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International audience; Background & aimsIn most cases, Roux-en-Y gastric bypass (RYGBP) is an efficient intervention to lose weight, change eating behavior and improve metabolic outcomes in obese patients. We hypothesized that weight loss induced by RYGBP in obese Yucatan minipigs would induce specific modifications of the gut–brain axis and neurocognitive responses to oral sucrose stimulation in relationship with food intake control.MethodsAn integrative study was performed after SHAM (n = 8) or RYGBP (n = 8) surgery to disentangle the physiological, metabolic and neurocognitive mechanisms of RYGBP. BOLD fMRI responses to sucrose stimulations at different concentrations, brain mRNA expression, cecal microbiota, and plasma metabolomics were explored 4 months after surgery and integrated with WGCNA analysis.ResultsWe showed that weight loss induced by RYGBP or SHAM modulated differently the frontostriatal responses to oral sucrose stimulation, suggesting a different hedonic treatment and inhibitory control related to palatable food after RYGBP. The expression of brain genes involved in the serotoninergic and cannabinoid systems were impacted by RYGBP. Cecal microbiota was deeply modified and many metabolite features were differentially increased in RYGBP. Data integration with WGCNA identified interactions between key drivers of OTUs and metabolites features linked to RYGBP.ConclusionThis longitudinal study in the obese minipig model illustrates with a systemic and integrative analysis the mid-term consequences of RYGBP on brain mRNA expression, cecal microbiota and plasma metabolites. We confirmed the impact of RYGBP on functional brain responses related to food reward, hedonic evaluation and inhibitory control, which are key factors for the success of anti-obesity therapy and weight loss maintenance.

International audience; Evidences suggest that inflammation is increased in a subgroup of patients with depression. Moreover, increased peripheral inflammatory markers (cells and proteins) are associated with some, but not all depressive symptoms. On the other hand, similar studies on bipolar disorders mainly focused on blood cytokines. Here, we analysed data from a large (N = 3440), well-characterized cohort of individuals with bipolar disorder using Kendall partial rank correlation, multivariate linear regression, and network analyses to determine whether peripheral blood cell counts are associated with depression severity, its symptoms, and dimensions. Based on the self-reported 16-Item Quick Inventory of Depressive Symptomatology questionnaire scores, we preselected symptom dimensions based on literature and data-driven principal component analysis. We found that the counts of all blood cell types were only marginally associated with depression severity. Conversely, white blood cell count was significantly associated with the sickness dimension and its four components (anhedonia, slowing down, fatigue, and appetite loss). Platelet count was associated with the insomnia/restlessness dimension and its components (initial, middle, late insomnia and restlessness). Principal component analyses corroborated these results. Platelet count was also associated with suicidal ideation. In analyses stratified by sex, the white blood cell count-sickness dimension association remained significant only in men, and the platelet count-insomnia/restlessness dimension association only in women. Without implying causation, these results suggest that peripheral blood cell counts might be associated with different depressive symptoms in individuals with bipolar disorder, and that white blood cells might be implicated in sickness symptoms and platelets in insomnia/agitation and suicidal ideation.

Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity.To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data.Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue.The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.

International audience; Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 is particularly severe in older individuals because of an impaired immune response.1 The vaccines presently available are less efficacious in older individuals, because of the senescence of their immune systems.2 A recent letter in Journal of Infection showed the need of a third vaccine dose due to a waning antibody response against new SARS-CoV-2 variants in healthy and immunocompromised individuals.3 In this study, we analysed the protection against Omicron provided by the immune responses of nursing home residents (NHRs) and a population of healthcare workers (HCWs).

International audience; Une polémique sur une page Facebook® fréquentée majoritairement par des médecins a suscité cet article. Cette dernière a éclaté à propos d’une femme qui demandait à être examinée par une femme médecin, dans un contexte d’examen gynécologique faisant suite à un viol. La teneur des positions qui ont été exprimées donne l’occasion de discuter du rôle des soignants dans un contexte de traumatisme, présent comme passé. Deux approches ont été mobilisées pour guider l’analyse : le pragmatisme et le modèle de l’université de Buffalo axé sur la non-réactivation des traumatismes. Selon l’acception pragmatiste, le premier devoir des soignants est de faire en sorte que l’expérience de soins soit la plus positive possible. Quant au modèle de Buffalo, il précise qu’il s’agit plus particulièrement de favoriser la sécurité émotionnelle des patients et que cet objectif devrait orienter tous les services de soins rendus. Il invite à réaliser que les personnes ayant subi des traumatismes sont devenues réactives à des situations auxquelles des individus non concernés ne seraient pas sensibles, parmi lesquelles en particulier, le manque de contrôle sur leur situation. Enfin, si le modèle de Buffalo est particulièrement pertinent dans le cadre de services de santé accueillant un public susceptible d’avoir connu des traumatismes, les mêmes principes pourraient être convoqués au-delà. En effet, ils valent de manière générale car ils correspondent à ce que l’on a raison d’estimer : le développement de l’empowerment des personnes, au sein d’institutions justes et bientraitantes.

International audience; Dominant centronuclear myopathy (CNM) is a rare form of congenital myopathy associated with a wide clinical spectrum, from severe neonatal to milder adult forms. There is no available treatment for this disease due to heterozygous mutations in the DNM2 gene encoding Dynamin 2 (DNM2). Dominant DNM2 mutations also cause rare forms of Charcot-Marie-Tooth disease and hereditary spastic paraplegia, and deleterious DNM2 overexpression was noticed in several diseases. The proof of concept for therapy by allele-specific RNA interference devoted to silence the mutated mRNA without affecting the normal allele was previously achieved in a mouse model and patient-derived cells, both expressing the most frequent DNM2 mutation in CNM. In order to have versatile small interfering RNAs (siRNAs) usable regardless of the mutation, we have developed allele-specific siRNAs against two non-pathogenic single-nucleotide polymorphisms (SNPs) frequently heterozygous in the population. In addition, allele-specific siRNAs against the p.S619L DNM2 mutation, a mutation frequently associated with severe neonatal cases, were developed. The beneficial effects of these new siRNAs are reported for a panel of defects occurring in patient-derived cell lines. The development of these new molecules allows targeting the large majority of the patients harboring DNM2 mutations or overexpression by only a few siRNAs.

