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Asymptomatic malaria: a hidden reservoir for the transmission and circulation of artemisinin partial-resistant Plasmodium falciparum in Tanzania.
Get PDFAsymptomatic malaria infections contribute substantially to silent transmission, but the prevalence of artemisinin resistance (ART-R) markers in these carriers remains poorly understood. A community-based cross-sectional study was conducted in Tanzania from December 2022 to July 2023, enrolling 3,489 participants from high-transmission regions of Geita and Kigoma and a low-transmission region of Arusha. Four villages per region were randomly selected, and venous blood samples were tested using rapid diagnostic tests, microscopy, and qPCR, revealing overall positivity rate of 24.4%, 15.8%, and 26.2%, respectively, which indicate a significant proportion of submicroscopic infections. Among the 802 isolates successfully sequenced for pfk13 and pfmdr1, 24 (3.0%) isolates from high-transmission areas carried validated pfk13 partial-resistance markers Y493H (0.2%), R561H (2.0%), and A675V (0.7%), while all low-transmission isolates were wild-type. All isolates retained the pfmdr1 N86 codon, and the NFD haplotype associated with reduced susceptibility to lumefantrine was detected in 48.1% and 48.4% of isolates in high- and low-transmission areas, respectively. Mutations were more frequent in children under five and in females. Artemether-lumefantrine (AL, 64.7%) was the most commonly used antimalarial in high-transmission areas, whereas sulfadoxine-pyrimethamine (SP, 75.9%) predominated in low-transmission areas. Higher AL use correlated with increased pfmdr1 mutation prevalence in high-transmission regions, while NFD detection in low-transmission areas may reflect gene flow from high-transmission settings. These findings demonstrate that asymptomatic carriers are a substantial hidden reservoir of ART-resistant parasites, emphasizing the importance of integrating molecular surveillance and demographic information on asymptomatic infections into malaria control programs to detect emerging resistance and guide targeted interventions in Tanzania
Exploring geographic differences in IgE response through network and manifold analyses.
Get PDFBACKGROUND: Component-resolved diagnostics allow detailed assessment of IgE sensitization to multiple allergenic molecules (component-specific IgEs, or c-sIgEs) and may be useful for asthma diagnosis. However, to effectively use component-resolved diagnostics across diverse settings, it is crucial to account for geographic differences. OBJECTIVE: We investigated spatial determinants of c-sIgE networks to facilitate development of diagnostic algorithms applicable globally. METHODS: We used multiplex component-resolved diagnostics array to measure c-sIgE to 112 proteins in an international collaboration of several studies: WASP (World Asthma Phenotypes; United Kingdom, New Zealand, Brazil, Ecuador, and Uganda), U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes; 7 European countries), and MAAS (Manchester Asthma and Allergy Study, a UK population-based birth cohort). Hierarchical clustering on low-dimensional representation of co-occurrence networks ascertained sensitization and c-sigE clusters across populations. Cross-country comparisons focused on a common subset of 18 c-sIgEs. We investigated sensitization networks across regions in relation to asthma severity. RESULTS: Sensitization profiles shared similarities across regions. For 18 c-sIgEs shared across study populations, the response structure enabled differentiation between different geographic areas and study designs, revealing 3 clusters: (1) Uganda, Ecuador, and Brazil, (2) U-BIOPRED children and adults, and (3) New Zealand, United Kingdom, and MAAS. Spectral clustering identified differences between clusters. We observed constant, almost parallel shifts between severe and nonsevere asthma in each country. CONCLUSIONS: Patterns of c-sIgE response reflect geographic location and study design. However, despite geographic differences in c-sIgE networks, there is a remarkably consistent shift between networks of subjects with nonsevere and severe asthma
Lower limb amputation in incident dialysis patients in England: incidence, outcomes, and inter-centre variation from a national registry study
Get PDFBackground: Lower limb amputation (LLA) is a devastating complication in dialysis patients, often related to diabetes and peripheral vascular disease. National data on LLA incidence, variation, and outcomes in England are limited.
