Clinical trials

This European observational cohort follows patients with cystinosis, a rare lysosomal storage disease caused by CTNS mutations leading to cystine accumulation and multisystem involvement. It aims to describe the long-term clinical course under current treatments, focusing on renal and extra-renal complications, survival, and quality of life. It also evaluates treatment effects and explores biomarkers, including inflammatory markers, with biobanking for future research.

Student financial insecurity has become a major public health and societal issue affecting a growing proportion of young adults in higher education, exacerbated by the COVID-19 pandemic and more recently by inflation. Health students may be particularly exposed because of the demanding and lengthy nature of their training, often combined with limited opportunities for paid work due to hospital placements and academic workload. A national study conducted in 2024 by the Unit Institut national de la santé et de la recherche médicale U1073 under the supervision of the Conférence Nationale des Doyens de Médecine among more than 12,000 health students showed that 12% experienced severe financial insecurity, characterized by insufficient monthly resources, recurrent bank overdrafts, and frequent food deprivation, while 20% reported moderate insecurity. Financial insecurity was strongly associated with anxiety, depression, and emotional exhaustion, while vulnerable students were also more likely to forgo healthcare, including psychological consultations, for financial reasons. This vicious circle between financial hardship and mental health may compromise academic success and justifies targeted intervention. Although support systems such as Santé Psy Étudiant and free psychological consultations at the faculty already exist, they remain underused because of stigma, insufficient information, or perceived barriers to access. The PRISMES project proposes a participatory, adaptive, and real-world intervention designed to improve mental health support for financially vulnerable health students. Students directly participate in the co-construction of interventions together with researchers, student associations, health professionals, academic representatives, and a sociologist involved in understanding social determinants, mental health representations, and barriers to participation. Three intervention formats will initially be proposed, Three types of interventions are offered to students. Intervention I consists of four individual psychological consultations. Intervention II includes two collective workshops focused on stress and budget management, combined with two sophrology sessions. Intervention III comprises one psychological consultation and two collective workshops on stress and budget management.. This non-randomized design reflects real-life implementation conditions and improves future transferability. The main objective is to provide concrete support to financially vulnerable students by improving well-being, mental health, and knowledge of available support systems. Secondary objectives are to evaluate intervention effects on anxiety, depression, stress, quality of life, and emotional exhaustion, to adapt interventions according to feedback, and to improve awareness and use of social and health support services. A mixed-method design will combine quantitative and qualitative data. Quantitative assessments will be conducted monthly during the three months following the first intervention and again three months after the final intervention. Validated questionnaires will assess perceived stress (Cohen scale), anxiety and depression (HAD score), quality of life, and emotional exhaustion (MBI-SS). Qualitative interviews and focus groups conducted at the end of the intervention will explore perceived benefits, barriers, and implementation factors among students and professionals. The adaptive design allows continuous adjustment according to interim findings. For example, if attendance is limited by timetable constraints, sessions may be rescheduled. Feedback loops involving participants and stakeholders will guide iterative improvement. Eligible participants are health students aged 18-30 enrolled at Université de Rouen Normandie presenting at least one indicator of financial insecurity: insufficient monthly resources, recurrent overdraft, or frequent food deprivation. Students currently receiving psychological follow-up are excluded. Assuming a reduction in anxiety prevalence from 55% to 45%, 88 participants are required; with 20% loss to follow-up, 110 students will be included. Among approximately 4,500 health students in Rouen, about 540 are estimated to experience severe insecurity and 900 moderate insecurity, ensuring strong feasibility. PRISMES aims to generate directly transferable recommendations for university support policies and improve resilience, well-being, and academic success.

This prospective, single-center clinical investigation conducted in France will evaluate two non-invasive investigational devices (HEMI and SPG-NINOX) designed to assess microcirculation in adults. The study will include 165 participants divided into five groups (33 per group): healthy volunteers, patients with hypertension without chronic kidney disease (CKD), patients with type 2 diabetes without CKD, patients with moderate CKD, and patients with severe CKD. The primary objective is to compare baseline small vessel pressure measured with the HEMI (Multi-spectral optical system for microcirculation hemodynamics) device across groups in order to identify microvascular alterations associated with cardiometabolic and renal disease. Secondary objectives include assessment of microvascular responses after post-ischemic hyperemia, evaluation of SPG-derived (Speckle plethysmography) small vessel flow and volume parameters, comparison with reference vascular measurements (including SphygmoCor and ultra-high frequency ultrasound), and evaluation of feasibility, acceptability, and measurement reproducibility. Participation is non-randomized, based on participants' pre-existing clinical condition, and study procedures are non-invasive with an expected visit duration of approximately 60 minutes.

