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Monitoring the Long-Term Effectiveness of Miltefosine in Indian Post-Kala-Azar Dermal Leishmaniasis.
Post-kala-azar dermal leishmaniasis (PKDL), the dermal sequel to visceral leishmaniasis (VL), is characterized by hypopigmented macules (macular) and/or papules and nodules (polymorphic). Post-kala-azar dermal leishmaniasis plays a significant role in disease transmission, emphasizing the need for monitoring chemotherapeutic effectiveness. Accordingly, this study aimed to quantify the parasite burden in PKDL patients after treatment with miltefosine by a quantitative polymerase chain reaction (qPCR). A Leishmania kinetoplastid gene-targeted qPCR was undertaken using DNA from skin biopsy specimens of patients with PKDL at three time points, i.e., at disease presentation (week 0, n = 157, group 1), upon completion of treatment (week 12, n = 39, group 2), and at any time point 6 months after completion of treatment (week ≥36, n = 54, group 3). A cycle threshold (Ct) <30 was considered the cutoff for positivity, and load was quantified as the number of parasites/µg genomic DNA (gDNA); cure was considered when samples had a Ct >30. The parasite load at disease presentation (group 1) was 10,769 (1,339-80,441)/µg gDNA (median [interquartile range]). In groups 2 and 3, qPCR results were negative in 35/39 cases (89.7%) and 48/54 cases (88.8%), respectively. In the 10/93 (10.8%) qPCR-positive cases, the parasite burdens in groups 2 and 3 were 2,420 (1,205-5,661)/µg gDNA and 22,195 (5,524-100,106)/µg gDNA, respectively. Serial monitoring was undertaken in 45 randomly selected cases that had completed treatment; all cases in groups 2 or 3 had a Ct >30, indicating cure. Overall, qPCR confirmed an 89.2% cure (as 83/93 cases showed parasite clearance), and the persistent qPCR positivity was attributed to nonadherence to treatment or unresponsiveness to miltefosine and remains to be investigated.
Global spatiotemporal analysis of suicide epidemiology and risk factor associations from 2000 to 2019 using Bayesian space time hierarchical modeling.
Suicide is a significant global public health issue, with marked disparities in rates between countries. Much of the existing research has concentrated on high-income nations, creating a gap in the understanding of global suicide epidemiology. This study aims to address this gap through a comprehensive spatiotemporal analysis of global suicide trends from 2000 to 2019. Data were collected from the Global Health Observatory, encompassing 183 countries across five regions. Bayesian spatiotemporal modeling and cluster detection techniques were employed to assess variations in suicide rates and identify high-risk clusters, alongside examining associations with various risk factors. The findings indicate diverse global and regional age-standardized suicide trends, with overall rates decreasing from an average of 12.97 deaths per 100,000 population in 2000 to 9.93 deaths per 100,000 in 2019. Significant regional variations were noted, particularly in Europe, Asia, and Africa, where high-risk clusters were identified. Additionally, age and sex-specific trends revealed consistently higher rates among males, although these rates have been declining over time. Spatial maps illustrated hotspots of elevated suicide rates, which can inform targeted intervention strategies. Risk factor analysis further revealed associations with socioeconomic and health indicators. The results underscore the necessity for tailored prevention strategies and highlight the importance of international collaboration and surveillance systems in addressing the complexities of global suicide epidemiology. This study contributes valuable insights into suicide patterns and offers implications for mental health policies worldwide.
Neurological manifestations of COVID-19 in adults and children.
Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.
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.
Creating different global health futures: mapping the health research ecosystem and taking decolonial action.
This paper promotes reflexive consideration of health research practices using a decolonisation lens. We propose both incremental and more radical action in five domains: knowledge production, funding and programmes, dissemination, uptake, and education and training. We suggest four steps towards transformation and share a reflexive tool to operationalise these steps.
Infant-level and child-level predictors of mortality in low-resource settings: the WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort
Background: Despite impressive reductions in overall global child mortality, the rate of decline has slowed during the past decade. Current guidelines for the care of paediatric patients in low-resource settings mostly focus on broad clinical syndromes or undernutrition rather than children's individual contextualised risk. We aimed to identify readily assessable child-level characteristics that can predict mortality risk in a range of community and health-care settings in high-burden settings. Methods: The WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort (WHO-CMRS) included pooled data from individual children enrolled in observational or randomised controlled trials in low-income and middle-income countries. The criteria for inclusion of a dataset were documentation of age, weight, vital status, and date of death, and at least two observations per participant younger than 60 months. To calculate odds ratios, we built generalised linear mixed effects regression (glmer) models with each child and each study as random intercepts and time interval as the offset. In all analyses, the outcome was defined as death within the respective observation period of the child. From the glmer models, we predicted absolute risk of death per child-month associated with risk exposures separately and combined with anthropometry according to the following age groups: 0–5 months, 6–11 months, 12–23 months, and 24–59 months. Studies were grouped according to population types studied: the general population, populations selected based on anthropometric criteria, and populations selected based on the presence of illness. Findings: We analysed pooled data from WHO-CMRS, including 75 287 children from 33 studies done in 17 countries between Jan 1, 2001, and Dec 31, 2021. During a total of 69 085 child-years of follow-up, 2805 (3·7%) children died. Age younger than 24 months, low anthropometry, preterm birth, low birthweight, and absence of breastfeeding (either was breastfeeding not offered or an underlying illness interfered with breastfeeding practices) were each associated with increased mortality: risks declined with increasing age. The highest absolute mortality risk was among the youngest children (age 0−5 months), with a weight-for-age Z score of less than −3 (ie, a predicted absolute risk of 11·0 [95% CI 6·2−19·5] per 1000 child-months in general population studies). Risks were additive: underlying risk exposures such as low birthweight and preterm birth added to the mortality risks in children with anthropometric deficit. For example, children aged 0−5 months with a weight-for-age Z score of less than −3 and a history of preterm birth had a predicted absolute mortality risk of 40·1 (95% CI 22·0−72·1). However, overall mortality and the association between child-level characteristics and mortality differed according to the type of study population and child age. Interpretation: Risk assessments combining individual child-level characteristics including anthropometry can enable programmes to identify children at high and lower risk of mortality and, thereafter, differentiate care accordingly. Such a strategy could reduce mortality and optimise health system efficiency and effectiveness. Funding: US Agency for International Development. Translations: For the Spanish and French translations of the abstract see Supplementary Materials section.