Methods: A retrospective cohort study conducted using linked data from the UK Renal Registry (UKRR) and Hospital Episode Statistics (HES) for incident dialysis patients in England (2003–2017). Cumulative incidence plots assessed LLA rates across three patient subgroups- Primary renal disease (PRD) Diabetes, Diabetes as comorbidity and no-diabetes. Fine-Gray competing risk models identified independent risk factors for LLA. One-year mortality following LLA was presented as Kaplan-Meier curves and analysed using age- and sex-adjusted standardised mortality rates (SMR).
Results: Among 69 701 incident dialysis patients, 9.1% with PRD diabetes underwent LLA within three years, versus 2.6% with diabetes as comorbidity and 0.6% without diabetes. Risk factors for LLA included diabetes (sHR 9.3 for PRD diabetes, sHR 3.6 for diabetes as comorbidity), peripheral vascular disease (sHR 2.11), prior amputation (sHR 2.19), ischaemic heart disease and white ethnicity. Major amputation rates declined over time, while minor amputation rates remained stable. Significant inter-centre variation was observed after adjustment. One-year mortality after LLA exceeded 40% in all subgroups. SMRs were highest in the PRD diabetes group compared to the general population (34.7), but highest in the diabetes as comorbidity group compared to the dialysis population (5.31).
Conclusion: Incident dialysis patients, particularly with PRD diabetes, face high LLA risk and very poor survival after amputation. Persistent inter-centre variation suggests scope for national audit, standardised foot care, and preventive strategies
Developing a Global Eye Health Research Agenda: protocol for a priority setting process
Get PDFBackground Vision impairment remains a major global health issue, affecting an estimated 1.1 billion people in 2020, 90% of whom have preventable or treatable conditions. The magnitude of eye health conditions continues to rise, disproportionately affecting low-income and middle-income countries. The World Health Assembly has called for the development of a global research agenda for eye health, with the aim of highlighting the evidence required to inform national policy and service delivery decisions, ultimately contributing to increased access to high-quality eye care services worldwide. Objective This protocol outlines the methodology for a global research priority setting process that will inform the development of the World Health Organization (WHO) Global Eye Health Research Agenda. The Agenda aims to highlight the evidence required to inform national policy and service delivery decisions, ultimately contributing to increased access to high-quality eye care services worldwide. The goal is to identify and prioritize research questions across key eye health themes, with an emphasis on health systems and policy research, innovation, and equity. Methods A structured, multi-phase process will be used, including the development of Theory of Change frameworks to guide question formulation, wide engagement with stakeholders through open consultation, ensuring regional balance and diversity, consolidation and mapping of research questions, and a two-stage prioritization process involving ranking and scoring of potential research questions based on predefined criteria. The framework for this project has been informed by the WHO guidance for research priority-setting exercisees, and will be reported in accordance with the REporting guideline for PRIority SEtting of Health Research (REPRISE). Impact The resulting Research Agenda is intended to galvanize better-focused and coordinated action and funding to close the evidence gaps, leading to the delivery of effective and equitable eye care. Outputs will be disseminated through WHO and peer-reviewed publications, with recommendations for implementation and future evaluation.</ns3:p
The incidence and antimicrobial resistance of Shigella-attributable diarrhoea in young children in low-income and middle-income countries from the multicountry Enterics for Global Health (EFGH) Shigella Surveillance Study: a prospective, facility-based hybrid surveillance study.
