Université de Rennes 2

Many human teratogens are associated with a spectrum of congenital anomalies rather than a single defect, and therefore the identification of congenital anomalies occurring together more frequently than expected may improve the detection of teratogens. Thirty-two EUROCAT congenital anomaly registries covering 6,599,765 births provided 123,566 cases with one or more major congenital anomalies (excluding chromosomal and genetic syndromes) for the birth years 2008–2016. The EUROCAT multiple congenital anomaly algorithm identified 8804 cases with two or more major congenital anomalies in different organ systems, that were not recognized as part of a syndrome or sequence. For each pair of anomalies, the odds of a case having both anomalies relative to having only one anomaly was calculated and the p value was estimated using a two-sided Fisher’s exact test. The Benjamini–Hochberg procedure adjusted p values to control the false discovery rate and pairs of anomalies with adjusted p values < 0.05 were identified. A total of 1386 combinations of two anomalies were analyzed. Out of the 31 statistically significant positive associations identified, 20 were found to be known associations or sequences already described in the literature and 11 were considered “potential new associations” by the EUROCAT Coding and Classification Committee. After a review of the literature and a detailed examination of the individual cases with the anomaly pairs, six pairs remained classified as new associations. In summary, systematically searching for congenital anomalies occurring together more frequently than expected using the EUROCAT database is worthwhile and has identified six new associations that merit further investigation.

Antimony triselenide (Sb 2 Se 3 ) has possessed excellent optoelectronic properties and has gained interest as a light‐harvesting material for photovoltaic technology over the past several years. However, the severe interfacial and bulk recombination obviously contribute to significant carrier transport loss thus leading to the deterioration of power conversion efficiency (PCE). In this work, we synergistically employ buried interface and heterojunction engineering to regulate the film growth kinetic and optimize the band alignment. Through this approach, the orientation of the precursor films is successfully controlled, promoting the preferred orientational growth of the ( hk 1) of the Sb 2 Se 3 films. Besides, interfacial trap‐assisted non‐radiative recombination loss and heterojunction band alignment are successfully minimized and optimized. As a result, the champion device presents a PCE of 9.24% with short‐circuit density ( J SC ) and fill factor (FF) of 29.47 mA/cm ² and 63.65%, respectively, representing the highest efficiency in sputtered‐derived Sb 2 Se 3 solar cells. This work provides an insightful prescription for fabricating high‐quality Sb 2 Se 3 thin film and enhancing the performance of Sb 2 Se 3 solar cells. This article is protected by copyright. All rights reserved

Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed‐effects modelling software Monolix 2018R2. A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days–21 months; median weight 4.3 kg (2.2–12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9–138.1) L/h for spironolactone, 9.7 (1.5–66.9) L/h for TMS, and 1.0 (0.2–5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period. The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013–001189-40).

Recent advances in technology integration have introduced new on-chip interconnects, such as wireless Network-on-Chips (NoCs), making the design space too large to be efficiently explored with time-consuming standard simulators. In this paper, we propose an analytical model based on queuing theory to evaluate the latency of manycore architecture interconnects. We consider a hybrid interconnection that utilizes electrical and wireless NoCs for both intra- and inter-cluster communications. The results demonstrate that our proposed model significantly reduces the simulation execution time by up to 500× while maintaining an error rate of less than 5% compared to the Noxim cycle-accurate simulator.

Objective: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma. Design and methods: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least one major criterion (necrolytic migratory erythema (NME) and/or recent-onset diabetes and/or weight loss ≥ 5 kg) associated with either glucagonemia >2xULN or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT). Results: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonomas symptoms at diagnosis were NME (86.8%), weight loss (68.4%) and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75% and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8) and somatostatin analogues (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival was 17.3 years. The Ki-67 index >3% was associated with shorter OS (HR 5.27, 95%CI [1.11-24.96], p = 0.036). Conclusion: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, PRRT or liver-directed therapy seem to provide both substantial antitumor and antisecretory efficacy.

