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Rationale and objectivesIntroduction of post-mortem imaging has helped improve sudden unexpected death in infancy (SUDI) management in Europe. French guidelines were issued in 2007 to homogenise SUDI investigations including imaging. The aim of this study was to evaluate current imaging management of SUDI in France.Material and methodsBetween January 2022 and July 2022, all 35 SUDI French referral centres were invited to answer an e-mailed online survey including 29 questions divided into four different sections covering imaging practices for SUDI including radiology department organisation, imaging modalities performed, methods of reading, and current training resources. Partial responses were secondarily completed by a personal call to the SUDI imaging consultant. The current implementation of the 2007 recommendations was compared with a previous evaluation from 2015 and with current North American practices.ResultsThe participation rate of centres performing SUDI imaging was 100% (35/35). Imaging was systematically performed in 94.3% (33/35) of the centres: 74.3% (26/35) using radiography; 5.7% (2/35) using ultrasound; 94.3% (33/35) using computed tomography (CT), including 89% (31/35) whole-body CT and 5.7% (2/35) brain CT; and 20% (7/35) using magnetic resonance imaging (MRI). Two centres (5.7%, 2/35) did not systematically perform brain imaging. One (2.9%, 1/35) used ultrasound-guided biopsy. In comparison with 2015, rates of brain imaging increased by 25.4% (P=0.008). There was no significant difference in the number of forensic MRIs performed between France and North America (P=0.663).ConclusionDespite improvements since 2015, full compliance with French guidelines for SUDI investigations remains incomplete. The use of imaging, particularly CT and brain imaging, has increased. Further efforts are needed to standardise imaging practices for optimal SUDI investigations.

Aims: To emphasize the functional vision characteristics in visually impaired multiple disabled children (MDVI) aged 2 to 9 years old related to brain damages on magnetic resonance imaging in different cortical and subcortical areas and in the corpus callosum region. Material and Method: 12 MDVI children with severe and mild neurological disorders were medically and neuropsychological assessed. The clinical - psychological, neurological and ophthalmological - and paraclinical methods - visual evoked potential (VEP) and magnetic resonance imaging (MRI) were carried out in order to outline the complete profile of each child. The assessment was completed by morphometric measurement of corpus callosum and brain. Results: 10 of infants with severe neurological disorders showed ocular disorders such as ocular motility and visual function abnormalities. Severe cognitive and psychomotor retardation were associated in visual disorders in MDVI children. Significant correlation between neurological disorders, neuropsychological [τ(12) = 0.783, p = 0.001] evaluation and visual acuity [τ(12) = 0.783, p = 0.001] were found in multiple disabled children. The significant difference of diameter [t(22) = -4.858, p = 0.000] and surface of corpus callosum [t(22) = -6.254, p = 0.000] in multiple disabled children compared with control group was found. Conclusion: The structured assessment of visually impaired children due to neurological disorders, as early as possible, is the remarkably key which reveals the functionality of child and outlines the appropriate developmental and educational rehabilitation. [PUBLICATION ABSTRACT]

Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in M. tuberculosis, circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.

Psychiatric symptoms are common in neurodevelopmental movement disorders, including some types of dystonia. However, research has mainly focused on motor manifestations and underlying circuits. Myoclonus-dystonia is a rare and homogeneous neurodevelopmental condition serving as an illustrative paradigm of childhood-onset dystonias, associated with psychiatric symptoms. Here, we assessed the prevalence of psychiatric disorders and the severity of depressive symptoms in patients with myoclonus-dystonia and healthy volunteers (HV). Using resting-state functional neuroimaging, we compared the effective connectivity within and among non-motor and motor brain networks between patients and HV. We further explored the hierarchical organization of these networks and examined the relationship between their connectivity and the depressive symptoms. Comparing 19 patients to 25 HV, we found a higher prevalence of anxiety disorders and more depressive symptoms in the patient group. Patients exhibited abnormal modulation of the cerebellum on the cerebral cortex in the sensorimotor, dorsal attention, salience, and default mode networks. Moreover, the salience network activity was directed by the cerebellum in patients and was related to depressive symptoms. Altogether, our findings highlight the role of the cerebellar drive on both motor and non-motor cortical areas in this disorder, suggesting cerebellar involvement in the complex phenotype of such neurodevelopmental movement disorders.

IntroductionMindfulness meditation is likely to promote better management of stress, pain and negative emotions. We propose to address the benefit of meditation in an open setting associating people with cancer (target population), medical staff and witnesses (neither patient nor medical staff). This study aims (1) to evaluate the effects of meditation on wellness improvement and (2) to identify criteria and modalities for a subsequent randomised study.Methods and analysisWe propose a longitudinal pilot study consisting of a non-randomised experimental preintervention/postintervention survey. The intervention consists in delivering a meditation programme (12 weekly meditation sessions of 1.5 hours each), specifically adapted to our target population and addressing our research hypothesis in an open setting involving people with cancer, medical staff and witnesses (equally distributed in two groups of 15 participants). The main objective is to evaluate participants’ adherence to the programme. The effects of meditation will be evaluated on stress, quality of life, feeling of personal effectiveness, on the development of mindfulness and empathy, and on satisfaction and perception of a change in quality of life. We will also measure the putative added value of ‘meditating together’. This study is expected to allow validating the evaluation tools and refining the modalities of the workshops. We expect to demonstrate the evolution that this meditation-based intervention induces in the participants. We aim to promote bridge-building, between patients, medical staff but also others. In this way, one’s own suffering may be understood in the light of others’ suffering, thereby promoting the sense of otherness and giving insights into ‘living better with’. This exploratory study will investigate the relevance of this hypothesis, which could then be explored by a randomised study.Ethics and disseminationThe protocol was approved by the local ethics committee (Comité de Protection des Personnes Est II). Trial findings will be published in peer-reviewed journals.Trial registration numberNCT04410185.

Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered “booster” molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, “green” β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.

Tourette disorder (TD), which is characterized by motor and vocal tics, is not in general considered as a product of impulsivity, despite a frequent association with attention deficit hyperactivity disorder and impulse control disorders. It is unclear which type of impulsivity, if any, is intrinsically related to TD and specifically to the severity of tics. The waiting type of motor impulsivity, defined as the difficulty to withhold a specific action, shares some common features with tics. In a large group of adult TD patients compared to healthy controls, we assessed waiting motor impulsivity using a behavioral task, as well as structural and functional underpinnings of waiting impulsivity and tics using multi-modal neuroimaging protocol. We found that unmedicated TD patients showed increased waiting impulsivity compared to controls, which was independent of comorbid conditions, but correlated with the severity of tics. Tic severity did not account directly for waiting impulsivity, but this effect was mediated by connectivity between the right orbito-frontal cortex with caudate nucleus bilaterally. Waiting impulsivity in unmedicated patients with TD also correlated with a higher gray matter signal in deep limbic structures, as well as connectivity with cortical and with cerebellar regions on a functional level. Neither behavioral performance nor structural or functional correlates were related to a psychometric measure of impulsivity or impulsive behaviors in general. Overall, the results suggest that waiting impulsivity in TD was related to tic severity, to functional connectivity of orbito-frontal cortex with caudate nucleus and to structural changes within limbic areas.

The immunological profiles of CD4 T lymphocytes (TLs) from patients with hematological malignancies differ between patients who have and have not received transfusions. There may be several reasons for these differences, including the presence of extracellular vesicles (EVs) derived from plasma membrane budding and present in the platelet concentrates. Indeed, EVs can modulate the immune system through interactions with many immune cells, but the underlying mechanisms remain incompletely understood. We therefore investigated how interactions with CD41a EVs cause immune cells to change phenotype and function. CD41a EVs were cultured with TLs, B lymphocytes, and monocytes. Given the potential involvement of monocytes in leukemia progression, we performed a new original multi-omics study to confirm the protein changes and gene activation observed following interaction with CD41a EVs. The CD41a EVs had immunomodulatory effects on all these cell types but this effect depended on the numbers of EVs. CD4 TLs required large numbers of CD41a EVs for activation, whereas monocytes were the most sensitive. With the new multi-omics technique, we confirmed the direct effects of CD41a EVs on protein phenotype and gene activation. Transfusion EVs should be considered during the immunological follow-up of patients after transfusion to detect immunological effects on malignant hemopathies, and during the development of new immunotherapies.

CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles (EVs) budding from the plasma membrane. Platelet transfusion may induce alloimmunization against HLA-I antigens, leading to refractoriness to platelet transfusion with severe consequences for patients. Tregs may play a key role in determining whether alloimmunization occurs in patients with hematologic disorders. We hypothesized that CD39 EVs might play an immunoregulatory role, particularly in the context of platelet transfusions in patients with hematologic disorders. Such alloimmunization leads to the production of alloantibodies and is sensitive to the regulatory action of CD39. We characterized CD39 EVs in platelet concentrates by flow cytometry. The absolute numbers and cellular origins of CD39 EVs were evaluated. We also performed functional tests to evaluate interactions with immune cells and their functions. We found that CD39 EVs from platelet concentrates had an inhibitory phenotype that could be transferred to the immune cells with which they interacted: CD4 and CD8 T lymphocytes (TLs), dendritic cells, monocytes, and B lymphocytes (BLs). Moreover, the concentration of CD39 EVs in platelet concentrates varied and was very high in 10% of concentrates. The number of these EVs present was determinant for EV-cell interactions. Finally, functional interactions were observed with BLs, CD4 TLs and CD39 EVs for immunoglobulin production and lymphoproliferation, with potential implications for the immunological management of patients.

Reward sensitivity has been suggested as one of the central pathophysiological mechanisms in Tourette disorder. However, the subjective valuation of a reward by introduction of delay has received little attention in Tourette disorder, even though it has been suggested as a trans-diagnostic feature of numerous neuropsychiatric disorders. We aimed to assess delay discounting in Tourette disorder and to identify its brain functional correlates. We evaluated delayed discounting and its brain functional correlates in a large group of 54 Tourette disorder patients and 31 healthy controls using a data-driven approach. We identified a subgroup of 29 patients with steeper reward discounting, characterised by a higher burden of impulse-control disorders and a higher level of general impulsivity compared to patients with normal behavioural performance or to controls. Reward discounting was underpinned by resting-state activity of a network comprising the orbito-frontal, cingulate, pre-supplementary motor area, temporal and insular cortices, as well as ventral striatum and hippocampus. Within this network, (i) lower connectivity of pre-supplementary motor area with ventral striatum predicted a higher impulsivity and a steeper reward discounting and (ii) a greater connectivity of pre-supplementary motor area with anterior insular cortex predicted steeper reward discounting and more severe tics. Overall, our results highlight the heterogeneity of the delayed reward processing in Tourette disorder, with steeper reward discounting being a marker of burden in impulsivity and impulse control disorders, and the pre-supplementary motor area being a hub region for the delay discounting, impulsivity and tic severity.