Clinical trials

Neurodevelopmental disorders (NDDs), including intellectual disability (ID), represent the most common indication for genetic testing. Affecting up to 3% of the general population, NDDs are characterized by significant clinical and genetic heterogeneity. Although short-read genome sequencing (srGS) has driven major advances through the France Genomic Medicine 2025 Plan (PFMG2025), a substantial proportion of patients still lack a molecular diagnosis. These results are partly explained by the limitations of short-read genome sequencing (srGS). Although effective in many cases, this technology performs poorly in detecting complex structural rearrangements, anomalies within repetitive or GC-rich regions, epigenetic variations, and certain intronic variants. Furthermore, srGS does not allow for the direct assessment of the functional impact of genetic variations on splicing or gene expression. Following a negative srGS result, periodic reanalysis of sequencing data via the PFMG2025 laboratories (AURAGEN and SeqOIA) is the only diagnostic option currently available in routine practice. However, these reanalyses are constrained by financial and staffing limitations as well as strict eligibility criteria, making it difficult for many patients-particularly those with stable neurodevelopmental disorders (NDDs)-to obtain a diagnosis. Moreover, they often consist merely of a data review without bioinformatic updates, and the turnaround times-frequently exceeding one year-contribute to the diagnostic odyssey. Utilizing updated pipelines tailored to the specific characteristics of NDDs for the re-examination of srGS data could serve as an initial source of new diagnoses. Complementary technologies-such as messenger RNA sequencing (mRNA-seq), optical genome mapping (OGM), and long-read genome sequencing (lrGS)-are available and offer solutions to overcome the limitations of short-read genome sequencing (srGS). In particular, they enable the identification of complex structural variants and the assessment of the functional impact of point variants. Despite their potential, their routine use remains limited due to cost and technical complexity. Our study proposes a combined strategy to address the limitations of current approaches and improve the diagnosis of neurodevelopmental disorders (NDDs) that remain unresolved after short-read genome sequencing (srGS). It begins with a re-analysis of sequencing data using customized bioinformatics pipelines tailored to the patients' specific clinical profiles. In cases of inconclusive results, innovative multi-omics analyses (mRNA-seq, OGM, and long-read genome sequencing/lrGS) will be employed to investigate complex genetic variants. As multi-omics approaches are not currently integrated into the PFMG2025 framework, the project's findings will be crucial in demonstrating their added value for NDD diagnosis and could pave the way for their inclusion in a future PFMG. By anticipating these developments, NextOmix will help define the diagnostic strategies of the future, aligned with technological advancements and patient needs.

Retinal and choroidal microcirculation is a relevant biomarker of systemic vascular health and lies at the heart of eye-heart interactions. Noninvasive retinal imaging, particularly OCT angiography (OCT-A), now makes it possible to examine retinal and choroidal microvascularization in vivo and to study its relationship with systemic cardiovascular and neurovascular mechanisms. Ultra-endurance activities, such as ultra-trail races, induce significant systemic hemodynamic changes, including dehydration, variations in perfusion pressure, prolonged sympathetic activation, and redistribution of blood flow. These physiological adaptations could lead to acute and reversible changes in retinal and choroidal vascular parameters as measured by retinophotography and OCT angiography. Several studies suggest that intense physical exercise may be accompanied by significant changes in retinal and choroidal microvascular perfusion. In particular, a significant decrease in the vascular density of the superficial retinal plexus has been observed following intense exercise in a healthy population, suggesting a transient change in retinal microcirculation. Similarly, following a marathon, a decrease in the retinal vascular density index (RVDI) has been reported, likely related to exercise-induced vasoconstriction and a transient reduction in retinal blood flow. This decrease may also be exacerbated by the drop in systemic blood pressure and the relative dehydration observed after the race. More broadly, intense endurance exercise is accompanied by cardiovascular and neurohormonal adaptations, particularly through activation of the renin-angiotensin-aldosterone system, which may modulate ocular perfusion. Scott et al. demonstrated, following a 160-km ultramarathon, significant alterations in left ventricular function and a major elevation in NT-pro-BNP, indicating systemic cardiovascular stress that was markedly greater than that observed after a standard marathon. Furthermore, a multi-omics study conducted during the Ultra-Trail du Mont-Blanc (171 km) revealed systemic oxidative stress, marked inflammation with elevated IL-6 levels, and profound metabolic changes affecting red blood cells-mechanisms recognized as being involved in microvascular dysfunction. However, these variations primarily reflect functional changes in perfusion related to hemodynamic status and autonomic tone, rather than true structural microvascular remodeling or angiogenesis. Metrics derived from OCT angiography, such as vascular density or perfusion density, are in fact sensitive to systemic variations in circulating volume, perfusion pressure, and the quality of the acquired signal. In this context, the effects of ultra-endurance exercise on the eye remain poorly characterized. Research in this area is necessary to better understand the acute physiological adaptations of ocular microcirculation and to highlight the value of retinal imaging as a tool for cardiovascular research and prevention within an integrated eye-heart approach.

