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Scientists in Oxford and Dundee, including Professor Martin Bachmann of the Jenner Institute, were able to take the protein coat of cucumber mosaic virus and incorporate a tetanus vaccine-derived protein structure known to stimulate the immune system in order to create vaccines to treat multiple chronic diseases.
Defining and subphenotyping ARDS: insights from an international Delphi expert panel.
Although the definition of acute respiratory distress syndrome (ARDS) has undergone numerous revisions aimed at enhancing its diagnostic accuracy and clinical practicality, the usefulness and precision of these definitions remain matters of ongoing discussion. In this Position Paper, we report on a Delphi study to reach a consensus on the conceptual model of ARDS, specifically identifying its defining components within clinical, research, and educational contexts as well as exploring the potential role of subphenotyping. We did a four-round Delphi study, involving experts in ARDS research and management from a diverse range of geoeconomic regions and professional backgrounds. Consensus was achieved for the conceptual model of ARDS; key components to be included for an ARDS definition in the context of research, education, and patient management; and the need for further research in subphenotyping ARDS. Additionally, we highlight knowledge gaps and research priorities that could guide future investigations in this area. Our study builds on previous non-Delphi-based consensus processes (eg, the new global definition of ARDS and recent society-based guidelines) by using a rigorous Delphi method that ensured panellist anonymity and used clear quantitative criteria to mitigate potential peer pressure and group conformity. The findings underscore the need to refine the ARDS definition to better account for the heterogeneity of clinical presentations and underlying pathophysiology, and to improve diagnostic precision, including the use of subphenotyping where appropriate.
Use of the pragmatic-explanatory continuum indicator summary tool in low- and middle-income country settings: Systematic review.
ObjectiveTo systematically review and characterize the literature on using the PRagmatic-Explanatory Continuum Indicator Summary (PRECIS) tools in low- and middle-income countries (LMICs), focusing on successes, challenges, and potential improvements to enhance applicability across diverse settings.Study design and settingA systematic search of PubMed to identify peer-reviewed articles applying PRECIS tools to LMIC-based research. Data extraction focused on trial characteristics, modifications, and use of PRECIS tools. Narrative synthesis was used to outline successes, challenges, and recommendations.ResultsA total of 40 articles met the selection criteria. The PRECIS tools were mostly (n=39, 97.5%) used for purposes other than trial design. Significant variation was seen in methods of use and reporting. Most (n=32, 80%) used PRECIS-2, valued for its reliability, ability to quantify pragmatism, assess trial design, and identify research gaps. Challenges included the tools' subjectivity, absence of information needed for scoring, interpretation of scores, and application to non-Western contexts and multinational trials. Recommendations for improvement included refining scoring criteria, translating guidance, and developing additional educational resources.ConclusionThe PRECIS tools have successfully supported research globally and are perceived as reliable research tools with multiple strengths. Further guidance and refinement would enable consistent application and reporting, particularly as the tools have frequently been used for purposes other than their original intention. Most challenges were similar to high-income settings, however, translation and application of the tools to traditional medicine, international trials and research-naïve settings were highlighted as LMIC-focused issues requiring consideration.
The aetiologies, mortality, and disability of non-traumatic coma in African children: a systematic review and meta-analysis.
BackgroundNon-traumatic coma in African children is a common life-threatening presentation often leading to hospital attendance. We aimed to estimate the distribution of non-traumatic coma causes and outcomes, including disease-specific outcomes, for which evidence is scarce.MethodsWe systematically reviewed MEDLINE, Embase, and Scopus databases from inception to Feb 6, 2024. We included studies recruiting children (aged 1 month to 16 years) with non-traumatic coma (Blantyre Coma Scale score ≤2, ie deep coma or comparable alternative) from any African country. Disease-specific studies were included if outcomes were reported. Primary data were requested where required. We used a DerSimonian-Laird random effects model to calculate pooled estimates for prevalence of causes, mortality, and morbidity (in-hospital and post-discharge), including analysis of mortality by temporality. This study was registered with PROSPERO (CRD4202014193).FindingsWe screened 16 666 articles. 138 studies were eligible for analysis, reporting causes, outcome data, or both from 35 027 children with non-traumatic coma in 30 African countries. 114 (89%) of 128 studies were determined to be high quality. Among the causes, cerebral malaria had highest pooled prevalence at 58% (95% CI 48-69), encephalopathy of unknown cause was associated with 23% (9-36) of cases, and acute bacterial meningitis was the cause of 10% (8-12) of cases, with all other causes representing lower proportions of cases. Pooled overall case-fatality rates were 17% (16-19) for cerebral malaria, 37% (20-55) for unknown encephalopathy, and 45% (34-55) for acute bacterial meningitis. By meta-regression, there was no significant difference in cerebral malaria (p=0·98), acute bacterial meningitis (p=0·99), or all-cause coma (p=0·081) mortality by year of study. There was no substantial difference in deaths associated with cerebral malaria in-hospital compared with post-discharge (17% [16-19] vs (18% [16-20]). Mortality was higher post-discharge than in-hospital in most non-malarial comas, including acute bacterial meningitis (39% [26-52]) vs 53% [38-69]). Disability associated with cerebral malaria was 11% (9-12). Pooled disability outcomes associated with other non-malarial diseases were largely absent.InterpretationThe prevalence and outcomes of cerebral malaria and meningitis associated with non-traumatic coma were strikingly static across five decades. Enhanced molecular and radiological diagnostics, investment, policy making, community awareness, and health service provision are all required to facilitate earlier referral to specialist centres, to drive a step-change in diagnostic yield and treatment options to improve these outcomes.FundingWellcome Trust.TranslationsFor the Chichewa, French and Portuguese translations of the abstract see Supplementary Materials section.
