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AbstractThe International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.
\n \n\n \n \nBackgroundIndividuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease\u00a0that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes.MethodsHere, we use data from an international consortium to study this\u00a0question and assess whether differences between these groups are\u00a0context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed.FindingsWhile typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed.ConclusionsThese findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history.FundingThis work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill\u00a0& Melinda Gates\u00a0Foundation (OPP1209135); and the philanthropic support of the donors\u00a0to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the \"acknowledgments\" section.
\n \n\n \n \nAbstract\n\nBackground\nThe mainstay of diagnostic confirmation of acute Japanese encephalitis (JE) involves detection of anti-JE virus (JEV) immunoglobulin M (IgM) by enzyme-linked immunosorbent assay (ELISA). Limitations in the specificity of this test are increasingly apparent with the introduction of JEV vaccinations and the endemicity of other cross-reactive flaviviruses. Virus neutralization testing (VNT) is considered the gold standard, but it is challenging to implement and interpret. We performed a pilot study to assess IgG depletion prior to VNT for detection of anti-JEV IgM neutralizing antibodies (IgM-VNT) as compared with standard VNT.\n\n\nMethods\nWe evaluated IgM-VNT in paired sera from anti-JEV IgM ELISA-positive patients (JE n=35) and negative controls of healthy flavivirus-na\u00efve (n=10) as well as confirmed dengue (n=12) and Zika virus (n=4) patient sera. IgM-VNT was subsequently performed on single sera from additional JE patients (n=76).\n\n\nResults\nAnti-JEV IgG was detectable in admission serum of 58% of JE patients. The positive, negative and overall percentage agreement of IgM-VNT as compared with standard VNT was 100%. A total of 12/14 (86%) patient samples were unclassified by VNT and, with sufficient sample available for IgG depletion and IgG ELISA confirming depletion, were classified by IgM-VNT. IgM-VNT enabled JE case classification in 72/76 (95%) patients for whom only a single sample was available.\n\n\nConclusions\nThe novel approach has been readily adapted for high-throughput testing of single patient samples and it holds promise for incorporation into algorithms for use in reference centres.\n
\n \n\n \n \nBackgroundCommunity-based health programmes have been a cornerstone of primary care in Laos for decades. The study presented here aimed to document prospects for the development of current programmes, considering perceptions about health and health care priorities in the communities, implementation challenges, the policy landscape and opportunities associated with the availability of new technologies.MethodsThe research design primarily involved qualitative in-depth interviews with stakeholders (n\u2009=\u200935) responsible for the planning, management, or implementation of community-based care in Laos at different levels of the health system. These included health managers at central departments or institutes of the Ministry of Health, provincial health departments, district health offices, heads of health centres, village health volunteers, community representatives, and international stakeholders.ResultsThere was consensus that service delivery is still a challenge in many areas, due to geographic inaccessibility of health facilities, communication barriers, health-seeking behaviour, trust, and gender discrimination, particularly among ethnic minorities. In these settings, community health workers have the potential to extend the reach of the formal health system, acting as cultural brokers across sectors of society, ethnicities, and worldviews. To maximise impact, planners need to carefully consider the implementation model, financing arrangements, health system integration, and changing health priorities in the communities.ConclusionsThis study examined challenges to, and opportunities for, the expansion and health system integration of community-based care in Laos. Further development and horizontal integration of community-based care remains a complex financing and governance challenge, although the renewed emphasis on primary care and the ongoing process of decentralisation provide a favourable policy environment in the country to sustain and potentially expand existing programmes.