Every year in the fall and winter, numerous respiratory viruses (such as influenza viruses, SARS-CoV-2 (COVID-19), RSV, rhinovirus, and metapneumovirus) circulate in mainland France, causing acute respiratory infections (ARIs). These viruses can cause epidemics of varying severity, requiring close monitoring to determine their circulation levels and adapt public health measures accordingly. In France, ARI surveillance relies on two networks: the Sentinelles network in primary care and the RENAL network in hospitals. The Sentinelles surveillance is conducted in collaboration with Santé publique France, the National Reference Center for Respiratory Infection Viruses (Institut Pasteur and Hospices Civils de Lyon), and the University of Corsica. As part of the virological surveillance of ARIs, Sentinelles physicians are asked to collect nasopharyngeal swabs or saliva samples from a sample of patients presenting with an ARI during their clinic visits. This surveillance makes it possible to identify respiratory viruses circulating in primary care (general practice and pediatrics), to describe confirmed cases for each of the circulating viruses, and to estimate the impact of each on general practice. This surveillance also allows for the evaluation of the effectiveness of vaccines against influenza and COVID-19.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and verbal and non-verbal communication (DSM-5, 2013), affecting approximately 2% of the general population. In 5 to 40% of cases, genetic factors are identified as the cause of these disorders, with prevalence depending on the technique used (exomes and/or SNP arrays) and the associated intellectual deficit. In the majority of cases, the etiology remains unknown. Studies of microdeletions/microduplications (copy number variants) or Whole Exome Sequencing and Whole Genome Sequencing (Single Nucleotide Variants) show the involvement of numerous genes in the predisposition to autism. ASD remains a genetically heterogeneous disorder, as more than 250 genes have been associated with ASD to date. The main objective of the project is to continue identifying genetic factors, and also to understand the biological mechanisms involved in the emergence of autistic symptoms. Identifying biological pathways is an essential step in developing new therapeutic strategies. In addition, one of the major challenges of this study is to better understand the phenotype/genotype relationships in ASD. This requires in-depth knowledge of the phenotypic characteristics of participants with ASD and their families, as well as neurotypical populations. This study combines the scientific expertise of researchers specializing in molecular biology, phenotypic exploration (clinical, cognitive, MRI, EEG, biochemistry, immunology), and the use of pre-therapeutic cellular models (iPSCs, neural precursors, organoids). The objective of this work is the identification of numerous genes associated with ASD and involved in synaptic formation and regulation: NLGN3-4, SHANK1 and SHANK3, CNTN-6, and CNTNAP4. This work was combined with in-depth phenotypic explorations of ASD participants and their relatives. It has made it possible to clarify the neuroanatomical characteristics of participants with ASD and their genetic substrate, as well as the underlying cognitive processes. All of this work opens up new prospects for identifying new therapeutic targets using preclinical cell models (IPSCs Induced pluripotent stem cells, neural progenitors, organoids) developed in particular by I-Stem and Human Technopole.