Impact of the Global Fund Regional Artemisinin-resistance Initiative on malaria control and elimination in the Greater Mekong subregion of southeast Asia.
Responding to the emergence of Plasmodium falciparum partial resistance to artemisinins and partner drugs of artemisinin-based combination therapies in the Greater Mekong subregion (GMS) of southeast Asia, the Regional Artemisinin-resistance Initiative (RAI) was established in 2014 and has made remarkable progress in eliminating falciparum malaria. In Cambodia, Laos, and Viet Nam, the number of malaria cases has declined from hundreds of thousands in 2010 to 2313 cases in 2023, with only 246 caused by falciparum malaria. The key components of this success have been an effective package of interventions curbing malaria transmission, with an emphasis on early diagnosis and treatment in hard-to-reach populations through an extended and well organised network of community and mobile malaria workers; improved surveillance systems; and evidence-driven implementation of intensified approaches such as active case detection, chemoprevention in specific risk groups, and targeted drug administration. The RAI is funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria and governed by a closely collaborating Regional Steering Committee, including technical partners, key development partners, and stakeholders from ministries of health, national malaria control programmes, civil society organisations, the private sector, academia, and regional multilateral organisations. The RAI has brought the countries of the eastern GMS close to eliminating P falciparum, the deadliest malaria-causing Plasmodium species. Nonetheless, a worrying rise in malaria cases in Myanmar with cross-border spillover requires urgent action. Lessons learned from the RAI's approach to antimalarial drug resistance in the GMS can inform countries in sub-Saharan Africa, where artemisinin partial resistance has now also emerged.
Operational evaluation of the deployment of Malaria/CRP Duo and Dengue Duo rapid diagnostic tests for the management of febrile illness by village malaria workers in rural Cambodia
Abstract Introduction The decline in malaria cases in Cambodia has led to a relative increase in non-malarial febrile illness. In rural Cambodia, village malaria workers (VMWs) provide early diagnosis and treatment for malaria, but their role and relevance are diminishing as malaria cases decline. Expanding VMW roles would ensure continued utilisation of their services until malaria elimination is achieved and strengthen community health services. Methods A mixed methods operational research study was implemented to evaluate the use of two combination-RDTs (combo-RDTs) as an expansion of the VMW role, enabling VMWs in Cambodia to test for diseases other than malaria for the first time. VMWs in 78 villages in Battambang and Pailin Provinces were trained and provided with either a Malaria/CRP Duo or Dengue Duo RDT to assess febrile patients. Data were collected on VMW consultations, and combo-RDT usage and results. Focus group discussions (FGDs) and competency assessments of combo-RDT usage were conducted with VMWs. The main objectives were to determine whether VMWs could perform these combo-RDTs correctly and follow management algorithms, and whether deployment had an impact on VMW consultation rates. Perspectives concerning role expansion and the feasibility of conducting additional tests were also explored. Results Between June 2022, and May 2023, a total of 2,425 febrile patients were assessed with either a Malaria/CRP Duo or Dengue Duo RDT. Active dengue infection (NS1- and/or IgM-positive) was identified in 1.2% (11/915) of patients. Positive CRP results (> 20 mg/L) were found for 3.2% (48/1,510) of patients. Following deployment, there was an immediate mean increase of 4.4 VMW consultations per month, from 9.0 to 13.4 (p < 0.01). Competency assessments revealed that some VMWs had difficulty performing the Dengue Duo RDT, particularly in collecting the correct blood volume. This limitation may have led to false-negative dengue NS1 results. VMWs and community members were keen to broaden the skills and responsibilities of VMWs. Conclusions Deploying combo-RDTs to VMWs led to a higher utilization of their services. Difficulties performing some aspects of the Dengue Duo RDT, low positivity rates, and a lack of actionable outcomes within the existing context of VMW services suggest that alternative interventions may be better suited for VMW role expansion at this time. Overall, VMWs and community members were receptive to the expansion of the VMW role for a wider range of diseases other than malaria.
