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Comprehensive analysis of stroke epidemiology in Vietnam: Insights from GBD 1990–2019 and RES-Q 2017–2023
Background: Stroke is a significant health burden in Vietnam, with substantial impacts on mortality, morbidity, and healthcare resources. An up-to-date report on stroke epidemiology and associated risk factors in Vietnam was missing. Method: We analyzed the data published in the Global Burden of Disease (GBD) 2019, in combination with the first-time analysis of the Registry of Stroke Care Quality Improvement (RES-Q) initiative in Vietnam from 2017 to 2023. Findings: Comparative analysis globally revealed that Vietnam had one of the highest stroke incidence and prevalence rates in Southeast Asia and ranked 4th in stroke mortality among 11 neighbouring countries. In the RES-Q dataset, 95,696 patients (77 %) were ischemic stroke, 23,203 (18 %) were intracerebral haemorrhage, and 2816 (2 %) were subarachnoid haemorrhage. In GBD 2019, stroke was the leading cause of death among cardiovascular diseases in Vietnam, accounting for 135,999 fatalities. The incidence of stroke was 222 (95 % UIs 206–242) per 100,000 population, with a prevalence of 1541 (1430-1679) per 100,000. Results align with the report from the RES-Q dataset in two megacities of Vietnam: Hanoi (incidence rate of 168.9, prevalence rate of 1182.2) and Ho Chi Minh City (incidence rate of 207.1, prevalence rate of 1221.8). Key risk factors for stroke mortality are high systolic blood pressure (79,000 deaths), unhealthy dietary (43,000 deaths), high fasting plasma glucose (35,000 deaths), and air pollution (33,000 deaths). Incidence is lower in rural Vietnam, but availability and quality of care are higher in megacities. Interpretation: The results promote a further understanding of stroke and risk factors for the Vietnamese population and suggest prevention and treatment strategies for the Vietnamese government, including facility and capacity improvement and applications of advanced technologies.
Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment failure.
Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.
Autovaccination revisited: potential to boost antiviral immunity and facilitate HIV-1 cure/remission in children.
PURPOSE OF REVIEW: To review the concept of autovaccination as a strategy to boost anti-HIV-1 immunity and improve immune control, especially as a means to facilitate cure/remission in paediatric HIV-1 infection, where effective interventions in clinical testing remain limited compared to adults. RECENT FINDINGS: Early autovaccination studies, conducted 15-25 years ago, suggested potential immunological benefits from exposure to autologous virus in both children and adults, specifically when antiretroviral therapy (ART) was initiated during acute infection. More recent work in nonhuman primates (NHPs) has shown that early ART initiation can significantly reduce the viral setpoint following treatment interruption, primarily through CD8+ T-cell responses, and prevent early immune escape - a phenomenon commonly observed in ART-naive acute infections. Additionally, NHP studies indicate that multiple, short analytical treatment interruptions (ATIs) can delay viral rebound and further lower the viral setpoint via enhanced CD8+ T-cell responses. SUMMARY: Recent studies in NHP support the potential for autovaccination via short ATIs to enhance antiviral immunity and improve immune control of HIV-1. With well tolerated, well monitored ATI protocols, autovaccination could be a valuable approach to facilitating cure/remission in children living with HIV (LWH), in whom very early-ART initiation and early-life immunity are associated with low viral reservoirs and high cure/remission potential.
Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals.
With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments.
A putative hepatitis B virus sequence motif associated with hepatocellular carcinoma in South African adults.
INTRODUCTION AND OBJECTIVES: Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). In African populations, HCC frequently presents at an advanced stage with poor outcomes. We applied whole genome sequencing (WGS) to compare HBV genomes in individuals with and without HCC. MATERIALS AND METHODS: We identified adults with HBV infection, with and without complicating HCC, in Cape Town, South Africa. We generated HBV WGS using pan-genotypic probe-based enrichment followed by Illumina sequencing. RESULTS: Compared to the non-HCC group, HCC patients were more likely to be male (p
Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050.