Repeated transcranial magnetic stimulation (rTMS) is mainly used to treat mood disorders by addressing differences in brain function, particularly in the dorsolateral prefrontal cortex (DLPFC), which affects emotions and executive functions. The therapy aims to enhance the left DLPFC or suppress the right. It has been approved for severe major depression in several countries (Canada and Israel since 2002, USA since 2008) and is in the process of being validated in Europe but is not yet reimbursed in France. due to variable results from one study to another and lack of standardization issues. In a previous study, by recording electroencephalographic (EEG) rhythms before and after rTMS treatment of the DLPFC, the investigators showed on a small cohort of patients (n=17) with major or bipolar depression, that the responder patients showed higher EEG theta rhythms in the DLPFC but also and especially in parietal regions. This suggests that the DLPFC is part of the fronto-parietal central executive network (CEN), which is important for working memory and cognitive control. The CEN is not well connected in severe resistant depression, possibly leading to negative emotional bias. The rTMS cure of DLPFC can be interpreted as improving depressive symptoms through the normalization of the CEN by increasing DLPFC excitability and its downward connectivity. However experimental and clinical evidence for this mechanism, among others, is still to be demonstrated, and remission rates of rTMS from DLPFC in drug-resistant depression are still low (20-40%). To improve these response rates to rTMS in DLPFC, it is essential to continue research aimed at improving clinical practices through a better knowledge of the functional neuroanatomy and mechanisms of action of rTMS. This will require the definition of biomarkers allowing in particular to better target the DLPFC, this structure beeing indeed relatively poorly defined on the neuroanatomical level (large portion of the medial frontal gyrus). To this end, the investigators have set up a collaborative research program with Dr. Corey Keller, psychiatrist at Stanford University USA, which was jointly funded in 2022 by the Agence Nationale pour la Recherche (ANR) and the National Institute of Health (NIH) - FrontalProbe project "Probing the dorsolateral prefrontal cortex and central executive network for improving neuromodulation in depression". The ultimate aim of this project is to develop and test different strategies for targeting the DLPFC in the rTMS treatment of pharmaco-resistant depressive patients, following the fundamental neuroanatomical and pathophysiological hypothesis that patients will respond better to therapy if their CEN network is better modulated. This clinical trial will take place in Stanford, USA, in the years 2025-2026. Previously, the investigators are working on the development of methodological strategies aimed at preferentially activating, in a personalized way, the part of the DLPFC that projects onto the PPC. This is the subject of the present protocol, which aims to identify this subpart of the DLPFC to be targeted as a priority for modulating the CEN, through neuroanatomical measurements with high-field MRI and cortical excitability by TMS-EEG in healthy subjects. To this end, the investigators will use a small cohort of healthy subjects who will have one multimodal MRI acquisition session of at 7T and one TMS-EEG session. The 7T MRI data, acquired at the Centre de Résonance Magnétique en Biologie et Médecine (CRMBM), will be used to obtain anatomical markers of the DLPFC. TMS-EEG data, acquired at the Institut de Neurosciences de Systèmes (INS), will be used for cortical excitability measurements of the DLPFC and its projection sites, notably the PPC. At this stage, no data exchange is planned with our American partners. Firstly, the processing of MRI data will include segmentation of gray and white matter, reconstruction of the cortical surface and estimation of the different cortical layers, mainly by monitoring variations in the T1 parameter along the cortical mantle. Other MRI parameters will also be acquired to maximize the specificity of the segmentation of the DLPFC into sub-regions, firstly by identifying the part of the DLPFC that connects preferentially to the PPC using the reconstruction of fiber bundles from diffusion MRI and functional resting MRI. Secondly, during TMS-EEG acquisitions, participants will be stimulated in 3 sub-regions of the DLPFC. For each target, the analyses of the EEG data will focus on quantifying connectivity with the PPC as well as their spectral signature, which is possibly an indirect reflection of the neuronal composition of the stimulated regions. Correlation of 7T MRI and TMS-EEG data will help set optimal DLPFC targeting criteria for PPC activation. The aim is to create an MRI-based targeting procedure for clinical practice. In this sense, TMS-EEG will serve as validation of MRI markers.