Shaft fractures account for 20% of humeral fractures and 3% of all adult fractures in France, with an estimated incidence of 13 to 20/100,000 people. Men aged 21 to 30 years and women aged 60 to 80 years are particularly affected. Intramedullary nailing is among the standard treatments for humeral shaft fractures (when surgery is required). Once inserted, the nail is locked in order to limit stress on the fractured bone, as well as possible secondary rotational displacements or malunion. Bipolar interlocking (BI) is typically performed on both sides (proximal and distal) of the fracture site. This procedure is performed under radiological control, exposing the patient and care team to radiation (during the entire procedure). The objective of the treatment is to obtain consolidation of the fracture within 12 months, and to limit the occurrence of irreversible complications such as malunion or nonunion (2-10% at 12 months post-surgery). The "unipolar interlocking" (UI) technique has recently been introduced. In this technique, locking is performed only on the proximal side of the fracture site. By avoiding the distal approach, potential complications such as radial nerve damage, with the risk of irreversible paralysis (3.8-14.2% in studies of the BI technique in this indication) or the risk of infection on the distal side can be avoided. It also reduces operative time, and consequently the radiation received by patients and caregivers. However, the UI may be poorly positioned, resulting in malunion that requires revision surgery. Despite the absence of recommendations due to the lack of existing data, several teams use the UI in routine care. In this context, a descriptive cohort of 121 patients operated on at the Dijon University Hospital5 showed similar rates of consolidation between the 2 techniques (93.8% for UI versus 95.2% for BI, p=0.64), functional scores, and complications, as well as a significant 29% decrease in operating time in the UI group (mean + SD: 63.1±21.3 min versus 88.0±30.1 min for VB, p\<0.01). These encouraging results, although limited by the retrospective and observational nature of the data, justify a prospective randomized trial comparing these two techniques.

Foot wounds in patients with diabetes are one of the most frequent complications associated with diabetes. Despite the progress made in its management in recent years, the risk of amputation remains high in cases of diabetic foot wounds. Several studies have highlighted the value of analyzing the psychological profile A or B, defined by self-questionnaire using Bortner's method. The A personality profile is characterized by hyperactivity, combativeness and exaggerated ambition, while the B profile is characterized by less sensitivity to stress and reduced combativeness. Type A personality profile is associated with reduced cardiovascular mortality in type 1 diabetes. Type B personality profiles have also been shown to be associated with inflammation in both type 1 and type 2 diabetes. Our group showed that patients with diabetes and a foot wound were more likely to have a type B psychological profile than patients with diabetes and no foot wound. However, to our knowledge, it has never been determined whether the psychosomatic profile type A or B assessed by the Bortner self-questionnaire influenced wound healing and the risk of amputation. The aim of this study is to determine whether type A or B psychosomatic profile influences wound healing in diabetic feet. This study will be carried out in the endocrinology, diabetology and nutrition department of the Dijon Bourgogne University Hospital. 308 patients will be included in the study.

Heart surgery is a complex and delicate procedure that affects more than one million people worldwide each year. Patients who undergo this surgery are generally elderly and have multiple comorbidities, which places them in high-risk categories (ASA III or IV). This frailty, combined with a loss of physiological reserve, makes these patients particularly vulnerable to postoperative complications, which can range from cardiovascular disorders to neurological, respiratory, renal, gastrointestinal, infectious, and hematological complications. In this context, the quality of postoperative recovery is crucial because it reflects the patient's postoperative health status. The quality of recovery encompasses several dimensions, such as pain, return to independence, sleep quality, and mental state. Optimal anesthesia-which goes beyond simply minimizing pain-requires proactive management of all these dimensions. Current research in cardiac surgery focuses on optimizing anesthesia strategies, particularly the choice between opioid and non-opioid anesthesia, as well as the complementary use of regional analgesia. However, studies providing clear recommendations on these topics are still limited. Among the techniques explored, the ultrasound-guided stellate ganglion block (SGB) stands out due to its numerous positive clinical effects. This block, which involves the ultrasound-guided injection of a local anesthetic into the stellate ganglion, produces a temporary sympathetic block that reduces the activity of the autonomic nervous system during surgery. Several studies suggest that SGB could significantly improve the quality of postoperative recovery, particularly in terms of pain reduction, sleep quality, and a lower incidence of cardiac arrhythmias. A meta-analysis has shown that SGB promotes the recovery of gastrointestinal function following various surgical procedures. In major thoracic surgery, it has been observed that SGB reduces the incidence of perioperative atrial and ventricular fibrillation. Although these results are promising, data from randomized trials in cardiac surgery are still limited. A pilot study demonstrated the feasibility and safety of SGB in this type of surgery, with a reduced incidence of atrial fibrillation. However, further studies are essential to confirm these results and assess the impact of SGB on the quality of recovery following anesthesia in cardiac surgery. The hypothesis of this study is that performing a stellate ganglion block during general anesthesia improves the quality of recovery in all its aspects (pain, well-being, sleep, etc.). This hypothesis warrants in-depth exploration to optimize postoperative care and improve long-term outcomes for patients undergoing complex cardiac surgery.

