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Analysis of infectious complications in paediatric autoimmune neutropenia: a French nationwide retrospective cohort study
No full textInternational audienceBackground: Autoimmune neutropenia (AIN) is the main cause of chronic neutropenia in children, but its infectious consequences remain poorly studied. The primary objective of this study was to evaluate infectious events leading to emergency department or hospital admissions during the first 2 years following the diagnosis of AIN in children.Methods: We performed a retrospective, multicentre analysis of medical records from 21 French university hospitals of patients aged under 18 years diagnosed with AIN with positive antineutrophils autoantibodies. We collected data on emergency room visits and hospitalisations in the 2 years following diagnosis, causes of these events, microbiology results, management and outcome.Results: One hundred and sixty-eight patients were enrolled. Median age at diagnosis of AIN was 13 months. AIN was predominantly diagnosed during an infectious episode (n=120, 71%). In the 2 years of follow-up after diagnosis, 248 events of emergency room visits and/or hospitalisations were reported (0.77 per patient-year). The most frequent diagnoses were common childhood viral or bacterial infections. The incidence rate of severe infections was 0.003 per patient-year. Despite the predominance of viral infections, 177 episodes (71%) led to hospitalisation and 166 (68%) to the initiation of antibiotic therapy, for a median duration of 7 days (IQR 3-10).Conclusion: The risk of severe infections in children with AIN is low. During follow-up, we suggest being attentive to signs of severity during fever, particularly in children over 3 years of age and/or with other immunological comorbidities but not proposing systematic hospitalisation or additional antibiotic therapy
Epromoters bind key stress-related transcription factors to regulate clusters of stress response genes
No full textInternational audienceStress insults trigger the rapid and global reprogramming of gene transcription by coordinated recruitment of a limited number of key inducible transcription factors to cis-regulatory elements. Here, we performed a comprehensive analysis of different stress models and observed that co-induced genes are generally located in close genomic proximity. By integrating gene expression and transcription factor binding resources in different stress models, we found an enrichment for clusters whereby only one of the promoters of the cluster recruits the key transcription factors, reminiscent of Epromoters, a type of cis-regulatory elements displaying both promoter and enhancer function. Epromoter-regulated clusters were frequently found irrespectively of the stress or inflammatory response. Predicted Epromoters displayed enhancer activity and regulated clusters of stress-response genes independently of their genomic location.These findings have significant implications for understanding complex gene regulation following the response to acute perturbations..</div
Safety and efficacy of 6% hydroxyethyl starch in patients undergoing major surgery
No full textInternational audienceBACKGROUND Hydroxyethyl starch (HES) is often used for maintaining vascular volume during major surgery. Long-term high-dose HES in septic patients promotes renal injury, whereas meta-analyses of current HES products in surgical patients do not show such effects. OBJECTIVE We studied if the peri-operative use of HES is noninferior to crystalloids in terms of acute kidney injury. Secondary outcome was the noninferiority of HES on worsening of renal injury and/or the incidence of a composite endpoint of major complications and mortality until postoperative day 90. DESIGN Randomised double-blind trial in patients undergoing elective abdominal surgery with expected blood loss at least 500 ml. SETTING Multicentre trial at 53 study sites in 10 European countries. PATIENTS One thousand nine hundred and eighty-five (HES 977, crystalloid-only 981) patients aged 40 to 85 years with ASA status II-III. INTERVENTION Either 6% HES 130/0.4 or a crystalloid solution. Dosing was guided by mean arterial pressure and/or routine haemodynamic variables. MAIN OUTCOME MEASURE Change from pre-operative to lowest cystatin C-based eGFR during the first 3 postoperative days. Key secondary outcome was a composite endpoint