\n \n\n \n \nAbstract\nIn 2022, WHO released the WHO AWaRe (Access, Watch, Reserve) antibiotic book to promote the rational use of antibiotics. Here, we review the AWaRe antibiotic book from the perspective of implementation in low-resource settings, using the Lao PDR (Laos) as a case study. Not all recommendations in the AWaRe antibiotic book match the epidemiology of infectious diseases and antimicrobial susceptibility patterns in Laos and other low- and middle-income countries (LMICs), e.g. melioidosis, rickettsial disease and leptospirosis are common causes of sepsis and febrile illness in Laos but do not feature in the AWaRe book. Conversely, some infectious diseases like Clostridioides difficile-associated diarrhoea are in the AWaRe antibiotic book but rarely considered in Laos with no diagnostic tests available. Only 29/39 antibiotics in the AWaRe book are available in Laos, with no Reserve group antimicrobials available. The AWaRe book stimulates countries such as Laos to consider alternative diagnoses and include additional antimicrobials in the national essential medicines list (NEML). However, it should be updated to include regional important pathogens that are not included. Comprehensive antibiotic use guidelines alone might not assure appropriate use or control overuse of antibiotics. Access to antibiotics is challenging in low-resource settings in terms of unavailability in the country (low demand or small market size), patchy access, especially for those living in remote areas, and unaffordability. All these systemic factors can contribute to inappropriate use of antibiotics. Improved access to antibiotics, strengthening diagnostic capacity and promoting antibiotic stewardship should be combined.
\n \n\n \n \nBackgroundCritical illness is a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and potential for reversibility. The burden of critical illness is high, especially in low- and middle-income countries. Critical care can be provided as Essential Emergency and Critical Care (EECC)- the effective, low-cost, basic care that all critically ill patients should receive in all parts of all hospitals in the world- and advanced critical care- complex, resource-intensive care usually provided in an intensive care unit. The required resources may be available in the hospital and yet not be ready in the wards for immediate use for critically ill patients. The ward readiness of these resources, although harder to evaluate, is likely more important than their availability in the hospital. This study aimed to assess the ward readiness for EECC and the hospital availability of resources for EECC and for advanced critical care in hospitals in Tanzania.MethodsAn in-depth, cross-sectional study was conducted in five purposively selected hospitals by visiting all wards to collect data on all the required 66 EECC and 161 advanced critical care resources. We defined hospital-availability as a resource present in the hospital and ward-readiness as a resource available, functioning, and present in the right place, time and amounts for critically ill patient care in the wards. Data were analyzed to calculate availability and readiness scores as proportions of the resources that were available at hospital level, and ready at ward level respectively.ResultsAvailability of EECC resources in hospitals was 84% and readiness in the wards was 56%. District hospitals had lower readiness scores (less than 50%) than regional and tertiary hospitals. Equipment readiness was highest (65%) while that of guidelines lowest (3%). Availability of advanced critical care resources was 31%.ConclusionHospitals in Tanzania lack readiness for the provision of EECC- the low-cost, life-saving care for critically ill patients. The resources for EECC were available in hospitals, but were not ready for the immediate needs of critically ill patients in the wards. To provide effective EECC to all patients, improvements are needed around the essential, low-cost resources in hospital wards that are essential for decreasing preventable deaths.
\n \n\n \n \nWe report on a 2023 outbreak of severe hand, foot, and mouth disease in southern Vietnam caused by an emerging lineage of enterovirus A71 subgenogroup B5. Affected children were significantly older than those reported during previous outbreaks. The virus should be closely monitored to assess its potential for global dispersal.
\n \n\n \n \nBackgroundOne Health focuses on sustainable health for humans, animals, and ecosystems. The approach has been well demonstrated, yet most efforts have not been scaled up. Understanding the organisations involved in scaling up processes is critical to translating research into practice. The Lao People's Democratic Republic has successfully implemented One Health projects for multiple decades; however, the organisational network has not been described and scaling up efforts have been limited.MethodsData from organisations involved in One Health projects over the past five years were collected by key-informant interview or workshop. The network was investigated using a mixture of quantitative network analysis and qualitative thematic analysis.ResultsThe organisational network was quantitatively described as sparse and centralised. Organisations were required to harness pre-existing relationships to maximise scarce resources and make co-ordination and alignment of priorities more efficient. A lack of international organisations in the top 10% of resource sharing metrics suggests a potential disconnect between donors. This was reflected in the challenges faced by national organisations and a feeling of being stretched thin over numerous externally funded projects with donor-driven priorities.ConclusionsIt appears that high-level political support for country ownership of development and aid priorities remains unrealised. Developing network capacity and capability may assist scaling up efforts and build resilience in the network and its core organisations. This may allow for the inclusion of more development, education, environment, and water, sanitation, and hygiene organisations that were perceived to be lacking. Future One Health programmes should focus on practical activities that do not overload staff capacity. There is much for One Health to learn about the art of scaling up and organisations are encouraged to include implementation science in their research to inform future scaling up efforts.
