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Journal articleImada S, Khawaled S, Shin H, et al., 2024,
Short-term post-fast refeeding enhances intestinal stemness via polyamines.
, Nature, Vol: 633, Pages: 895-904For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans1-6. However, how fasting and post-fast refeeding affect adult stem cells and tumour formation has yet to be explored in depth. Here we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation; post-fast refeeding augments the regenerative capacity of Lgr5+ ISCs, and loss of the tumour suppressor gene Apc in post-fast-refed ISCs leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum-fed states, demonstrating that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust mTORC1 induction in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production or protein synthesis abrogates the regenerative or tumorigenic effects of post-fast refeeding. Given our findings, fast-refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity.
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Journal articleWilliams LR, Emary KRW, Phillips DJ, et al., 2024,
Implementation and adherence to regular asymptomatic testing in a COVID-19 vaccine trial.
, Vaccine, Vol: 42BACKGROUND: For pathogens which cause infections that present asymptomatically, evaluating vaccine efficacy (VE) against asymptomatic infection is important for understanding a vaccine's potential epidemiological impact. Regular testing for subclinical infections is a potentially valuable strategy but its success hinges on participant adherence and minimising false positives. This paper describes the implementation and adherence to weekly testing in a COVID-19 vaccine trial. METHODS: COV002 was a phase 2/3 trial assessing the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Asymptomatic infections were detected using weekly self-administered swabs for RT-PCR testing. We analysed adherence using mixed-effects regression models and estimated the probability of true and false positive asymptomatic infections using estimates of adherence and testing characteristics. FINDINGS: 356,551 tests were self-administered by 10,811 participants during the 13-month follow-up. Median adherence was 75.0% (IQR 42·6-90·9), which translated to a 74·5% (IQR 50·9-78·8) probability of detecting a positive asymptomatic infection during the swabbing period, and between 21 and 96 false positives during VE evaluation. The odds of returning a swab declined by 8% per week and further after testing positive and unblinding. Adherence was higher in older age groups, females and non-healthcare workers. INTERPRETATION: The COV002 trial demonstrated the feasibility of running a long-term regular asymptomatic testing strategy. This information could be valuable for designing future phase III vaccine trials in which infection is an outcome. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, AstraZeneca.
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Journal articleGrassly N, Shaw AG, Owusu M, 2024,
Global wastewater surveillance for pathogens with pandemic potential: opportunities and challenges
, The Lancet Microbe, ISSN: 2666-5247Wastewater surveillance holds great promise as a sensitive method to detect spillover of zoonotic infections and early pandemic emergence, thereby informing risk mitigation and public health response. Known viruses with pandemic potential are shed in human stool or urine, or both, and the experiences with SARS-CoV-2, monkeypox virus, and Zika virus highlight the feasibility of community-based wastewater surveillance for pandemic viruses that have different transmission routes. We reviewed human shedding and wastewater surveillance data for prototype viruses representing viral families of concern to estimate the likely sensitivity of wastewater surveillance compared with that of clinical surveillance. We examined how data on wastewater surveillance detection, together with viral genetic sequences and animal faecal biomarkers, could be used to identify spillover infections or early human transmission and adaptation. The opportunities and challenges associated with global wastewater surveillance for the prevention of pandemics are described in this Personal View, focusing on low-income and middle-income countries, where the risk of pandemic emergence is the highest. We propose a research and public health agenda to ensure an equitable and sustainable solution to these challenges.
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Journal articleRhodes J, 2024,
Genomic epidemiology of Candida auris introduction and outbreaks in the United Kingdom
, npj Antimicrobials and Resistance, ISSN: 2731-8745Candida auris is a globally emerged fungal pathogen causing nosocomial invasive infections. Here, we use cutting-edge genomic approaches to elucidate the temporal and geographic epidemiology of drug-resistant C. auris within the UK. We analysed a representative sample of over 200 isolates from multiple UK hospitals to assess the number and timings of C. auris introductions, and infer subsequent patterns of inter- and intra-hospital transmission of azole drug resistant isolates. We identify at least one introduction from Clade I and two from Clade III into the UK, and observe temporal and geographical evidence for multiple transmission events of antifungal drug resistant isolates between hospitals and identified local within-hospital patient-to-patient transmission events. Our study confirms outbreaks of drug resistant C. auris are linked and that transmission amongst patients occurs, explaining local hospital outbreaks, and demonstrating a need for improved epidemiological surveillance of C. auris to protect patients and healthcare services.
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Journal articleSmith DRM, Turner J, Fahr P, et al., 2024,
Health and economic impacts of Lassa vaccination campaigns in West Africa.