BACKGROUND: Antimicrobial resistance (AMR) poses an important global health challenge in the 21st century. A previous study has quantified the global and regional burden of AMR for 2019, followed with additional publications that provided more detailed estimates for several WHO regions by country. To date, there have been no studies that produce comprehensive estimates of AMR burden across locations that encompass historical trends and future forecasts. METHODS: We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen-drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; the proportion of infectious deaths attributable to a given infectious syndrome; the proportion of infectious syndrome deaths attributable to a given pathogen; the percentage of a given pathogen resistant to an antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level. FINDINGS: In 2021, we estimated 4·71 million (95% UI 4·23-5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00-1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000-372 000] and 57 200 attributable deaths [34 100-80 300] in 1990, to 550 000 associated deaths [500 000-600 000] and 130 000 attributable deaths [113 000-146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000-834 000) in 1990, to 1·03 million associated deaths (909 000-1·16 million) in 2021, and from 127 000 attributable deaths (82 100-171 000) in 1990, to 216 000 (168 000-264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56-2·26) deaths attributable to AMR and 8·22 million (6·85-9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2-69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5-89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (-6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8-102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08-13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths. INTERPRETATION: This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050. FUNDING: UK Department of Health and Social Care's Fleming Fund using UK aid, and the Wellcome Trust.
Long-term non-progression in children living with HIV: estimates from international cohort data.
OBJECTIVES: To estimate the probability of long-term nonprogression (LTNP) in the absence of antiretroviral treatment (ART) in children with perinatally acquired HIV, and the impact of LTNP definitions on these estimates. DESIGN: Analysis of longitudinal routine care data (follow-up to 2016) collected through a collaboration of cohorts of children in routine HIV care across Europe and Thailand. METHODS: LTNP was defined as reaching age 8 years without disease progression (defined as an AIDS diagnosis or immunosuppression based on WHO immunosuppression-for-age thresholds, age-adjusted CD4+z-scores or CD4+ counts). ART initiation was treated as a competing risk (children initiating ART before age 8 were not considered to have LTNP). We included children born domestically in six national HIV cohorts (n = 2481). Additional analyses included domestic-born children enrolled in national cohorts in infancy (aged <12 months, n = 1144, six cohorts), or all domestic-born children in national and nonnational cohorts (n = 4542, 18 cohorts). Results were stratified by birth year. RESULTS: Among children born domestically in national cohorts in 2004-2007, the probability [95% confidence interval (CI)] of LTNP at age 8 years was 10% (6-15%) based on WHO immunosuppression-for-age criteria. This was lower for children born earlier when ART use was less frequent. Results were similar using other immunosuppression thresholds. Estimates were lower when restricted to domestic-born children in national cohorts enrolled in infancy, and higher when including all domestic-born children. CONCLUSION: Up to 10% of children born during 2004-2007 had LTNP at age 8. Our findings may help identify participants with LTNP for research into posttreatment control and HIV cure.
Characterising the molecular epidemiology of human parechovirus in young infants in the UK and Canada.
OBJECTIVES: We evaluated the extent of virus heterogeneity in PeV infected infants in the UK, Canada and Australia. METHODS: Samples were collected from PeV infected infants during 2013-16. Next generation sequencing was used to obtain sequencing data and construct phylogenetic trees based on analysis of the VP1 region. Comparison was made with sequencing data available from an outbreak in Australia. RESULTS: We amplified and sequenced 58 samples. All obtained PeV sequences were genotype 3 apart from one UK sample which was PeV-A5. Phylogenetic analysis revealed that all strains clustered together on the same clade and showed no significant genetic variation. We saw no significant evidence of association between sequence and either clinical severity (defined by admission to paediatric intensive care), geographical origin (compared between Canada and U.K) or year of sample collection (samples sequenced during 2013 - 2018). CONCLUSIONS: In this small cohort, sequencing data indicate that PeV circulating in the UK and Canada from 2013 to 18 are derived from a common ancestor. No association between disease severity and genetic sequence was seen in the UK or Canadian cohorts. Larger studies are required to support these findings.
Whole genome sequencing of hepatitis B virus using tiled amplicon (HEPTILE) and probe based enrichment on Illumina and Nanopore platforms.
Hepatitis B virus (HBV) whole genome sequencing (WGS) is currently limited as the DNA viral loads (VL) of many clinical samples are below the threshold required to generate full genomes using current sequencing methods. We developed two pan-genotypic viral enrichment methods, using probe-based capture and tiled amplicon PCR (HEP-TILE) for HBV WGS. We demonstrate using mock samples that both enrichment methods are pan-genotypic (genotypes A-J). Using clinical samples, we demonstrate that HEP-TILE amplification successfully amplifies full genomes at the lowest HBV VL tested (30 IU/ml), and the PCR products can be sequenced using both Nanopore and Illumina platforms. Probe-based capture with Illumina sequencing required VL > 300,000 IU/ml to generate full length HBV genomes. The capture-Illumina and HEP-TILE-Nanopore pipelines had consensus sequencing accuracy of 100% in mock samples with known DNA sequences. Together, these protocols will facilitate the generation of HBV sequence data, enabling a more accurate and representative picture of HBV molecular epidemiology, cast light on persistence and pathogenesis, and enhance understanding of the outcomes of infection and its treatment.