Studying the interactions between humans, land‐cover and biodiversity is necessary for the sustainable management of socio‐ecosystems and requires long‐term reconstructions of past landscapes, improving the integration of slow processes. The main source of information on past vegetation is fossil pollen, but pollen data are biased by inter‐taxonomic differential production and dispersal. The landscape reconstruction algorithm (LRA) approach is the most widely used to correct for these biases. The LOVE algorithm (LOcal Vegetation estimates), the second step in the LRA approach, also estimates the spatial extent of the local vegetation reconstruction zone (the relevant source area of pollen, RSAP). While LRA estimates have already been integrated into certain past land‐cover mapping approaches, none have been designed to allow the diachronic reconstruction of a land‐cover mosaic over the long term combining the following points: the direct integration of LOVE estimates as a source of variability in the composition and distribution of pollen taxa, without multiple scenarios, and the integration of spatiotemporal autocorrelation in the taxa distribution between periods. Here, we propose an innovative approach for BACKward LAND‐cover reconstruction (BACKLAND), combining these points and estimating the past land‐cover mosaic within a set of RSAPs. Based on three stages using parsimonious assumptions and easy‐to‐implement probabilistic and statistical tools, this approach requires LOVE estimates of sites close enough to each other for their RSAPs to overlap, botanical data, a digital elevation model and two recent land‐cover maps. Developed and tested on a small study area within the mountain landscape of the Bassiès valley (French Pyrenees), BACKLAND achieved the reconstruction of a past land‐cover map representing eight land‐cover types at a spatial resolution of 20 m with a good level of accuracy. We show in this study the originality of this approach and discuss its potential for palaeoenvironmental studies, historical ecology and the management of socio‐ecosystems.

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients aged over 65. We have now re-examined the classic prognostic factors, adding an assessment of the mutation status of TP53. Patients (n=74; median age 73 years) were treated with the RiBVD combination. Median Progression Free Survival (mPFS) was 79 months, and median Overall Survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level below 3.6 g/dL (Alb

Introduction We assessed the impact of a nationwide screening programme to reduce the risk of anal cancer in a large cohort of high‐risk patients with HIV. Methods From a large database from one referral centre, all high‐risk patients with HIV (men who have sex with men, history of anal or genital warts, or previous cervix human papillomavirus‐related lesions) who were eligible to enter the French anal cancer screening programme (2011–2020) were retrospectively included. Adherence to the screening programme was defined as no interval >18 months between two visits. Standardized management included perianal visualization and standard anoscopy with biopsies of macroscopic abnormalities. Results Overall, 700 patients with HIV were included (median follow‐up 8.4 years [interquartile range 4.3–9.2] and 1491.6 patient‐years), and 336 had one or more proctology visit. A total of 13 patients were diagnosed with anal squamous cell carcinomas. The risk of anal cancer was higher with anal intra‐epithelial neoplasia grade 3 (AIN3; hazard ratio [HR] 44.5 [95% confidence interval {CI} 11.2–176.6], p < 0.001), AIN2 (HR 11.9 [95% CI 2.1–66.9], p = 0.005), or high‐grade dysplasia (HR 23.4 [95% CI 7.9–69.1], p < 0.001) than with low‐grade dysplasia or no lesion. Among the patients who were strictly adherent to the screening programme (4.6% [32/700]), we did not report any AIN or anal cancer, but we also did not observe any significant reduction in the risk of anal cancer ( p = 0.51), AIN3 ( p = 0.28), high‐grade dysplasia ( p = 0.19), or any AIN lesions ( p = 0.10) compared with non‐adherent patients. In contrast, screened patients were more likely to be diagnosed with anal warts (HR 3.71 [95% CI 2.14–6.42], p < 0.001). Conclusion Macroscopic high‐grade dysplasia lesions are associated with a higher risk of developing anal cancer. Despite finding no cases of cancer during the screening programme, we also did not demonstrate a clear benefit from our screening programme for the prevention of anal cancer in high‐risk patients with HIV.

