantified. The COVID-19 pandemic, which disrupted RSV transmission, provides a unique opportunity to explore these dynamics and the potential impact of maternal vaccination. We developed a compartmental model of childhood RSV disease incorporating maternal infection history, maternally-derived immunity, waning protection in infants, and age-dependent disease risk. Calibrated to Scottish surveillance data (2016-2024), the model estimated non-linear functions for maternal immunity and RSV risk by age, and projected burden from 2024 to 2028 under vaccination and no-vaccination scenarios. Following pandemic-related disruption, RSV burden shifted to older children due to delayed primary exposure. Infants who missed their typical first RSV season in 2020 experienced higher disease rates at later ages, in subsequent seasons. Maternal immunity conferred protection only when infection occurred in late pregnancy, with infant protection waning to negligible levels by six months of age. Maternal vaccination at current coverage rates was projected to reduce RSV disease cases in infants ≤ 6 months by 15.3% (95% CI: 11.9-18.5%) in 2024-25 and 18.4% (95% CI: 12.8-23.6%) in 2025-26. Our findings highlight the role of the timing and immunological mechanisms of maternally-derived immunity in shaping RSV dynamics in young children and demonstrate how disruptions-whether through pandemic-related changes or maternal vaccination-can alter age-specific disease patterns