International audience; Suicidal ideation (SI) is a major suicide risk factor; therefore, it is crucial to identify individuals with SI. Discrepancies between the clinicians and patients' estimation of SI may lead to under-evaluating the suicide risk. Yet, studies on discrepancies between self- and clinician-rated SI are lacking, although identifying the patients' sociodemographic and clinical characteristics associated with such discrepancies might help to reduce the under-evaluation risk. Therefore, the aim of this study was to identify features associated with SI rating discrepancies in patients with bipolar disorder (BD) because of the high prevalence of suicide in this population. Among the patients recruited by the French network of FondaMental expert centers for BD, patients with SI (i.e. ≥2 for item 12 of the Quick Inventory of Depressive Symptomatology-Self Report and/or ≥3 for item 10 of the clinician-rated Montgomery and Åsberg Depression Rating Scale) were selected and divided in concordant (i.e. SI in both self- and clinician-rated questionnaires; n = 130; 25.6%), and discordant (i.e. SI in only one questionnaire; n = 377; 74.4%). Depression severity was the feature most associated with SI evaluation discrepancy, especially in patients with SI identified only with the self-rated questionnaire. Clinician may under-evaluate SI presence in patients with low depression level.

International audience; Tracheal intubation in the critically ill is associated with serious complications, mainly cardiovascular collapse and severe hypoxemia. In this narrative review, we present an update of interventions aiming to decrease these complications. MACOCHA is a simple score that helps to identify patients at risk of difficult intubation in the intensive care unit (ICU). Preoxygenation combining the use of inspiratory support and positive end-expiratory pressure should remain the standard method for preoxygenation of hypoxemic patients. Apneic oxygenation using high-flow nasal oxygen may be supplemented, to prevent further hypoxemia during tracheal intubation. Face mask ventilation after rapid sequence induction may also be used to prevent hypoxemia, in selected patients without high-risk of aspiration. Hemodynamic optimization and management are essential before, during and after the intubation procedure. All these elements can be integrated in a bundle. An airway management algorithm should be adopted in each ICU and adapted to the needs, situation and expertise of each operator. Videolaryngoscopes should be used by experienced operators

International audience; MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by degrading or repressing the translation of their target messenger RNAs. As miRNAs are critical regulators of cellular homeostasis, their dysregulation is a crucial component of cell and organ injury. A substantial body of evidence indicates that miRNAs are involved in the pathophysiology of acute kidney injury (AKI), chronic kidney disease and allograft damage. Different subsets of miRNAs are dysregulated during AKI, chronic kidney disease and allograft rejection, which could reflect differences in the physiopathology of these conditions. miRNAs that have been investigated in AKI include miR-21, which has an anti-apoptotic role, and miR-214 and miR-668, which regulate mitochondrial dynamics. Various miRNAs are downregulated in diabetic kidney disease, including the miR-30 family and miR-146a, which protect against inflammation and fibrosis. Other miRNAs such as miR-193 and miR-92a induce podocyte dedifferentiation in glomerulonephritis. In transplantation, miRNAs have been implicated in allograft rejection and injury. Further work is needed to identify and validate miRNAs as biomarkers of graft function and of kidney disease development and progression. Use of combinations of miRNAs together with other molecular markers could potentially improve diagnostic or predictive power and facilitate clinical translation. In addition, targeting specific miRNAs at different stages of disease could be a promising therapeutic strategy.

Introduction: The encouraging efficacy and safety data on intravenous thrombolysis with tenecteplase in ischemic stroke and its practical advantages motivated our centers to switch from alteplase to tenecteplase. We report its impact on treatment times and clinical outcomes. Methods: We retrospectively analyzed clinical and procedural data of patients treated with alteplase or tenecteplase in a comprehensive (CSC) and a primary stroke center (PSC), which transitioned respectively in 2019 and 2018. Tenecteplase enabled in-imaging thrombolysis in the CSC. The main outcomes were the imaging-to-thrombolysis and thrombolysis-to-puncture times. We assessed the association of tenecteplase with 3-month functional independence and parenchymal hemorrhage (PH) with multivariable logistic models. Results: We included 795 patients, 387 (48.7%) received alteplase and 408 (51.3%) tenecteplase. Both groups (tenecteplase vs alteplase) were similar in terms of age (75 vs 76 years), baseline NIHSS score (7 vs 7.5) and proportion of patients treated with mechanical thrombectomy (24.1% vs 27.5%). Tenecteplase patients had shorter imaging-to-thrombolysis times (27 vs 36 min, p a 1.68, 95% CI 1.15–2.48, p a 0.68, 95% CI 0.41–1.12, p = 0.13). Conclusion: Switch from alteplase to tenecteplase reduced process times and may improve functional outcome, with similar safety profile.

International audience

International audience; BackgroundIt is currently unknown whether early B cell reconstitution (EBR) in MS patients under rituximab is associated with a risk of relapse or progression.ObjectivesAnalyzing EBR in rituximab-treated patients and its putative association with clinical findings.MethodsProspective lymphocytes immunophenotyping was performed in a monocentric cohort of MS patients treated by rituximab for 2 years. EBR was defined when B cells concentration was > 5 cells/mm3. B cell subsets were retrospectively associated with clinical data. Clinical and radiological monitoring included relapses, EDSS (Expanded Disability Status Scale), SDMT (Symbol Digit Modalities Test), and MRI.Results182 patients were analyzed (61 remitting-relapsing and 121 progressive-active). 38.5% experienced EBR at least once, but very few (7/182) showed systematic reconstitution. Most patients remained stable upon treatment, regardless of the occurrence of EBR. Dynamics of B cell reconstitution featured increased naïve/transitional B cells, and decreased memory subsets. Homeostasis of the B cell compartment differed at baseline between patients experiencing or not EBR upon treatment. In patients with EBR, reciprocal dynamics of transitional and pro-inflammatory double-negative B cell subsets was associated with better response to rituximab treatment.ConclusionEBR is common in rituximab-treated MS patients and is not associated with clinical disease activity. EBR in the peripheral blood may reflect regulatory immunological phenomena in subgroup of patients.

International audience; The term neurovascular unit (NVU) describes the structural and functional liaison between specialized brain endothelium, glial and mural cells, and neurons. Within the NVU, the blood-brain barrier (BBB) is the microvascular structure regulating neuronal physiology, immune cross-talk, and its properties adapt to brain aging. Here, we analyze a research framework where NVU dysfunction, caused by acute insults or disease progression in the aging brain, represents a converging mechanism underlying late-onset seizures or epilepsy and neurological or neurodegenerative sequelae. Alongside, seizure activity may accelerate brain aging by sustaining regional NVU dysfunction, and a cerebrovascular pathology may link seizures to comorbidities. Next, we focus on NVU diagnostic approaches that could be tailored to seizure conditions in the elderly. We also examine the impending disease-modifying strategies based on the restoration of NVU cells and, more in general, the homeostatic control of anti- and pro-inflammatory players. We conclude with an outlook on current pre-clinical knowledge gaps and clinical challenges pertinent to seizure onset and conditions in an aging population.

