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Post-mortem study of endemic human coronaviruses (HCoV-NL63, OC43, 229E and HKU-1) in deaths of children under five in low- and middle-income countries: Findings from the Child Health and Mortality Prevention Surveillance (CHAMPS) study
No full textBackground: Endemic human coronaviruses (HCoV-229E, HKU1, NL63, and OC43) are common causes of mild or asymptomatic respiratory infections in children but are considered rare causes of death. Methods: We evaluated pediatric deaths from January 2017 through December 2022. A panel of experts determined the cause of death (CoD) by reviewing available data, including pathological and molecular findings from minimally invasive tissue sampling (lung tissues, blood, CSF, and nasopharyngeal swabs), clinical records, and verbal autopsies. Results: Endemic HCoV were detected in the respiratory samples of 3 % (n = 86/3357) of enrolled decedents: 1 % (n = 12/2043) of neonates, 5 % (n = 35/681) of infants and 6 % (n = 39/633) of children deaths. However, HCoVs were attributed as the CoD in only two cases — both involving young infants with underlying birth defects and severe wasting, who succumbed to polymicrobial hospital-acquired infections involving HCoV-OC43, Klebsiella pneumoniae, and Acinetobacter baumannii. Amongst the remaining 84 decedents in whom an HCoV was detected, 82 % (n = 69/84; median Ct of 25.34; range: 15.28–36.17) were deaths attributed to other infections, including 54 % (n = 32/69; median Ct of 23.86; range: 15.28–35.2) with lower respiratory infections determined to be the CoD. The bulk of these deaths (96 %, n = 66/69) were attributed to other pathogens – Plasmodium falciparum (27 %, n = 19/69), K. pneumoniae (23 %, n = 16/69), Streptococcus pneumoniae (20 %, n = 14/69), Escherichia coli (16 %, n = 11/69) and Cytomegalovirus (10 %, n = 7/69). Conclusion: Although endemic HCoV was identified in children who died of respiratory infections, it was rarely attributed to being in the CoD. Nevertheless, further research is warranted to explore the potential role of HCoVs in LRTI pathogenesis and their impact on facilitating more pathogenic infections.</p
The Effects on the Growth of HIV-exposed Uninfected Infants of Initiating Dolutegravir-based Versus Efavirenz-based cART in Late Pregnancy (DolPHIN-2)
Get PDFBackground: In 2019, the World Health Organization (WHO) changed its recommendations for pregnant women living with HIV from efavirenz-based to dolutegravir-based therapy due to its superior efficacy, tolerability and resistance profile. Perinatal exposure to antiretrovirals may influence infant growth, but limited data exist on the effects of specific regimens over time. Aim: This study aimed to compare growth trajectories over the first 72 weeks of life among infants exposed to dolutegravir-based versus efavirenz-based therapy during late pregnancy. Methods: The DolPHIN-2 trial was a randomized, open-label trial conducted in South Africa and Uganda, researching the efficacy of dolutegravir-based versus efavirenz-based therapy in pregnant women living with HIV, initiating treatment in the third trimester. In this secondary analysis, we compared growth trajectories until 72 weeks postpartum between HIV-exposed uninfected infants perinatally exposed to dolutegravir-based versus efavirenz-based therapy. Measures of infant weight, length and head circumference were converted to WHO-defined weight-for-age, weight-for-length, length-for-age and head circumference-for-age Z-scores. Subsequently, Z-scores were compared across treatment arms, using linear mixed-effect models. Results: After exclusions, 232 infants remained (dolutegravir: n = 116; efavirenz: n = 116). In both crude models and models adjusted for study site and maternal height, length-for-age Z-scores were 0.277 units higher in the dolutegravir arm. No statistically significant impact of treatment was observed for other outcomes. In both study arms, a decline in mean length-for-age Z-scores occurred over the first 72 weeks, while mean weight-for-age Z-scores declined between weeks 48 and 72. Conclusion: Our data support the WHO in recommending dolutegravir-based therapy over efavirenz-based therapy in pregnant women living with HIV.</p
The WHO Bacterial Priority Pathogens List 2024: a prioritisation study to guide research, development, and public health strategies against antimicrobial resistance
