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Identifying modifiable factors and their joint associations on late-onset schizophrenia risk in the UK Biobank: a prospective exposure-wide association study.
Get PDFBACKGROUND: One in four cases of schizophrenia begins in late life, resulting in high unemployment and reduced life expectancy. However, knowledge of the modifiable risk factors for late-onset schizophrenia and their combined effects is limited.
AIMS: To identify modifiable risk factors for late-onset schizophrenia and estimate their joint disease risk effects.
METHODS: This prospective cohort study using UK Biobank data included 482 708 participants without late-onset schizophrenia at baseline, followed up for a mean of 14.36 years. We conducted an exposure-wide association study of 232 potentially modifiable factors linked to late-onset schizophrenia risk. Late-onset schizophrenia is diagnosed using ICD-10 (International Classification of Diseases, 10th Revision) criteria. Cox proportional hazard models identified significant factors across six domains: lifestyle, environment, medical history, physical measures, mental health and socioeconomic status (SES). Domain-specific weighted scores were calculated from Cox model coefficients and stratified into tertiles (favourable, intermediate, unfavourable) for risk assessment. Population attributable fractions (PAFs) quantified prevention potential.
RESULTS: During follow-up, 1276 participants developed late-onset schizophrenia. We identified 109 significant potentially modifiable factors, with intellectual disability (HR 35.15, 95% CI 11.23 to 110.09), manic episode (HR 33.14, 95% CI 21.16 to 51.90) and bipolar affective disorder (HR 32.91, 95% CI 27.07 to 40.01) showing the strongest risks, while higher household income (>£100 000: HR 0.14, 95% CI 0.09 to 0.22), regular friends/family visits (HR 0.23, 95% CI 0.18 to 0.28) and higher hand grip strength (HR 0.35, 95% CI 0.29 to 0.44) showed the strongest protection. PAF estimations indicated that shifting individuals from unfavourable to intermediate/favourable risk profiles could prevent 71.3% (95% CI 71.2% to 71.4%) of late-onset schizophrenia cases, mainly from mental health (25.1%, 95% CI 25.0% to 25.2%), medical history (13.6%, 95% CI 13.5% to 13.7%) and SES domain (11.2%, 95% CI 11.1% to 11.3%); shifting individuals from intermediate/unfavourable risk profiles to favourable could prevent 89.2% of cases.
CONCLUSIONS: A substantial proportion of late-onset schizophrenia risk appears modifiable, with mental health and medical history as key contributors. Physical health and natural environment exposure provided protective benefits. Findings supported integrating clinical interventions and structural changes addressing socioeconomic and environmental factors to reduce late-onset schizophrenia burden
Typhi Mykrobe: fast and accurate lineage identification and antimicrobial resistance genotyping directly from sequence reads for the typhoid fever agent Salmonella Typhi.
Get PDFBACKGROUND: Typhoid fever results from systemic infection with Salmonella enterica serovar Typhi (Typhi) and causes 10 million illnesses annually. Disease control relies on prevention (water, sanitation, and hygiene interventions or vaccination) and effective antimicrobial treatment. Antimicrobial-resistant (AMR) Typhi lineages have emerged and become established in many parts of the world. Knowledge of local pathogen populations informed by genomic surveillance, including of lineages (defined by the GenoTyphi scheme) and AMR determinants, is increasingly used to inform local treatment guidelines and to inform vaccination strategy. Current tools for genotyping Typhi require multiple read alignment or assembly steps and have not been validated for analysis of data generated with Oxford Nanopore Technologies (ONT) long-read sequencing devices. Here, we introduce Typhi Mykrobe, a command line software tool for rapid genotyping of Typhi lineages, AMR determinants, and plasmid replicons direct from sequencing reads.