Cerebrovascular accidents (strokes) are a major public health issue. Stroke is the 3rd leading cause of death and the leading cause of disability and loss of autonomy. In France, there are currently 130,000 new cases per year, and the aging of the population will lead to an increase in this number over the next few years. Among post-stroke impairments, motor deficit of the upper limb is the most common disability, affecting 73-88% of first-time stroke patients and 55-75% of chronic patients. Associated deficits can complicate rehabilitation management and affect recovery. The clinical profile of patients with motor deficits is therefore varied and complex, requiring an individualized approach. At present, only physiotherapy is recommended, with modest results. Repeated transcranial magnetic stimulation is a therapy that can improve motor recovery, but currently has a low level of evidence according to the HAS (French Hight Health Authority), notably because of variability in efficacy due to heterogeneity in the clinical profile of patients. Nevertheless, it is still recommended for the recovery of cognitive functions, but also for resistant depression, and could be used to stimulate motor imagery (MI). MI training also has the advantage of stimulating the motor network. Difficult to achieve for a number of patients, the use of rTMS could facilitate this cognitive task and, in particular, provide better access to brain-computer interfaces (BCI). Indeed, among the innovative rehabilitation therapies, BCIs have emerged as the most promising. By translating brain activity during a cognitive task into a command such as electrical muscle stimulation, BCIs would restore the damaged motor network and induce motor recovery. The main obstacle to their widespread use in clinical practice is their lack of reliability, as almost 30% of patients are unable to control them correctly, either because of difficulty in performing the MI task, or because of difficulty in identifying a universal brain signature. The BCINET project aims to improve the reliability of BCIs in two ways: by improving detection of the motor imagination task using new brain signatures, and through cognitive facilitation using rTMS. 1. \- Using the dynamic communication of different brain areas during the MI task (or functional connectivity), we can identify patient-specific signatures. Studies of functional connectivity in healthy subjects performing an MI task without associated BCI have shown the interest of certain measures such as node degree or clustering coefficient. To find out whether functional connectivity parameters can be used in BCI algorithms, we will evaluate their effectiveness on an initial group of 5 patients to define their performance in discriminating the MI task and to determine their evolution over time in the absence of brain stimulation in stroke patients. Their initial study will also enable us to identify their evolution when TMS stimulation is applied. 2. \- Cerebral magnetic stimulation could facilitate the MI task and enable better BCI rehabilitation for a number of patients. Two studies using either an inhibitory or excitatory stimulation protocol showed an improvement in spectral power signal and better discrimination of the MI task. However, the results were acquired using a single pre- and post-therapy measurement, and did not take into account behavioral variability in the use of BCIs or variability in TMS response according to patient profile. Therefore, in order to identify whether rTMS would improve BCI control, we would perform 9 Single-Case Experimental Design (SCED) studies in multiple baselines on a group of 5 patients according to 3 clinical profiles and 3 rTMS stimulation strategies. SCEDs are suitable experimental models for heterogeneous populations, particularly when the intervention presents some inter-individual variability in efficacy. They have the advantage of being able to demonstrate, on an individual scale, the effectiveness of the intervention on a small group of patients. Replication of the SCED allows us to increase the external validity of the intervention on sub-groups of patients (clinical severity, presence of associated hemineglect) and to study modifications in the interventional strategy (stimulation frequency, stimulation site).

The main objective of this study is to investigate in real-time the neuronal correlates of paroxysmal dyskinesia episodes related to the PRRT2 mutation within this subgroup of patients (who can control paroxysmal dyskinesia episodes), and more specifically, the pathological role of the reciprocal influence between the striatum and the cerebellum in paroxysmal dyskinesia episodes.

National multi-center non-interventional case-control cohort study with collection of biological samples to characterize the autoimmune T and B lymphocytes involved in the development of type 1 diabetes.

Congenital heart disease (CHD) is the leading cause of congenital malformations, representing 1% of live births. Progress in surgical care have led to the dramatic increase in the population of children and adults living with heart disease. As survival is no longer a concern, long-term outcomes have become the major public health issue. Prenatal diagnosis of CHD requiring open-heart surgery can be a traumatic event for expecting mothers and fathers. In the general population, maternal mental health distress is associated with fetal disturbances in the hypothalamic-adrenal-pituitary system axis, restricted intrauterine growth and adverse outcomes in the offspring. It is unknown whether prenatal maternal psychological distress have an impact on neurodevelopmental outcomes in CHD. Our national study seeks to (1) characterize the impact of prenatal maternal psychological distress on neurodevelopmental outcomes at age 1 for children with CHD who undergo neonatal open-heart surgery; (2) investigate the sociodemographic and medical determinants associated with prenatal maternal mental health of women carrying a foetus diagnosed with complex CHD; (3) explore the mediating role of prenatal risk factors (i.e., sociodemographic, medical and maternal coping mechanisms) in the association of prenatal maternal mental health (i.e., distress, anxiety and depression) and neurodevelopment in children with CHD; and (4) explore the impact of paternal or the co-parent's mental health impact on neurodevelopmental outcomes at age 1 in children with CHD. This study is a non-interventional, prospective, and longitudinal study of prenatal maternal mental health and subsequent child's neurodevelopmental and behavioural outcomes. It includes a follow-up period from the 3rd trimester of pregnancy until the child's first year of life. It will include children with a prenatally diagnosed heart defect requiring open-heart surgery within the first weeks of life. Understanding and preventing the neurodevelopmental sequelae of heart disease diagnosed in-utero is a public health priority.