Get PDFBackground: The 2017 WHO Bacterial Priority Pathogens List (BPPL) has been instrumental in guiding global policy, research and development, and investments to address the most urgent threats from antibiotic-resistant pathogens, and it is a key public health tool for the prevention and control of antimicrobial resistance (AMR). Since its release, at least 13 new antibiotics targeting bacterial priority pathogens have been approved. The 2024 WHO BPPL aims to refine and build on the previous list by incorporating new data and evidence, addressing previous limitations, and improving pathogen prioritisation to better guide global efforts in combating AMR. Methods: The 2024 WHO BPPL followed a similar approach to the first prioritisation exercise, using a multicriteria decision analysis framework. 24 antibiotic-resistant bacterial pathogens were scored based on eight criteria, including mortality, non-fatal burden, incidence, 10-year resistance trends, preventability, transmissibility, treatability, and antibacterial pipeline status. Pathogens were assessed on each of the criteria on the basis of available evidence and expert judgement. A preferences survey using a pairwise comparison was administered to 100 international experts (among whom 79 responded and 78 completed the survey) to determine the relative weights of the criteria. Applying these weights, the final ranking of pathogens was determined by calculating a total score in the range of 0–100% for each pathogen. Subgroup and sensitivity analyses were conducted to assess the impact of experts’ consistency, background, and geographical origin on the stability of the rankings. An independent advisory group reviewed the final list, and pathogens were subsequently streamlined and grouped into three priority tiers based on a quartile scoring system: critical (highest quartile), high (middle quartiles), and medium (lowest quartile). Findings: The pathogens’ total scores ranged from 84% for the top-ranked bacterium (carbapenem-resistant Klebsiella pneumoniae) to 28% for the bottom-ranked bacterium (penicillin-resistant group B streptococci). Antibiotic-resistant Gram-negative bacteria (including K pneumoniae, Acinetobacter spp, and Escherichia coli), as well as rifampicin-resistant Mycobacterium tuberculosis, were ranked in the highest quartile. Among the bacteria commonly responsible for community-acquired infections, the highest rankings were for fluoroquinolone-resistant Salmonella enterica serotype Typhi (72%), Shigella spp (70%), and Neisseria gonorrhoeae (64%). Other important pathogens on the list include Pseudomonas aeruginosa and Staphylococcus aureus. The results of the preferences survey showed a strong inter-rater agreement, with Spearman's rank correlation coefficient and Kendall's coefficient of concordance both at 0·9. The final ranking showed high stability, with clustering of the pathogens based on experts’ backgrounds and origins not resulting in any substantial changes to the ranking. Interpretation: The 2024 WHO BPPL is a key tool for prioritising research and development investments and informing global public health policies to combat AMR. Gram-negative bacteria and rifampicin-resistant M tuberculosis remain critical priority pathogens, underscoring their persistent threat and the limitations of the current antibacterial pipeline. Focused efforts and sustained investments in novel antibacterials are needed to address AMR priority pathogens, which include high-burden antibiotic-resistant bacteria such as Salmonella and Shigella spp, N gonorrhoeae, and S aureus. Beyond research and development, efforts to address these pathogens should also include expanding equitable access to existing drugs, enhancing vaccine coverage, and strengthening infection prevention and control measures. Funding: This work is based on the development of the 2024 WHO BPPL, which was conducted by the WHO AMR Division through grants from the Government of Austria, the Government of Germany, the Government of Saudi Arabia, and the European Commission's Health Emergency Preparedness and Response Authority.</p
The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake
Get PDFBackgroundInsecticide resistance in disease-transmitting arthropods of agricultural, veterinary, and public health significance poses a significant threat to vector control programs worldwide. Previous studies demonstrated that blood-feeding arthropod vectors experience high mortality when ingesting blood containing inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPPD), the second enzyme in tyrosine metabolism. This study investigated the mosquitocidal efficacy of HPPD inhibitors from the β-triketone class of herbicides against both susceptible and pyrethroid-resistant strains of three major disease vector species, including mosquitoes that transmit historical diseases such as malaria, reemerging infections such as dengue and Zika, and emerging viral threats such as Oropouche and Usutu viruses.MethodsFour HPPD inhibitors (nitisinone, mesotrione, sulcotrione, and tembotrione) were screened using glass plate tarsal bioassays at 125 mg/m2 against bloodfed Anopheles gambiae s.s. Kisumu. Nitisinone was selected for evaluation against susceptible and pyrethroid-resistant strains of An. gambiae s.s. Kisumu, An. gambiae s.l. Tiassalé 13, An. coluzzii VK7 2014, Culex quinquefasciatus Muhezha, and Aedes aegypti New Orleans. Mosquitocidal activity was assessed using glass plate tarsal contact bioassays, topical application assays (0.0001% to 1% w/v), and modified Centers for Disease Control and Prevention (CDC) bottle bioassays (0–30 μg per bottle). Female mosquitoes aged 3–5 days were bloodfed within 1 h before exposure. Mortality was recorded at 30 min and 24, 48, and 72 h post-exposure under controlled conditions. A total of 3 biological replicates of 30 mosquitoes per treatment were used.ResultsOnly nitisinone, and not mesotrione, sulcotrione, or tembotrione, exhibited significant mosquitocidal activity when bloodfed mosquitoes were exposed to treated surfaces. No significant differences in susceptibility to nitisinone were observed between insecticide-susceptible An. gambiae and strains harboring multiple insecticide-resistance mechanisms. The compound demonstrated consistent efficacy across all three mosquito species tested, indicating broad-spectrum activity against major disease vectors.ConclusionsThis study demonstrates that nitisinone exhibits a novel mode of action distinct from current Insecticide Resistance Action Committee (IRAC) classifications by specifically targeting blood digestion processes. Its efficacy against resistant strains and potential for integration into existing vector control interventions, such as treated bednets and indoor residual spraying, highlight nitisinone as a promising candidate for expanding strategies against malaria, dengue, Zika, and other emerging viral diseases
The CSF transcriptome in adults with pneumococcal meningitis reveals compartmentalised host inflammatory responses associated with mortality
Get PDFPneumococcal meningitis (PM) has persistently poor clinical outcomes, especially in sub-Saharan Africa. To better characterise the inflammatory response and identify factors associated with mortality we compared paired peripheral blood and cerebrospinal fluid (CSF) transcriptomes before the initiation of antibiotics in Malawian adults with proven PM. Blood transcriptional profiles were obtained in 28 patients with PM, with simultaneous paired with CSF profiles available for 13 patients. 15/28 (52 %) patients died. Comparison of the transcriptome between CSF and blood compartments showed upregulation of 2293 differentially expressed genes in CSF and 909 in blood; enriched pathways in CSF included inflammasome activity and neutrophil migration/activation, contrasting with enrichment for pathways including platelet and endothelial activation, cell cycle, cytokine release and oxidative stress in the blood transcriptome. Comparison of CSF profiles between survivors and non-survivors revealed 1829 differentially expressed genes. Non-survivor CSF was enriched for multiple innate inflammatory pathways, including IL-17A and Type 1 interferons and proteolysis. In contrast, minimal transcriptomic differences between outcome groups were detected in blood. Inflammation in PM is characterised by compartmentalised responses in blood and CSF. Poorer outcomes are associated with an dysregulated innate immune host response to S. pneumoniae in the CSF compartment.<p/
Mapping and phylogeny of Biomphalaria snail in the Adamawa Region of Cameroon:A step towards vector control and schistosomiasis elimination