The general aim of this exploratory study is therefore to investigate and quantify the functional capacities of patients with lower limb amputations (transtibial and transfemoral), with no change in their management, and to describe any changes in these capacities. The volunteers included in this study will be testing new equipment, all of which will be CE-marked, and will therefore meet all the safety and performance conditions required for use by these patients (equipment that is likely to be prescribed as standard). These devices could benefit from current technological advances that could improve these patients' functional abilities. They will be chosen and adapted according to the volunteer's activity and current equipment. This is a local project of the CHU Dijon Bourgogne which will take place on the Technological Investigation Platform located at the Centre de Rééducation et de Réadaptation of the CHU Dijon Bourgogne. A maximum of 100 patients will take part in the study, divided into two sub-groups of between 5 and 50 patients, depending on the type of brace worn and the level of amputation. After the inclusion visit, each volunteer will undergo 2 assessment visits (the order of assessment of the devices will depend on randomisation) separated by 3 to 6 weeks. Follow-up is for a maximum of 14 weeks.

Visual impairment, whether central or peripheral, may influence the plasticity of other sensory modalities, such as taste and smell. Taste-evoked potentials (TEPs) and smell-evoked potentials (SEPs)-methods for analyzing brain activity in response to taste and smell stimuli-allow for the objective assessment of these interactions. This approach has already demonstrated its value in the study of cognitive disorders. This study aims to demonstrate an enhancement of taste and smell capabilities that could compensate for specific visual impairments, particularly in situations involving food choices.

Ascending aortic aneurysms (AAAs) are serious conditions that can lead to aortic dissections or ruptures, carrying a high risk of mortality. Their pathophysiology is based on complex mechanisms involving inflammatory and metabolic processes, as well as alterations in mitochondrial function. The presence of a bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV) significantly influences the progression and severity of aneurysms. Bicuspid aortic valve (BAV) patients often develop aortic aneurysms earlier, as early as age 40-50, whereas tricuspid aortic valve (TAV) patients generally present with a degenerative condition that appears later (after age 50). The objective of this study is to compare the inflammatory, metabolic, and transcriptomic signatures of myeloid cells and total aortic tissue between BAV and TAV patients. These analyses will help identify specific molecular mechanisms, potential biomarkers, and therapeutic targets. To ensure pathophysiological homogeneity, patients with aneurysms of genetic origin (Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, etc.) will be excluded.

Based on the use of the patient's natural defences, immunotherapy mobilizes the immune system to recognize and destroy cancer cells, and it has revolutionized the treatment of lung cancer. However, the effectiveness of immunotherapy varies from patient to patient. At present, we have no weak markers to predict with certainty the efficacy of immunotherapy treatment in a given individual. Current scientific data identifies a number of molecules produced by the cancer cells and their environment which can be detected by various means (blood tests, breath analysis, etc.). The aim of this study is to understand whether the amount of nitric oxide (NO) present in the breath is a more accurate predictor of response to immunotherapy. Participation in this study involves breath testing (to measure FeNO (Fractional exhaled Nitric Oxide)) before receiving the first infusion of immunotherapy, and at the follow-up visit after the 4th course of immunotherapy.

The objective of CIRCULATE trial is to improve care of patients after colon tumor surgery, based on an innovative marker: circulating tumor DNA.

According to the World Health Organization, one in eight people worldwide has a mental disorder, defined as a significant impairment in thinking, emotional regulation, or behavior. These disorders are classified according to the DSM-5. These psychiatric disorders may be atypical in terms of their age of onset, course of the illness, unusual response to treatment, or classification (significant impact but classified as a "disorder not otherwise specified" by the DSM-5). These disorders can occur sporadically or run in families. In France, there are no genetic testing recommendations for these patients. A CGH-array analysis may be ordered as part of patient care, as may testing for Fragile X syndrome, depending on the clinical context. The main hypothesis is that atypical psychiatric disorders result from multifactorial inheritance, involving a combination of common genetic variations and environmental factors. Pangenomic association studies and twin studies have already demonstrated heritability in these psychiatric disorders. It has now been shown that some neurodevelopmental disorders (NDDs) and psychiatric disorders-such as autism spectrum disorders or schizophrenia, for which similar hypotheses were proposed in the past-may result from monogenic inheritance. Furthermore, preliminary indications now allow for the prescription of genome sequencing on the platforms of the France Genomic Medicine Plan 2025. To date, no study has evaluated the role of high-throughput sequencing in an etiological approach to atypical, non-syndromic psychiatric disorders. Through this study, we aim to assess whether genome sequencing (GS) could be relevant for atypical, non-syndromic psychiatric disorders, which would be the case if it leads to an etiological diagnosis in at least 12% of cases. The establishment of the GénoPsy network (Centers of Excellence for Behavioral Disorders in Developmental Disorders) creates an environment that is highly conducive to the development of this project.