The neural correlates of consciousness have been studied at the macroscopic level. However, the neurochemical basis of these processes remains poorly understood. The mesocircuit theory challenges the cortico-centric view of consciousness. It highlights the role of subcortical regulation by dopaminergic circuits, including the ventral tegmental area and striatal loops. Experimental data show the importance of dopamine in consciousness recovery. Animal TBI studies link dopamine deficits to loss of consciousness and recovery. In humans, imaging studies show disrupted dopaminergic networks in chronic consciousness disorders. Yet, early-phase dopaminergic disruptions in acute coma remain underexplored. Molecular imaging with PET or SPECT offers insights into dopamine system disturbances. The novel radiotracer 18F-LBT-999 enables detailed imaging of dopaminergic circuits, providing better spatial resolution and quantification than SPECT. This proof of concept study aims to explore acute subcortical dopaminergic loop disruptions. It will combine 18F-LBT-999 PET with structural and functional MRI in post-traumatic coma. Methods : Patients with severe traumatic brain injury (TBI) admitted to the intensive care unit state will be evaluated within 30 days post-injury. Participants will undergo clinical assessment after sedation clearance and will be categorized into three groups: (1) TBI-COMA (severe TBI with persistent coma), (2) TBI-REC (severe TBI with recovery of command-following), and (3) healthy controls. All participants will undergo clinical evaluations, anatomical and functional MRI, and molecular imaging: 18F-LBT-999-PET. Neurological outcome (CRS-r scale), Disability rating scale (DRS), Quality of life (QUOLIBRI) and axtrapyramidal symptoms (MDS-UPDRS) will be assessed at 3 month. Primary Hypothesis: Acute post-traumatic severe TBI patients with persistent coma (TBI-COMA) show reduced presynaptic dopamine receptor levels in the striatum, compared to healthy controls. Secondary Hypotheses: * Dopaminergic disruptions correlate with the severity of consciousness impairment, differentiating TBI-COMA and TBI-REC groups. * Structural damage in the striatum and nigrostriatal tract, identified via MRI, aligns with dopaminergic abnormalities. * Multimodal imaging findings during the acute phase can predict long-term neurological and quality-of-life outcomes. * Characterizing structural, functional, and metabolic variations in dopaminergic networks may guide personalized pharmacological treatments.

Prostate cancer is the most common male cancer in industrialized countries, including France, with over 60,000 new cases each year, and represents the third leading cause of cancer-related death in men. The only known risk factors are age, ethnic origin and family history of prostate cancer. Indeed, there are considerable ethnic disparities in prostate cancer risk, with an incidence rate 60% higher in African-American men than in European-American men (Evans 2008). Similarly, in the French West Indies, where over 90% of the population is of Afro-Caribbean origin, the incidence of prostate cancer is twice as high as in mainland France. In 2015, the annual incidence was 88.5 cases per 100,000 in mainland France (Defossez 2021), while it was 184.1 cases per 100,000 in Guadeloupe, over the period 2008-2013 (Desloumeaux 2017), and 161.1 cases per 100,000 in Martinique, over the period 2005-2014 (Joachim 2019). The incidence rates observed in the French West Indies are of the same order as those observed in Afro-Caribbean populations in the UK and African-American populations in the USA (Ben Schlomo 2008, Evans 2008). The reasons for these ethnic disparities in incidence are still poorly understood, but the role of genetic factors has been suggested. Indeed, certain genetic polymorphisms have been associated with an increased individual risk of prostate cancer in men of sub-Saharan African origin (Conti 2021; Karunamuni 2021; Marlin 2021). In addition, certain environmental factors (in the broadest sense) such as obesity, chronic inflammation, diet and certain environmental pollutants, including persistent organic pollutants (POPs) such as certain organochlorine pesticides, are also strongly suspected. Among the suspected organochlorine pesticides is chlordecone, an insecticide used in the French West Indies until 1993, strongly suspected of playing a role in the occurrence of prostate cancer, particularly in the West Indies. Indeed, the Kannari study (Dereumeaux and Saoudi 2018), supported by Santé publique France, assessed the exposure of the West Indian population (Martinique and Guadeloupe) in 2013-2014 to chlordecone and certain organochlorine compounds , measured by serum levels, and quantified the determinants of this impregnation. The results of the study show that 90% of the West Indian population is indeed exposed to chlordecone, and demonstrate that chlordecone is still present in the environment (water and soil) and in food products, despite the cessation of its use in the West Indies in 1993. To date, only one epidemiological study has explored the link between chlordecone exposure and the occurrence of prostate cancer, the Karuprostate study, a case-control study carried out between 2004 and 2007 in Guadeloupe, including 623 prostate cancer cases and 671 controls (Multigner 2010). Chlordecone exposure was measured by serum levels with an initial detection limit of 0.25 μg/L (Multigner 2010), then improved to 0.06 μg/L (Emmeville 2015). The authors highlighted a significant association between chlordecone exposure and prostate cancer, with a positive dose-response relationship (OR=1.77; 95% CI, 1.21 to 2.58 for the highest tercile). This association was more specifically observed in subjects with a family history of prostate cancer and in men who had lived in a Western country, requiring further investigation. The Karuprostate study also showed that serum levels of dichlorodiphenyldichloroethylene (DDE), the main and most stable metabolite of DDT, were significantly associated with the occurrence of CaP (Emmeville 2015). These results underline the interest of assessing, along with chlordecone, co-exposure to other persistent organic or organochlorine pollutants. Furthermore, DDE exhibits anti-androgenic effects and has been shown to repress the production of Prostatic-Specific Antigen (PSA) (target gene of the androgen receptor) by human prostate cancer cell lines (Wong 2015). The supposed effect of other organochlorines such as chlordecone on androgen receptors and thus on PSA levels could thus have important repercussions in terms of prostate cancer diagnosis. Individual screening for prostate cancer is based on serum PSA levels, followed in cases of elevated PSA (\> 3-4 ng/ml) by multiparametric Magnetic Resonance Imaging (mpMRI). A recent study showed that performing pre-biopsy mpMRI, regardless of PSA level, could lead to more men being diagnosed with clinically significant prostate cancer (Eldred-Evans 2021). Finally, there is a lack of preclinical studies to investigate the distribution of chlordecone in blood and tissues, as well as the link between chlordecone and markers of prostate cancer aggressiveness. We therefore propose a case-control study in the general population of Martinique. This study will enable us to understand the nature of the link between chlordecone and prostate cancer.

