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High versus low dose of 14 days treatment of primaquine in Plasmodium vivax infected patients in Cambodia: a randomised open-label efficacy study
No full textBackground The WHO malaria treatment guidelines recommend a total dose in the range of 3·5 to 7·0 mg/kg of primaquine to eliminate Plasmodium vivax ( P. vivax ) hypnozoites and prevent relapses. There are however indications that for tropical P. vivax isolates, notably from Southeast Asia, the lower dose of 3·5 mg/kg is insufficient. Determining the most effective regimen to eliminate P. vivax hypnozoites is needed to achieve elimination of this malaria parasite. Methods We conducted an open-label randomised controlled trial in Kampong Speu province, Western Cambodia. P. vivax infected patients with uncomplicated malaria, diagnosed at the community level or in health centres of the province, were offered to participate. Patients aged less than 15 years old, and pregnant or breastfeeding women were excluded. Enrolled patients were treated with a blood schizonticidal artesunate regimen of 2 mg/kg/day for 7 days. Upon enrolment, patients’ glucose-6-phosphate dehydrogenase (G6PD) activity was determined. G6PD normal patients were randomly assigned (2:2:1) to receive either (i) 3·5 mg/kg (low dose as 0·25 mg/kg/day) or (ii) 7·0 mg/kg (high dose as 0·5 mg/kg/day) of primaquine over 14 days or (iii) no primaquine as comparator arm. G6PD deficient patients were assigned to the no-primaquine comparator arm. Randomisation was done by blocks of 5 using sealed envelopes. Upon enrolment, patients were relocated to the study site in Aoral town where no malaria transmission occurs to ensure that they were not reinfected during their 90-day follow-up. After 90 days of relocation, G6PD normal patients in the no-primaquine arm were provided 3·5 mg/kg for 14 days of primaquine to be taken unsupervised. At day 90, all the patients returned home and they were further followed monthly for three months until day 180. The primary outcome was the treatment failure rate defined as the proportion of patients with at least one P. vivax recurrence within 90 days of relocated follow-up. All patients that completed treatment and complied with relocation without interruption before any recurrence was detected were included in the primary efficacy analysis. All patients enrolled and assigned to an intervention arm were included in the safety analysis. The study is registered on ClinicalTrials.gov ( NCT04706130 ). Findings Between Nov 10, 2021, and Feb 10, 2024, a total of 160 patients were enrolled and 156 were allocated to one of the three study arms. Of these, 37 G6PD deficient patients were assigned to the no primaquine arm and 119 G6PD normal patients were randomised: 24 in the no primaquine arm, 49 in the primaquine 3·5 mg/kg arm, and 46 in the primaquine 7·0 mg/kg arm. The proportion of participants with at least one P. vivax recurrence within 90 days in the no primaquine arm was 81·4% (95% CI 69·6-89·2). The proportion of participants with recurrence was higher in the low dose primaquine arm (24·4%, 95% CI 14·2-38·7) compared to the high primaquine arm (4·7%, 95% CI 0·8-15·5, p=0·0141) resulting in a hazard ratio of high dose primaquine compared to low dose of 0·17 (95% CI 0·04-0·79, p=0·0229). Both primaquine arms were well tolerated. Interpretation Not providing primaquine to patients led to a considerable rate of P. vivax recurrence. The risk of P. vivax recurrence was 5·9 times lower for the 7·0 mg/kg of primaquine treatment compared to 3·5 mg/kg. Tolerability and safety of both primaquine regimens in G6PD normal individuals was comparable. Policy makers in Cambodia and most likely in other Southeast Asian countries should endorse the 7·0 mg/kg of primaquine regimen to reduce the risk of P. vivax relapses. Funding National Institutes of Health (R01AI146590) Research in context Evidence before this study The WHO treatment guidelines for preventing Plasmodium vivax relapses using primaquine recommend a range of 3·5-7·0 mg/kg. These guidelines mention that for P. vivax infections acquired in Southeast Asia and Oceania, 7·0 mg/kg should be preferred. We searched Pubmed for randomized controlled trials studies containing the terms “vivax” and “primaquine” published between 1990 and November 2024, with no language restrictions, to identify studies comparing primaquine regimen to treat P. vivax infections. Our search retrieved only two studies comparing head-to-head the efficacy of 3·5mg/kg with 7·0 mg/kg primaquine administered over a same duration of 14 days but were both conducted in South Asia and both showed similar efficacy of high dose compared to low dose primaquine. No studies compared 3·5 and 7·0 mg/kg of primaquine administered over 14 days in South East Asian countries. Added value of this study This randomised controlled trial compared the efficacy of a total dose of 3·5 mg/kg and 7·0 mg/kg of primaquine over 14 days to prevent relapses of P. vivax in Cambodia. Our study design minimized confounding factors affecting therapeutic efficacy evaluation. This study confirms that 7·0 mg/kg has greater efficacy to prevent recurrences than the low 3·5mg/kg regimen, with comparable safety and tolerability in G6PD normal patients from Cambodia. Implications of all the available evidence Our results confirm that 7·0 mg/kg of primaquine should be recommended to prevent relapses in P. vivax infections acquired in Cambodia and most likely in South East Asia. National treatment guidelines in those countries should be changed to endorse this regimen rather than the 3·5 mg/kg
Complete genome sequence of two Hominenteromicrobium mulieris strains CIP 112194 and CIP 112527, isolated from a human fecal sample