International audience; Patients with chronic pain, especially orofacial pain, often suffer from affective disorders, including anxiety. Previous studies largely focused on the role of the caudal anterior cingulate cortex (cACC) in affective responses to pain, long-term potentiation (LTP) in cACC being thought to mediate the interaction between anxiety and chronic pain. But recent evidence indicates that the rostral ACC (rACC), too, is implicated in processing affective pain. However, whether such processing is associated with neuronal and/or synaptic plasticity is still unknown. We addressed this issue in a chronic facial inflammatory pain model (complete Freund's adjuvant model) in rats, by combining behavior, Fos protein immunochemistry and ex vivo intracellular recordings in rACC slices prepared from these animals. Facial mechanical allodynia occurs immediately after CFA injection, peaks at post-injection day 3 and progressively recovers until post-injection days 10-11, whereas anxiety is delayed, being present at post-injection day 10, when sensory hypersensitivity is relieved, but, notably, not at post-injection day 3. Fos expression reveals that neuronal activity follows a bi-phasic time course in bilateral rACC: first enhanced at post-injection day 3, it gets strongly depressed at post-injection day 10. Ex vivo recordings from lamina V pyramidal neurons, the rACC projecting neurons, show that both their intrinsic excitability and excitatory synaptic inputs have undergone long-term depression (LTD) at post-injection day 10. Thus chronic pain processing is associated with dynamic changes in rACC activity: first enhanced and subsequently decreased, at the time of anxiety-like behavior. Chronic pain-induced anxiety might thus result from a rACC deactivation-cACC hyperactivation interplay.

Aims To assess the characteristics, management, and survival of patients with multiple native valvular heart disease (VHD). Methods and results Among the 5087 patients with ≥1 severe left-sided native VHD included in the EURObservational VHD II Survey (maximum 3-month recruitment period per centre between January and August 2017 with a 6-month follow-up), 3571 had a single left-sided VHD (Group A, 70.2%), 363 had one severe left-sided VHD with moderate VHD of the other ipsilateral valve (Group B, 7.1%), and 1153 patients (22.7%) had ≥2 severe native VHDs (left-sided and/or tricuspid regurgitation, Group C). Patients with multiple VHD (Groups B and C) were more often women, had greater congestive heart failure (CHF) and comorbidity, higher left atrial volumes and pulmonary pressures, and lower ejection fraction than Group A patients (all P ≤ 0.01). During the index hospitalization, 36.7% of Group A (n = 1312), 26.7% of Group B (n = 97), and 32.7% of Group C (n = 377) underwent valvular intervention (P Conclusion Multiple VHD is common, encountered in nearly 30% of patients with left-sided native VHD, and associated with greater cardiac damage and leads to higher mortality and more heart failure at 6 months than single VHD, yet with lower rates of surgery.

International audience; Les interactions structurelles et fonctionnelles entre le réticulum endoplasmique (RE) et les mitochondries au niveau des sites de contact appelés MAMs (Membranes associées aux mitochondries), régulent l'homéostasie cellulaire. Récemment, de nouvelles fonctions dans la détection des signaux nutritionnels et hormonaux leur confèrent un rôle majeur dans le contrôle de l'homéostasie du glucose, et des altérations des MAM dans les tissus sensibles à l'insuline et sécrétant de l'insuline sont associées à l'hyperglycémie. Ainsi, le ciblage des MAM devrait permettre dans un futur proche, d'améliorer à la fois l'action et la sécrétion de l'insuline et de lutter contre le diabète de type 2.

International audience; PURPOSE: Severely ill patients affected by coronavirus disease 2019 (COVID-19) develop circulatory failure. We aimed to report patterns of left and right ventricular dysfunction in the first echocardiography following admission to intensive care unit (ICU). METHODS: Retrospective, descriptive study that collected echocardiographic and clinical information from severely ill COVID-19 patients admitted to 14 ICUs in 8 countries. Patients admitted to ICU who received at least one echocardiography between 1st February 2020 and 30th June 2021 were included. Clinical and echocardiographic data were uploaded using a secured web-based electronic database (REDCap). RESULTS: Six hundred and seventy-seven patients were included and the first echo was performed 2 [1, 4] days after ICU admission. The median age was 65 [56, 73] years, and 71% were male. Left ventricle (LV) and/or right ventricle (RV) systolic dysfunction were found in 234 (34.5%) patients. 149 (22%) patients had LV systolic dysfunction (with or without RV dysfunction) without LV dilatation and no elevation in filling pressure. 152 (22.5%) had RV systolic dysfunction. In 517 patients with information on both paradoxical septal motion and quantitative RV size, 90 (17.4%) had acute cor pulmonale (ACP). ACP was associated with mechanical ventilation (OR\,>\,4), pulmonary embolism (OR\,>\,5) and increased PaCO(2). Exploratory analyses showed that patients with ACP and older age were more likely to die in hospital (including ICU). CONCLUSION: Almost one-third of this cohort of critically ill COVID-19 patients exhibited abnormal LV and/or RV systolic function in their first echocardiography assessment. While LV systolic dysfunction appears similar to septic cardiomyopathy, RV systolic dysfunction was related to pressure overload due to positive pressure ventilation, hypercapnia and pulmonary embolism. ACP and age seemed to be associated with mortality in this cohort.

International audience; Purpose: The purpose of this study was to report the initial results of the declaration of care-related adverse events (CRAEs) in radiology in the French National Authority for Health (HAS) database for accreditation of radiological medical teams.Materials and methods: Between October 2018 and December 2020, 48 radiological teams (32 teams in 2019 and 16 teams in 2020; 471 registered radiologists) signed up to the team accreditation process, a system supported by the HAS. Reports of the CRAEs in radiology started in September 2019 after the team registration phase.Results: Among the 89 CRAEs reported, 28 (31%) were targeted as interventional radiology, 27 (30%) as linked to contrast media and 11 (12%) as related to MRI care; the 23 other CRAEs reported included five defaults in the transmission of requests or results, five delays in diagnosis or treatment, four patient-identity monitoring events, four diagnostic radiology complications, four radiation protection events and one patient information problem. The severity was rated as "minor" for 53% of CRAEs and as "serious to critical" or "catastrophic" for 8% and 9% of CRAEs, respectively. They were preventable or probably preventable in 84% of all events.Conclusion: These early results of this nation-wide CRAEs declaration database show the diversity of all CRAEs and their causes in radiological practice in France, and provide a global vision of areas for improvement of the quality of care in radiology. This should convince other radiologists to declare CRAEs and allow, in time, the production of recommendations and patient safety solutions as to limit the risks associated with radiological care.