Newborn Screening (NBS) based on genome sequencing (GS) is currently the subject of particular attention at both European and international levels. Over the past three years, several publications have discussed the opportunities and challenges of using GS for NBS. To date, only two Chinese programs have published their results, the first on a series of 29,601 healthy newborns and the second on a series of 10,334 healthy newborns and 668 high-risk infants. Globally, more than twenty pilot projects are underway, although none has been initiated within the French context thus far. Across the different pilot projects, various study designs are used. Most have opted for a targeted GS-based analysis to screen for pediatric-onset diseases. Some projects focus solely on diseases for which effective drugs or interventions exist to prevent or reduce symptoms. In contrast, others offer parents the option to screen their newborns for diseases without current treatment options, but for which a treatment is underdevelopment, or with interest in early management, a choice exercised by most parents. Indeed, early diagnosis of these diseases can help to introduce treatments or interventions when they become available, to participate in research trials on new treatments and to receive early management and genetic counseling. In France, the national NBS program has long been recognized worldwide for its organizational quality and comprehensiveness, although, until recently, it has one of the lowest numbers of diseases screened in Europe. As of mid-2024, the French NBS only includes 14 serious diseases. Recently, the French bioethics law has evolved to allow the use of genetic testing as a first-line procedure for NBS. At the same time, the development and efficiency of genomic techniques and the rapid increase in the number of treatable rare diseases (RDs) raise questions about the acceptability and relevance of these genomic methods for NBS and its possible extension. The extension of NBS to many RDs of early onset represents a real public health challenge as RDs, 80% of which are of genetic origin, account for 10% of deaths before the age of 5. The FHU TRANSLAD has elaborated the PERIGENOMED Project, a large-scale project which aims to assess the relevance of pGS-NBS in France (analytical and clinical validity, clinical utility and psychosocial, ethical and organizational issues). The pGS-NBS (also known as in silico panel-based GS, i.e. an analysis carried out entirely using informatic tools) consists of bioinformatics filtering steps that return only selected variants and/or rare variants from targeted genes issued from GS. So, even if the source data comes from the GS, it is possible to configure the pipeline to return only those variations known to be responsible for specific RDs. the PERIGENOMED Project will be led in two steps. The first pilot step (PERIGENOMED-CLINICS 1 - PGC1 Study), presented in this protocol, aims to evaluate the feasibility and acceptability of pGS-NBS France. This pilot study plans to screen 2,500 newborns using pGS-NBS targeting two lists of genes (1 corresponding to genes variables responsible of treatable rare diseases, 2 including genes variation leading to actionable rare diseases). In both lists only RDs of early onset are considered. PGC1 study will be carried in 5 healthcare centers in France, with results expected to be returned to clinicians within less than 4 weeks. It will also provide an understanding of the optimal information and analytical pathways, and the possible organizational repercussions of pGS-NBS as well as a first insight about the validity of the pGS-NBS and about the clinical course of newborns screened positive and with a confirmed RD Two studies in humanities and social sciences (HSS) will also be linked to PGC1 Study. The first will focus on the reasons given by decliners and on the medical and socio-economic characteristics (at the individual and contextual level) of decliners versus participants. The second will assess the psychosocial impact of result disclosure on families of positive newborns, comparatively of negative ones. These initial results will provide the first outcomes before the launch of a second larger phase PERIGENOMED-CLINICS 2 (PGC2 Study - 22,000 newborns), designed for studying the implementation of such pGS-NBS in routine on a regional level.

Cardiac amyloidosis (CA) is an infiltrative disease characterized by deposits of amyloid proteins of genetic or acquired origin (often in elderly patients), leading to heart failure and arrhythmias. More than 98% of currently diagnosed cases of cardiac amyloidosis result from fibrils composed of monoclonal immunoglobulin light chains (AL) or transthyretin (ATTR), in its hereditary (ATTRv) or acquired (ATTRwt) form. Its prevalence is rising sharply due to an aging population and improved diagnostic techniques. Atrial fibrillation is responsible, in particular, for heart failure, arrhythmias, conduction disorders, and ischemic strokes, and is associated with significant morbidity and mortality. These patients have a much higher-than-normal risk of stroke because they are in a procoagulant state in the left atrium, even in the absence of atrial fibrillation. Intracardiac thrombi (ICTs) are present in 28% of patients with AC requiring cardioversion, compared with 2.5% of patients without AC, 50% of whom are on anticoagulants. It has also been shown that the CHA2DS2-VASc score is not effective in predicting thromboembolic risk, and that direct oral anticoagulants (DOACs) are as effective as vitamin K antagonists (VKAs) in preventing embolisms. The prevalence and factors associated with the development of intracardiac thrombi in patients with cardiac amyloidosis are unknown, as the available retrospective studies focused only on selected high-risk patients. Furthermore, tafamidis is now available to stabilize the course of cardiac amyloidosis and improve prognosis, but its effect on thromboembolic risk remains unknown.

The Direction Générale de l'Organisation des Soins (DGOS) and the Banque Nationale de Données Maladies Rares (BNDMR) have launched a call for a letter of commitment for the implementation of a diagnostic observatory in order to fight against diagnostic wandering and impasse. In this context, the AnDDI-Rares network proposes 3 work packages (WP) to respond to the missions entrusted to it. Work package 1 of the diagnostic observatory includes a retrospective and prospective study to evaluate how diagnostic wandering and impasse has evolved within the network, with regard to the integration of new technologies, and the expectations of patients and their families. Work package 2 of the diagnostic observatory includes a reassessment of sporadic copy number variations (CNV) of unknown significance of more than 1 Mb obtained since the beginning of CGH array analyses in the territory. Work package 3 of the diagnostic observatory aims to help put an end to diagnostic wandering for patients with certain emblematic syndromes by proposing genome and RNA analysis, which provides a certain diagnosis and negative targeted molecular study.