Shared spaces are urban areas without physical separation between motorised and non-motorised users. Previous research has suggested that it is difficult for users to appropriate these spaces and that the advent of self-driving cars could further complicate interactions. It is therefore important to study the perception of these spaces from the users’ perspectives to determine which conditions may promote their acceptance of the vehicles. This study investigates the perceived collision risk of a self-driving car’s passenger when pedestrians cross the vehicle’s path. The experiment was conducted with a driving simulator. Seven factors were manipulated to vary the dynamics of the crossing situations in order to analyse their influence on the passenger’s perception of collision risk. Two measures of perceived risk were obtained. A continuous subjective assessment, reflecting an explicit risk evaluation, was reported in real time by participants. On the other hand, their skin conductance responses, which reflects implicit information processing, were recorded. The relationship between the factors and the risk perception indicators was studied using Bayesian networks. The best Bayesian networks demonstrate that subjective collision risk assessments are primarily influenced by the factors that determine the relative positions of the vehicle and the pedestrian as well as the distance between them when they are in close proximity. The analysis further reveals that variations in skin conductance response indicators are more likely to be explained by variations in subjective assessments than by variations in the manipulated factors. These findings could benefit the development of self-driving navigation among pedestrians by improving understanding of the factors that influence passengers’ feelings.

Near‐infrared (NIR) laser annealing is successfully used to crystallize TiO 2 thin films from a sol–gel solution deposited on gold nanoparticle arrays (AuNPs). The AuNPs are used as nano‐heaters allowing a local temperature increase up to 500 °C in the film. The temperature reached under the laser is deduced from the presence of the anatase phase in the samples obtained by laser exposure, showing that crystallized TiO 2 can be obtained by the photothermal effect. Different analytical techniques supported this study, such as grazing X‐ray diffraction (GIXRD), UV–vis, and Raman spectroscopy. The temperature increase is confirmed by a numerical model that emphasizes the role of NPs coupling in the photothermal effect. Direct laser patterning by NIR laser and in combination with Deep‐UV photolithography (DUV) are demonstrated. This fabrication method opens new perspectives in applications such as photonics, photocatalysis, or biosensing.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. However, studies of hospitalisation patterns with replacement treatment are scarce. The aim of this study was to investigate the current therapeutic management of VWD and determine the key drivers of coagulation factor uses in patients during hospitalisation. Hopscotch-WILL was a multi-centric retrospective study conducted over a 48-month period in any patients with VWD. The data were collected from the BERHLINGO Research Database and the French Hospital database. A total of 988 patients were included; 153 patients (15%) were hospitalised during 293 stays requiring treatment with von Willebrand factor (VWF) concentrates—pure or in association with Factor VIII (FVIII). Their median basal concentrations of VWF and FVIII were significantly lower than in untreated patients: VWF antigen < 30 IU/dL, VWF activity < 20 IU/dL and FVIII:C < 40 IU/dL. The median (interquartile range) concentrate consumption was similar between highly purified VWF or VWF combined with FVIII (72 [110] vs 57 [89] IU/kg/stay, p = 0.154). The use of VWF was highly heterogeneous by VWD type; type 3 had a particularly high impact on VWF consumption in non-surgical situations. The main admissions were for ear/nose/throat, hepato-gastroenterology, and trauma/orthopaedic conditions, besides gynaecological-obstetric causes in women. The use of VWF concentrates is mostly influenced by low basal levels of VWF and FVIII, but also by VWD type or the cause for hospitalisation. These results could inform future studies of newly released recombinant VWF.

Importance Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain. Objective To determine the effect of intubation withholding vs routine practice on clinical outcomes of comatose patients with acute poisoning and a Glasgow Coma Scale score less than 9. Design, Setting, and Participants This was a multicenter, randomized trial conducted in 20 emergency departments and 1 intensive care unit (ICU) that included comatose patients with suspected acute poisoning and a Glasgow Coma Scale score less than 9 in France between May 16, 2021, and April 12, 2023, and followed up until May 12, 2023. Intervention Patients were randomized to undergo conservative airway strategy of intubation withholding vs routine practice. Main Outcomes and Measures The primary outcome was a hierarchical composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Key secondary outcomes included adverse events resulting from intubation as well as pneumonia within 48 hours. Results Among the 225 included patients (mean age, 33 years; 38% female), 116 (16%) were in the intervention group and 109 (58%) in the control group. No patients died during the in-hospital stay. There was a significant clinical benefit for the primary end point in the intervention group, with a win ratio of 1.85 (95% CI, 1.33 to 2.58). In the intervention group, there was a lower proportion with any adverse event (6% vs 14.7%; absolute risk difference, 8.6% [95% CI, −16.6% to −0.7%]) compared with the control group, and pneumonia occurred in 8 (6.9%) and 16 (14.7%) patients, respectively (absolute risk difference, −7.8% [95% CI, −15.9% to 0.3%]). Conclusions and Relevance Among comatose patients with suspected acute poisoning, a conservative strategy of withholding intubation was associated with a greater clinical benefit for the composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Trial Registration ClinicalTrials.gov Identifier: NCT04653597