International audience; Background In acute ischemic stroke (AIS), fluid-attenuated inversion recovery (FLAIR) is used for treatment decisions when onset time is unknown. Synthetic FLAIR could be generated with deep learning from information embedded in diffusion-weighted imaging (DWI) and could replace acquired FLAIR sequence (real FLAIR) and shorten MRI duration. Purpose To compare performance of synthetic and real FLAIR for DWI-FLAIR mismatch estimation and identification of patients presenting within 4.5 hours from symptom onset. Materials and Methods In this retrospective study, all pretreatment and early follow-up ( .99). Conclusion Synthetic fluid-attenuated inversion recovery (FLAIR) had diagnostic performances similar to real FLAIR in depicting diffusion-weighted imaging-FLAIR mismatch and in helping to identify early acute ischemic stroke, and it may accelerate MRI protocols. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Carroll and Hurley in this issue.

High throughput sequencing in microbiological diagnosis The applications of next-generation sequencing (NGS) in health have recently become more widespread, at first in research studies and then in clinical microbiology. The use of NGS has mainly been developed in bacteriology and mycology, especially based on phylogenetic markers (hypervariable regions of rDNA 16S, 18S, or 28S) which allow by metataxonomy, to describe the physiopathological variations of microbiota. By non-targeted metagenomics approaches, the comparison of whole genome NGS data to international databases allows the detection of genomic antimicrobial resistance which is often correlated with the resistance phenotype. Similarly, different strategies to study virulence factors have been developed to compare the genomes of clinical isolates to reference strains and thus to analyze genomic islands. NGS has also shown its efficiency in determining an inter-individual transmission cluster, to identify the source patient or to improve collective management, to search for the etiological agent of an infection. Even though structures such as the Cofrac have taken NGS into account, the lack of standardization limits the routine development of these approaches, due to the need for bioinformatics., Les applications du séquençage haut débit (NGS) en santé se sont récemment démocratisées, d’abord en recherche puis en microbiologie clinique. L’utilisation du NGS a surtout des applications en bactériologie et mycologie, principalement basées sur les marqueurs phylogénétiques documentés (régions hypervariables du 16S, 18S, ou 28S) permettant, par métataxonomie, de décrire les variations physiopathologiques des microbiotes. En métagénomique non ciblée, la comparaison des données de séquençage de génomes complets à des banques de données internationales permet de détecter une antibiorésistance génomique, souvent corrélée au phénotype de résistance. De même, différentes stratégies d’étude des facteurs de virulence ont été développées pour comparer les génomes des souches isolées en clinique à des souches de référence et ainsi analyser les îlots génomiques. Le NGS a aussi montré son efficacité à déterminer une chaîne de transmission interindividuelle, afin de remonter au patient source ou d’améliorer la prise en charge collective. L'approche métagénomique a permis de rechercher l'agent étiologique d'une infection. Malgré la prise en compte par des structures comme le Comité français d'accréditation, l’absence de standardisation limite le développement en routine de ces approches, en particulier du fait des besoins en bioinformatique.

International audience; IntroductionSocioeconomic status (SES) is recognized as an important determinant of kidney health. We aimed to evaluate the association of social deprivation with different indicators at kidney replacement therapy (KRT) initiation in the French pediatric metropolitan population.MethodsAll patients with end-stage kidney disease (ESKD) who started KRT before 20 years old in France between 2002 and 2015 were included. We investigated different indicators at KRT initiation, which are as follows: KRT modality (dialysis vs. pre-emptive transplantation), late referral to a nephrologist, and dialysis modality (hemodialysis [HD] vs. peritoneal dialysis [PD], urgent vs. planned start of dialysis, use of catheter vs. use of fistula for HD vascular access). An ecological index (European Deprivation Index [EDI]) was used as a proxy for social deprivation.ResultsA total of 1115 patients were included (males 59%, median age at dialysis 14.4 years, glomerular/vascular diseases 36.8%). The most deprived group represented 38.7% of the patients, suggesting pediatric patients with ESKD come from a more socially deprived background. The most deprived group was more likely to initiate KRT with dialysis versus kidney transplantation. Among patients on HD, the odds of starting treatment in emergency with a catheter was >2-fold higher for the most deprived compared with the least deprived children (adjusted odds ratio [aOR] 2.35, 95% CI 1.16–4.78).ConclusionChildren from the most deprived area have lower access to pre-emptive transplantation, have lower access to PD, tend to be late referred to a nephrologist, and have more urgent initiation of HD with a catheter.

Background Genome-wide association studies have identified ATP2B4 as a severe malaria resistance gene. Recently, 8 potential causal regulatory variants have been shown to be associated with severe malaria. Methods Genotyping of rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452 was performed in 154 unrelated individuals (79 controls and 75 mild malaria patients). rs10751450, rs10751451 and rs10751452 were genotyped by Taqman assays, whereas the fragment of the ATP2B4 gene containing the remaining SNPs was sequenced. Logistic regression analysis was used to assess the association between the SNPs and mild malaria. Results The results showed that mild malaria was associated with rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452. The homozygous genotypes for the major alleles were associated with an increased risk of mild malaria. Furthermore, the haplotype containing the major alleles and that containing the minor alleles were the most frequent haplotypes. Individuals with the major haplotypes had a significantly higher risk of mild malaria compared to the carriers of the minor allele haplotype. Conclusions ATP2B4 polymorphisms that have been associated with severe malaria are also associated with mild malaria.

International audience; Objectives - Persistent post-acute coronavirus disease 2019 (COVID-19) symptoms (PACSs) have been reported up to 6 months after hospital discharge. Herein we assessed the symptoms that persisted 12 months (M12) after admission for COVID-19 in the longitudinal prospective national French coronavirus disease cohort. Methods - Hospitalized patients with a confirmed virological diagnosis of COVID-19 were enrolled. Follow-up was planned until M12 after admission. Associations between persistence of ≥3 PACSs at M12 and clinical characteristics at admission were assessed through logistic regression according to gender. Results - We focused on participants enrolled between 24 January 2020 and 15 July 2020, to allow M12 follow-up. The M12 data were available for 737 participants. Median age was 61 years, 475 (64%) were men and 242/647 (37%) were admitted to intensive care units during the acute phase. At M12, 27% (194/710) of the participants had ≥3 persistent PACS, mostly fatigue, dyspnoea and joint pain. Among those who had a professional occupation before the acute phase, 91 out of 339 (27%) were still on sick leave at M12. Presence of ≥3 persistent PACS was associated with female gender, both anxiety and depression, impaired health-related quality of life and Medical Muscle Research Council Scale