of mortality and major postoperative complications after 90 days. RESULTS Mean change in eGFR from baseline to minimum was -3.4 ± 17.7 ml min -1 1.73 m -2 in HES patients and -1.0 ± 17.1 ml min -1 1.73 m -2 in crystalloid-only patients ( P < 0.001 for noninferiority). The key secondary endpoint occurred in 35% of patients in each group. There were no clinically relevant differences in any safety endpoint including 90-day renal function. Any cause mortality-difference until the end of 1-year follow-up was not significantly different (8.6% in HES and 10.1% in crystalloid patients). CONCLUSION Peri-operative use of HES was noninferior to crystalloids in short-term renal function or a composite of mortality and major complications at 90 days. PHOENICS provides robust evidence that peri-operative in-label use of HES is well tolerated. TRIAL REGISTRATION AND FUNDING EudraCT no. 2016-002162-30, clinicaltrials.gov ID NCT03278548
Genomics of Long-Term Complications of Childhood Leukemia: Rationale and Design of the GenLEA Study
No full textCited by: 0International audienceBackground: Survivors of childhood acute leukemia are at risk of long-term treatment-related complications, but the role of genetic susceptibility remains unclear. We describe here the GenLEA project, which was established to investigate genetic determinants of long-term complications. Methods: GenLEA builds on the French LEA cohort, which prospectively follows acute leukemia survivors since 2004 through standardized dedicated consultations every 2 to 4 years. Patients were selected from the nested CryoLEA biobank. Cases were defined as survivors with at least one of four major complications (anthracycline-related cardiomyopathy, secondary malignant neoplasms, metabolic syndrome, or osteonecrosis) while controls were survivors without these complications, selected with the objective of a 1:3 case-to-control ratio. Genetic data were generated using genome-wide genotyping and whole-exome sequencing. Results: After quality control, 743 patients were included for analyses (241 cases and 502 controls). Fifty-one percent were male with a median age at diagnosis of 7.3 years (IQR 3.9–13.0), and median follow-up reached 14 years (IQR 7.9–19.8). Among the cases, 44 had cardiomyopathy, 50 osteonecrosis, 37 secondary malignant neoplasms, and 163 metabolic syndrome. Planned analyses include genome-wide association studies (GWAS) and downstream analyses such as transcriptome-wide association studies (TWAS) and Mendelian randomization on genotyping data, as well as gene-based tests on exome sequencing data. Perspectives: By integrating these approaches with high-quality clinical information, GenLEA offers a unique opportunity to identify molecular determinants of late complications after childhood acute leukemia. This collaborative resource will support replication efforts, meta-analyses, and ultimately the development of personalized long-term follow-up strategies. © 2026 Wiley Periodicals LLC
Division of labor in trypanosome RNA processing and export through expanded Mex67 paralogs
No full textInternational audienceIn animals and fungi, bulk messenger RNA (mRNA) export to the cytoplasm is mediated by the Mex67/Mtr2 (NXF1/NXT1) heterodimer and driven by an ATP-dependent remodeling machinery on the cytoplasmic side of nuclear pore complexes, the exclusive gateways of nucleocytoplasmic transport. Uniquely, we show that trypanosomes have three distinct Mex67 paralogs (TbMex67, TbMex67b, and TbMex67L); each having a different non-redundant role in ribosomal RNA (rRNA) processing and mRNA export. Specifically, TbMex67 and TbMex67b retain canonical roles in mRNA export, albeit associating with specific mRNA cohorts and differing protein and mRNA interactomes in the vertebrate host and insect vector forms of the parasite. Further, TbMex67 and TbMex67b paralogs associate with the GTPase Ran export machinery, rather than ATP-dependent helicases, demonstrating significant departure in RNA export mechanisms in trypanosomes. In contrast, TbMex67L is not involved in mRNA export but primarily associates with ribosome biogenesis factors. Thus, in trypanosomes Mex67 paralogs have diverse functionalities with implications for evolutionary origins and diversity of the control of gene expression
Neoantigenic properties of TP53 variants influence cancer risk in individuals with Li-Fraumeni syndrome