Get PDFBACKGROUND: Shigella is a leading cause of dysentery and watery diarrhoea in low-income and middle-income countries (LMICs) with consequences beyond diarrhoea for children younger than 5 years, including environmental enteric dysfunction and linear growth impairment. We established the burden, serotypes, and antibiotic resistance patterns of Shigella-diarrhoea among young children in LMICs to inform vaccine trial planning and eventual vaccine introduction in high-burden countries. METHODS: The Enterics for Global Health (EFGH) study was a prospective, facility-based hybrid surveillance study conducted from June 21, 2022, to Aug 25, 2024, across seven countries: Kenya, Malawi, Mali, The Gambia, Bangladesh, Pakistan, and Peru. Children aged 6-35 months presenting at selected health-care facilities with acute diarrhoea (three or more abnormally loose or watery stools in the last 24-h period lasting less than 14 days) were enrolled. We calculated care-seeking adjusted incidence estimates from contemporaneous population enumeration and by ascertaining health-care seeking patterns from a health-care utilisation survey conducted in children aged 6-35 months in the health-facility catchment area. We deemed Shigella to be attributable if detected by microbiological culture or by quantitative PCR (qPCR) using an ipaH quantification cycle threshold of less than or equal to 29·5 from rectal swabs. We determined antimicrobial resistance to commonly used antibiotics by disc diffusion. We calculated adjusted incidence for all participating country sites and by key subgroups of interest (age, diarrhoea severity, study month, Shigella species, and serotype). FINDINGS: Of the 9476 enrolled children, 4316 (45·5%) were female and 5160 (54·5%) were male, 881 (9·3%) had Shigella detected by culture and 1870 (20·0%) by qPCR (among 9354 children with qPCR results available). Shigella flexneri dominated (497 [56·2%] of 881 by culture and 756 [39·4%] of 1870 by qPCR), with S flexneri 2a and S flexneri 6 being the most common serotypes by both methods. Across study sites, the adjusted incidences of Shigella-attributed diarrhoea by culture ranged from 2·7 per 100 child-years (95% CI 1·9-4·3) in Malawi to 11·7 per 100 child-years (8·3-24·2) in Peru and by qPCR ranged from 3·5 per 100 child-years (2·5-5·4) in Malawi to 26·9 per 100 child-years (19·0-40·9) in The Gambia. Shigella isolates exhibited resistance to WHO-recommended antibiotics for dysentery with variability across sites: ciprofloxacin (37·2% [range 14·0-74·0]), azithromycin (22·1% [1·2-34·2]), and ceftriaxone (16·2% [0·0-64·4]). INTERPRETATION: Shigella-attributed diarrhoea is common among young children in LMICs, with its escalating antimicrobial resistance posing a serious threat to global public health. The leading quadrivalent vaccine candidates cover the majority of Shigella serotypes identified in this study. These data affirm both the need for Shigella vaccines and readiness of EFGH sites to conduct rigorous vaccine trials. FUNDING: The Gates Foundation
Integrated community-based versus facility-based care for people with HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-COMM): an open-label, multicountry, cluster-randomised trial.