Get PDFBACKGROUND: Schistosomiasis is the world's second-most important parasitic disease affecting humans. Among the two main forms of the disease, intestinal schistosomiasis due to Schistosoma mansoni is predominant in Cameroon, where its intermediate host Biomphalaria spp. is widely distributed, particularly in the Adamawa plateau. As a prerequisite to targeted vector control for effective elimination of intestinal schistosomiasis infection, we mapped the geographical distribution of Biomphalaria snails in the Adamawa Region. METHODOLOGY/PRINCIPAL FINDINGS: A total of 43 human-water contact sites were visited across the Adamawa Region for snail collection. Snail species were identified morphologically and with PCR-RFLP technique at the ITS2 rDNA region using the HpaII restriction enzyme. The genus Biomphalaria was identified at 13 sites (30.2%), four sites (9,3%) harboured Gyraulus species firstly identified as Biomphalaria with shell morphology, and 22 sites (51,16%) were free from any snail species. Two Biomphalaria species were identified, Biomphalaria pfeifferi in 12 water contact sites, and Biomphalaria camerunensis was found only in one site (Djalingo, Vina Division), and it was the first report of this species in the Northern Cameroon (above the 6° latitude North). Morphologic identification was supported by PCR-RFLP results and sequencing revealed three haplotypes for Biomphalaria pfeifferi and one haplotype for Biomphalaria camerunensis. The studied populations were stable according to neutrality tests (Tajima's D and Fu Fs) and no signal of gene flow was observed between them.CONCLUSIONS/SIGNIFICANCE: This study confirmed the presence of Biomphalaria pfeifferi in the Adamawa Region and reported for the first time B. camerunensis above 6° of Latitude North, thus deserving further monitoring to assess its current distribution in Cameroon.</p
Spatial regulation of CD8<sup>+</sup> T cells at the HLA-E-NKG2A axis drives HIV persistence in lymph node B cell follicles
Get PDFB cell follicles (BCFs) in the lymph node are a major sanctuary for HIV reservoirs. Immune regulatory mechanisms hindering cytolytic CD8+ responses at these sites are poorly characterized, likely enabling HIV persistence. Spatial transcriptomics and high-dimensional histocytometry were used to define CD8+ T cell function and immune regulation in lymph node (LN) follicles of people living with HIV (PLWH), at various stages of antiretroviral therapy (ART) treatment. Histocytometry demonstrated that CD8+ T cells infiltrating BCFs mostly lacked granzyme B expression, coinciding with reduced chromatin access at cytolytic gene loci in dissociated lymph node cells. Spatial transcriptomics confirmed the immune regulatory microenvironment of HIV-infected BCFs, particularly exhibiting upregulation of HLA-E. Additional fluorescence-activated cell sorting (FACS) analysis identified a subset of LN CD8+ T cells expressing the NKG2A-interacting partner of HLA-E, with reduced granzyme B expression. These findings suggest that regulation of follicular CD8+ T cells at the HLA-E-NKG2A axis may be a key mechanism for HIV immune evasion.</p
Novel Microwave Sensor for Quality Assurance of Indoor Residual Spraying
Get PDFVector-borne diseases, such as visceral leishmaniasis or malaria, are a significant global burden, particularly in low- and middle-income countries in regions with high parasite prevalence. Indoor residual spraying is one of the most effective control tools, if performed effectively. Current World Health Organization (WHO)-recommended quality assurance methods are costly, require skilled staff, and are time consuming. This letter presents the development of a novel microwave sensor for quality assurance of indoor residual spraying. The developed prototype was tested in controlled laboratory settings, and during two field studies conducted during dry and wet seasons in Bihar, India. The results demonstrated the potential of a rapid, nondestructive microwave sensor system for detecting alpha-cypermethrin residues, offering an improvement over current quality assurance methods. The sensor achieved high cross-validation accuracy in controlled laboratory settings (mean 100%, standard deviation 0%), while the performance in the field studies was reduced (mean 84.63%, standard deviation 1.98%) due to real-world complexities. Future development steps will include the miniaturization of the sensor system and the implementation of advanced signal processing techniques to reduce noise and compensate for environmental effects
Prolonged Hospitalization Among Children Aged < 5 Years Admitted With Acute Gastroenteritis at Siaya County Referral Hospital, in Rural Western Kenya:2010–2020