Safety and efficacy of single-dose primaquine to interrupt Plasmodium falciparum malaria transmission in children compared with adults: a systematic review and individual patient data meta-analysis.
BackgroundAdding a single dose of primaquine to artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria can reduce the transmission of Plasmodium falciparum and could limit the spread of artemisinin partial resistance, including in Africa, where the disease burden is greatest. We aimed to compare the safety and efficacy of single-dose primaquine plus ACT between young children (aged <5 years) and older children (aged 5 years to <15 years) and adults (aged ≥15 years), and between low and moderate-to-high transmission areas.MethodsFor this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, OpenGrey.eu, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform, from database inception to April 3, 2024, with no language restrictions. We included prospective studies on efficacy against falciparum malaria that enrolled at least one child younger than 15 years and involved a study group given a single dose of primaquine (≤0·75 mg/kg) plus ACT. Studies involving mass drug administration, healthy volunteers, or patients with severe malaria or mixed (with non-falciparum) infections were excluded. For inclusion in the efficacy analysis, data on transmission potential (as determined by gametocytaemia, infectivity, or both) at enrolment and follow-up (day 3, day 7, or day 14) were required; the safety analysis required data on haemoglobin concentrations or haematocrit values at enrolment and at one or more follow-up visits by day 7, any data on adverse events, or both. After independent screening of the search results by two reviewers, the investigators of eligible studies were invited to contribute individual patient data. We quantified day 7 gametocyte carriage, probability of infecting a mosquito, decreases (>25%) in haemoglobin concentration associated with anaemia, and adverse events until day 28 using regression analyses, with random study-site intercepts to account for clustered data. These analyses were registered with PROSPERO, CRD42021279363 (safety) and CRD42021279369 (efficacy).FindingsOf 5697 records identified by the search, 30 studies were eligible for analysis. Of these, individual patient data were shared for 23 studies, including 6056 patients from 16 countries: 1171 (19·3%) young children (aged <5 years), 2827 (46·7%) older children (aged 5 years to <15 years), and 2058 (34·0%) adults (aged ≥15 years). Adding a single low dose of primaquine (0·2-0·25 mg/kg) to ACTs reduced day 7 gametocyte positivity (adjusted odds ratio [aOR] 0·34, 95% CI 0·22-0·52; p<0·001) and infectivity to mosquitoes over time (aOR per day 0·02, 0·01-0·07, p<0·001). No difference was found in the effect of single low-dose primaquine both on gametocyte positivity in young children compared with older children (1·08, 0·52-2·23; p=0·84) and adults (0·50, 0·20-1·25; p=0·14) and between low-transmission and moderate-to-high transmission settings (1·07, 0·46-2·52; p=0·86), and on infectivity to mosquitoes in young children compared with older children (1·36, 0·07-27·71; p=0·84) and adults (0·31, 0·01-8·84; p=0·50) and between low-transmission and moderate-to-high transmission settings (0·18, 0·01-2·95; p=0·23). Gametocyte clearance was also similar for different ACTs (dihydroartemisinin-piperaquine vs artemether-lumefantrine) when combined with a primaquine target dose of 0·25 mg/kg (1·56, 0·65-3·79; p=0·32 at day 7). However, patients given a primaquine dose of less than 0·2 mg/kg with dihydroartemisinin-piperaquine were more likely to have gametocytaemia than those treated with artemether-lumefantrine (5·68, 1·38-23·48; p=0·016 at day 7). There was no increase in anaemia-associated declines in haemoglobin concentration (>25%) at a primaquine dose of 0·25 mg/kg, regardless of age group, transmission setting, and glucose-6-phosphate dehydrogenase status. The risks of adverse events of grade 2 or higher and of serious adverse events were similar between primaquine and no-primaquine groups, including in young children.InterpretationRegardless of malaria transmission intensity and age group, a single dose of 0·25 mg/kg primaquine is safe and efficacious for reducing P falciparum transmission. These findings underscore the need for primaquine formulations suitable for young children, and also provide supportive evidence to expand the use of single low-dose primaquine in regions with a moderate-to-high transmission rate that are threatened by artemisinin partial resistance.FundingThe EU and the Bill & Melinda Gates Foundation.