Evaluate the efficiency of audiovisual stimulation in virtual reality for improving the visual perception of children, adolescents, and young adults with hemianopia resulting from pediatric brain tumors. These individuals can lose up to 50% of their visual field, significantly impacting their independence, mobility, and daily lives.

Central post-stroke pain (CPP) is extremely difficult to relieve and responds very poorly to analgesics targeting neuropathic pain, probably because the mechanisms underlying this pain remain poorly understood. Stroke pain is traditionally considered to be of central origin and related to changes in the spinal cord and/or brain nociceptive systems. However, a recent study in a small cohort of patients has suggested that the peripheral nervous system (PNS) may have a role in the initiation and persistence of APD. The main objective of this prospective randomised controlled bicentric study (Raymond Poincaré and Ambroise Paré) in double blind and parallel groups against placebo (3 arms) will be to evaluate the efficacy of two peripheral nerve blocks performed 14 days apart on spontaneous neuropathic pain after stroke. The active treatments used for the blocks will be either lidocaine 20 mg/ml or levobupivacaine 1.25 mg/ml or placebo (saline)

Developmental Language Disorder (DLD) refers to children who present with language difficulties that are not due to a known biomedical condition or associated with autism spectrum disorder (ASD) or intellectual disability. The prevalence of DLD is \~7%-8% or 2% if severe forms are considered. However, the clinical heterogeneity of language disorders, the presence of co-morbidities and the inconsistent terminology used for many years have hindered research and clinical practice. Distinguishing sub-groups of children with language problems is crucial when tackling the underlying genetic causes of this disease. Recently, several studies using high-throughput sequencing have better define the genetic basis of CAS but such studies focusing on DLD are limited. The investigation of more homogeneous cohorts of individuals that clearly distinguish DLD cases, from ID and not including children with CAS should improve our understanding of the genetic basis of this disorder. In this study, we aim to built and investigate a well-characterized cohort of DLD patients using pangenomic approaches to better define the molecular basis of this disorder. All individuals will be analyzed using chromosomal microarray analysis and whole genome sequencing. Multiple observations and preliminary results suggest strong links with the genetic basis of other neurodevelopmental disorders. The goal is to identify CNV or SNV as causative allele or risk factor and already known to be involved in other neurodevelopmental disorders as well as potential new variants.