Putting health facilities on the map: a renewed call to create geolocated, comprehensive, updated, openly licensed dataset of health facilities in sub-Saharan African countries.
BackgroundHealthcare service provision, planning, and management depend on the availability of a geolocated, up-to-date, comprehensive health facility database (HFDB) to adequately meet a population's healthcare needs. HFDBs are an integral component of national health system infrastructure forming the basis of efficient health service delivery, planning, surveillance, and ensuring equitable resource distribution, response to epidemics and outbreaks, as well as for research. Despite the value of HFDBs, their availability remains a challenge in sub-Saharan Africa (SSA). Many SSA countries face challenges in creating a HFDB; existing facility lists are incomplete, lack geographical coordinates, or contain outdated information on facility designation, service availability, or capacity. Even in countries with a HFDB, it is often not available open-access to health system stakeholders. Consequently, multiple national and subnational parallel efforts attempt to construct HFDBs, resulting in duplication and lack of governmental input, use, and validation.Main bodyIn this paper, we advocate for a harmonized SSA-wide HFDB. To achieve this, we elaborate on the steps required and challenges to overcome. We provide an overview of the minimum attributes of a HFDB and discuss past and current efforts to collate HFDBs at the country and regional (SSA) levels. We contend that a complete HFDB should include administrative units, geographic coordinates of facilities, attributes of service availability and capacity, facilities from both public and private sectors, be updated regularly, and be available to health system stakeholders through an open access policy. We provide historical and recent examples while looking at key issues and challenges, such as privacy, legitimacy, resources, and leadership, which must be considered to achieve such HFDBs.ConclusionA harmonized HFDB for all SSA countries will facilitate efficient healthcare planning and service provision. A continental, cross-border effort will further support planning during natural disasters, conflicts, and migration. This is only achievable if there is a regional commitment from countries and health system stakeholders to open data sharing. This SSA-wide HFDB should be a government-led initiative with contributions from all stakeholders, ensuring no one is left behind in the pursuit of improved health service provision and universal health coverage.
Wrangling Real-World Data: Optimizing Clinical Research Through Factor Selection with LASSO Regression.
Data-driven approaches to clinical research are necessary for understanding and effectively treating infectious diseases. However, challenges such as issues with data validity, lack of collaboration, and difficult-to-treat infectious diseases (e.g., those that are rare or newly emerging) hinder research. Prioritizing innovative methods to facilitate the continued use of data generated during routine clinical care for research, but in an organized, accelerated, and shared manner, is crucial. This study investigates the potential of CURE ID, an open-source platform to accelerate drug-repurposing research for difficult-to-treat diseases, with COVID-19 as a use case. Data from eight US health systems were analyzed using least absolute shrinkage and selection operator (LASSO) regression to identify key predictors of 28-day all-cause mortality in COVID-19 patients, including demographics, comorbidities, treatments, and laboratory measurements captured during the first two days of hospitalization. Key findings indicate that age, laboratory measures, severity of illness indicators, oxygen support administration, and comorbidities significantly influenced all-cause 28-day mortality, aligning with previous studies. This work underscores the value of collaborative repositories like CURE ID in providing robust datasets for prognostic research and the importance of factor selection in identifying key variables, helping to streamline future research and drug-repurposing efforts.
A comparison of national seasonal influenza treatment guidelines across the Asia Pacific region.
Seasonal influenza leads to 2-3 million infections and up to 650,000 global deaths annually, with particularly high mortality in Asia and relatively low annual vaccination rates for prevention. Relatively lower attention is paid to antiviral treatment as a facet of influenza response strategy both in research and national policy. This study compares national influenza treatment guidelines across countries in the Asia Pacific region, and assesses the antiviral recommendations, comprehensiveness, availability, and quality, compared with World Health Organisation (WHO) guidelines. Ministry of Health websites were searched, and key stakeholders were contacted to obtain national influenza treatment guidelines. Official guidelines detailing pharmacologic treatment for seasonal influenza were included. Key data for comparison were extracted and quality appraisal was conducted using the AGREE II instrument. Out of 49 countries and areas in the World Health Organisation Western Pacific and South-East Asia regions, under half (14/49; 28.6%) had established national influenza treatment guidelines. Nine (9/49; 18.4%) reported no seasonal flu guidelines at all, and information could not be obtained for 25 (51.0%). All guidelines recommend oseltamivir in line with WHO recommendations, although rationale and evidence reviews were often missing. There was variation in recommendations for other antivirals, indications for treatment, definitions of severity and recency of publication. The AGREE II tool quality assessments revealed the highest average scores were observed in the 'presentation' domain and lowest scores in 'editorial independence' and 'rigour of development' domains, demonstrating limited evidence-based guideline development. The variability in recommendations and definitions highlight the need for a stronger evidence base with direct comparisons of antiviral treatment for hard and soft endpoints, and improvements in systematic guideline development. Established treatment guidelines are a key component of national influenza response strategy and in the post-covid pandemic era, renewed attention to seasonal influenza management is surely warranted.