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Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.

National audience; Un portulan décrivant les côtes et les ports, leurs accès, les risques encourus accompagnait autrefois les navigateurs. Avec ses 400 kilomètres de cours d'eau, ses 220 000 croisiéristes et son grand port industriel rhénan, Strasbourg possède un réseau hydrologique étendu, complexe et très sollicité, porteur d'enjeux et de questionnements importants. Esquisser le portulan contemporain du territoire fluvial strasbourgeois, c'est le pari du travail collectif en cours, qui repère les interactions liant fonctions portuaires et urbaines comme de possibles leviers de métropolisation. Les cahiers POPSU rassemblent les connaissances produites au fil des travaux de recherche-action menés par la Plateforme d'observation des projets et stratégies urbaines (POPSU) dans le cadre du programme « Métropoles ».

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSRbinding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR., Instituto Multidisciplinario de Biología Celular

HgCdTe Avalanche Photo Diodes (APDs) are developed at CEA/Leti to enable applications that require the detection of information contained in a low number of photons in each spatial and/or temporal bin, such as LiDAR and free space optical communications. The requirements for such detectors are strongly application dependent, which is why both the HgCdTe APD technology and the proximity electronics, used to extract the detected photocurrent, needs to be optimized for each application. The present communication reports results obtained from the development of detectors for high dynamic range LiDAR applications, made within the scope of the H2020 project HOLDON, and high data rate FSO, made in collaboration with Mynaric Lasercom AG. For FSO applications, we have measured 10 GHz bandwidth at unity gain for APDs with 10 μm diameter. At higher APD gain and diameter, the BW is presently limited by carrier transit and by resistance-capacitance product in small and large area APDs, respectively. For LiDAR we have developed APDs with an made of an array of diodes in parallel with a diameter up to 200 μm and large avalanche gain, M

Total hip arthroplasty (THA) has been quoted as one of the most successful and cost-effective procedures in Orthopaedics. The last decade has seen an exponential rise in the number of THAs performed globally and a sharp increase in the percentage of young patients hoping to improve their quality of life and return to physically demanding activities. Hence, it is imperative to review the various applications of technology in total hip arthroplasty for improving outcomes. The development of state-of-the-art robotic technology has enabled more reproducible and accurate acetabular positioning, while long-term data are needed to assess its cost-effectiveness. This opinion piece aims to outline and present the advances and innovations in total hip arthroplasty, from virtual reality and three-dimensional printing to patient-specific instrumentation and dual mobility bearings. This illustrates and reflects the debate that will be at the centre of hip surgery for the next decade.

The clinical results of total ankle replacement are becoming increasingly consistent and acceptable due to longer surgical experience with these prostheses and improved design features. Survivorship remains a concern, however, and ankle or tibio-talocalcaneal arthrodesis cannot continue to be the sole revision options. The frequency of revision procedures is likely to increase due to the growing number of primary total ankle replacement operations. Revision total ankle replacement is technically challenging and requires special prostheses. We have used the Salto Talaris XT revision ankle prosthesis since 2012. It consists of a tibial component with a long keel and three types of talar component (i.e., flat cut, short stem; flat cut, long stem; and sloped cut, long stem), designed to accommodate the majority of revision total ankle replacement cases. The Salto Talaris XT revision ankle prosthesis is compatible with the Salto Talaris primary total ankle replacement, as the two models are designed with identical articular geometry and have similar surface coating for cementless fixation (outside the United States), as well as fixed-bearing polyethylene insert. This chapter describes the principles of revision total ankle replacement, on which the Salto Talaris XT revision ankle prosthesis system is based, and describes the surgical technique. The clinical performance of this prosthesis appears promising at short-term follow-up, though the ongoing prospective study would yield more accurate and conclusive results in time.

International audience

Shwachman–Diamond syndrome with Shwachman–Bodian–Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Severe Chronic Neutropenia Registry, three were identified original with malignant solid tumors (ovary, breast and esophagus). All cancers occurred in the fifth decade and, despite being at localized stages at diagnosis, they were rapidly fatal thereafter. No cancer was observed in the 14 HSCT survivors post transplantation. Based on our experience and the literature, age >40 years was the only apparent risk factor.

International audience; GHSR controls, among others, growth hormone and insulin secretion, adiposity, feeding and glucose metabolism. Therefore, an inverse agonist ligand capable of selectively targeting GHSR and reducing its high constitutive activity appears to be a good candidate for the treatment of obesity-related metabolic diseases. In this context, we present a study that led to the development of several highly potent and selective inverse agonists of GHSR based on the 1,2,4-triazole scaffold. We demonstrate that, depending on the nature of the substituents on positions 3, 4 and 5, 2 this scaffold leads to ligands that exert an intrinsic inverse agonist activity on GHSR-catalyzed G protein activation through the stabilization of a specific inactive receptor conformation. Thanks to an in vivo evaluation, we also show that one of the most promising ligands not only exerts an effect on insulin secretion in rat pancreatic islets but also affects the orexigenic effects of ghrelin in mice.