Optimization of heat inactivation protocols for Orientia and Rickettsia species.
Heat treatment, or thermal disinfection, is one of the simplest and most widely used methods for microbial inactivation. Proper heat inactivation protocols are essential to ensure the safe transportation and handling of infectious materials, particularly for organisms in risk group 3, such as Rickettsia and Orientia. In this study, we examined the inactivation of four bacterial species-Orientia tsutsugamushi, Rickettsia typhi, Rickettsia conorii, and Rickettsia honei-at temperatures of 56 °C, 80 °C, and 90 °C for durations of 5, 15, 30, and 60 min. Observations were made at 0, 1, 3, 7, 10, and 14 days post-infection (dpi) to assess bacterial infectivity by monitoring bacterial DNA copies in newly infected cells. Our results indicate that 56 °C for 5 min was the minimum temperature and time required to inactivate O. tsutsugamushi, R. typhi, R. conorii, and R. honei. O. tsutsugamushi exhibited a higher reduction factor at 56 °C compared to R. typhi, R. conorii, and R. honei. Additionally, a strong inverse correlation between incubation time and log10 reduction factor was observed for O. tsutsugamushi and R. typhi, underscoring the importance of both time and temperature in effective heat treatment. However, no such correlation was observed for R. conorii and R. honei. These findings highlight the variable responses of bacteria to heat, emphasizing the need for pathogen-specific approaches in inactivation protocols. Optimizing heat treatment strategies based on these insights is critical for enhancing biosafety and ensuring effective pathogen eradication.
Incidence and prevalence of asthma, chronic obstructive pulmonary disease and interstitial lung disease between 2004 and 2023: harmonised analyses of longitudinal cohorts across England, Wales, South-East Scotland and Northern Ireland.
BackgroundWe describe the epidemiology of asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) from 2004 to 2023 in England, Wales, Scotland and Northern Ireland (NI) using a harmonised approach.MethodsData from the National Health Service England (NHSE), Clinical Practice Research Datalink Aurum in England, Secure Anonymised Information Linkage Databank in Wales, DataLoch in South-East Scotland and the Honest Broker Service in NI were used. A harmonised approach to COPD, asthma and ILD case definitions, study designs and study populations across the four nations was performed. Age-sex-standardised incidence rates and point prevalence were calculated between 2004 and 2023 depending on data availability. Logistic and negative binomial regression compared incidence and prevalence rates between the start and end of each study period. Linear extrapolation projected incidence rates between 2020 and 2023 to illustrate how observed and projected rates differed.ResultsIncidence rates were lower in 2019 versus 2005 for asthma (England: incidence rate ratio 0.89, 95% CI 0.88 to 0.90; Wales: 0.66, 0.65 to 0.68; Scotland: 0.67, 0.64 to 0.71; NI: 0.84, 0.81 to 0.86), COPD (England: 0.83, 0.82 to 0.85; Wales: 0.67, 0.65 to 0.69) and higher for ILD (England: 3.27, 3.05 to 3.50; Wales: 1.39, 1.27 to 1.53; Scotland: 1.63, 1.36 to 1.95; NI: 3.03, 2.47 to 3.72). In NHSE, the incidence of asthma was similar in June 2023 versus November 2019, but lower for COPD and higher for ILD. Prevalence of asthma in 2019 in England, Wales, Scotland and NI was 9.7%, 15.9%, 13.2% and 7.0%, respectively, for COPD 4.5%, 5.1%, 4.4% and 3.0%, and for ILD 0.4%, 0.5%, 0.6% and 0.3%. Projected incidence rates were 2.8, 3.4 and 1.8 times lower for asthma, COPD and ILD compared with observed rates at the height of the pandemic.InterpretationAsthma, COPD and ILD affect over 10 million people across the four nations, and a substantial number of diagnoses were missed during the pandemic.
Impact of COVID-19 pandemic on rates of congenital heart disease procedures among children: prospective cohort analyses of 26 270 procedures in 17 860 children using CVD-COVID-UK consortium record linkage data.