International audience; Over its 30 years of existence, functional near-infrared spectroscopy (fNIRS) has matured into a highly versatile tool to study brain function in infants and young children. Its advantages, amongst others, include its ease of application and portability, the option to combine it with electrophysiology, and its relatively good tolerance to movement. As shown by the impressive body of fNIRS literature in the field of cognitive developmental neuroscience, the method's strengths become even more relevant for (very) young individuals who suffer from neurological, behavioral, and/or cognitive impairment. Although a number of studies have been conducted with a clinical perspective, fNIRS cannot yet be considered as a truly clinical tool. The first step has been taken in this direction by studies exploring options in populations with well-defined clinical profiles. To foster further progress, here, we review several of these clinical approaches to identify the challenges and perspectives of fNIRS in the field of developmental disorders. We first outline the contributions of fNIRS in selected areas of pediatric clinical research: epilepsy, communicative and language disorders, and attention-deficit/hyperactivity disorder. We provide a scoping review as a framework to allow the highlighting of specific and general challenges of using fNIRS in pediatric research. We also discuss potential solutions and perspectives on the broader use of fNIRS in the clinical setting. This may be of use to future research, targeting clinical applications of fNIRS in children and adolescents.

In viremia controlled PWH, CD4 decline was a rare event, with global lymphopenia. Older age and lower viral load at treatment initiation were associated with CD4 decline. It was associated with the risk of severe morbidity during the first six months.

La mention ' Activité Physique Adaptée et Santé ' (APA) permet aux étudiants de travailler auprès d'un public atteint de pathologies ou nécessitant une réadaptation à l'activité physique. Cette formation englobe le développement des connaissances sur les pathologies, la conception de projet ou encore, la conduite et l'évaluation de programmes spécifiques de réadaptation afin de devenir EAPA (enseignants en activité physique adaptée).A travers 4 grandes parties, cet ouvrage permet aux candidats à l'entrée dans le cursus et aux étudiants en cours de formation, de :1. de visualiser l'ensemble des métiers liés à l'APA et d'en connaître les différentes spécificités ;2. connaître les compétences transversales aux métiers associés à la mention : développement des qualités physiques et prophylaxie, les publics, leurs besoins et les modalités d'intervention, la ou les prévention(s) par l'exercice physique, la Loi Santé et ses champs d'application¿;3. développer des connaissances professionnelles nécessaires au futur parcours professionnel (douleur, lombalgie, bases de la préparation physique...) ;4. développer des compétences disciplinaires¿: nutrition, micronutrition, interventions non-médicamenteuses etc.Chaque chapitre est traversé de témoignages (étudiants, enseignants, formateurs universitaires), autant de regards croisés sur le parcours universitaire et les contenus de la formation, et se conclut par des quiz et des questions, qui permettent de tester ses connaissances. Grâce aux nombreux encarts ' Le saviez-vous ', ' Astuce pratique ' et ' Focus ', cet ouvrage offre toutes les clés pour réussir en STAPS.

Node role explainability in complex networks is very difficult, yet is crucial in different application domains such as social science, neurosciences or computer science. Many efforts have been made on the quantification of hubs revealing particular nodes in a network using a given structural property. Yet, in several applications, when multiple instances of networks are available and several structural properties appear to be relevant, the identification of node roles remains largely unexplored. Inspired by the node automorphically equivalence relation, we define an equivalence relation on graph nodes associated with any collection of nodal statistics (i.e. any functions on the node-set). This allows us to define new graph global measures: the power coefficient, and the orthogonality score to evaluate the parsimony and heterogeneity of a given nodal statistics collection. In addition, we introduce a new method based on structural patterns to compare graphs that have the same vertices set. This method assigns a value to a node to determine its role distinctiveness in a graph family. Extensive numerical results of our method are conducted on both generative graph models and real data concerning human brain functional connectivity. The differences in nodal statistics are shown to be dependent on the underlying graph structure. Comparisons between generative models and real networks combining two different nodal statistics reveal the complexity of human brain functional connectivity with differences at both global and nodal levels. Using a group of 200 healthy controls connectivity networks, our method computes high correspondence scores among the whole population, to detect homotopy, and finally quantify differences between comatose patients and healthy controls., Comment: 15 pages, 16 figures

Grâce à l’efficacité des médicaments antirétroviraux (ARV), la mortalité et la morbidité liées à l’épidémie de VIH ont considérablement diminué au cours des dernières décennies. Néanmoins en Afrique, la persistance de nouvelles infections et le développement de résistances aux ARV traduisent les difficultés dans la prévention et la prise en charge. Ces difficultés concernent en particulier les enfants et les adolescents vivant avec le VIH (EAvVIH). En 1998, le Sénégal fut le premier pays d’Afrique de l’Ouest à mettre en place un programme gouvernemental d’accès aux ARV. Mais la prise en charge des EAvVIH reste difficile. Une enquête nationale réalisée en 2015 a montré que 64% des EAvVIH (0-19 ans) suivis dans des sites hors de Dakar, étaient en échec thérapeutique. Cet article présente les résultats d’une étude anthropologique qui visait à examiner les modalités de prise en charge médicale et sociale des EAvVIH ; à identifier les déterminants structurels et sociaux de l’échec – ou du succès – thérapeutique ; et à analyser leurs influences respectives. L'enquête ethnographique a été conduite entre juillet 2020 et novembre 2021, dans 11 des 14 régions du Sénégal, dans 14 structures de santé (11 Centres de santé et 4 hôpitaux régionaux). Les entretiens et les observations ont été menés auprès de 87 enfants et adolescents, 97 parents ou tuteurs et 47 agents de santé qui leur prodiguent des soins. Les résultats montrent que les situations d’échec ou de succès thérapeutique résultent de configurations plus ou moins favorables qui mettent en jeu différents acteurs – enfants, parents, professionnels de santé et leurs interactions avec et dans des contextes socio-culturels et structurels variés. Cette recherche s’inscrit dans l’apport de l’anthropologie à l’analyse et la compréhension des systèmes de soins. Dans une perspective de santé publique, nos analyses plaident pour une approche différenciée du renforcement de compétence du personnel des structures sanitaires, tenant compte de la spécificité de chaque site.