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers. Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. In bone marrow samples, clones were found in almost 40% of healthy volunteers more than 50 years old. The most frequent mutations were found in DNMT3A and TET2, with 1 individual carrying 3 variants. Variant allele frequencies were highly concordant between blood and bone marrow samples. Blood parameters were normal except for those in 2 individuals: 1 had a mild macrocytosis and 1 had a mild thrombocytosis. Furthermore, no morphologic abnormalities or dysplasia were detected when bone marrow smears were carefully evaluated. Individuals with CH differed from others by age (62.8 vs 38.6 years; P < .0001) and platelet count (294 vs 241 ×109/L; P = .0208), the latter being no more significant when removing the 2 individuals who carried the JAK2 p.V617F mutation. These results confirm that CH is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or the bone marrow.

International audience; We present herein the synthesis of biotin-functionalized polymers (BNAPols) that have been developed for the fixation of membrane proteins (MPs) onto surfaces. BNAPols were synthesized by free-radical polymerization of a tris(hydroxymethyl)acrylamidomethane (THAM)-derived amphiphilic monomer in the presence of a thiol-based transfer agent with an azido group. Then a Huisgen-cycloaddition reaction was performed with Biotin-(PEG) 8-alkyne that resulted in formation of the biotinylated polymers. The designed structure of BNAPols was confirmed by NMR spectroscopy, and a HABA/avidin assay was used for estimating the percentage of biotin grafted on the polymer end chain. The colloidal characterization of these biotin-functionalized polymers was done using both dynamic light scattering (DLS) and small angle X-ray scattering (SAXS) techniques. These BNAPols were used to stabilize a model G protein-coupled receptor (GPCR), the human Growth Hormone Secretagogue Receptor (GHSR), out of its membrane environment. Subsequent immobilization of the BNAPols:GHSR complex onto a streptavidin-coated surface allowed screening of ligands based both on their ability to bind the immobilized receptor and to trigger GHSR conformational changes using the fluorescence energy transfer (FRET)-based assay. This opens the way to the use of biotinylated NAPols to immobilize functional, unmodified, membrane proteins, providing original sensor devices for multiple applications including innovative ligand screening assays.

Background Hip resurfacing has been the focus of many evaluations based on international registries but, to date, no prospective studies have evaluated this procedure in France. In 2015, the French Society for Orthopaedics and Traumatology (SoFCOT) and the French Hip and Knee Society concluded an agreement with the French Medicines Agency (ANSM) and French National Health Authority (HAS) to establish an exhaustive observational hip resurfacing registry. The primary objective of this study was to evaluate the hip resurfacing survival rate since the creation of the registry 5 years ago. The secondary objectives were to evaluate the clinical, functional, and radiological outcomes of hip resurfacing and to check the absence of specific complications related to this implant. Hypothesis The hypothesis was that the registry survival rate was below 0.5% per year. Methods Since 2015, data from all patients undergoing hip resurfacing were collected into a monitored database using the software suite OrthoWave. The following were collected for each patient: demographics, anthropometric characteristics, clinical parameters (Postel Merle d’Aubigne score, Harris Hip Score, Oxford Hip Score, and UCLA Activity Score), and radiological findings. Completeness of data collection was checked once a year. Results In total, 1650 hip resurfacings in 1506 patients (1409 males and 97 females) with a mean age of 50.7 years (range, 17–70 years) were included. Mean follow-up was 3.8 years (range, 2–4.8 years). Mean completeness of data recording was 98.2%. All clinical scores improved significantly. Hip revision was required for 7 (0.4%) complications including 4 femoral neck fractures, 1 aseptic lymphocyte-dominant vasculitis-associated lesion with a large joint effusion, 1 femoral component loosening, and 1 delayed sepsis requiring bipolar removal. At 5 years, the survival rate without hip revision for any cause was 99.6% (95% confidence interval, 99.3–100%). Discussion The short-term outcomes of patients in the French registry are encouraging in terms of complication and surgical revision rates. The near absence of complications related to metal-on-metal bearing surfaces demonstrates that the criteria used in France (at least 48 mm head diameter, use of implants for which long-term data are available, and specific training of surgeons) ensure successful long-term outcomes. Level of evidence II.

Que cela soit clair d’emblée, les auteurs de cet ouvrage collectif s’inscrivent tous dans des approches de formation par l’analyse de vidéos de situations de classe. Ils ne présentent pas l’utilisation de la vidéo comme une panacée, mais un ensemble de modalités sujettes à d’éventuelles dérives. S’il fallait ne retenir qu’une condition pour éviter des dérives de son utilisation vers le formatage, ce serait la nécessité de maintenir la dialectique entre recherche et formation afin de ne pas cé...