BackgroundThe COVID-19 pandemic necessitated major reallocation of healthcare services. Our aim was to assess the impact on paediatric congenital heart disease (CHD) procedures during different pandemic periods compared with the prepandemic period, to inform appropriate responses to future major health services disruptions.Methods and resultsWe analysed 26 270 procedures from 17 860 children between 1 January 2018 and 31 March 2022 in England, linking them to primary/secondary care data. The study period included prepandemic and pandemic phases, with the latter including three restriction periods and corresponding relaxation periods. We compared procedure characteristics and outcomes between each pandemic period and the prepandemic period. There was a reduction in all procedures across all pandemic periods, with the largest reductions during the first, most severe restriction period (23 March 2020 to 23 June 2020), and the relaxation period following second restrictions (3 December 2020 to 4 January 2021) coinciding with winter pressures. During the first restrictions, median procedures per week dropped by 51 compared with the prepandemic period (80 vs 131 per week, p=4.98×10-08). Elective procedures drove these reductions, falling from 96 to 44 per week (p=1.89×10-06), while urgent (28 vs 27 per week, p=0.649) and life-saving/emergency procedures (7 vs 6 per week, p=0.198) remained unchanged. Cardiac surgery rates increased, and catheter-based procedure rates reduced during the pandemic. Procedures for children under 1 year were prioritised, especially during the first four pandemic periods. No evidence was found for differences in postprocedure complications (age-adjusted OR 1.1 (95% CI 0.9, 1.4)) or postprocedure mortality (age and case mix adjusted OR 0.9 (95% CI 0.6, 1.3)).ConclusionsPrioritisation of urgent, emergency and life-saving procedures during the pandemic, particularly in infants, did not impact paediatric CHD postprocedure complications or mortality. This information is valuable for future major health services disruptions, though longer-term follow-up of the effects of delaying elective surgery is needed.
Ebola virus persistence: implications for human-to-human transmission and new outbreaks
Ebola virus (EBOV) infection usually leads to highly lethal EBOV disease (EVD) with associated viraemia. Viraemia is cleared in those that do survive, however, EBOV may remain hidden in the testes and other immune privileged niches (IPNs) where it can persist for years during asymptomatic convalescence. Viral shedding into seminal fluid may result in sexual transmission to naive contacts years after EBOV outbreaks have been declared over. This leads to flare-ups of cases, redefining our understanding of the shaping and origin of EBOV outbreaks. Such delayed sexual transmission eliminates the geographical boundaries which typically constrain EBOV outbreaks, thus posing a significant global health security threat. Despite hints of EBOV persistence dating over half a century, it was only until the unprecedented scale of the 2013–2016 Western Africa EBOV epidemic that the true importance of this phenomenon was revealed to scientists, public health officials and policy makers alike. This review summarises the evidence for EBOV persistence, suggests the possible underlying molecular mechanisms and proposes future directions for research in the field. A meta-analysis is presented to further investigate the duration of EBOV shedding in seminal fluid. The ultimate aim is to develop therapeutics that clear sites of persistence. Such therapeutics could prevent the re-emergence of the persistent virus, eliminating the chance of new outbreaks whilst alleviating the severe stigmatisation facing the EBOV survivor population.
Analysis of the senescence-associated cell surfaceome reveals potential senotherapeutic targets.
The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related pathologies. Targeting senescence-associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence-specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or "surfaceome", in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types. Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age-related diseases.
Premorbid brain structure influences risk of amyotrophic lateral sclerosis
BackgroundAmyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known.MethodsThis study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis.ResultsIncreased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule.ConclusionsThis study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.
Deep learning of causal structures in high dimensions under data limitations
AbstractCausal learning is a key challenge in scientific artificial intelligence as it allows researchers to go beyond purely correlative or predictive analyses towards learning underlying cause-and-effect relationships, which are important for scientific understanding as well as for a wide range of downstream tasks. Here, motivated by emerging biomedical questions, we propose a deep neural architecture for learning causal relationships between variables from a combination of high-dimensional data and prior causal knowledge. We combine convolutional and graph neural networks within a causal risk framework to provide an approach that is demonstrably effective under the conditions of high dimensionality, noise and data limitations that are characteristic of many applications, including in large-scale biology. In experiments, we find that the proposed learners can effectively identify novel causal relationships across thousands of variables. Results include extensive (linear and nonlinear) simulations (where the ground truth is known and can be directly compared against), as well as real biological examples where the models are applied to high-dimensional molecular data and their outputs compared against entirely unseen validation experiments. These results support the notion that deep learning approaches can be used to learn causal networks at large scale.