Postoperative pain is a significant issue following surgery, and pain that is either inadequately treated or, conversely, overtreated can increase morbidity. For example, severe chest pain following cardiac or pulmonary surgery impairs the patient's respiratory rehabilitation, which can lead to fluid retention and, consequently, pneumonia. Conversely, overtreatment through excessive use of opioids can cause drowsiness and respiratory depression. Currently, planning postoperative pain management for intubated, ventilated, and sedated patients relies on indirect signs of pain assessed using scales, and on the clinician's subjective judgment. It is only after sedation is discontinued that the actual level of pain can be assessed, once the patient becomes communicative, which then allows analgesic treatment to be adjusted to the pain. This approach inevitably results in a period of discomfort and pain for the patient. In addition to semi-quantitative and subjective scales, a number of analgesia monitoring tools have been developed. Among these, the use of pupillometry and the Pupillary Pain Index (PPI) during surgeries (gynecological, pediatric, cardiac) has been associated with a reduction in intraoperative opioid doses and a decrease in postoperative pain. In our department, pupillometry is routinely used to assess analgesia in intubated, ventilated, and sedated patients undergoing painful procedures. This method is integrated into standard care in the operating room in accordance with the PUCCAR study algorithm, as well as in the intensive care unit according to a specific departmental protocol, in addition to standard assessment scores. We hypothesize that performing pupillometry with a PPI score is predictive of pain intensity at extubation. If our hypothesis is confirmed, this would allow us to tailor analgesic management for each patient prior to discontinuing sedation.

trial fibrillation (AF) is the most common cardiac arrhythmia worldwide, and its prevalence continues to rise. AF is associated with serious complications, including embolic strokes, heart failure, and mortality. Characterized by rapid, irregular, and weakened contractions of the atria, AF is considered one of the "visible" electrophysiological manifestations of a broader condition known as atrial cardiomyopathy (ACM). Disruption of normal blood flow in the atrium, particularly in the context of an endocardium predisposed to thrombosis, predisposes to thrombus formation. Once dislodged from the atrial cavity and migrating to the cerebral arteries, these thrombi can cause a cardioembolic stroke. The main risk factors for ACI/AF are metabolic syndrome and aging. CMA is a condition that is difficult to diagnose because it is not clearly defined, except through histological analysis. Guided by the results of our experimental approaches, we aim to address this challenge by approaching CMA through one of its complications: persistent atrial fibrillation. Indeed, CMA can be assessed using electroanatomical mapping during atrial fibrillation ablation (AFA) procedures. During radiofrequency ablation of AF, electroanatomical mapping of the left atrium is performed to measure left atrial voltage, which serves as an indirect marker of the presence of atrial fibrosis, strongly associated with CMA. Other parameters relevant to the identification of CMA can be assessed during this procedure, such as conduction velocities and specific electrographic characteristics. We plan to include 150 patients undergoing ablation for persistent atrial fibrillation at the Dijon Bourgogne University Hospital and to correlate circulating levels of BDNF (brain-derived neurotrophic factor) with electroanatomical mapping data of the left atrium. The electrical remodeling of the left atrium, including low-voltage areas and conduction velocity, as well as left atrial morphology assessed by pre-procedural cardiac computed tomography using the ADAS3 Galgo LA Module software, will be correlated with BDNF levels. Blood samples for BDNF assessment will be collected before or at the start of the ablation procedure, prior to any catheter insertion into the vessels. While investigating the association between BDNF levels and CMA characteristics during AF ablation, thereby confirming the pathophysiological relationship with atrial remodeling, our objective is also to evaluate the prognostic role of BDNF levels in clinical and rhythm outcomes following AF ablation. Thus, we will compare changes in BDNF levels after AF ablation at one-year follow-up, correlating them with the evolution of CMA-based on left atrial parameters assessed by echocardiography or cardiac computed tomography-autonomic nervous system balance and heart rhythm obtained via Holter monitoring, as well as clinical outcomes.

Presbyacusis, or age-related hearing loss, is a public health problem, affecting 20% of men and 30% of women over the age of 70 according to the WHO. In the most incapacitating cases, hearing aids are required. Numerous studies have evaluated the benefits of hearing aids, particularly in terms of improved hearing and quality of life. However, the specific effect of music on language skills has not yet been studied in hearing-impaired older adults. In this context, it was decided to study the effect of musical priming on the syntactic abilities of adults aged 70 or older with presbyacusis. This study is based on the hypothesis that music priming with regular music optimizes the syntax language skills of people with presbyacusis, as has already been proven in adults and normal-hearing children.