Purpose The Covid-19 pandemic has disrupted health care systems all over the world. Elective surgical procedures have been postponed and/or cancelled. Consensus is, therefore, required related to the factors that need to be in place before elective surgery, including hip and knee replacement surgery, which is restarted. Entirely new pathways and protocols need to be worked out. Methods A panel of experts from the European Hip Society and European Knee Association have agreed to a consensus statement on how to reintroduce elective arthroplasty surgery safely. The recommendations are based on the best available evidence and have been validated in a separate survey. Results The guidelines are based on five themes: modification and/or reorganisation of hospital wards. Restrictions on orthopaedic wards and in operation suite(s). Additional disinfection of the environment. The role of ultra-clean operation theatres. Personal protective equipment enhancement. Conclusion Apart from the following national and local guidance, protocols need to be put in place in the patient pathway for primary arthroplasty to allow for a safe return.

International audience; The rising number of attacks targeting processors at micro-architecture level encourages more research on hardware level solutions.In this position paper, we specify a new RV32S “secure” instruction set architecture (ISA) derived from the RV32I RISC-V ISA.We propose modifications in the ISA to prevent timing side-channels, strengthen control flow integrity and ensure micro-architectural state isolation.The goal is to provide a new minimal hardware/software approach through which software attacks exploiting hardware vulnerabilities can be circumvented.

Les objectifs du programme « Mine du Futur, Automatisation de la mine et mutualisation des moyens » sont d’explorer les voies possibles d’automatisation par intégration de technologies innovantes dans le processus minier, et d’étudier les possibilités de mutualisation de moyens entre les compagnies minières opérant en Nouvelle-Calédonie. Le terme d’automatisation doit s’entendre dans un sens très large comme une approche technologique permettant un meilleur contrôle des opérations minières.- Dans ce cadre, il a semblé utile et nécessaire de mieux connaitre les compétences numériques des personnels travaillant dans les différentes mines de Nouvelle-Calédonie pour, d’une part savoir quelle est leur maîtrise de certains outils numériques, avoir leur perception sur leur capacité à les utiliser, etd’autre part identifier les attentes et les craintes légitimes des personnels vis-à-vis du développement d’outils numériques dans leur corps d’emploi. - Ce portrait des compétences numériques des employés représente une étape incontournable pour bien choisir les formations à offrir et les outils adaptés àdéployer en réponse aux attentes et aux besoins.

In the era of personalized medicine, we aim to reproduce the patient’s native anatomy and the physiological articular environment. Our new quest is to offer a forgotten hip joint to our patients. Currently, two factors may compromise this achievement: hip range of motion restrictions and hip instability. The supra-physiologic arc of motion provided by the large head–neck ratio of large diameter head (>36 mm) THA makes it a forgiving procedure, leaving some room for imprecision by the surgeon (especially in presence of spinopelvic variations). It also permits a better reproduction of individual patient anatomy (femoral offset and leg length). Bilateral and outpatient procedures are simplified. It allows unrestricted range of motion (ROM), for activities and work occupations. For these reasons, it may increase the likelihood of having a forgotten hip. LDH THA is currently available with ceramic bearing or metal on polyethylene dual mobility design.

International audience; Growth hormone deficiency (GHD) is a severe pathology that greatly affects the quality of life, and increases morbidity and mortality of patients owing to the augmentation of cardiovascular events. Treatment of GHD is challenging, mainly because there is no specific characteristic sign or symptom that can be used to make a clear diagnosis. There is need for an unequivocal diagnosis of GHD to avoid unnecessary treatment with GH, because the available provocative tests (GH stimulation tests) are not specific and sensitive enough, and are contraindicated in some patients. Ghrelin is an endogenous peptide that stimulates GH secretion by interacting with a G-protein-coupled receptor named ghrelin receptor (GH secretagogue receptor 1a, GHS-R1a). Given this, a GH stimulation test using ghrelin or its analogues appears to be attractive. In this paper, a modified tripeptide first named JMV-1843 in the laboratory is briefly presented. It is potent and selective in stimulating the release of GH and is orally active. It has been recently commercialized for the diagnosis of adult growth hormone deficiency under the tradename Macrilen TM. The test using this compound appears to be reliable, well tolerated and simple.