Get PDFBACKGROUND: In sub-Saharan Africa, the burden of diabetes and hypertension is high, alongside a high prevalence of HIV. Whether these conditions can be managed in an integrated way in the community is unknown. We aim to compare integrated community-based care with integrated facility-based care for people with HIV, diabetes, and hypertension in Tanzania and Uganda. METHODS: This open-label, multicountry, cluster-randomised trial was conducted in 14 primary care facilities across Tanzania and Uganda. Adults aged 18 years or older with a diagnosis of HIV, type 2 diabetes, or hypertension (or a combination); receiving regular care at the health facility for at least 6 months; considered clinically stable; living within the catchment area and planning to stay for at least 6 months; and willing to receive care in the community were enrolled. In each facility, patients were grouped into clusters of 8-14. Each group was randomly assigned (1:1) using an online data management system, to integrated facility care or community care. In facility care, participants shared the same registration and waiting areas, were managed by the same physicians and health-care workers, and used the same pharmacy and laboratory services. In community care, a nurse and a trained lay worker supported the groups at focal points in the community with groups meeting once per month. Follow-up was 12 months. The first coprimary endpoint was a composite of blood pressure or fasting glucose control (defined as blood pressure <140/90 mm Hg in participants with hypertension alone, fasting glucose <7·0 mmol/L in those with diabetes alone, or both indicators controlled in those with both conditions) and the second was plasma viral load suppression for participants with HIV alone (defined as <1000 copies per mL or undetectable viral load). Both endpoints were assessed in the intention-to-treat population. Generalised estimating equation models accounted for clustering. This trial was registered with the ISRCTN registry, ISRCTN15319595 (completed). FINDINGS: Between Jan 30 and Oct 6, 2023, 2940 patients with HIV, diabetes, or hypertension (or a combination of these conditions) who lived close enough together to be placed into a group were identified as having appointments to attend at the participating facilities. 765 (26·0%) patients were not screened and 2175 (74·0%) were screened for eligibility. 203 (9·3%) patients were ineligible, four (0·2%) did not consent, and 104 (4·8%) could not be grouped into viable clusters. 1864 (63·4%) patients were assigned into 124 groups, and groups were randomised (62 to community care and 62 to facility care). There were more females than males (1302 [76·6%] of 1700 vs 398 [23·4%]). Among those with diabetes or hypertension (or both), 38 (6·3%) of 602 in the community care group versus 43 (7·1%) of 609 in the facility care group were excluded, with nine (3·7%) of 242 versus ten (4·0%) of 247 excluded among participants with HIV. The composite of blood pressure or fasting glucose control did not significantly differ between the two groups in participants with hypertension or diabetes (or both; 317 [55·2%] of 574 in the community care group vs 304 [53·2%] of 571 in the facility care group; adjusted risk difference 1·80 [95% CI -4·52 to 8·12]; p=0·58), whereas most participants with HIV alone reached viral suppression (227 [99·1%] of 229 vs 229 (98·7%) of 232; adjusted risk difference 0·44 [-1·12 to 1·99]; pnon-inferiority<0·0001). There were seven deaths in each study group. INTERPRETATION: In sub-Saharan Africa, integrated community care could reach a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. FUNDING: National Institute for Health and Care Research
Cause-specific mortality transition among women of reproductive age with special reference to maternal mortality: the Magu health and demographic surveillance system, Tanzania, 1995–2022
Get PDFBackground: Limited population data exist on mortality and causes of death among women of reproductive age, including maternal mortality.
Objective: To present trends from 1995 to 2022 in mortality, cause of death, maternal mortality ratio and place of death from the rural Magu health and demographic surveillance site in north-west Tanzania.
Methods: Data on residency, fertility, and verbal autopsy were analysed to compute trends in all-cause and cause-specific mortality for women 15–49 years, using InSilicoVA, a Bayesian probabilistic model. Maternal mortality was estimated for three periods: 1995–2002, 2005–2011 and 2015–2022. We described place of death and healthcare utilization leading up to death by calendar time and broad cause of death.
Results: All-cause mortality among women 15–49 declined from a peak of 9.0 deaths per 1000 person-years in the late 1990s to 3.5 in 2020. HIV/TB contributed 61% of this reduction. During 1995–2022, infectious diseases were the leading cause (54%), followed by NCD (29%). Maternal mortality declined but stagnated from approximately 2010 at 281 per 100,000 live births in 2015–2022 and remained a leading cause of death (12%). Comparing 2009–2015 and 2016–2022, more deaths occurred in health facilities (37.3%–45.9%), and more women sought care during terminal illness or maternity (85%–93%).
Conclusion: Despite a major reduction in all-cause mortality among women 15–49 years, mainly due to decreased HIV/AIDS deaths, infectious diseases remain the leading cause alongside a much-increased share of NCD. While maternal mortality levels have decreased, its share of total deaths has remained unchanged compared to 25 years ago
Effect of the time of day for vaccination on the immune response to Ebola Virus Disease vaccines: A modeling study from PREVAC randomized trial.