\n \n\n \n \nWe explored whether isotope ratio mass spectrometry (IRMS) is useful to investigate the origin of falsified antimalarials. Forty-four falsified and genuine antimalarial samples (artesunate, artemether-lumefantrine, dihydroartemisinin-piperaquine and sulphamethopyrazine-pyrimethamine) were analyzed in bulk for carbon (C), nitrogen (N), and oxygen (O) element concentrations and stable isotope ratios. The insoluble fraction (\"starch\") was extracted from 26 samples and analyzed. Samples of known geographical origin maize, a common source of excipient starch, were used to produce a comparison dataset to predict starch source. In both an initial (n\u2009=\u200918) and a follow-on set of samples that contained/claimed to contain artesunate/artemether (n\u2009=\u200926), falsified antimalarials had a range of C concentrations less than genuine comparator antimalarials and \u03b413C values higher than genuine comparators. The \u03b413C values of falsified antimalarials suggested that C4 plant-based organic material (e.g., starch derived from maize) had been included. Using the known-origin maize samples, predictions for growth water \u03b418O values for the extracted \"starch\" ranged from\u2009-\u20096.10 to\u2009-\u20091.62\u2030. These findings suggest that IRMS may be a useful tool for profiling falsified antimalarials. We found that C4 ingredients were exclusively used in falsified antimalarials versus genuine antimalarials, and that it may be possible to predict potential growth water \u03b418O values for the starch present in falsified antimalarials.
\n \n\n \n \nTo limit the catastrophic effects of the increasing bacterial resistance to antimicrobials on health, food, environmental, and geopolitical security, and ensure that no country or region is left behind, a coordinated global approach is required. In this Viewpoint, we argue that the diverging resource availabilities, needs, and priorities of the Global North and the Global South in terms of the actions required to mitigate the antimicrobial resistance pandemic are a direct threat to success. We argue that evidence suggests a need to prioritise and support infection prevention interventions (ie, clean water and safe sanitation, increased vaccine coverage, and enhanced infection prevention measures for food production in the Global South contrary to the focus on research and development of new antibiotics in the Global North) and to recalibrate global funding resources to address this need. We call on global leaders to redress the current response, which threatens mitigation of the antimicrobial resistance pandemic.
\n \n\n \n \n[This corrects the article DOI: 10.1371/journal.pone.0204509.].
\n \n\n \n \nThere was, and possibly still is, potential for COVID-19 to disrupt power inequities and contribute to positive transformation in global health research that increases equity. While there is consensus about the need to decolonise by transforming global health, and a roadmap outlining how we could approach it, there are few examples of steps that could be taken to transform the mechanics of global health research. This paper contributes lessons learnt from experiences and reflections of our diverse multinational team of researchers involved in a multicountry research project. We demonstrate the positive impact on our research project of making further steps towards improving equity within our research practices. Some of the approaches adopted include redistributing power to researchers from the countries of interest at various stages in their career, by involving the whole team in decisions about the research; meaningfully involving the whole team in research data analysis; and providing opportunities for all researchers from the countries of interest to voice their perspectives as first authors in publications. Although this approach is consistent with how research guidance suggests research should be run, in reality it does not often happen in this way. The authors of this paper hope that by sharing our experience, we can contribute towards discussions about the processes required to continue developing a global health sector that is equitable and inclusive.