RESULTS: We validated Typhi Mykrobe lineage genotyping by comparison with the current standard read mapping-based approach and demonstrated 99.8% concordance across nearly 13,000 genomes sequenced with Illumina platforms. For the few isolates with discordant calls, we show that Typhi Mykrobe results are better supported by the evidence from raw sequence read data than the results generated using the mapping-based approach. We also demonstrate 99.9% concordance for detection of AMR determinants compared with the current standard assembly-based approach, with similar results for plasmid marker detection. Typhi Mykrobe predicts clinical resistance categorization (S/I/R) for eight drug classes, and we show strong agreement with phenotypic categorizations generated from reference laboratory minimum inhibitory concentration (MIC) data for n = 1572 Illumina-sequenced isolates (> 99% agreement within one doubling dilution). We show strong concordance (> 96% for genotype and > 98% for AMR and plasmid) between calls made from ONT reads and those made from Illumina reads for isolates sequenced on both platforms (n = 93 genomes). Typhi Mykrobe takes less than a minute per sample and is available at https://github.com/typhoidgenomics/genotyphi.
CONCLUSIONS: Typhi Mykrobe provides rapid and sensitive genotyping of Typhi genomes direct from Illumina and ONT reads, although lower accuracy was observed for R9 ONT data. It demonstrated accurate assignment of GenoTyphi lineage, detection of AMR determinants and prediction of corresponding AMR phenotypes, and identification of plasmid replicons
Tailoring malaria control interventions to suit local context: codesign of perennial malaria chemoprevention (PMC) programmes through the Plus Project.
Get PDFWith global malaria cases on the rise, the WHO has placed increased emphasis on National Malaria Programmes to tailor interventions to country and programmatic needs. This paper presents the Plus Project's experience of applying a codesign approach to design country-specific models of perennial malaria chemoprevention (PMC), a chemoprevention intervention aimed at reducing morbidity and mortality due to malaria and anaemia in children. Codesign workshops were held in each of the project's focus countries (Benin, Cameroon, Côte d'Ivoire and Mozambique) with the primary objective of designing the country-specific PMC model. The three-and-a-half-day workshops were adapted to each country's context and included stakeholders from national and subnational malaria, immunisation and child health programmes, as well as national and international development partners and research institutions. The meetings were iterative and collaborative, harnessing a variety of participatory methods including journey mapping and surveys to reach group consensus on the PMC models best suited to each country's specific context. The Plus Project's codesign approach resulted in four different PMC strategies, with a range from four to eight contact points and different codelivery interventions, each taking advantage of country-specific health system delivery platforms, operational logistics and political contexts. This collaborative, codesign process also helped gather additional programmatic insights to aid PMC implementation while providing an opportunity to increase stakeholder buy-in. With an emphasis on collaborative decision-making, the learnings collected through these workshops can be applied to a variety of programmatic applications, extending beyond malaria
Whole-Genome Sequencing Analysis of Drug-Resistant Salmonella Typhi in Children.
Get PDFUNLABELLED: Typhoid fever, caused by Salmonella enterica subsp. enterica serovar Typhi (S. typhi), remains a major public health concern, particularly in low-resource settings with poor sanitation. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains have significantly complicated treatment, especially in vulnerable pediatric populations. This study aimed to characterize the genetic profiles of drug resistance in MDR and XDR S. typhi isolates from pediatric patients.
METHODS: A cross-sectional study was conducted on 800 blood samples from pediatric typhoid patients. S. typhi isolates were identified using the BacT/ALERT 3D system, followed by culture on MacConkey and blood agar. Antimicrobial susceptibility was assessed using the disk diffusion method according to CLSI 2022 guidelines. Whole-genome sequencing (WGS) was performed on 29 isolates using Illumina MiSeq technology, and resistance genes and mutations were analyzed.
RESULTS: Antimicrobial susceptibility testing revealed that 68 (48.57%) of S. typhi isolates were XDR and 61 (43.57%) were MDR, exhibiting widespread resistance to ciprofloxacin, ampicillin, chloramphenicol, ceftriaxone, and co-trimoxazole. WGS identified key resistance genes across all 29 isolates, including bla_CTX-M-15, bla_TEM-1B, qnrS1, aac(6')-Iaa, catA1, dfraA7, sul1, qacEΔ1, and the gyrA-S83F mutation. Notably, gyrA-S83F and qnrS1 were detected in all isolates and strongly correlated with ciprofloxacin resistance. Virulence genes were consistently present in all isolates, indicating a high pathogenic potential. The IncY plasmid, found in four (14%) isolates, was linked to resistance against third-generation cephalosporins, including ceftriaxone.
