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Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial
Background Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. Methods and findings Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. Interpretation In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. Trial registration ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.
Hypertension in Sub-Saharan Africa: Burden, Barriers and Priorities for Improving Treatment Outcomes.
The burden of hypertension is rising rapidly in sub-Saharan Africa (SSA), posing significant health challenges and economic costs that hinder national development. Despite being well-studied in clinical medicine, the detection, treatment, and control of hypertension in SSA remain inadequate. This is due to barriers across the care continuum, including individual-, provider-, and system-level obstacles within the health system. A critical issue is the lack of contextualized mechanistic research to understand the mechanisms, phenotypes, and treatment responses in native SSA populations. Current treatment approaches are often based on data from diaspora Africans, particularly African Americans. Consequently, most guidelines do not recommend angiotensin system drugs as first-line agents for Black patients, a stance that should be reconsidered given some evidence of their effectiveness in native SSA populations. Addressing these barriers requires a comprehensive, multisectoral strategy that includes both preventative and clinical measures at the population and individual levels. Preventative approaches should encompass health and nutrition education, improving food supply quality, and implementing comprehensive transportation and environmental policies. In addition, strategies should be developed to increase the detection of undiagnosed cases through enhanced screening and treatment access to those not receiving care, and revisit current treatment approaches to ensure that they are more tailored to the specific populations and settings. In conclusion, innovative strategies are needed to identify and overcome barriers to hypertension diagnosis and management. A coordinated, multisectoral approach that includes a contextualized mechanistic research agenda, as well as task shifting and task sharing, will help prevent and reduce hypertension in SSA.
Use of minimally invasive tissue sampling to determine the contribution of diarrheal diseases to under-five mortality and associated co-morbidities and co-infections in children with fatal diarrheal diseases in Africa and Bangladesh.
Achieving the Sustainable Development Goal of reducing child mortality to <25 deaths per 1000 live births by 2030 requires strategies to prevent diarrheal disease-related morbidity and mortality. Accurate etiological diagnosis is essential. This study used postmortem diagnostics to investigate the contribution of diarrhea to under-5 mortality and examine co-morbidities and co-infections in Africa and South Asia. Child Health and Mortality Prevention Surveillance (CHAMPS) generates data on child deaths through minimally invasive tissue sampling, clinical record review, and verbal autopsies. Multidisciplinary panels assign cause(s) of death using WHO International Classification of Diseases. This analysis included deaths among children aged 1-59 months enrolled from 18 December 2016-31 December 2023 across six African sites (Ethiopia, Mali, Kenya, Sierra Leone, Mozambique, South Africa) and Bangladesh. Of 1517 deaths assessed, diarrhea was in the causal pathway in 240 (15.8%). The proportion of diarrhea-related deaths was highest in Ethiopia (41.0%, 34/83), followed by Bangladesh, (30.0%, 3/10), Mozambique (21.7%, 56/258), Mali (17.5%, 18/103), Kenya (13.9%, 51/366), Sierra Leone (12.8%, 46/358), and South Africa (9.4%, 32/339). Diarrhea was underlying cause in 44.2% (106/240) of cases and immediate/antecedent cause in 58.3% (140/240), with some deaths involving multiple roles in the causal chain. When diarrhea was underlying cause, sepsis (33.0%) and lower respiratory infections (25.5%) were common downstream conditions; when an antecedent/immediate cause, leading underlying causes were malnutrition (64.3%) and HIV (13.6%). No pathogen was identified in 49.6% (119/240) of diarrhea-related deaths; among these, diarrhea was underlying cause in 42.9%. Among the 121 pathogen-attributed deaths, the most frequent were EAEC (34.7%), typical EPEC (15.7%), Shigella/EIEC (14.0%), ST-ETEC (12.4%), rotavirus (26.4%), and adenovirus (non-40/41: 19.0%; 40/41: 5.0%). These pathogens were frequently identified as co-infections. Diarrheal disease accounted for a substantial share of child deaths across CHAMPS sites. Reducing mortality will require preventing diarrhea and addressing key contributors such as malnutrition and HIV.