To evaluate the proportion, baseline predictors, and outcomes of neovascular age-related macular degeneration (nAMD) patients treated with a high burden of vascular endothelial growth factor (VEGF) inhibitor intravitreal injections (IVT) at two years in routine clinical practice. European retrospective data analysis from a prospectively designed observational outcomes registry: the Fight Retinal Blindness! (FRB!) Project. Treatment-naïve eyes (one eye per patient) initiating VEGF inhibitors IVT from January 2017 to March 2020 with 24 months of follow-up, a minimum of 3 injections, and no gap between visits exceeding 365 days were tracked in the registry. We analyzed three treatment burden (TB) groups defined by the mean interval of the three closest injections to the 24-month visit: (1) those with a high TB had injection interval ≤ 42 days, (2) those with a low TB had injection interval between >42 and

Tools based on deep learning models have been created in recent years to aid radiologists in the diagnosis of breast cancer from mammograms. However, the datasets used to train these models may suffer from class imbalance, i.e., there are often fewer malignant samples than benign or healthy, which can bias the model towards the healthy class. In this study, we systematically evaluate several popular techniques to deal with this class imbalance, namely, class weighting, over-sampling, and under-sampling, as well as a synthetic lesion generation approach to increase the number of malignant samples. These techniques are applied when training on three diverse Full-Field Digital Mammography datasets, and tested on in-distribution and out-of-distribution samples. The experiments show that a greater imbalance is associated with a greater bias towards the majority class, which can be counteracted by any of the standard class imbalance techniques. On the other hand, these methods provide no benefit to model performance with respect to Area Under the Curve of the Recall Operating Characteristic (AUC-ROC), and indeed under-sampling leads to a reduction of 0.066 in AUC in the case of a 19:1 benign to malignant imbalance. Our synthetic lesion methodology leads to better performance in most cases, with increases of up to 0.07 in AUC on out-of-distribution test sets over the next best experiment.

International audience; Deregulated lipid metabolism is a common feature of liver cancers needed to sustain tumor cell growth and survival. We aim at taking advantage of this vulnerability and rewiring the oncogenic metabolic hub by targeting the key metabolic player pro-protein convertase subtilisin/kexin type 9 (PCSK9). We assessed the effect of PCSK9 inhibition using the three hepatoma cell lines Huh6, Huh7 and HepG2 and validated the results using the zebrafish in vivo model. PCSK9 deficiency led to strong inhibition of cell proliferation in all cell lines. At the lipid metabolic level, PCSK9 inhibition was translated by an increase in intracellular neutral lipids, phospholipids and polyunsaturated fatty acids as well as a higher accumulation of lipid hydroperoxide. Molecular signaling analysis involved the disruption of the sequestome 1/Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (p62/Keap1/Nrf2) antioxidative axis, leading to ferroptosis, for which morphological features were confirmed by electron and confocal microscopies. The anti-tumoral effects of PCSK9 deficiency were validated using xenograft experiments in zebrafish. The inhibition of PCSK9 was effective in disrupting the oncometabolic process, inducing metabolic exhaustion and enhancing the vulnerability of cancer cells to iron-triggered lipid peroxidation. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat liver cancers.

International audience; Alterations in lipid handling are an important hallmark in cancer. Our aim here is to target key metabolic enzymes to reshape the oncogenic lipid metabolism triggering irreversible cell breakdown. We targeted the key metabolic player proprotein convertase subtilisin/kexin type 9 (PCSK9) using a pharmacological inhibitor (R-IMPP) alone or in combination with 3-hydroxy 3-methylglutaryl-Coenzyme A reductase (HMGCR) inhibitor, simvastatin. We assessed the effect of these treatments using 3 hepatoma cell lines, Huh6, Huh7 and HepG2 and a tumor xenograft in chicken choriorallantoic membrane (CAM) model. PCSK9 deficiency led to dose-dependent inhibition of cell proliferation in all cell lines and a decrease in cell migration. Co-treatment with simvastatin presented synergetic anti-proliferative effects. At the metabolic level, mitochondrial respiration assays as well as the assessment of glucose and glutamine consumption showed higher metabolic adaptability and surge in the absence of PCSK9. Enhanced lipid uptake and biogenesis led to excessive accumulation of intracellular lipid droplets as revealed by electron microscopy and metabolic tracing. Using xenograft experiments in CAM model, we further demonstrated the effect of anti-PCSK9 treatment in reducing tumor aggressiveness. Targeting PCSK9 alone or in combination with statins deserves to be considered as a new therapeutic option in liver cancer clinical applications.

Background Obsessive–compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms. Methods We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning. Results A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear mixed models demonstrated that OCS in patients treated with clozapine were associated with significantly worse wellbeing scores, independently of depression and psychotic symptoms, but OCS did not impair general functioning. Obsessional thinking and hoarding behaviour, but not compulsions, were significantly associated with the impact on wellbeing, which may be attributable to the ego-syntonic nature of the compulsions. Conclusions Given the frequent occurrence of OCS and their negative impact on wellbeing, we encourage clinicians to routinely assess and treat OCS in patients who are taking clozapine.

Over the last decade, the greenspace sector has considerably developed and employs today over 100,000 people in France: landscapers, gardeners, civil servants, public facility operators, golf-course employees and other sports facilities, horticulturists, plant and tree nursery workers, etc. Numerous occupational risks and hazards have been highlighted in this population. However, knowledge of their health status is scarce in France and on a worldwide scale. During their lifetime at work, these workers are very often exposed to pesticides. The health impacts of these substances have mainly been studied among farmers. However, pesticide use in the greenspace sector has some specificities in terms of applied substances, equipment, application scenario, frequency and type of contact with treated plants and regulation. This thesis aims at studying past and present pesticide exposures and health effects amongst greenspace workers. To meet this objective, the work will build on a multidisciplinary approach (epidemiology, expology, toxicology and ergonomy) and is articulated around three lines: i) To identify the types of pesticides used in greenspaces; ii) to describe the health condition of this population and the incidence of cancers in order to understand their aetiology and iii) to characterise the occupational exposure (dermal and respiratory) to pesticides in real work conditions. The results presented in this thesis highlight the necessity to carry out studies on this sector thus improving knowledge of past and present exposure. This in turn will enhance the strength of epidemiological studies and allow preventive measures to be tailored specifically to this work force., Au cours des dix dernières années, le secteur des espaces verts a connu une très forte évolution et emploie aujourd’hui près de 100 000 personnes en France : paysagistes, jardiniers des propriétés privées, des parcs publics, des pelouses des terrains de sport et parcours de golf, travailleurs de l’entretien routier et ferroviaire, horticulteurs, pépiniéristes, etc. Les données concernant la santé de ces travailleurs sont très limitées, bien qu’ils soient exposés à de nombreux risques professionnels physiques, biologiques et chimiques, notamment les pesticides. Le rôle de ces substances sur la santé a principalement été exploré dans les populations agricoles au cours des dernières décennies. Les usages de pesticides dans ce secteur ont des spécificités en termes de substances utilisées, de matériel utilisé, de contextes d’usage, fréquence des contacts avec des végétaux lors de tâches diverses et de réglementation. Les objectifs de la thèse étaient donc d’étudier les expositions aux pesticides, passées et présentes, chez les travailleurs des espaces verts et d’analyser des effets de santé. Pour y répondre, ce travail s’appuie sur une démarche pluridisciplinaire associant épidémiologie, expologie, toxicologie et ergonomie et s’articule autour de trois axes : i) développer des outils pour retracer l’historique des utilisations de pesticides dans le secteur des espaces verts ; ii) décrire l’état de santé de cette population, la survenue de certains cancers et comprendre leur étiologie — à partir des données de la cohorte AGRICAN et iii) déterminer les niveaux d’exposition cutanée et respiratoire aux pesticides en conditions réelles de travail afin d’en identifier les déterminants. Les résultats présentés dans cette thèse soulignent l’importance de mener des études spécifiquement dédiées à ces travailleurs et d’améliorer les connaissances sur leurs expositions passées et présentes afin d’augmenter la robustesse des études épidémiologiques et proposer des mesures de prévention adaptées à ce secteur.