No full textInternational audienceThe human gut microbiota is dominated by obligately anaerobic bacteria. A method based on species-targeted sorting using flow cytometry under anaerobic conditions has been performed to analyze the gut microbiome. This report describes the complete genome sequences of two Hominenteromicrobium mulieris strains CIP 112194 and CIP 112527 that were isolated from the feces of a healthy adult from France. This volunteer is a young adult having a vegetarian diet
Myocarditis and neutrophil-mediated vascular leakage but not cytokine storm associated with fatal murine leptospirosis
No full textInternational audienceBackgroundLeptospirosis is a globally neglected re-emerging zoonosis affecting all mammals, albeit with variable outcomes. Humans are susceptible to leptospirosis; infection with Leptospira interrogans species can cause severe disease in humans, with multi-organ failure, mainly affecting kidney, lung and liver function, leading to death in 10% of cases. Mice and rats are more resistant to acute disease and can carry leptospires asymptomatically in the kidneys and act as reservoirs, shedding leptospires into the environment. The incidence of leptospirosis is higher in tropical countries, and countries with poor sanitation, where heavy rainfall and flooding favour infection. Diagnosis of leptospirosis is difficult because of the many different serovars and the variety of clinical symptoms that can be confused with viral infections. The physiopathology is poorly understood, and leptospirosis is often regarded as an inflammatory disease, like sepsis.MethodsTo investigate the causes of death in lethal leptospirosis, we compared intraperitoneal infection of male and female C57BL6/J mice with 108Leptospira of two strains of pathogenic L. interrogans. One strain, L. interrogans Manilae L495, killed the mice 4 days after infection, whereas the other strain, L. interrogans Icterohaemorrhagiae Verdun, did not induce any major symptoms in the mice. On day 3 post infection, the mice were humanely euthanised and blood and organs were collected. Bacterial load, biochemical parameters, cytokine production and leucocyte population were assessed by qPCR, ELISA, cytometry and immunohistochemistry.FindingsNeither lung, liver, pancreas or kidney damage nor massive necroptosis or cytokine storm could explain the lethality. Although we did not find pro-inflammatory cytokines, we did find elevated levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES in the serum and organs of Leptospira-infected mice. In contrast, severe leptospirosis was associated with neutrophilia and vascular permeability, unexpectedly due to neutrophils and not only due to Leptospira infection. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.InterpretationDespite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed, in particular a lack of cytokine storm in acute leptospirosis. The fact that IL-10 was increased in infected mice may explain the lack of pro-inflammatory cytokines, emphasising the covert nature of Leptospira infections.Neutrophilia is a hallmark of human leptospirosis. Our findings confirm the ineffective control of infection by neutrophils and highlight their deleterious role in vascular permeability, previously only attributed to the ability of leptospires to damage and cross endothelial junctions.Finally, the identification of death due to myocarditis rather than kidney, liver or liver failure may reflect an overlooked but common symptom associated with poor prognosis in human leptospirosis.These features of neutrophilia and myocarditis are also seen in patients, making this mouse model a paradigm for better understanding human leptospirosis and designing new therapeutic strategies
Impacts of the COVID-19 pandemic on sepsis incidence, etiology and hospitalization costs in France: a retrospective observational study
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SifA-mediated Remodeling of the<i>Salmonella</i>-Containing Vacuole Prevents Bacterial Dormancy by Promoting Nutrient Accessibility
No full textInternational audienceSalmonella exploits a range of intracellular niches within host cells, adapting to different microenvironments that support its survival and replication. This niche diversity is mediated by bacterial effectors injected via the two type 3 secretion systems (T3SS). Salmonella resides either within membrane-bound Salmonella containing vacuoles (SCV) or they grow rapidly within the cytosol upon SCV rupture. Recently, we identified a third intracellular subpopulation, dormant Salmonella within modified vacuoles in epithelial cells, which can survive for up to 7 days in vitro. To explore how bacterial effectors influence the balance of these three subpopulations, we constructed a panel of mutants lacking genes encoding key effectors and examined their intracellular behaviors at 6 and 24 hours post-infection (hpi). Deletion of the T3SS-2 effector SifA significantly increased the dormant subpopulation at later infection time points, identifying SifA as the first known effector regulating bacterial dormancy in epithelial cells. SifA-induced Salmonella-induced filaments (SIFs) characterize the mature Salmonella-containing vacuole (SCV), and we observed that SIFs were needed for intravacuolar growth of Salmonella. We could show that SIF formation was critical for nutrient acquisition within the SCV; inhibition of SIF formation resulted in a higher proportion of dormant bacteria, akin to the effect of reduced glucose availability during infection. Both bacterial and host glycolysis pathways were required to prevent dormancy, as proper nutrient scavenging through SIF-mediated modification of the SCV is essential for maintaining a replicative, non-dormant state. These results underscore the importance of nutrient access, facilitated by reprogramming host endomembrane trafficking, for Salmonella to avoid dormancy and sustain active replication within its intracellular niche.</div