The general purpose of this research project is to analyze the specific role of motor imagery on motor learning, assessed through corticospinal excitability measurements and behavioral data collection. This project is based on four sequences. For Sequence 1, the main objective is to examine the effect of mental training on movement speed and accuracy in a manual motor sequence task, as well as the influence of sensory feedback in immediate post-test (i.e., execution of a similar, but not identical, manual motor sequence, other manual tasks) on performance in delayed post-test. The secondary objective will be to examine corticospinal changes (i.e., amplitude of motor evoked potentials) induced by mental training, by measuring the amplitude of motor evoked potentials before and after mental training. For Sequence 2, the main objective is to examine the impact of a motor disturbance induced by a robotic arm at different intervals during the motor imagery process. The secondary objective will be to examine the corticospinal changes (i.e. amplitude of evoked motor potentials) induced by mental training as a function of the applied perturbations, before and after perturbation. For Sequence 3, the main objective will be to examine the influence of neuroplasticity on the quality of mental training. More specifically, the investigators will study the links between brain plasticity and motor learning through mental training. The secondary objective will be to examine the corticospinal changes (i.e. amplitude of evoked motor potentials) induced by mental training at different levels of the neuromuscular system (cortical, cervicomedullar, peripheral) after a training period. For Sequence 4, the main objective will be to examine the effect of short-term arm-immobilization of on the retention of motor learning induced by mental training. The secondary objective will be to examine the corticospinal changes (i.e., amplitude of motor evoked potentials) induced by of short-term arm-immobilization, or by transcranial direct current stimulation (tDCS), on motor learning. The results of this fundamental research project will allow a better understanding of neurophysiological and behavioral mechanisms that underlie motor learning through motor imagery. The results will allow to efficiently consider inter-individual specificities and will thus open up to clinical research perspectives, towards the establishment of adapted motor rehabilitation protocols.

The CERSTIM study is a physiopatholgical study investigating transcranial alternating current stimulation in stroke patients in the cerebello-motor loop. The design is a cross over design testing two frequencies in the gamma band and one placebo. We will use behavioural data, functional MRI, and Electroencephalography to disentangle the effect of tACS and its frequency. Healthy participants will be also recruited.

The goal of this observational study is to identify diagnostic and prognostic biomarkers for endometriosis using menstrual blood, an easily accessible yet overlooked biological fluid in women of reproductive age, affected or not by endometriosis The main questions it aims to answer are: * are there relevant differences in the menstrual blood of women affected by endometriosis compared to women without endometriosis? * do some of these differences disappear or lessen when the disease is treated by surgery? Participants will answer questions relevant to endometriosis and provide menstrual blood 1 to 3 times (self-collected with a menstrual cup). A subgroup of participants affected by endometriosis that will undergo surgery for their regular care will provide menstrual blood before and after their surgery. Researchers will compare the menstrual blood of women with and without endometriosis, and before and after surgery to see if they can identify significant differences.

The ductus arteriosus (DA) is a large channel connecting the main pulmonary trunk with the descending aorta. In extremely preterm infants, the DA frequently fails to close and this results in a condition called patent ductus arteriosus (PDA). In these patients, PDA has been associated with increased mortality and morbidity in the neonatal period, and neonatal morbidities may in turn be associated with later deficits in cognitive functioning. PDA treatment with COX inhibitors, as ibuprofen or indomethacin, aiming at closing the PDA have been associated with numerous adverse effects and failed to demonstrate significant clinical benefits. Early treatment of PDA with paracetamol (acetaminophen ) has been proposed as an alternative to COX inhibitors. The ongoing pan-European TREOCAPA phase III study (NCT04459117) is a multicentre, double-blind, randomised, placebo-controlled superiority trial that assesses prophylactic use of paracetamol to improve survival without severe neonatal morbidity until discharge from hospital in infants of 23-28 weeks of gestational age. As long-term follow-up was not planned by the TREOCAPA protocol, TREOCAPA-LT study will use an existing European research infrastructure, the RECAP Preterm platform (https://recap-preterm.eu/), to follow-up the patients enrolled in the TREOCAPA trial using a parent-report questionnaire at 2 years of corrected age. The TREOCAPA-LT primary hypothesis is that there will be improved cognitive outcome at 2 years of corrected age in children born at less than 29 weeks of gestational age who were treated with paracetamol during the first 5 days of life in the TREOCAPA phase III trial.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are myeloid malignancies resulting from the transformation of a multipotent hematopoietic stem cell (HSC) caused by mutations activating the JAK2/STAT pathway. The most prevalent mutation is JAK2V617F. Type 1 and Type 2 calreticulin (CALR) and thrombopoietin receptor (MPL) mutations are also observed in ET and PMF. Additional non-MPN mutations affecting different pathways are also found, particularly in PMF, and are involved in disease initiation and/or in phenotypic changes and /or disease progression and/or response to therapy. There is an obvious and urgent need for an efficient therapy for MPN. In particular, PMF remain without curative treatment, except allogeneic HSC transplantation and JAK inhibitors have limited effects on the disease outcome. Among novel therapeutic approaches, Peg-IFNα2a (IFN) is the most efficient harboring both high rates of hematological responses in JAK2V617F and CALRmut MPN patients and some molecular responses mainly in JAK2V617F patients including deep molecular response (DMR). Nevertheless, several studies, including our own, have demonstrated that the IFN molecular response in CALRmut patients is heterogeneous and overall much lower than in JAK2V617F patients. Moreover, some JAK2V617F MPN patients do not respond to IFN, and DMR is only observed in around 20% of JAK2V617F patients. Finally, long-term treatments are needed (2-5 years) to obtain a DMR, jeopardizing its success due to possible long-term toxicity. The underlying reasons for failure, drug resistance, heterogeneous molecular response in CALRmut patients and the long delays for DMR in JAK2V617F patients remain unclear, largely because the mechanisms by which IFNα targets MPN malignant clones remain elusive. Significant improvement of IFN efficacy cannot be achieved without basic and clinical research. Hence our two lines of research are to * Understand how IFNα specifically targets neoplastic HSCs * Predicting and improving patient response during IFNα therapy