, Nat MedLassa fever is a zoonotic disease identified by the World Health Organization (WHO) as having pandemic potential. This study estimates the health-economic burden of Lassa fever throughout West Africa and projects impacts of a series of vaccination campaigns. We also model the emergence of 'Lassa-X'-a hypothetical pandemic Lassa virus variant-and project impacts of achieving 100 Days Mission vaccination targets. Our model predicted 2.7 million (95% uncertainty interval: 2.1-3.4 million) Lassa virus infections annually, resulting over 10 years in 2.0 million (793,800-3.9 million) disability-adjusted life years (DALYs). The most effective vaccination strategy was a population-wide preventive campaign primarily targeting WHO-classified 'endemic' districts. Under conservative vaccine efficacy assumptions, this campaign averted $20.1 million ($8.2-$39.0 million) in lost DALY value and $128.2 million ($67.2-$231.9 million) in societal costs (2021 international dollars ($)). Reactive vaccination in response to local outbreaks averted just one-tenth the health-economic burden of preventive campaigns. In the event of Lassa-X emerging, spreading throughout West Africa and causing approximately 1.2 million DALYs within 2 years, 100 Days Mission vaccination averted 22% of DALYs given a vaccine 70% effective against disease and 74% of DALYs given a vaccine 70% effective against both infection and disease. These findings suggest how vaccination could alleviate Lassa fever's burden and assist in pandemic preparedness.
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Journal articleWalters M, Korenromp E, Yakusik A, et al., 2024,
Guidance for triangulating data and estimates of HIV prevalence among pregnant women and coverage of PMTCT using the Spectrum AIDS Impact Module
, JAIDS: Journal of Acquired Immune Deficiency Syndromes, ISSN: 1525-4135Background: Most countries use the Spectrum AIDS Impact Module (Spectrum-AIM), antenatal care routine HIV testing, and antiretroviral treatment data to estimate HIV prevalence among pregnant women. Non-representative programme data may lead to inaccurate estimates HIV prevalence and treatment coverage for pregnant women. Setting: 154 countries and subnational locations across 126 countries.Methods: Using 2023 UNAIDS HIV estimates, we calculated three ratios: (1) HIV prevalence among pregnant women to all women 15-49y (prevalence), (2) ART coverage before pregnancy to women 15-49y ART coverage (ART pre-pregnancy), and (3) ART coverage at delivery to women 15-49y ART coverage (PMTCT coverage). We developed an algorithm to identify and adjust inconsistent results within regional ranges in Spectrum-AIM, illustrated using Burkina Faso’s estimates.Results: In 2022, the mean regional ratio of prevalence among pregnant women to all women ranged from 0.68 to 0.95. ART coverage pre-pregnancy ranged by region from 0.40 to 1.22 times ART coverage among all women. Mean regional PMTCT coverage ratios ranged from 0.85 to 1.51. The prevalence ratio in Burkina Faso was 1.59, above the typical range 0.62-1.04 in western and central Africa. Antenatal clinics reported more PMTCT recipients than estimated HIV-positive pregnant women from 2015 to 2019. We adjusted inputted PMTCT programme data to enable consistency of HIV prevalence among pregnant women from programmatic routine HIV testing at antenatal clinics with values typical for Western and central Africa. Conclusion: These ratios offer Spectrum-AIM users a tool to gauge the consistency of their HIV prevalence and treatment coverage estimates among pregnant women with other countries in the region.
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Journal articleHuong NHT, Toan ND, Khanh TH, et al., 2024,
A cost of illness analysis of children with encephalitis presenting to a major hospital in Vietnam
, American Journal of Tropical Medicine and Hygiene, ISSN: 0002-9637Encephalitis is a significant global health problem, especially in children. Knowledge of its economic burden is essential for policymakers in prioritizing the development and implementation of interventions but remains limited. An observational study was prospectively conducted at a major children’s hospital in Ho Chi Minh City, Vietnam, from 2020 to 2022. Data on direct medical costs, direct non-medical costs and productivity costs were collected alongside demographic information, clinical features, diagnosis, severity, and outcomes of study participants. This was used to undertake a cost of illness analysis from a societal perspective. Data were collected from a total of 164 pediatric patients. The median cost of illness was estimated at US$1,859 (interquartile range (IQR), US$1,273–US$3,128). The direct costs were the main cost driver, accounting for 83.9% of the total cost of illness (US$1,560 (IQR: US$975–US$2,460)). The productivity costs accounted for a median of US$275 (IQR, US$154–US$474). The cost of illness was higher in more severe patients, patients with sequelae, patients with morbidities, and ventilated patients. Most of direct medical costs attributed to hospitalization and resulted in out-of-pocket payments from the patient’s family (30.2%, US$316). The results showed that the cost of illness of encephalitis in children is considerable and will be useful for policymakers in prioritizing resources for the development and implementation of intervention strategies to reduce the burden of pediatric encephalitis.
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Journal articleLiu C, Cheng S, Shi M, et al., 2024,
IMITATE: Clinical Prior Guided Hierarchical Vision-Language Pre-training.