Purpose The COVID-19 pandemic has disrupted the health care system around the entire globe. A consensus is needed about resuming total hip and knee procedures. The European Hip Society (EHS) and the European Knee Association (EKA) formed a panel of experts that have produced a consensus statement on how the safe re-introduction of elective hip and knee arthroplasty should be undertaken. Methods A prospective online survey was done among members of EHS and EKA. The survey consisted of 27 questions. It includes basic information on demographics and details the participant’s agreement with each recommendation. The participant could choose among three options (agree, disagree, abstain). Recommendations focussed on pre-operative, peri-operative, and post-operative handling of patients and precautions. Results A total of 681 arthroplasty surgeons participated in the survey, with 479 fully completing the survey. The participants were from 44 countries and 6 continents. Apart from adhering to National and Local Guidelines, the recommendations concerned how to make elective arthroplasty safe for patients and staff. Conclusion The survey has shown good-to-excellent agreement of the participants with regards to the statements made in the recommendations for the safe return to elective arthroplasty following the first wave of the COVID-19 pandemic.

The city of Zigong faces severe seismic hazards because of the amplifying effects of its topography and geology. To estimate the local site effects, an array of 8 accelerographs has been in operation along the Xishan Park ridge since 2007. In this study, site amplifications associated with the ground motion produced by the 2008 Wenchuan earthquake is evaluated using the Standard Spectral Ratio (SSR) technique and root-mean-square acceleration (arms) method. 2D numerical analysis using finite difference method is then performed and results are compared with monitoring data. The results show that topography and local presence of soft materials significantly increase the ground motion in both field observations and the numerical model. Along the ridge slope, the maximum ground motion amplification was obtained at the hilltop for a frequency range 1–10 Hz for both NS and EW components. Significant amplifications occurred at higher frequencies (>10 Hz) and are considered to result from local specific conditions such as rock fracturing and ridge steps; thus they do not necessarily occur at the hilltop. A slight difference between the two horizontal components (NS and EW) was observed and this is possibly due to the azimuthal dependence of site effect. The computed amplification ratios give amplitudes that are comparable to those indicated by field observations. However, the calculated spectral amplifications are underestimated at frequencies larger than 3 Hz. This can be due to the fact that a signal damping ratio used for the whole model does not adequately represent the energy dissipation at high frequency.

Liver-expressed antimicrobial peptide 2 (LEAP2) was recently recognized as an endogenous ligand for the growth hormone secretagogue receptor (GHSR), which also is a receptor for the hormone ghrelin. LEAP2 blocks ghrelin-induced activation of GHSR and inhibits GHSR constitutive activity. Since fluorescence-based imaging and pharmacological analyses to investigate the biology of GHSR require reliable probes, we developed a novel fluorescent GHSR ligand based on the N-terminal LEAP2 sequence, hereafter named F-LEAP2. In vitro, F-LEAP2 displayed binding affinity and inverse agonism to GHSR similar to LEAP2. In a heterologous expression system, F-LEAP2 labeling was specifically observed in the surface of GHSR-expressing cells, in contrast to fluorescent ghrelin labeling that was mainly observed inside the GHSR-expressing cells. In mice, centrally-injected F-LEAP2 reduced ghrelin-induced food intake, in a similar fashion to LEAP2, and specifically labeled cells in GHSR-expressing brain areas. Thus, F-LEAP2 represents a valuable tool to study the biology of GHSR in vitro and in vivo.

Ces dernières décennies, dans de nombreux pays, la profession enseignante a été au cœur de transformations de divers ordres : de nouvelles tâches, de nouvelles compétences et des responsabilités professionnelles accrues ; les caractéristiques des contextes scolaires, notamment vis-à-vis des besoins particuliers des élèves, du rôle des parents au sein de l’école ou de la prégnance des nouvelles technologies ; la formation initiale et continue, l’entrée dans le métier ; l’évaluation des enseign...

Objective: The octanoylated peptide hormone ghrelin regulates appetite and glycaemic control. Des-acyl ghrelin abolishes some effects of ghrelin, but does not bind to ghrelin receptor. LEAP2 is a novel ligand for ghrelin receptor that blocks the effects of ghrelin. Some evidences show that plasma levels of these peptides are altered in adults with obesity, but their levels in childhood obesity remain poorly studied. Therefore, the objective of this study was to assess fasting plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with normoweight, overweight/obesity and their association with different anthropometric and metabolic variables. Design: A total of 42 females and 40 males, ages 3–12 years old were enrolled as a cross-sectional cohort. Results: Plasma levels of des-acyl ghrelin and LEAP2 (but not ghrelin) were lower and ghrelin/des-acyl ghrelin ratio was higher in children with overweight/obesity. Des-acyl ghrelin negatively correlated with age, BMI z-score, insulin and HOMA index, and the correlations were stronger in children with overweight/obesity. LEAP2 levels negatively correlated with BMI z-score. No gender differences were found. Conclusions: Our findings suggest that ghrelin tone is increased in childhood obesity, due to a decrease on plasma levels of des-acyl ghrelin and LEAP2, and that des-acyl ghrelin is associated to insulin resistance, particularly in children with overweight/obesity., Facultad de Ciencias Médicas, Instituto Multidisciplinario de Biología Celular, Facultad de Ciencias Exactas