The aim is to determine the metabolic factors, host immune factors, and medical imaging data associated with the development of HepatoCellular Carcinoma (HCC) in patients with alcohol-related liver disease or dysmetabolic steatosis/Non-Alcoholic SteatoHepatitis. The investigators will include patients with and without cirrhosis in order to identify early molecular mechanisms involved in the development of HCC especially in non-cirrhotic patients.

The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice, in a randomized trial. Notably, the questions it aims to answer are: * The feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes, * The contribution of WGS coupled with MCM on number of genetic alterations likely causal of diabetes identified and with a modification in care and support of patients. After inclusion and sampling for genotyping, patients will be followed for 5 years. The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.

To investigate in a prospective way changes in Mucosal-Associated Invariant T (MAIT) cells frequency, phenotype and function in link with the gut microbiota, gut integrity and the presence of Coxsackie virus B in two cohorts of pediatric patients: patients with a high genetic risk of type 1 diabetes and pediatric patients with recently diagnosed T1D by comparison with control subjects Tasks: 1. To measure blood MAIT cells frequency, phenotype and function in the three cohorts 2. To analyze gut microbiota and the presence of Coxsackie B enterovirus (CVB) and their impact on MAIT cell function 3. To evaluate gut integrity and analyze the gut mucosa 4. To integrate all the data obtained with T1D development and evolution

The aim of this observational study is to develop an alternative database model for genetically originated intellectual disabilities. This model will take the form of an online cohort study, where the majority of clinical information will be provided by the families of the patients. Questionnaires developed by professionals but formulated in a way understandable to families will be used to gather this information. Specifically, this study aims to collect relevant information for personalized medical management. This includes understanding the risks of specific pathological complications and potential iatrogenic effects of symptomatic treatments. The primary goal is to establish groups of individuals with intellectual disabilities and/or autism spectrum disorders (ASD) sharing the same genetic mutation. This approach will provide a better understanding of the natural history of the disease and associated comorbidities. It is important to note that this project will only focus on patients for whom the identification of the causal mutation or penetrant copy number variation (CNV) has been determined. It excludes individuals for whom the cause of intellectual disability is unknown. This approach will contribute to a better understanding of the genetic aspects of intellectual disabilities and ASD, while facilitating more targeted and personalized medical care for the affected patients.

Time processing, the ability to process and encode temporal information, is essential for cognitive functioning and for a large number of daily life activities. In particular, the processing of durations of several seconds is central to cognition, impaired in several pathologies, and has been associated with cognitive changes with advancing age. While behavioral studies have been conducted to specify the neural bases of temporal cognition and their association with other cognitive functions, the mechanisms underlying age-related changes, and individual differences, remain unknown. The project will characterize ageing effects on timing mechanisms and their neural underpinnings. Building on recent advances from neuroscience and age-related cognitive changes, the project focuses on the precision of duration processing, that declines with age, and the associated neural bases. Participants will perform a duration judgement task while (a) electroencephalography, and (b) functional magnetic resonance imaging activity are simultaneously recorded to investigate age effects on structural and functional network connectivity. In addition, striatal dopamine will be measured using a FDOPA PETscan. Evaluation of other temporal cognition processes and general cognition will also be performed. This combination offers a unique opportunity to accurately specifying the neurophysiological underpinning of aging effects on time processing changes. This project will further our understanding of the variability of cognitive performance with advancing age, and contribute to identifying new measures of temporal impairments.