Atrial fibrillation (AF) is associated with serious complications, including embolic strokes, heart failure, and mortality. Disruption of normal blood flow in the atrium, particularly in the context of an endocardium predisposed to thrombosis, increases the risk of thrombus formation. Once dislodged from the atrial cavity and traveling to the cerebral arteries, these thrombi can cause a cardioembolic stroke. The main risk factors for atrial cardiomyopathy (ACM) and AF are metabolic syndrome and aging. ACM is a condition that is difficult to diagnose because it is not clearly defined, except through histological analysis. Guided by the results of our experimental approaches, the investigators aim to address this challenge by examining ACM through the lens of one of its complications: cardioembolic stroke. BDNF (Brain-Derived Neurotrophic Factor) is a neurotrophic factor involved in inflammatory and metabolic processes that may play a key role in the development of these complications. This study explores the association between circulating levels of BDNF and the morphological and metabolic characteristics of ACM, as assessed by cardiac and brain imaging studies

For a newborn, locating and latching onto the mother's breast is the foundational social interaction. This pivotal moment not only influences the newborn's survival but also determines the mother's physiological (lactation) and psychological (attachment) engagement, as well as the long-term health of both the child and the mother. However, according to the WHO, three out of five newborns are not exclusively breastfed for the recommended 6 months, and several recent studies point to suboptimal rates of breastfeeding initiation in the maternity ward, partly due to difficulties with oral latching, insufficient sucking, or refusal of the breast. This situation compromises the initial intake of colostrum/milk, as well as the establishment of early emotional bonds. A wealth of research data from biology, psychology, and pediatrics shows that neonatal and maternal sensory experiences play a central role in the initiation of breastfeeding. However, our understanding of the sensory and behavioral mechanisms at play remains unclear. While visual and auditory interactions have been extensively documented, other sensory modalities-touch, chemoreception, and kinesthesia-remain largely overlooked, even though their critical role has been documented in other mammals. The inves will focus on the role of olfaction in organizing the adaptive responses of the newborn to the mother's breast and of the mother to her baby. A wealth of research data from biology, psychology, and pediatrics shows that neonatal and maternal sensory experiences play a central role in the initiation of breastfeeding. However, our understanding of the sensory and behavioral mechanisms involved remains unclear. While visual and auditory interactions have been extensively documented, other sensory modalities-touch, chemoreception, and kinesthesia-have received little attention, even though their critical role has been documented in other mammals. Here, the investigators will focus on the role of olfaction in organizing the adaptive responses of the newborn to the mother's breast and of the mother to her baby. Research data in humans show that: 1) several mammary secretions (colostrum/milk, areolar secretions) emit odorous compounds, and 2) newborns respond to them in a stereotypical and repeatable manner. These odors, which are specific to the mammary gland, serve to facilitate the very first mother-infant interactions. However, the source of these odorous compounds remains unclear, and their chemical nature is unknown. Without precise chemical identification, it is difficult to fully understand the mechanisms by which odors influence the newborn's behavior toward the mother's breast at the start of breastfeeding. Conversely, the newborn's body odors could also convey information about its emotional or metabolic state and influence maternal motivation and behavior. Based on research conducted on other mammals, as well as studies focused on our own species, the investigators know that: 1) postpartum mothers are highly receptive to the body odor of their newborns, and 2) newborns emit odor compounds that are appreciated by mothers (even if the infants are not their own) . It cannot therefore be ruled out that human mothers react, even unconsciously, to these infant odors and that these odors could help regulate maternal psychophysiology (particularly that underlying lactation and the related chemocommunication mechanisms). The OD-ALL project aims to unravel the chemical basis of the olfactory interactions that lead to the establishment of the breastfeeding relationship between each member of the mother-newborn dyad. To this end, the investigators will apply an innovative technology, proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS), which has previously been used to monitor volatile organic compounds (VOCs) in the environment. Unlike conventional techniques (such as gas chromatography coupled with mass spectrometry; GC-MS), which allow only sporadic and somewhat disruptive measurements, PTR-ToF-MS records odor emissions in real time, without any disruption to the natural interactions taking place. It is capable of providing a true "chemical video" of the dynamic variations in VOCs of mammary or infant origin (whereas conventional GC-MS provides only a "chemical snapshot"). These fluctuations can thus be correlated with the behaviors and physiological responses of mothers and newborns, which will be recorded concurrently. This approach opens up entirely new avenues for understanding the chemosensory foundations of early human interactions, particularly those that occur during the initiation of breastfeeding. Alongside this fundamental approach, the OD-ALL project aims to raise awareness among healthcare professionals, the general public and health policy makers regarding the role of smell in early interactions between mother and newborn.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease with a high degree of penetrance (\>80% of patients). It is caused by the presence of the MEN1 mutation located on chromosome 11q13. The prevalence of this mutation is estimated at approximately 1/30,000. This hereditary syndrome is characterized by the presence of tumours of the endocrine system (adenoma of the parathyroid, pituitary and adrenal glands, neuroendocrine tumors - NETs - of the endocrine pancreas, duodenum, lung or thymus), which threaten the health of these patients. Other malignant tumors such as breast cancer are also more common in patients with MEN1. The clinical manifestations of MEN1 are linked to the location of the adenomas and NETs and their secretory products. Indeed, most NETs produce and secrete numerous peptide hormones (in the case of Insulinomas, Gastrinomas, VIPomas, Glucagonomas or PPomas for example). This causes a specific clinical syndrome, which can be detected in the blood serum. However, most NETs are "non-functional" tumors, which do not have specific secretions. Among general tumor markers, chromogranin A (CgA) is widely used as a biomarker for monitoring NETs. CgA is a secretory protein released into the blood by neuroendocrine cells. However, the performance of CgA as a diagnostic biomarker is too limited to be used for the early identification of NETs, particularly in patients with MEN1. This is why patients with MEN1 undergo regular biological and morphological examinations, at least once a year, to screen for the development of adenomas and NETs. However, CgA or hormone secretions assays, and imaging examinations (MRI, CT scan, or duodenopancratic endoscopic ultrasound (EUS)) are tedious and stressful for patients; in addition, they all have their limitations (poor performance for biological tests; irradiation for CT scan; need for anesthesia for endoscopic ultrasound, etc.). Consequently, there is a need for new markers to identify NETs in this population as early as possible. Progastrin is a pro-hormone that, under physiological conditions, is matured into gastrin in the G cells of the antrum of the stomach. The role of gastrin is to stimulate gastric acid secretion during digestion. It also plays an important role in regulating cell growth in the gastric mucosa. In pathological situations, it has been shown that the GAST gene, which codes for progastrin, is over-expressed in human tumor cells of different origins, leading to the accumulation of progastrin within them. Tumor cells that are unable to mature progastrin into gastrin, either because the maturation enzymes are not expressed or are inhibited, will secrete it. This circulating progastrin is then called hPG80 (to differentiate it from intracellular progastrin) and is detectable in patient blood. hPG80 is a new biomarker for the detection of different types of cancer. It appears to be elevated in the early stages of the disease, potentially more so than other biomarkers such as circulating tumor DNA (ctDNA) or NETest. In addition, hPG80 is easily measured in plasma using the DxPG80.Lab ELISA (Progastrin Manufacturing). The analytical characteristics of this CE-marked in vitro diagnostic test have been published in the Analytical Methods journal. It has been validated in numerous studies of various cancers, including NET patients. In addition, a study conducted by the team at Progastrin Manufacturing (formerly ECS-Progastrin) showed that hPG80 was unequivocally present in the peripheral blood of patients with 11 different types of cancer, with a concentration significantly higher than that found in blood donors considered to be healthy. We therefore hypothesize that hPG80 could also be a biomarker for NETs in MEN1.