A genome-wide investigation of Mycoplasma hominis genes associated with gynecological infections or infertility
No full textInternational audienceBackground and aim Mycoplasma hominis is a human pathogenic bacterium that causes a wide range of genital infections and reproductive issues. Previously, based on an extended multilocus sequence typing scheme, we provided evidence for the segregation of M. hominis clinical strains into two distinct pathotypes: gynecological infections or infertility. Here, based on whole genome sequencing (WGS) data, we sought to provide a more refined picture of the phylogenetic relationship between these two M. hominis pathotypes, with the aim to delineate the underlying genetic determinants. Methods We carried out WGS of 62 Tunisian M. hominis clinical strains collected over a 17-year period. The majority of these clinical strains are associated with infertility ( n = 53) and the remaining nine isolates are from gynecological infections cases. An alignment-free distance-based procedure (Jolytree) was used to infer phylogenetic relationships among M. hominis isolates, while the phylogenetic method treeWAS was used to determine the statistical association between pathotypes of interest and genotypes at all loci. Results The total pangenome of M. hominis strains was found to contain 1,590 genes including 966 core genes and 592 accessory genes, representing 60 and 37% of the total genome, respectively. Collectively, phylogenetic analyses based on WGS confirmed the distinction between the two M. hominis pathotypes. Strikingly, genome wide association analyses identified 4 virulence genes associated with gynecological infections, mainly involved in nucleotide salvage pathways and tolerance to oxidative stress, while five genes have been associated with infertility cases, two of which are implicated in biofilm formation. Conclusion In sum, this study further established the categorization of M. hominis into two pathotypes, and led to the identification of the associated genetic loci, thus holding out promising prospects for a better understanding of the differential interaction of M. hominis with its host
La dengue en Asie du Sud-Est. Enjeux pour un système de surveillance transnational : Thaïlande, Laos, Cambodge et Viêtnam
No full textInternational audienceDengue is a disease caused by an arbovirus transmitted by mosquito vectors of the Aedes genus, primarily Aedes aegypti and Aedes albopictus, which are widely distributed across Southeast Asia. The region’s climatic conditions favor their proliferation, while increasing urbanization provides abundant breeding sites and opportunities for human-mosquito contact. In the absence of an effective vaccine, monitoring and controlling mosquito populations remain essential strategies for combating the disease, alongside tracking the dynamics of local and regional epidemics. This requires regular monitoring of two key factors: meteorological parameters, which influence the growth and decline of vector populations, and human mobility at local, regional and transnational scales, which shape the spatio-temporal dynamics of dengue transmission. Dengue is therefore a complex pathogenic system, with a geography influenced by both local and transnational factors, requiring multi-scale intervention strategies. This chapter aims to present dengue epidemic surveillance systems in four countries (Thailand, Laos, Cambodia and Vietnam) and to outline the requirements for establishing a transnational surveillance system.La dengue est une maladie virale transmise par les moustiques vecteurs du genre Aedes largement présents dans tous les pays d’Asie du Sud-Est. On y trouve en effet des conditions climatiques favorables à leur prolifération et des taux d’urbanisation croissants qui leur procurent une infinité de lieux de ponte et d’opportunités de piqure. La lutte contre cette maladie passe par la surveillance et le contrôle des populations de moustique, ainsi que par le suivi des dynamiques des épidémies locales et régionales. Cela implique entre autres le suivi régulier de deux facteurs essentiels : les paramètres météorologiques qui impactent directement la croissance et décroissance des populations de vecteur ; les flux des populations humaine aux échelles locales, régionales et transnationales qui orientent les dynamiques spatio-temporelles des cas de dengue. La dengue est ainsi un système pathogène complexe dont la géographie dépend aussi bien de conditions locales que transnationales, nécessitant des interventions à plusieurs échelles. L’objectif de ce chapitre est de présenter les systèmes de surveillance des épidémies de dengue dans quatre pays (Thaïlande, Laos, Cambodge et Viêtnam) et de poser les conditions de la mise en place d’un système de surveillance transnational
The diagnosis of mucormycosis by PCR in patients at risk: a systematic review and meta-analysis
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Photorealistic rendering of fetal faces from raw magnetic resonance imaging data
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Influenza vaccine effectiveness against detected infection in the community, France, October 2024 to February 2025
No full textInternational audienceInfluenza circulates at high levels in Europe since November 2024. Using a test-negative study based on data from French community laboratories between October 2024 and February 2025, we estimated vaccine effectiveness (VE) against PCR-detected influenza infection (44,420/15,052; positive/negative individuals). For all age groups, the overall VE was 42% (95% CI: 37–46%), with 26% (95% CI: 18–34%) against influenza A and 75% (95% CI: 66–82%) against influenza B. Among individuals ≥ 65-year-olds VE was 22% (95% CI: 13–30%) and among 0–64-year-olds, 60% (95% CI: 56–65%)