IntroductionThe management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producingEscherichia coli(CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer.Methods and analysisThis is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated.Ethics and disseminationMICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal.Trial registration numberNCT04103567.

France went through three deadly epidemic waves due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing major public health and socioeconomic issues. We proposed to study the course of the pandemic along 2020 from the outlook of two major Parisian hospitals earliest involved in the fight against COVID-19. Genome sequencing and phylogenetic analysis were performed on samples from patients and health care workers (HCWs) from Bichat (BCB) and Pitié-Salpêtrière (PSL) hospitals. A tree-based phylogenetic clustering method and epidemiological data were used to investigate suspected nosocomial transmission clusters. Clades 20A, 20B and 20C were prevalent during the spring wave and, following summer, clades 20A.EU2 and 20E.EU1 emerged and took over. Phylogenetic clustering identified 57 potential transmission clusters. Epidemiological connections between participants were found for 17 of these, with a higher proportion of HCWs. The joint presence of HCWs and patients suggest viral contaminations between these two groups. We provide an enhanced overview of SARS-CoV-2 phylogenetic changes over 2020 in the Paris area, one of the regions with highest incidence in France. Despite the low genetic diversity displayed by the SARS-CoV-2, we showed that phylogenetic analysis, along with comprehensive epidemiological data, helps to identify and investigate healthcare associated clusters.

Background Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research. Methods To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: “Anatomy and physiology”, “Transducer Settings”, “Ventilator Impact”, “Learning and expertise”, “Daily practice” and “Future directions”. Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question. Results Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established. Conclusion This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established. Trial registration The study was pre-registered on the Open Science Framework with registration digital object identifier https://doi.org/10.17605/OSF.IO/HM8UG.

Hereditary xerocytosis is a dominant red cell membrane disorder characterized by an increased leak of potassium from the inside to outside the red blood cell membrane, associated with loss of water leading to red cell dehydration and chronic hemolysis. 90% of cases are related to heterozygous gain of function mutations in PIEZO1, encoding a mechanotransductor that translates a mechanical stimulus into a biological signaling. Data are still required to understand better PIEZO1-HX pathophysiology. Recent studies identified proteomics as an accurate and high-input tool to study erythroid progenitors and circulating red cell physiology. Here, we isolated red blood cells from 5 controls and 5 HX patients carrying an identified and pathogenic PIEZO1 mutation and performed a comparative deep proteomic analysis. A total of 603 proteins were identified among which 56 were differentially expressed (40 over expressed and 16 under expressed) between controls and HX with a homogenous expression profile within each group. We observed relevant modifications in the protein expression profile related to PIEZO1 mutations, identifying two main “knots”. The first contained both proteins of the chaperonin containing TCP1 complex involved in the assembly of unfolded proteins, and proteins involved in translation. The second contained proteins involved in ubiquitination. Deregulation of proteins involved in protein biosynthesis was also observed in in vitro-produced reticulocytes after Yoda1 exposure. Thus, our work identifies significant changes in the protein content of PIEZO1-HX erythrocytes, revealing a “PIEZO1 signature” and identifying potentially targetable pathways in this disease characterized by a heterogeneous clinical expression and contra-indication of splenectomy.

International audience; Introduction: The ECG Bayesian filtering framework has been shown to be a promising method to extract the foetal electrocardiogram (FECG) from abdominal recordings. This framework requires an estimation of the ECG morphology, which is obtained by approximating an average beat with a number of Gaussian kernels. This approximation results in a high dimensional nonlinear optimization problem (finding ideal positions, width and height for these kernels). Methods: Proposed methodologies in the literature initialize the optimization algorithm using fixed positions for the kernel functions. This contribution benchmarks alternative schemes for finding the Gaussian parameters, namely an approach based on the stationary wavelet transform and random search. The goal is minimizing the normalized mean squared error between the average beat and the approximated model, while increasing foetal QRS detection accuracy. Results: The suggested methods are able to produce improved morphology approximations of the averaged beat up 4.05% (depending on the selected method). The proposed method using the stationary wavelet transform improves the goodness of the fit, while reducing the computational load. However, no immediate improvement on the accuracy of FQRS detections was noticed. Such findings render the proposed method a promising tool. However, further research should be directed at transferring the improved fit to an improvement of FQRS detections.

Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells.

International audience; Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.

Background: For individuals with dengue-like symptoms arriving at hospitals, early detection of those likely to progress to-or not progress to-severe dengue can be of great use. Methods: We studied 237 Cambodian children hospitalised in Kampong Cham hospital with dengue-like symptoms. Using dengue severity as primary endpoint, we ran univariate analyses and built multivariate random forest classifiers to predict this endpoint using early clinical and laboratory data. Findings: In a random forest analysis using 56 available variables we obtained AUC = 0•94, and for a sensitivity of 90%: specificity = 89%, positive predictive value (PPV) = 74%, and negative predictive value (NPV) = 96%. Platelet count, HDL cholesterol, and ultrasound pleural effusion and ascites were the four variables most associated with severe dengue outcomes. A random forest on only these four variables gave AUC = 0·88, and for a sensitivity of 90%: specificity = 82%, PPV = 64%, and NPV = 96%. Interpretation. Future severe dengue with significant vascular leakage can be correctly predicted at hospital arrival in a large majority of cases using multivariate random forests. In addition to platelet count and ultrasound pleural effusion and ascites, HDL cholesterol level on the day of admission is also a strong predictor of severe dengue.

International audience; Montazeri Moghadam et al. report an automated algorithm to visually convert EEG recordings to real-time quantified interpretations of EEG in neonates. The resulting measure of the brain state of the newborn (BSN) bridges several gaps in neurocritical care monitoring.