TBR1 is a human gene encoding a brain-specific transcription factor, principally expressed in the excitatory neurons of the neocortex. It regulates development of axonal projection and expression of numerous genes involved in autism spectrum disorders (ASD) and intellectual disability (ID). Recent progress in detection and analysis of rare variants allowed to identify group of genes with strong statistical evidence for association with ASD risk, of which TBR1. Numerous studies on mice showed that TBR1 heterozygous mice display autistic traits as deficiencies in social interaction, in cognitive flexibility, and in associative memory. Functional analyses on human cell lines have demonstrated that de novo truncating variants in TBR1 identified in patients with sporadic ASD disrupt transcriptional repression activity, localization, homodimerization of TBR1 product. In 2019, only 12 single nucleotide variants (SNVs) and few copy number variations (CNVs) involving TBR1 have been reported in the literature and clinical descriptions were poor. To provide details on the phenotype linked to TBR1 mutations, we and others gathered 25 new individuals with de novo TBR1 SNV and CNV, complemented by a review of individuals previously reported in the literature. On 38 individuals, all presented developmental delay (DD)/ID, ranging from mild to severe, and 76% of them presented autistic traits. Additional behaviour disorders were observed in 85% of individuals, mainly attention deficit and aggressive behaviour. However, the natural history of patients with TBR1 variations is not well known. Development of RNA-Seq allowed a better understanding of its transcription factor role and revealed that Tbr1 promotes expression of layer 6 markers as Wnt7b. In heterozygous and homozygous TBR1 mutant mice, Fazel Darbandi et al (1), observed that Wnt7b expression is reduced in cortical layer 6 and that neurons have reduced excitatory and inhibitory synaptic density. They showed that lithium chloride and lithium carbonate, WNT-signalling agonists, rescue the dendritic spines, the synaptic and the axonal defects in Tbr1layer5, Tbr1layer6 and Tbr1 constitutive (Tbr1+/-) mutant mice. They also observed an improvement of social interactions in mice after treatment by lithium. These results suggest an important and novel biological mechanism underlying ASD that may have implications for the treatment of patients with TBR1 variants. Moreover, lithium treatment has already been evaluated in patients with neurocognitive disorders not linked to TBR1 showing an improvement in the adaptative behaviour and cognition function. As of today, only symptomatic treatments are available. As lithium increase neuronal activity in mice, and may thus improve the symptoms of this disorder, we propose a clinical trial to study the security and efficacy of lithium carbonate targeting the patients with TBR1-related disorders, with specific and adapted endpoints. Lithium carbonate treatment will be administered after an observation period of 6 to 12 months, allowing to ascertain the stability of neurocognitive abnormalities.