The epidemiology and burden of ten mental disorders in countries of the Association of Southeast Asian Nations (ASEAN), 1990–2021: findings from the Global Burden of Disease Study 2021
Background: The Association of Southeast Asian Nations (ASEAN), a geopolitical and economic network of ten member states, recognises mental disorders as a health priority; however, sparse epidemiological data hinder the development of effective strategies to reduce their prevalence and burden. We aimed to examine the prevalence, morbidity, and disease burden associated with ten mental disorders from 1990 to 2021 in the ASEAN. Methods: As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2021), we analysed estimates for depressive disorders, anxiety disorders, bipolar disorders, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder (ADHD), eating disorders, idiopathic developmental intellectual disability, and other mental disorders in ten ASEAN member states (Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Viet Nam). Case definitions were based on Diagnostic and Statistical Manual of Mental Disorders or ICD criteria. Prevalence estimates by age, sex, year, and location were derived using DisMod-MR 2.1, a Bayesian meta-regression modelling tool. Disease burden was quantified by estimating years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs). Estimates are presented with 95% uncertainty intervals (UIs). Findings: In 2021, 80·4 million (95% UI 73·8–87·2) cases of mental disorders were reported across ASEAN countries, representing a 70·0% (63·5–77·2) increase since 1990. The age-standardised prevalence of mental disorders was 11·9% (10·9–12·9) in 2021, ranging from 10·1% (9·1–11·3) in Viet Nam to 13·2% (11·6–15·3) in Malaysia, with anxiety and depressive disorders being the most common. The age-standardised prevalence of mental disorders increased by 6·5% (3·7–9·8) between 1990 and 2021. Mental disorders accounted for 11·2 million (8·5–14·3) DALYs in 2021, representing an 87·4% (81·1–94·0) increase since 1990. The 10–14 years age group had the highest disease burden attributable to mental disorders, which accounted for 16·3% (12·7–20·5) of total DALYs in this age group. The largest relative increases in the number of cases of mental disorders between 1990 and 2021 were seen in older adults (182·8% [174·9–192·1] among those aged ≥70 years), despite small relative changes in prevalence in these age groups. Interpretation: The increase in mental disorder prevalence and burden found in this study might partly reflect recent improvements in detection. However, mental disorders now rank among the top ten causes of disease burden in all ASEAN countries except Myanmar, underscoring the urgent need for a comprehensive intersectoral approach to address prevention and treatment gaps across entire populations. Funding: Gates Foundation.
Pleural fluid proteomics from patients with pleural infection shows signatures of diverse neutrophilic responses: The Oxford Pleural Infection Endotyping Study (TORPIDS-2)
BackgroundPleural infection is a complex disease with poor clinical outcomes and increasing incidence worldwide, yet its biological endotypes remain unknown.MethodsWe analysed 80 pleural fluid samples from the PILOT study, a prospective study on pleural infection, using unlabelled mass spectrometry. A total of 449 proteins were retained after filtering. Unsupervised hierarchical clustering and UMAP analyses were used to cluster samples and pathway analysis was performed to identify the biological processes. Protein signatures as identified by the pathway analysis were compared to microbiology as defined by 16S rRNA next generation sequencing. Spearman and exact Fischer's methods were used for correlation assessment.ResultsHigher neutrophil degranulation was correlated with increased glycolysis (OR=281, p<2.2E−16) and pentose phosphate activation (OR=371.45, p<2.2E−16). Samples dominated byStreptococcus pneumoniaeexhibited higher neutrophil degranulation (OR=12.08, p=0.005), glycolysis (OR=11.4, p=0.006), and pentose phosphate activity (OR=12.82, p=0.004). On the other hand, samples dominated by anaerobes and Gram-negative bacteria exhibited lower neutrophil degranulation (OR=0.15, p=0.01, glycolysis (OR=0.14, p=0.01), and pentose phosphate activity (OR=0.07, p=0.001). Increased activity of the liver and retinoid X receptors (LXR-RXR) pathway was associated with lower risk of one-year mortality (OR=0.24, p=0.04).ConclusionsThese findings suggest that pleural infection patients exhibit diverse responses of neutrophil mediated immunity, glycolysis, and pentose phosphate activation which are associated with microbiology. Therapeutic targeting of the LXR-RXR pathway with agonists is a possible treatment approach.
Emergence and transmission dynamics of the FY.4 Omicron variant in Kenya.
The recombinant FY.4 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant was first reported in Kenya in March 2023 and was the dominant circulating variant between April and July 2023. The variant was characterized by two important mutations: Y451H in the receptor-binding domain of the spike protein and P42L in open reading frame 3a. Using phylogenetics and phylodynamic approaches, we investigated the emergence and spread of FY.4 in Kenya and the rest of the world. Our findings suggest FY.4 circulated early in Kenya before its export to North America and Europe. Early circulation of FY.4 in Kenya was predominantly observed in the coastal part of the country, and the estimated time to the most recent common ancestor suggests FY.4 circulated as early as December 2022. The collected genomic and epidemiological data show that the FY.4 variant led to a large local outbreak in Kenya and resulted in localized outbreaks in Europe, North America, and Asia-Pacific. These findings underscore the importance of sustained genomic surveillance, especially in under-sampled regions, in deepening our understanding of the evolution and spread of SARS-CoV-2 variants.
GRAPEVNE - Graphical Analytical Pipeline Development Environment for Infectious Diseases.