CONCLUSION: This study underscores the alarming prevalence of MDR and XDR S. typhi isolates among pediatric patients, driven by resistance genes such as bla_CTX-M-15, bla_TEM-1B, and gyrA-S83F. These findings highlight the urgent need for targeted therapeutic strategies and robust surveillance systems to combat the growing threat of drug-resistant typhoid fever
Trichiasis with and without tarsal conjunctival scarring: A multi-country observational study.
Get PDFThere has been discussion regarding the definition of the clinical sign trachomatous trichiasis (TT) for the purposes of determining elimination of trachoma as a public health problem, and whether the definition should include the presence of trachomatous scarring (TS). A multi-country observational study was conducted in Ethiopia, Uganda and Nigeria to assess whether TS grading by field graders using the WHO simplified system in trachoma surveys are comparable with expert grading of tarsal conjunctival scarring (TCS) using a detailed system. The primary outcome was the proportion of eyes graded as "No TS" in the surveys but with TCS from expert photographic grading (the negative predictive value, NPV). In Ethiopia, Uganda and Nigeria, 545 (438 trichiasis cases and 107 comparisons), 256 (156 trichiasis cases and 100 comparisons), and 468 (352 trichiasis cases and 116 comparisons) participants, respectively, were enrolled. In Ethiopia, among 111 trichiatic eyes graded "No TS" in the surveys, 103 (92.8%) had TCS in expert photo grading, NPV 7.2% (95% CI 3.2%-13.7%). In Uganda, among 28 trichiatic eyes graded "No TS" in the surveys, 19 (67.9%) had TCS in expert photo grading, NPV 32.1% (95% CI 15.9%-52.4%). In Nigeria, among 111 trichiatic eyes graded "No TS" in the surveys, 100 (90.1%) had TCS in expert photo grading, NPV 9.9% (95% CI 5.0%-17.0%). Across settings, among eyes misdiagnosed as "No TS" in the survey, 174/250 (69.6%) had extensive TCS (patches of scarring occupying ≥1/3 of the upper tarsal conjunctiva). Trichiatic eyes with TCS had more severe entropion, trichiasis, conjunctival inflammation, and corneal opacity than those without TCS. In all three settings, including TS to define a trichiasis "trachomatous" in a survey could result in the underestimation of the burden of TT. However, TCS can be effectively used to determine TT severity and management
Modelling the relative contribution of infection, routine vaccination and supplementary immunisation activities to measles seroconversion in Kenyan Children.
Get PDFBACKGROUND: Measles outbreaks continue to cause a large burden of disease in Africa including Kenya. We used information from regular serological surveys in Kilifi Health and Demographic Surveillance System (KHDSS) in combination with mathematical modelling to estimate the relative contribution of the vaccination programme to current measles immunity.
METHODS: We developed a static birth cohort model to track the proportion of children who are either measles naïve or seroconverted due to natural infection or vaccination through first dose of measles-containing vaccine (MCV1), the second dose (MCV2), or supplementary immunisation activities (SIAs). We fitted the model to biennial paediatric serological survey and case notification data and used vaccination coverage estimates from the KHDSS to estimate the relative contributions of vaccination and infection to measles immunity in Kilifi.
RESULTS: We estimated that between 2009 and 2021, 60% (95%CI 55-64%) of measles seroconversion in Kilifi was attributable to MCV1, with MCV2 contributing 1.0% (95%CI 0.9-1.1%) since its introduction. Natural infection and SIAs accounted for 24% (95%CI 17-31%) and 16% (95%CI 14-19%), respectively. A hypothetical 10% increase in MCV1 coverage increased the seroconversion attributed to MCV1 to 67% (95%CI 63-71%), with concurrent reductions in seroconversion from natural infection and SIAs to 13% (95%CI 9-18%) and 10% (95%CI 9-12%), respectively. Importantly, this same 10% increase in MCV1, if administered promptly at 9 months, could potentially reduce seroconversion from natural infection further from 24% to 11% (95%CI 07-15%) and reliance on SIAs from 16% to 8% (95% CI 7-10%).