Phase III multicentric, open-label, randomized study The main objective is to assess the efficacy on time to disease recurrence (TTR) of treating minimal residual disease diagnosed by the presence of ctDNA after full treatment (surgery + chemotherapy) in stage III or high-risk stage II colon or upper rectum adenocarcinoma

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive diffuse muscular paralysis due to the inexorable loss of motor neurons in the primary motor cortex, the corticospinal tract, the brain stem and the spinal cord. Over the course of the disease, when the phrenic motor neurons are involved, diaphragmatic weakness develops, leading to restrictive respiratory failure, which is the main cause of morbidity and mortality. Non-invasive ventilation (NIV) compensates for diaphragm failure and corrects the associated symptoms, and has been shown to prolong patient survival and improve quality of life. Undernutrition is another recognised prognostic factor. Several mechanisms have been described, foremost of which are a state of hypermetabolism and a reduction in food intake secondary to chewing difficulties, dysphagia, a loss of dexterity in the upper limbs, a disturbance in salivary secretion or psychological disorders. In addition, diaphragmatic dysfunction plays a direct role in the onset of undernutrition, as compensatory contraction of the accessory neck muscles increases resting energy expenditure. However, the hedonic sensations triggered by a meal play a role in controlling food intake beyond the simple energy balance between calorie intake and energy expenditure. Olfacto-gustatory sensoriality could therefore play a role in the nutritional status of patients suffering from ALS. Diaphragmatic dysfunction may also influence nutritional status by other mechanisms. For example, the reduction in inspiratory capacity associated with diaphragmatic insufficiency reduces olfaction in a group of tetraplegic patients. Central sensory impairment could exacerbate this phenomenon. Although it is conventionally considered that there are no sensory manifestations during the course of ALS, minor but diffuse abnormalities of the nerves and sensory action potentials have been observed. A central alteration in olfacto-gustatory sensoriality could be part of the neurological manifestations of ALS. In addition, olfactory deficits occur in other neuromuscular diseases with central involvement, such as myasthenia, Parkinson\&#39;s or Alzheimer\&#39;s disease, in the absence of concomitant cognitive or diaphragmatic impairment. Our hypothesis is that impaired olfacto-gustatory function favours the onset of undernutrition in ALS. Current nutritional management consists of ensuring adequate calorie intake by prescribing oral food supplements or inserting a gastrostomy. Taking personalised account of food preferences during dietary advice or of a potential olfacto-gustatory deficit, by reinforcing smells or tastes during food consumption, would be an interesting additional therapeutic avenue for improving patients\&#39; nutritional status, quality of life and prognosis

Swallowing disorders (SD) are particularly common after extubation in the ICU and may be associated with an increased risk of lung disease, increased length of hospital stay, and a higher risk of early reintubation. In contrast, early detection of SDs has been shown to be associated with a decrease in these complications. Thus, there is a need for rapid and reliable assessment of SDs in ICU patients before the withdrawal of mechanical ventilation. Videofluoroscopy (VFS) and nasofibroscopy (NF) are the gold standard examinations for diagnosing SD. However, these two examinations are not feasible in intubated patients. In this context, ultrasound appears to be a promising alternative to identify patients at risk of SD after extubation. This examination can be performed at the intubated patient's bedside and can be used evaluate the mobility of the structures involved in swallowing. Many studies have already shown the interest of ultrasound in the evaluation of SD but none has focused on intubated patients under respiratory assistance. The objective of the present study is to evaluate the value of ultrasound in identifying patients at risk of presenting SD after extubation. This monocentric study will take place in the Intensive Care Unit (ICU) of the Dijon University Hospital. The duration of participation in this research will be equal to the length of stay in the ICU. During their stay, patients will undergo ultrasound and nasofibroscopy. Information on the characteristics of the ICU stay will be collected at discharge.

Abdominal obesity and type 2 diabetes are associated with hyperactivation of the endocannabinoid system. Several animal and human studies indicate that circulating endocannabinoid levels correlate with body fat mass. Thus, adipose tissue, which possesses the enzymatic machinery of the endocannabinoid system, may be the primary producer of plasma endocannabinoids. Today, it is well established that stimulation of the endocannabinoid system, through the activation of cannabinoid receptor 1 (CB1R) located in the brain, leads to increased food intake and weight gain. Furthermore, peripheral CB1R present in adipose tissue are also directly involved in energy storage processes. Indeed, activation of the endocannabinoid system in adipose tissue is associated with stimulation of pathways leading to the uptake of carbohydrates and fatty acids, as well as their storage in the form of triglycerides. Adipose tissue consists primarily of mature adipocytes, and activation of the endocannabinoid system appears to play a key role in increasing fat mass by promoting the hypertrophy of these adipocytes through the stimulation of lipogenesis. However, the vascular stromal fraction also contains stem cells capable of generating new adipocytes, and an autocrine action of endocannabinoids on progenitor cells could also contribute to its expansion by promoting hyperplasia. That is why, in this project, the investigators aim to study the impact of endocannabinoids on the differentiation of stem cells from the stromal-vascular fraction into adipocytes. In particular, the investigators will seek to compare the impact of endocannabinoids on the differentiation capacity of stem cells derived from adipose tissue collected from patients with obesity, with or without diabetes, compared to controls. These data, combined with those obtained in parallel in mice, could help determine whether adipose tissue (visceral and/or subcutaneous) is a priority target for the development of CB1R-blocking molecules (such as rimonabant) with exclusively peripheral action (which do not cross the blood-brain barrier to avoid psychiatric side effects) for the treatment of metabolic obesity and type 2 diabetes.