\n \n\n \n \nBackgroundVentilator-associated pneumonia (VAP) is associated with increased mortality, prolonged hospitalisation, excessive antibiotic use and, consequently, increased antimicrobial resistance. In this phase 4, randomised trial, we aimed to establish whether a pragmatic, individualised, short-course antibiotic treatment strategy for VAP was non-inferior to usual care.MethodsWe did an individually randomised, open-label, hierarchical non-inferiority-superiority trial in 39 intensive care units in six hospitals in Nepal, Singapore, and Thailand. We enrolled adults (age \u226518 years) who met the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria for VAP, had been mechanically ventilated for 48 h or longer, and were administered culture-directed antibiotics. In culture-negative cases, empirical antibiotic choices were made depending on local hospital antibiograms reported by the respective microbiology laboratories or prevailing local guidelines. Participants were assessed until fever resolution for 48 h and haemodynamic stability, then randomly assigned (1:1) to individualised short-course treatment (\u22647 days and as short as 3-5 days) or usual care (\u22658 days, with precise durations determined by the primary clinicians) via permuted blocks of variable sizes (8, 10, and 12), stratified by study site. Independent assessors for recurrent pneumonia and participants were masked to treatment allocation, but clinicians were not. The primary outcome was a 60-day composite endpoint of death or pneumonia recurrence. The non-inferiority margin was prespecified at 12% and had to be met by analyses based on both intention-to-treat (all study participants who were randomised) and per-protocol populations (all randomised study participants who fulfilled the eligibility criteria, met fitness criteria for antibiotic discontinuation, and who received antibiotics for the duration specified by their allocation group). This study is registered with ClinicalTrials.gov, number NCT03382548.FindingsBetween May 25, 2018, and Dec 16, 2022, 461 patients were enrolled and randomly assigned to the short-course treatment group (n=232) or the usual care group (n=229). Median age was 64 years (IQR 51-74) and 181 (39%) participants were female. 460 were included in the intention-to-treat analysis after excluding one withdrawal (231 in the short-course group and 229 in the usual care group); 435 participants received the allocated treatment and fulfilled eligibility criteria, and were included in the per-protocol population. Median antibiotic treatment duration for the index episodes of VAP was 6 days (IQR 5-7) in the short-course group and 14 days (10-21) in the usual care group. 95 (41%) of 231 participants in the short-course group met the primary outcome, compared with 100 (44%) of 229 in the usual care group (risk difference -3% [one-sided 95% CI -\u221e to 5%]). Results were similar in the per-protocol population. Non-inferiority of short-course antibiotic treatment was met in the analyses, although superiority compared with usual care was not established. In the per-protocol population, antibiotic side-effects occurred in 86 (38%) of 224 in the usual care group and 17 (8%) of 211 in the short-course group (risk difference -31% [95% CI -37 to -25%; p<0\u00b70001]).InterpretationIn this study of adults with VAP, individualised shortened antibiotic duration guided by clinical response was non-inferior to longer treatment durations in terms of 60-day mortality and pneumonia recurrence, and associated with substantially reduced antibiotic use and side-effects. Individualised, short-course antibiotic treatment for VAP could help to reduce the burden of side-effects and the risk of antibiotic resistance in high-resource and resource-limited settings.FundingUK Medical Research Council; Singapore National Medical Research Council.TranslationsFor the Thai and Nepali translations of the abstract see Supplementary Materials section.