Get PDFBackground: Acute gastroenteritis (AGE) causes substantial morbidity and mortality in children < 5 years old accounting for 9 million hospitalizations. Prolonged hospitalization can cause dire consequences to the patient and healthcare system. However, data on factors associated with prolonged hospitalization for AGE in developing countries are limited. Objectives: We aim to describe trends and assess factors associated with prolonged hospitalization among children < 5 years admitted with AGE in western Kenya. Methods: Children with AGE (≥ 3 loose stools and/or ≥ 1 episode of unexplained vomiting with loose stool within 24 h) hospitalized at Siaya County Referral Hospital from January 2010 through December 2020 were included. Prolonged hospitalization was defined as admission for ≥ 5 days. Trends of prolonged AGE hospitalizations were assessed using Cochran–Armitage trend test, while factors associated with prolonged hospitalization for AGE were determined by unconditional logistic regression. Results: Of the 12,546 all-cause admissions among children < 5 years, 2271 (18.1%) children had AGE; 681 (32.8%) had prolonged hospitalization. There was a significant difference in the prevalence of prolonged hospitalization over time, with a peak in 2010 (42.8%) and a low in 2016 (10.8%). Older children (12–23 months: (adjusted odds ratio [aOR]: 0.69; 95% confidence interval [95% CI]: 0.49–0.97)) and those who vomited everything (aOR: 0.69; 95% CI: 0.52–0.90) were less likely to have prolonged hospitalization. Children who had a bulging fontanel (aOR: 3.21; 95% CI: 1.12–9.20) or chest in drawing (aOR: 1.49; 95% CI: 1.02–2.18) or were severely stunted (aOR: 2.67; 95% CI: 1.89–3.79) or severely wasted (aOR: 2.34; 95% CI: 1.65–3.30) were more likely to have prolonged hospitalization. Conclusion: Children with severe diarrheal illness with malnutrition are at high risk of prolonged hospitalization. Targeted interventions such as increased clinical and diagnostics monitoring for at-risk children with AGE may need to be prioritized to reduce possible prolonged hospitalization.</p
Economic burden and cost-effectiveness of treatments for open tibia fractures in Malawi : Economic analysis of a multicentre prospective cohort study
Get PDFBackground Open tibia fractures result in substantial lifelong disability for patients, and are expensive to treat. As the injury typically affects young working men, the societal costs from open tibia fractures are likely to also be high in low income countries, but remain largely unknown. We therefore investigated the overall societal costs and cost-effectiveness of different orthopaedic treatments at one year following an open tibia fracture in Malawi. Methods This study was a cost-utility analysis nested in a prospective cohort study from the healthcare- and societal-payer perspectives with a one-year time horizon. We obtained quality-adjusted life years (QALYs) from the EuroQoL 5 Dimension 3 Level (EQ-5D-3L) and patient lost productivity estimates at 6 weeks, and 3, 6, and 12 months post-injury. QALYs were calculated from utility scores were modelled within a hierarchical Bayesian multivariate modelling framework that jointly estimated individual-level trajectories in EQ-5D-3L scores and costs over follow-up. Direct treatment costs were obtained from a micro-costing study, and staff interviews at tertiary and district hospitals. Cost-effectiveness was reported in terms of societal cost per quality-adjusted life year (QALY). All costs were reported in 2021 United States dollars (USD). Results Between February 2021 and March 2022, 287 participants with open tibia fractures were included. There were substantial costs to participants one year following injury with 42% (n = 112) working with a median monthly household income of US7−90) compared to 89% (n = 255) working pre-injury, with a median monthly household income of US36−144). The posterior median of societal costs at one year varied between US-751−2,389) for treatment with plaster of Paris (POP) in a district hospital for a Gustilo III injury, to US995−5027) for intramedullary nail in central hospital for a Gustilo III injury. The largest cost-effectiveness from a societal perspective was between an intramedullary nail and amputation for a Gustilo III injury with a posterior mean of US$2,290 (95%HDI: 36−4,547) per QALY.Conclusion The main finding was that open tibia fractures result in significant costs to patients, the healthcare system and society in Malawi. Although the funding of orthopaedic treatment can be difficult in countries with very limited healthcare budgets, the costs to society of ignoring this issue are very high. A re-balancing of health budgets (including from government and donors) is needed to prioritise trauma care to reduce the growing societal economic burden from injury.</p