Get PDFBACKGROUND: Emerging evidence suggests that the time in the day of vaccination may influence post-vaccination immunogenicity. The main objective of this study was to assess the association between the time of vaccination and the anti-EBOV GP1,2 IgG antibody response at 12 mo following vaccination against Ebola virus disease (EVD). METHODOLOGY/PRINCIPAL FINDINGS: This study utilized data from a randomized, double-blind, placebo-controlled international phase 2b clinical trial (PREVAC) evaluating the immunogenicity of three vaccination strategies against Ebola virus disease (rVSVΔG-ZEBOV-GP one and two doses, and Ad26.ZEBOV/MVA-BN-Filo) in 1,859 healthy Western Africans. In the overall population, we measured a statistically significant association between the time of day of first vaccination and anti-Ebola virus immunoglobulin G levels at 12 mo (p = 0.02). The magnitude of this association was small, participants vaccinated at 1600 h were estimated to have 1-7% lower antibody levels at 12 mo compared to those vaccinated at 1000 h. CONCLUSIONS/SIGNIFICANCE: An effect of the time of first vaccination on the antibody responses was found but remains modest and unlikely to impact the EVD vaccine effectiveness. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration: NCT02876328
Compliance With England's Calorie Labeling Regulations 3 Years After Policy Implementation.
Get PDFWe examined compliance with England's calorie labeling regulations, which require large out-of-home food businesses to display the calories of prepared food and drink at the point of choice, such as menus. By using website data from large out-of-home food businesses, we found that all businesses (n = 77) provided calorie labeling somewhere on their websites. However, fewer than half (48%; n = 37) did not provide calorie labels on the default menu (ie, the first menu that a consumer is likely to see). Compliance with the policy's implementation guidance was greatest for the label's position (81%; n = 62) and lowest for prominent formatting (40%; n = 31), while 71% (n = 55) of businesses provided the statement of daily calorie needs. We observed differences among types of out-of-home food businesses, but we did not test them because of the small sample size. Our results suggest imperfect adherence to England's calorie labeling regulations, thus undermining the policy's impact. As the policy's review approaches, policy makers should consider strategies for ensuring compliance
Plasmodium berghei High-Throughput (PbHiT): a CRISPR-Cas9 System to Study Genes at Scale.
Get PDFGenetic modification is essential for understanding parasite biology, yet it remains challenging in Plasmodium. This is partially due to the parasite's low genetic tractability and reliance on homologous recombination, since the parasites lack the canonical non-homologous end-joining pathway. Existing approaches, such as the PlasmoGEM project, enable genome-wide knockouts but remain limited in coverage and flexibility. Here, we present the Plasmodium berghei high-throughput (PbHiT) system, a scalable CRISPR-Cas9 protocol for efficient genome editing in rodent malaria parasites. The PbHiT method uses a single cloning step to generate vectors in which a guide RNA (gRNA) is physically linked to short (100 bp) homology arms, enabling precise integration at the target locus upon transfection. The gRNA also serves as a unique barcode, allowing pooled vector transfections and identification of mutants by downstream gRNA sequencing. The PbHiT system reliably recapitulates known mutant growth phenotypes and supports both knockout and tagging strategies. This protocol provides a reproducible and scalable tool for genome editing in P. berghei, enabling both targeted functional studies and high-throughput genetic screens. Additionally, we provide an online resource covering the entire P. berghei protein-coding genome and describe a step-by-step pooled ligation approach for large-scale vector production. Key features • PbHiT provides a high-throughput CRISPR-Cas9 genome editing platform optimised for Plasmodium berghei experimental infections in rodents. • This protocol enables efficient and reproducible generation of knockout and tagged parasite lines using short homology arms. • This protocol is supported by a free online resource for P. berghei gene construct design and requires basic knowledge of cloning. • Transfection of Plasmodium berghei requires experience in handling mice/rats, an ethical permit, and an animal facility