Kinetic Pattern Recognition in Home-Based Knee Rehabilitation Using Machine Learning Clustering Methods on the Slider Digital Physiotherapy Device: Prospective Observational Study
Background Recent advancements in rehabilitation sciences have progressively used computational techniques to improve diagnostic and treatment approaches. However, the analysis of high-dimensional, time-dependent data continues to pose a significant problem. Prior research has used clustering techniques on rehabilitation data to identify movement patterns and forecast recovery outcomes. Nonetheless, these initiatives have not yet used force or motion datasets obtained outside a clinical setting, thereby limiting the capacity for therapeutic decisions. Biomechanical data analysis has demonstrated considerable potential in bridging these gaps and improving clinical decision-making in rehabilitation settings. Objective This study presents a comprehensive clustering analysis of multidimensional movement datasets captured using a novel home exercise device, the “Slider”. The aim is to identify clinically relevant movement patterns and provide answers to open research questions for the first time to inform personalized rehabilitation protocols, predict individual recovery trajectories, and assess the risks of potential postoperative complications. Methods High-dimensional, time-dependent, bilateral knee kinetic datasets were independently analyzed from 32 participants using four unsupervised clustering techniques: k-means, hierarchical clustering, partition around medoids, and CLARA (Clustering Large Applications). The data comprised force, laser-measured distance, and optical tracker coordinates from lower limb activities. The optimal clusters identified through the unsupervised clustering methods were further evaluated and compared using silhouette analysis to quantify their performance. Key determinants of cluster membership were assessed, including demographic factors (eg, gender, BMI, and age) and pain levels, by using a logistic regression model with analysis of covariance adjustment. Results Three distinct, time-varying movement patterns or clusters were identified for each knee. Hierarchical clustering performed best for the right knee datasets (with an average silhouette score of 0.637), while CLARA was the most effective for the left knee datasets (with an average silhouette score of 0.598). Key predictors of the movement cluster membership were discovered for both knees. BMI was the most influential determinant of cluster membership for the right knee, where higher BMI decreased the odds of cluster-2 membership (odds ratio [OR] 0.95, 95% CI 0.94-0.96; P<.001) but increased the odds for cluster-3 assignment relative to cluster 1 (OR 1.05, 95% CI 1.03-1.06; P<.001). For the left knee, all predictors of cluster-2 membership were significant (.001≤P≤.008), whereas only BMI (P=.81) could not predict the likelihood of an individual belonging to cluster 3 compared to cluster 1. Gender was the strongest determinant for the left knee, with male participants significantly likely to belong to cluster 3 (OR 3.52, 95% CI 2.91-4.27; P<.001). Conclusions These kinetic patterns offer significant insights for creating personalized rehabilitation procedures, potentially improving patient outcomes. These findings underscore the efficacy of unsupervised clustering techniques in the analysis of biomechanical data for clinical rehabilitation applications.
Occult hepatitis B virus infection: risk for a blood supply, but how about individuals' health?
The implementation of effective blood donation screening for hepatitis B virus (HBV) anti-core antibodies with highly sensitive molecular HBV DNA detection in low-endemic countries like the United Kingdom has improved blood safety. However, the linkage to care and management for blood donors with occult HBV infection (OBI) is a complex dilemma involving virological, clinical, methodological, and social issues. Limited evidence suggests that OBI may accelerate the progression of liver disease and cancer. The need for a specialist referral for donors identified with OBI carries mixed opinions from blood establishments, hepatologists, and public health. Following extensive multidisciplinary discussions, experts agree upon a need for clear messaging for donors and to consider the oncogenic implications of OBI. Proposals for future studies are identified, and the applicability of the recommendations in low-resource, high-endemic regions is considered, as well as the inclusion of OBI in global hepatitis elimination targets.
Long COVID and cardiovascular disease: a prospective cohort study.
BACKGROUND: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. OBJECTIVES: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. METHODS: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. RESULTS: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). CONCLUSION: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need. TRAIL REGISTRATION NUMBER: ISRCTN10980107.
Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.
BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).