CONCLUSION: Optimizing routine coverage timing and uptake is crucial for reducing SIAs dependence and measles susceptibility. A 10% MCV1 coverage increase could have halved susceptibility and lessened SIA demand, highlighting the potential of minor improvements in coverage to alleviate measles and reduce costly SIAs
Physicochemical profiling of Bambara groundnut (Vigna subterranea L.) reveals variation in cooking quality relevant to breeding programs.
Get PDFUnderstanding seed physicochemical properties allows breeders to select traits that contribute to desirable cooking characteristics (texture, taste, and nutritional content). Breeding programs can optimize resources by focusing on traits directly related to cooking time and quality. A total of 156 Bambara groundnut (BGN) recombinant inbred lines were analysed for physicochemical properties [hydration capacity (HC), hydration index (HI), swelling index (SI), pH, texture and cooking time (CT)], proximate and nutrient compositions. Analysis of variance showed significant differences (p < 0.05) in variables measured. Shortest CT (40 min) was recorded in S19/Ankpa4-100-87, while S19/Ankpa4-106-92 has the longest CT (147 min). Cooking time was negatively correlated with HC (r = - 0.42), HI (r = - 0.45) and swelling capacity (SC) (r = - 0.55). Neutral Detergent Fibre (NDF) and protein content showed significant differences between raw and cooked BGN (p < 0.05). Cooking significantly increased protein, fat, NDF, Zn, and Cu; however, cooking also significantly reduced Fe and total mineral (ash). Texture, CT and electrical conductivity (EC) of the genotypes varied significantly, which aided classification into five groups, namely: A (soft-cooking genotypes), B (slightly soft-cooking genotypes), C (slightly hard-cooking genotypes), D (moderately hard-cooking genotypes) and E (hard-cooking genotypes). A total of 14 genotypes (DodR, BURKINA, ANKPA 4, TIGD, NAV 4, S19/Ankpa4-100-87 IITA686/LunT-292-233, IITA686/LunT, S19/Ankpa4-130-1, S19/Ankpa4-50-43, S19/Ankpa4-92, IITA686/LunT-403-314, S19/Ankpa4-141-121 and S19/Ankpa4-234-197) were grouped as soft-cooking. These soft-cooking genotypes could be available as genetic stock to confirm this attribute or reanalysis by breeders
Performance of the Self-Controlled Case Series With Active Comparators for Drug Safety Signal Detection Using the French Administrative Healthcare Database (SNDS).
Get PDFBACKGROUND: The self controlled case series (SCCS) is one of the most promising methods for drug safety signal detection using real world data (RWD), and incorporating active comparators could potentially improve its performance by addressing time-varying confounding by indication. The 'Système National des Données de Santé' (SNDS) is a large nationwide administrative claims database, which has not been used extensively for drug safety signal detection. While comparable in size to other RWD sources, it is unclear to what extent the performance of SCCS correlates with that in other sources. OBJECTIVES: This study aims to evaluate the performance of the SCCS with and without active comparators for signal detection in the French administrative healthcare database SNDS. METHODS: We applied the SCCS to macrolide and fluoroquinolone antibiotics, using amoxicillin as the active comparator. Amoxicillin was chosen as an active comparator with similar indications. In total, 7 drugs and 30 outcomes from all organ classes were selected. We developed a reference set of 104 positive controls and 58 negative controls, using a taxonomy framework to ensure the selected drug outcome pairs are theoretically well suited to the SCCS design. The observation period lasted 2 years, with a 30-day risk window after each dispensing. Diagnostic performance was measured using sensitivity and specificity with respect to the product labels. RESULTS: The sensitivity and specificity of the SCCS without active comparator were 0.89 and 0.43, respectively, when limited to pairs with satisfactory power. Specificity increased up to 0.91 with active comparators; however, sensitivity decreased to 0.52. CONCLUSIONS: The SNDS is a useful data source for signal detection, particularly for outcomes captured in hospitals. Using a carefully designed reference set of drug-outcome pairs well suited to the study design, the SCCS achieved satisfactory performance for signal detection in this database. In this study, the use of active comparators improved overall performance at the expense of greatly reduced sensitivity
Barriers and facilitators to quality mental health care for forcibly displaced children and adolescents in the WHO European Region: protocol for a scoping review.