\n \n\n \n \nBackgroundHospital patients can become critically ill anywhere in a hospital but their survival is affected by problems of identification and adequate, timely, treatment. This is issue of particular concern in lower middle-income countries' (LMICs) hospitals where specialised units are scarce and severely under-resourced. \"Cross-sectional\" approaches to improving narrow, specific aspects of care will not attend to issues that affect patients' care across the length of their experience. A simpler approach to understanding key issues across the \"hospital journey\" could help to deliver life-saving treatments to those patients who need it, wherever they are in the facility.MethodsWe carried out 31 narrative interviews with frontline health workers in five Kenyan and five Tanzanian hospitals from November 2020 to December 2021 during the COVID-19 pandemic and analysed using a thematic analysis approach. We also followed 12 patient hospital journeys, through the course of treatment of very sick patients admitted to the hospitals we studied.ResultsOur research explores gaps in hospital systems that result in lapses in effective, continuous care across the hospital journeys of patients in Tanzania and Kenya. We organise these factors according to the Systems Engineering Initiative for Patient Safety (SEIPS) approach to patient safety, which we extend to explore how these issues affect patients across the course of care. We discern three repeating, recursive phases we term Receive, Sustain, and Flow. We use this heuristic to show how gaps and weaknesses in service provision affect critically ill patients' hospital journeys.ConclusionReceive, Sustain, and Flow offers a heuristic for hospital management to identify and ameliorate limitations in human and technical resources for the care of the critically ill.
\n \n\n \n \nBackgroundTyphoid vaccination has been shown to be an effective intervention to prevent enteric fever and is under consideration for inclusion in the national immunization program in Lao PDR.MethodsA cost-utility analysis was performed using an age-structured static decision tree model to estimate the costs and health outcomes of introducing TCV. Vaccination strategies combined with five delivery approaches in different age groups compared to no vaccination were considered from the societal perspective, using the Gavi price of 1.5 USD per dose. The vaccination program was considered to be cost-effective if the incremental cost-effectiveness ratio was less than a threshold of 1 GDP per capita for Lao PDR, equivalent to USD 2,535 in 2020.ResultsIn the model, we estimated 172.2 cases of enteric fever, with 1.3 deaths and a total treatment cost of USD 7,244, based on a birth cohort of 164,662 births without TCV vaccination that was followed over their lifetime. To implement a TCV vaccination program over the lifetime horizon, the estimated cost of the vaccine and administration costs would be between USD 470,934 and USD 919,186. Implementation of the TCV vaccination program would prevent between 14 and 106 cases and 0.1 to 0.8 deaths. None of the vaccination programs appeared to be cost-effective.ConclusionsInclusion of TCV in the national vaccination program in Lao PDR would only be cost-effective if the true typhoid incidence is 25-times higher than our current estimate.
\n \n\n \n \nCare for the critically ill patients is often considered synonymous with a hospital having an intensive care unit. However, a focus on Essential Emergency and Critical Care (EECC) may obviate the need for much intensive care. Severe COVID-19 presented a specific critical care challenge while also being an exemplar of critical illness in general. Our multidisciplinary team conducted research in Kenya and Tanzania on hospitals' ability to provide EECC as the COVID-19 pandemic unfolded. Important basic inputs were often lacking, especially sufficient numbers of skilled health workers. However, we learnt that higher scores on resource readiness scales were often misleading, as resources were often insufficient or not functional in all the clinical areas they are needed. By following patient journeys, through interviews and group discussions, we revealed gaps in timeliness, continuity and delivery of care. Generic challenges in transitions between departments were identified in the receipt of critically ill patients, the ability to sustain monitoring and treatment and preparation for any subsequent transition. While the global response to COVID-19 focused initially on providing technologies and training, first ventilators and later oxygen, organisational and procedural challenges seemed largely ignored. Yet, they may even be exacerbated by new technologies. Efforts to improve care for the critically ill patients, which is a complex process, must include a whole system and whole facility view spanning all areas of patients' care and their transitions and not be focused on a single location providing 'critical care'. We propose a five-part strategy to support the system changes needed.