No full textInternational audienceBackground Li-Fraumeni Syndrome (LFS) is a heterogenous cancer predisposition condition caused by pathogenic TP53 variants, characterised by a lifelong high risk of a broad spectrum of cancers. Certain pathogenic TP53 variants have been shown be immunogenic in a somatic context. Whether neoantigenicity contributes to LFS heterogeneity is unknown. In this study we analysed the correlations between predicted neoantigenic properties of pathogenic TP53 missense variants and LFS phenotypes. MethodsMHC-I presentation scores were generated for the set of nonameric neo-peptides surrounding each TP53 missense variant against 145 different HLA-I using NetMHCpan 4.1 and the Allele Frequency Net Database. A predicted neoantigenic score (PNS) was calculated for each variant. Association study was performed between PNS, LFS presentation and individual HLA-I genotyping, in individuals carrying TP53 germline pathogenic variants using data from mutation databases and clinical registries. Genotype-phenotype data were leveraged from the public TP53 database (germline dataset, n = 3446; https://tp53.isb-cgc.org/) and two independent LFS clinical registries (n = 339). Individual correlations between HLA-I genotyping, TP53 missense variants and phenotypes were investigated in a group of 173 subjects with LFS. Findings Among individuals with frequent TP53 pathogenic variants, PNS was strongly correlated with median age at first cancer (range 18-43 years, R = 0.69, p = 0.0132). Compared to individuals with low PNS (<1) variants, those with high PNS (<1) variants showed delayed median age at first diagnosis (34 years vs. 25 years, p = 0.0009), fewer sarcomas (osteosarcoma [RR 0.29, p = 0.02]; soft-tissue [RR 0.41, p = 0.02]), and more cancer types typically not associated with LFS spectrum [RR 1.61, p = 0.02]. Interpretation MHC-I neoantigenic properties of TP53 variants are associated with differences in cancer risk and spectrum in individuals with pathogenic TP53 variants, suggesting that individual variant-specific immune response could contribute to the heterogenous presentation of LFS
Postictal self‐removal of intracerebral electrodes during stereoelectroencephalography monitoring: A case series
No full textInternational audienceEpilepsy surgery remains the most effective treatment for focal drug-resistant epilepsy, and stereoelectroencephalography (SEEG) is increasingly used to define the epileptogenic-zone network (EZN) and guide curative or palliative interventions. While SEEG is considered a safe invasive procedure, adverse events arising during monitoring itself are rarely described. We report three exceptional cases of postictal self-removal of intracerebral electrodes during SEEG monitoring. Among 591 implanted patients between January 2000 and October 2025 at Timone Hospital, Marseille, three patients (0.5%) met the inclusion criteria. All were young right-handed men with normal neurocognitive development, focal drug-resistant epilepsy and no psychiatric comorbidity. Self-removal occurred during the postictal phase of spontaneous seizures-two following focal-to-bilateral tonic-clonic seizures and one after a focal impaired-awareness seizure-on the second day of monitoring under complete or partial antiseizure medication withdrawal. Postictal behavior was characterized by agitation, wandering, and, in two cases, resistive aggression when nursing staff attempted to intervene. None of the patients sustained neurological sequelae or significant cerebrovascular complications. EZN involved the temporal lobe in all cases. These observations illustrate that postictal confusion, particularly under medication withdrawal, may occasionally manifest as resistive behavior capable of causing self-harm by means of device manipulation. Awareness of this rare, but potentially hazardous phenomenon, identification of at-risk patients, and implementation of tailored preventive measures may help improve the safety of invasive epilepsy monitoring
Persistent deficiency of mucosal-associated invariant T cells during dermatomyositis