The increase in volume and diversity of relevant data on infectious diseases and their drivers provides opportunities to generate new scientific insights that can support 'real-time' decision-making in public health across outbreak contexts and enhance pandemic preparedness. However, utilising the wide array of clinical, genomic, epidemiological, and spatial data collected globally is difficult due to differences in data preprocessing, data science capacity, and access to hardware and cloud resources. To facilitate large-scale and routine analyses of infectious disease data at the local level (i.e. without sharing data across borders), we developed GRAPEVNE (Graphical Analytical Pipeline Development Environment), a platform enabling the construction of modular pipelines designed for complex and repetitive data analysis workflows through an intuitive graphical interface. Built on the Snakemake workflow management system, GRAPEVNE streamlines the creation, execution, and sharing of analytical pipelines. Its modular approach already supports a diverse range of scientific applications, including genomic analysis, epidemiological modeling, and large-scale data processing. Each module in GRAPEVNE is a self-contained Snakemake workflow, complete with configurations, scripts, and metadata, enabling interoperability. The platform's open-source nature ensures ongoing community-driven development and scalability. GRAPEVNE empowers researchers and public health institutions by simplifying complex analytical workflows, fostering data-driven discovery, and enhancing reproducibility in computational research. Its user-driven ecosystem encourages continuous innovation in biomedical and epidemiological research but is applicable beyond that. Key use-cases include automated phylogenetic analysis of viral sequences, real-time outbreak monitoring, forecasting, and epidemiological data processing. For instance, our dengue virus pipeline demonstrates end-to-end automation from sequence retrieval to phylogeographic inference, leveraging established bioinformatics tools which can be deployed to any geographical context. For more details, see documentation at: https://grapevne.readthedocs.io.
Deploying Metagenomics to Characterize Microbial Pathogens During Outbreak of Acute Febrile Illness Among Children in Tanzania.
Outbreaks of infectious diseases contribute significantly to morbidity and mortality in resource-limited settings, yet the capacity to identify their etiology remains limited. We aimed to characterize microbes and antimicrobial resistance (AMR) genes in Tanzanian children affected by an acute febrile illness (AFI) outbreak using metagenomic next-generation sequencing (mNGS). A cross-sectional study was conducted on archived blood samples from children who presented with AFI between 2018 and 2019. Total nucleic acids were extracted from 200 µL of blood, and complementary DNA (cDNA), along with enriched pathogenic DNA, was sequenced using the Illumina MiSeq platform. mNGS data were analyzed using CZ-ID Illumina mNGS bioinformatics pipeline v7.0. Results were obtained from 25 participants (mean age: 11.6 years; SD ± 5), of whom 36% had a moderate to high-grade fever. The following five potential microbial causes of AFI were identified: Escherichia coli (n = 19), Paraclostridium bifermentans (n = 2), Pegivirus C (n = 2), Shigella flexneri (n = 1) and Pseudomonas fluorescens (n = 1), with E. coli being the most prevalent. Twelve AMR genes were detected, including mdtC, acrF, mdtF, and emrB. E. coli harbored most of the AMR genes previously associated with resistance to commonly used antibiotics. mNGS offers a promising complementary approach to conventional diagnostics for identifying pathogens and AMR profiles in vulnerable populations.
Efficacy of artemisinin-based combination therapy (ACT) in people living with HIV (PLHIV) diagnosed with uncomplicated Plasmodium falciparum malaria in Africa: a WWARN systematic review.
BackgroundAfrica bears the highest double burden of HIV and malaria worldwide. In 2023, an estimated 25.9 million people were living with HIV (PLHIV), and 246 million malaria cases were diagnosed in Africa. Malaria patients co-infected with HIV are considered at a higher risk of failing malaria treatment, according to the World Health Organization (WHO) guidelines. This systematic literature review aims to assess the treatment outcomes following artemisinin-based combination therapy (ACT) in PLHIV.MethodsThe literature search was conducted up to April 2022 in the following databases: MEDLINE, EMBASE, Web of Science, Cochrane Central, WHO Global Index Medicus, Clinicaltrials.gov, and the WorldWide Antimalarial Resistance Network (WWARN) Clinical Trial Library. Studies describing any malaria treatment outcomes or anti-malarial drug exposure in PLHIV treated for uncomplicated Plasmodium falciparum malaria infection were eligible for inclusion.ResultsA total of 26 articles describing 19 studies conducted between 2003 and 2017 in six countries were included in this review; it represented 2850 malaria episodes in PLHIV across various transmission settings. The most studied artemisinin-based combination was artemether-lumefantrine (in 16 studies). PLHIV were treated with various antiretroviral therapy (ART) regimens, namely efavirenz (EFV), nevirapine (NVP), atazanavir-ritonavir (ATVr), lopinavir-ritonavir (LPV/r), and/or on prophylaxis with trimethoprim-sulfamethoxazole (TS), or were untreated (in 3 studies). There was no evidence of an increased risk of recrudescence in PLHIV compared to those without HIV. When treated with artemether-lumefantrine, PLHIV receiving LPV/r had a lower risk of malaria recurrence compared to PLHIV on NVP-based or EFV-based ART, or those without HIV. LPV/r increased lumefantrine exposure and EFV-treated patients had a reduced exposure to both artemether and lumefantrine; NVP reduced artemether exposure only.ConclusionsLimited data on ACT outcomes or drug exposure in PLHIV in Africa remains a reality to date, and the effect of antivirals appears inconsistent in the literature. Considering the heterogeneity in study designs, these review's findings support conducting an individual patient data meta-analysis to explore the impact of antiretroviral therapy on anti-malarial treatment.Trial registrationThe protocol for the original search was published on PROSPERO with registration number CRD42018089860.
The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data
Abstract Background The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. Methods We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. Results We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7–15.7) for AL and 15.2 days (95% CI 12.8–18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7–18.6 days for AL and 10.2–18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission. Conclusion Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.