Get PDFINTRODUCTION: Forcibly displaced children and adolescents in the WHO European Region have high mental health needs, yet few manage to access mental health services and even fewer receive high-quality care. Addressing this gap is crucial, as inadequate mental health support has profound and lasting negative effects on individuals, families and communities. This scoping review aims to identify and synthesise the available evidence on the barriers and facilitators to quality mental healthcare for forcibly displaced children and adolescents in the WHO European Region.
METHODS AND ANALYSIS: Quantitative, qualitative and mixed-method studies that examine barriers and facilitators of quality mental healthcare for forcibly displaced children and adolescents in the WHO European Region will be included. Eligible participants include forcibly displaced children and adolescents, mental healthcare providers, policymakers and humanitarian actors in the mental health and psychosocial support field. We will adhere to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews) guidelines. A comprehensive search of databases, including Embase, Medline, PsycINFO, Scopus and Web of Science, will be conducted. We will systematically search for relevant studies published between January 2004 and December 2024. At least two reviewers will independently screen titles, abstracts and full texts. Data extraction will involve systematically charting relevant information from included studies. We will use the WHO Quality Standards for Child and Adolescent Mental Health Services as an analytical lens to map the evidence. Our study will provide a comprehensive overview of the barriers and facilitators to quality mental healthcare for forcibly displaced children and adolescents, and identify knowledge gaps and areas for potential quality improvement.
ETHICS AND DISSEMINATION: Ethical approval will not be required since this study will retrieve data from already published research and no new data will be collected. The results of this study will be published in a peer-reviewed journal and presented at international conferences in order to disseminate to academic and non-academic stakeholders such as non-governmental organisations, government bodies and community organisations involved in mental healthcare for forcibly displaced persons.
REVIEW REGISTRATION DETAILS: https://doi.org/10.17605/OSF.IO/AK74F
Ethnographic study of Buruli ulcer wound management practices in a traditional therapeutic setting in Ghana.
Get PDFINTRODUCTION: Buruli ulcer (BU) is a skin-related neglected tropical disease (skin NTD) considered to be a disease of the poor. This study explored BU wound management in a traditional therapeutic setting in the Atwima Mponua District of Ghana and described the social interactions observed.
METHOD: Ethnographic data about the practices of a herbalist renowned for his experience in treating BU wounds were obtained using direct observations, photography, and informal conversations.
RESULTS: At this therapeutic setting, we observed wounds cleaned and dressed using gloves, gauze, antiseptic solutions, non-sterile scissors, and a petrol and bark preparation supported with prayers. Most clients of the traditional healer indicated that they experienced their BU as a stubborn wound that needed powerful medicine to cure it, and believed the wounds might have supernatural origins. Key reasons clients provided for seeking care at the traditional therapeutic setting included trust in the traditional healer, his practices, respectful care, a friendly and non-stigmatising environment, low-cost and flexible payment options, and people's opinions about the potency of traditional plant medicines.
DISCUSSION: Our findings suggest that the traditional healer enjoyed substantial public legitimacy from his clients due to his perceived interest in helping affected individuals achieve cures using culturally and financially appropriate ways to manage wounds. However, we also observed the use of non-sterile procedures and unregulated preparations, which may be potentially deleterious. The willingness of the traditional healer to collaborate with the formal healthcare system to meet the health needs of people with wounds could form the basis for future collaborative approaches between the two healthcare systems to address inequities regarding clients' access to care