No full textInternational audienceObjectives: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are important for antibacterial immunity and may have regulatory roles. MAIT cells are decreased during SLE. However, their frequencies and phenotype have not been investigated in DM. We studied MAIT cell frequencies and phenotype in DM patients with active and inactive disease (after treatment).Methods: Peripheral blood flow cytometry analysis of MAIT cells was compared between DM (n = 22), SLE (n = 10), psoriasis (n = 7) and atopic dermatitis (n = 5) patients, and healthy controls (n = 19).Results: A dramatic decrease of circulating MAIT cell frequency was observed in active DM and SLE patients compared with healthy controls and other inflammatory skin diseases [active DM: median = 0.25% (interquartile range 0.19-0.6%), P < 0.0001; active SLE: median = 0.61 (0.55-0.77), P < 0.0001 vs healthy controls: 2.32% (1.18-4.45%)]. MAIT cells from active DM patients had an abnormal phenotype including increased expression of CD25 and cytotoxic T-lymphocyte-associated protein 4 that correlated with their low frequency in the blood.Conclusion: In DM, peripheral blood MAIT cells are dramatically reduced and have an activated/exhausted phenotype that may be linked to increased activation-induced cell death.Keywords: T-lymphocytes; autoimmunity; dermatomyositis; immunology; mucosal-associated invariant T cells
Validating and refining a psychoacoustic test to diagnose hyperacusis
No full textInternational audienceDecreased sound tolerance refers to conditions like hyperacusis and misophonia, in which everyday sounds may provoke discomfort or distress. Hyperacusis is characterized by exaggerated loudness perception and aversive reactions to moderate to loud sounds, often leading to significant impairment. Despite its estimated prevalence of 10–15 %, no objective clinical test exists. Current assessment relies on interviews, questionnaires, and loudness discomfort levels (LDLs), which lack reliability and ecological validity. Recent work has shown that pleasantness ratings of natural sounds can differentiate individuals with hyperacusis from controls. A subset of seven natural sounds, termed Core Discriminant Sounds (CDShyper), was identified post-hoc as particularly effective, yielding 81 % sensitivity and 88 % specificity in prior lab-based testing. A similar approach for misophonia identified ten distinct trigger sounds (CDSmiso). This study aimed to validate a tablet-based version of the CDS test to diagnose hyperacusis prospectively. Forty-nine participants (20 with hyperacusis, 29 controls) completed the test that presented randomly CDShyper and CDSmiso sounds at 60, 70, and 80 dBA. Participants rated each sound presentation on visual analog scales for pleasantness and loudness. Hyperacusis was defined by clinical complaints, Hyperacusis Questionnaire scores (≥22), and LDLs (≤77 dB HL). Results showed that individuals with hyperacusis rated CDShyper sounds as significantly less pleasant (means score of 39 vs 25 for hyperacusis vs controls, p = .002, η² = 0.185) and louder (means score of 71 vs 63 for hyperacusis vs controls, p = .024, η² = 0.104) than controls. No group differences emerged for misophonia trigger sounds (CDSmiso sounds). The sensitivity and specificity for the combined CDShyper scores of pleasantness and loudness at detecting hyperacusis were 90 % and 69 %, respectively. These findings validate the tablet-based test as an efficient, ecologically valid tool for diagnosing hyperacusis
Rapid cell turnover to model adipocyte size distribution
No full textInternational audienceWhite adipose tissue, composed of adipocyte cells, primarily stores energy as lipid droplets. The size of adipocytes varies significantly within the tissue according to the amount of stored lipids. A striking observation is that the adipocyte size distribution is bimodal, and thus, this tissue is lacking a characteristic size.We propose a novel dynamical model, based on a partial differential equation, to represent the adipocyte size distribution. The model assumes continuous adipocyte growth, with a velocity dependent on cell radius and extracellular lipid availability, together with constant rates of cell recruitment and death.We prove the existence and local stability of a unique stationary solution for a broad range of growth velocity functions. Choosing a parsimonious formulation, we show that only three parameters are enough to describe adipocyte size distributions measurements in rats. These parameters are robustly estimated through approximate Bayesian computation, and the model demonstrates excellent agreement with experimental data. This mechanistic, three-parameter framework offers a new and interpretable approach to characterizing adipocyte size distributions