\n \n\n \n \nLittle is known about diagnostic and antibiotic use practices in low and middle-income countries (LMICs) before and during COVID-19 pandemic. This information is crucial for monitoring and evaluation of diagnostic and antimicrobial stewardships in healthcare facilities. We linked and analyzed routine databases of hospital admission, microbiology laboratory and drug dispensing of Indonesian National Referral Hospital from 2019 to 2020. Patients were classified as COVID-19 cases if their SARS-CoV-2 RT-PCR result were positive. Blood culture (BC) practices and time to discontinuation of parenteral antibiotics among inpatients who received a parenteral antibiotic for at least four consecutive days were used to assess diagnostic and antibiotic use practices, respectively. Fine and Grey subdistribution hazard model was used. Of 1,311 COVID-19 and 58,917 non-COVID-19 inpatients, 333 (25.4%) and 18,837 (32.0%) received a parenteral antibiotic for at least four consecutive days. Proportion of patients having BC taken within \u00b11 calendar day of parenteral antibiotics being started was higher in COVID-19 than in non-COVID-19 patients (21.0% [70/333] vs. 18.7% [3,529/18,837]; p<0.001). Cumulative incidence of having a BC taken within 28 days was higher in COVID-19 than in non-COVID-19 patients (44.7% [149/333] vs. 33.2% [6,254/18,837]; adjusted subdistribution-hazard ratio [aSHR] 1.71, 95% confidence interval [CI] 1.47-1.99, p<0.001). The median time to discontinuation of parenteral antibiotics was longer in COVID-19 than in non-COVID-19 patients (13 days vs. 8 days; aSHR 0.73, 95%Cl 0.65-0.83, p<0.001). Routine electronic data could be used to inform diagnostic and antibiotic use practices in LMICs. In Indonesia, the proportion of timely blood culture is low in both COVID-19 and non-COVID-19 patients, and duration of parenteral antibiotics is longer in COVID-19 patients. Improving diagnostic and antimicrobial stewardship is critically needed.
\n \n\n \n \nAbstract\n\nBackground\nUncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines.\n\n\nMethods\nIn a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0\u20137) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907).\n\n\nResults\nThe 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%\u201373%).\n\n\nConclusions\nParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.\n
\n \n\n \n \nBackground Glucose-6-phosphate dehydrogenase (G6PD) deficiency represents a barrier to the full deployment of anti-malarial drugs for vivax malaria elimination and of first-line antibiotics. Lack of established reference ranges for G6PD activity in breast-fed infants puts them at risk of drug-induced haemolysis and restricts access to safe treatment of their mothers. Methods The present work was undertaken to establish age-specific G6PD normal values using the gold standard spectrophotometric assay to support the future clinical use of tafenoquine in lactating women and safer antibiotic treatment in infants. Results Spectrophotometric results collected at the Thai-Myanmar border from 78 healthy infants between the ages of 2 and 6 months showed a trend of decreased enzymatic activity with increasing age (which did not reach statistical significance when comparing 2\u20133 months old against 4\u20136 months old infants) and provided a reference normal value of 100% activity for infants 2\u20136 months old of 10.18IU/gHb. Conclusions Normal reference G6PD activity in 2\u20136-month-old infants was approximately 140% of that observed in G6PD normal adults from the same population. Age specific G6PD activity thresholds should be used in paediatric populations to avoid drug-induced haemolysis.
\n \n\n \n \nThe pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding parasite-induced intestinal injury and changes in the human intestinal microbiota composition in patients with Plasmodium falciparum malaria. During the blood stage of P. falciparum infection, infected red blood cells adhere to the vascular endothelium, leading to widespread microcirculatory obstruction in critical tissues, including the splanchnic vasculature. This process may cause intestinal injury and gut leakage. Epidemiological studies indicate higher rates of concurrent bacteraemia in severe malaria cases. Furthermore, severe malaria patients exhibit alterations in the composition and diversity of the intestinal microbiota, although the exact contribution to pathophysiology remains unclear. Mouse studies have demonstrated that the gut microbiota composition can impact susceptibility to Plasmodium infections. In patients with severe malaria, the microbiota shows an enrichment of pathobionts, including pathogens that are known to cause concomitant bloodstream infections. Microbial metabolites have also been detected in the plasma of severe malaria patients, potentially contributing to metabolic acidosis and other clinical complications. However, establishing causal relationships requires intervention studies targeting the gut microbiota.
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