Short communication 7 p.; International audience; Aging is a multifactorial process that affects the entire organism by cumulative alterations. Visual function impairments that go along with aging are commonly observed, causing lower visual acuity, lower contrast sensitivity, and impaired dark adaptation. Electroretinogram analysis revealed that the amplitudes of rod- and cone-mediated responses are reduced in aged mice and humans. Reports suggested that age-related changes observed in both rod and cone photoreceptor functionality were linked to oxidative stress regulation or free radical production homeostasis. Interestingly, several recent reports linked the fragile X mental retardation protein (FMRP) cellular activity with oxidative stress regulation in several tissue including brain tissue where FMRP participates to the response to stress via protein translation in neurite or is involved in free radical production and abnormal glutathione homeostasis. Based on these recent literatures, we raised the question about the effect of FMRP absence in the aging retina of Fmr1(-/y) compared to their WT littermates. Indeed, up to now, only young or adult mice (

Background We developed five tablet-based tasks (applications) to measure multiple components of manual dexterity. Aim: to test reliability and validity of tablet-based dexterity measures in healthy participants. Methods Tasks included: (1) Finger recognition to assess mental rotation capacity. The subject taps with the finger indicated on a virtual hand in three orientations (reaction time, correct trials). (2) Rhythm tapping to evaluate timing of finger movements performed with, and subsequently without, an auditory cue (inter-stimulus interval). (3) Multi-finger tapping to assess independent finger movements (reaction time, correct trials, unwanted finger movements). (4) Sequence tapping to assess production and memorization of visually cued finger sequences (successful taps). (5) Line-tracking to assess movement speed and accuracy while tracking an unpredictably moving line on the screen with the fingertip (duration, error). To study inter-rater reliability, 34 healthy subjects (mean age 35 years) performed the tablet tasks twice with two raters. Relative reliability (Intra-class correlation, ICC) and absolute reliability (Standard error of measurement, SEM) were established. Task validity was evaluated in 54 healthy subjects (mean age 49 years, range: 20–78 years) by correlating tablet measures with age, clinical dexterity assessments (time taken to pick-up objects in Box and Block Test, BBT and Moberg Pick Up Test, MPUT) and with measures obtained using a finger force-sensor device. Results Most timing measures showed excellent reliability. Poor to excellent reliability was found for correct trials across tasks, and reliability was poor for unwanted movements. Inter-session learning occurred in some measures. Age correlated with slower and more variable reaction times in finger recognition, less correct trials in multi-finger tapping, and slower line-tracking. Reaction times correlated with those obtained using a finger force-sensor device. No significant correlations between tablet measures and BBT or MPUT were found. Inter-task correlation among tablet-derived measures was weak. Conclusions Most tablet-based dexterity measures showed good-to-excellent reliability (ICC ≥ 0.60) except for unwanted movements during multi-finger tapping. Age-related decline in performance and association with finger force-sensor measures support validity of tablet measures. Tablet-based components of dexterity complement conventional clinical dexterity assessments. Future work is required to establish measurement properties in patients with neurological and psychiatric disorders.

International audience; The objective of forensic sciences is to find clues in a crime scene in order to reconstruct the scenario. Classical samples include DNA or fingerprints, but both have inherent limitations and can be uninformative. Another type of sample has emerged recently in the form of the microbiome. Supported by the Human Microbiome Project, the characteristics of the microbial communities provide real potential in forensics. They are highly specific and can be used to differentiate and classify the originating body site of a human biological trace. Skin microbiota is also highly specific and different between individuals, leading to its possibility as an identification tool. By extension, the possibilities of the microbial communities to be deposited on everyday objects has also been explored. Other uses include the determination of the post-mortem interval or the analysis of soil communities. One challenge is that the microbiome changes over time and can be influenced by many environmental and lifestyle factors. This review offers an overview of the main methods and applications to demonstrate the benefit of the microbiome to provide forensically relevant information.

International audience; No abstract available

International audience; Objectifs : La surcharge liquidienne augmente la morbidité et la mortalité chez les patients en USIP. L'élimination active des fluides améliore le pronostic mais peut aggraver le dysfonctionnement des organes. La dépendance à la précharge chez les adultes prédit l'instabilité hémodynamique induite par un défi d'élimination des fluides (FRC). Nous avons cherché à étudier la précision diagnostique des marqueurs dynamiques et statiques de la précharge dans la prédiction de l'instabilité hémodynamique et de la réduction du volume d'éjection systolique lors d'une CRF chez les enfants. Nous avons suivi la déclaration des normes de déclaration de l'exactitude diagnostique pour concevoir, mener et rapporter cette étude.Conception : Étude de cohorte prospective non interventionnelle.Contexte : De juin 2017 à avril 2019 dans une unité de soins intensifs cardiaques pédiatriques d'un hôpital tertiaire.Patients : Des patients âgés de 8 ans ou moins, présentant des symptômes de surcharge hydrique après une chirurgie cardiaque, ont été étudiés.Interventions : Nous avons confirmé la dépendance à la précharge par échocardiographie avant et pendant un test de compression abdominale calibré. Nous avons ensuite effectué un défi pour éliminer 10 ml/kg de liquide en moins de 120 minutes avec une infusion de diurétiques. L'instabilité hémodynamique était définie comme une diminution de 10 % de la pression artérielle moyenne.Mesure et principaux résultats : Nous avons comparé des patients présentant une instabilité hémodynamique avec des patients restant stables, et nous avons construit des courbes de caractéristiques opératoires du récepteur (ROC). Parmi 58 patients étudiés, 10 présentaient une instabilité hémodynamique. L'aire sous la courbe ROC était de 0,55 pour le test de dépendance de précharge (IC à 95 %, 0,34-0,75). En utilisant un seuil d'augmentation de 10 % de l'indice de volume systolique (SVi) pendant la compression abdominale calibrée, la spécificité était de 0,30 (IC à 95 %, 0,00-0,60) et la sensibilité était de 0,77 (IC à 95 %, 0,65-0,88). La variation moyenne de la pression artérielle et la variation du SVi n'étaient pas corrélées lors de l'élimination du liquide ; r = 0,19 ; IC à 95 % -0,07 à 0,43 ; p = 0,139.Conclusions : La dépendance à la précharge n'est pas précise pour prédire l'instabilité hémodynamique au cours d'une CRF. Nos données ne supportent pas une réduction du volume intravasculaire étant principalement responsable de la réduction de la pression artérielle lors d'une CRF chez les enfants.

International audience; In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri-operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein-1 (PD-1, invasive front, stromal, intra-epithelial compartments), and programmed death-ligand 1 (PD-L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD-L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD-L1 expressions on immune cells were predictive of better disease-free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD-L1 expression and tumor-infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.