, IEEE Trans Med Imaging, Vol: PPIn the field of medical Vision-Language Pretraining (VLP), significant efforts have been devoted to deriving text and image features from both clinical reports and associated medical images. However, most existing methods may have overlooked the opportunity in leveraging the inherent hierarchical structure of clinical reports, which are generally split into 'findings' for descriptive content and 'impressions' for conclusive observation. Instead of utilizing this rich, structured format, current medical VLP approaches often simplify the report into either a unified entity or fragmented tokens. In this work, we propose a novel clinical prior guided VLP framework named IMITATE to learn the structure information from medical reports with hierarchical vision-language alignment. The framework derives multi-level visual features from the chest X-ray (CXR) images and separately aligns these features with the descriptive and the conclusive text encoded in the hierarchical medical report. Furthermore, a new clinical-informed contrastive loss is introduced for cross-modal learning, which accounts for clinical prior knowledge in formulating sample correlations in contrastive learning. The proposed model, IMITATE, outperforms baseline VLP methods across six different datasets, spanning five medical imaging downstream tasks. Comprehensive experimental results highlight the advantages of integrating the hierarchical structure of medical reports for vision-language alignment.
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Journal articleIsaiah S, Westerhuis JA, Loots DT, et al., 2024,
The diagnostic potential of urine in paediatric patients undergoing initial treatment for tuberculous meningitis
, Scientific Reports, Vol: 14, ISSN: 2045-2322Tuberculous meningitis (TBM)—the extrapulmonary form of tuberculosis, is the most severe complication associated with tuberculosis, particularly in infants and children. The gold standard for the diagnosis of TBM requires cerebrospinal fluid (CSF) through lumbar puncture—an invasive sample collection method, and currently available CSF assays are often not sufficient for a definitive TBM diagnosis. Urine is metabolite-rich and relatively unexplored in terms of its potential to diagnose neuroinfectious diseases. We used an untargeted proton magnetic resonance (1H-NMR) metabolomics approach to compare the urine from 32 patients with TBM (stratified into stages 1, 2 and 3) against that from 39 controls in a South African paediatric cohort. Significant spectral bins had to satisfy three of our four strict cut-off quantitative statistical criteria. Five significant biological metabolites were identified—1-methylnicotinamide, 3-hydroxyisovaleric acid, 5-aminolevulinic acid, N-acetylglutamine and methanol—which had no correlation with medication metabolites. ROC analysis revealed that methanol lacked diagnostic sensitivity, but the other four metabolites showed good diagnostic potential. Furthermore, we compared mild (stage 1) TBM and severe (stages 2 and 3) TBM, and our multivariate metabolic model could successfully classify severe but not mild TBM. Our results show that urine can potentially be used to diagnose severe TBM.
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Journal articleMengistu B, Liyew EF, Chernet M, et al., 2024,
Soil-transmitted helminth (STH) infections in the Wolaita zone in Southern Ethiopia: mid-stage evaluation of the Geshiyaro project and progress towards the interruption of transmission.
, Parasit Vectors, Vol: 17BACKGROUND: This paper documents changes in the prevalence and intensity of soil-transmitted helminth (STH) infections in the Geshiyaro project in the Wolaita zone of Southern Ethiopia. METHODS: The Geshiyaro project comprises three intervention arms. Arm 1 is subdivided into the Arm 1 pilot (one district) and Arm 1 (four other districts), both receiving integrated community-wide mass drug administration MDA (cMDA) with intensive water, sanitation, and hygiene (WaSH) interventions. Arm 2 involves 18 districts with cMDA interventions plus the existing government-led One WaSH program, while Arm 3 serves as a control with school-based MDA (sMDA) interventions plus the existing government-led One WaSH program in three districts. The study is designed as a cohort investigation over time, with the establishment of longitudinal sentinel sites where infection levels are assessed annually. A total of 45 longitudinal parasitological surveillance sentinel sites are being used across all three intervention arms to monitor STH prevalence and intensity of infection. From each of the 45 sentinel sites, 150 individuals were randomly selected, stratified by age and gender. The t-test and analysis of variance (ANOVA) were employed to compare infection prevalence and intensity across the three study arms over time. RESULTS: The prevalence of STH decreased significantly from 34.5% (30.6%, 38.5%) in 2019 to 10.6% (8.3%, 13.4%) in 2022/2023 (df = 1, P < 0.0001) in the Arm 1 pilot, from 27.4% (25.2%, 29.7%) in 2020 to 5.5% (4.4%, 6.7%) in 2023 (df = 1, P < 0.0001) in Arm 1, from 23% (21.3%, 24.8%) in 2020 to 4.5% (3.7%, 5.3%) in 2023 (df = 1, P < 0.001) in Arm 2, and from 49.6% (47.4%, 51.7%) in 2021 to 26.1% in 2023 (df = 1, P < 0.0001) in Arm 3. The relative reduction in the prevalence of any STH was the highest in the arms employing cMDA, namely Arm 2, with a decr
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