Mature lymphoid stromal cells (LSCs) are key organizers of immune responses within secondary lymphoid organs. Similarly, inflammation-driven tertiary lymphoid structures depend on immunofibroblasts producing lymphoid cytokines and chemokines. Recent studies have explored the origin and heterogeneity of LSC/immunofibroblasts, yet the molecular and epigenetic mechanisms involved in their commitment are still unknown. This study explored the transcriptomic and epigenetic reprogramming underlying LSC/immunofibroblast commitment. We identified the induction of lysine demethylase 6B (KDM6B) as the primary epigenetic driver of early immunofibroblast differentiation. In addition, we observed an enrichment for KDM6B gene signature in murine inflammatory fibroblasts and pathogenic stroma of patients with autoimmune diseases. Last, KDM6B was required for the acquisition of LSC/immunofibroblast functional properties, including the up-regulation of CCL2 and the resulting recruitment of monocytes. Overall, our results reveal epigenetic mechanisms that participate in the early commitment and immune properties of immunofibroblasts and support the use of epigenetic modifiers as fibroblast-targeting strategies in chronic inflammation.

Recently, numerous physical attacks have been demonstrated against lattice-based schemes, often exploiting their unique properties such as the reliance on Gaussian distributions, rejection sampling and FFT-based polynomial multiplication. As the call for concrete implementations and deployment of postquantum cryptography becomes more pressing, protecting against those attacks is an important problem. However, few countermeasures have been proposed so far. In particular, masking has been applied to the decryption procedure of some lattice-based encryption schemes, but the much more difficult case of signatures (which are highly nonlinear and typically involve randomness) has not been considered until now. In this paper, we describe the first masked implementation of a lattice-based signature scheme. Since masking Gaussian sampling and other procedures involving contrived probability distributions would be prohibitively inefficient, we focus on the GLP scheme of Güneysu, Lyubashevsky and Pöppelmann (CHES 2012). We show how to provably mask it in the Ishai–Sahai–Wagner model (CRYPTO 2003) at any order in a relatively efficient manner, using extensions of the techniques of Coron et al. for converting between arithmetic and Boolean masking. Our proof relies on a mild generalization of probing security that supports the notion of public outputs. We also provide a proof-of-concept implementation to assess the efficiency of the proposed countermeasure.

The underlying mechanisms of asbestos-related autoimmunity are poorly understood. As the size, surface reactivity, and free radical activity of asbestos particles are considered crucial regarding the health effects, this study aims to compare the effects of exposure to pristine amosite (pAmo) or milled amosite (mAmo) particles on lung damage, autoimmunity, and macrophage phenotype. Four months after lung exposure to 0.1 mg of amosite, BAL levels of lactate dehydrogenase, protein, free DNA, CCL2, TGF-β1, TIMP-1, and immunoglobulin A of pAmo-exposed C57Bl/6 mice were increased when compared to fluids from control- and mAmo-exposed mice. Effects in pAmo-exposed mice were associated with lung fibrosis and autoimmunity including anti-double-strand DNA autoantibody production. mAmo or pAmo at 20 µg/cm² induced a pro-inflammatory phenotype characterized by a significant increase in TNFα and IL-6 secretion on human monocyte-derived macrophages (MDMs). mAmo and pAmo exposure induced a decrease in the efferocytosis capacities of MDMs, whereas macrophage abilities to phagocyte fluorescent beads were unchanged when compared to control MDMs. mAmo induced IL-6 secretion and reduced the percentage of MDMs expressing MHCII and CD86 markers involved in antigen and T-lymphocyte stimulation. By contrast, pAmo but not mAmo activated the NLRP3 inflammasome, as evaluated through quantification of caspase-1 activity and IL-1β secretion. Our results demonstrated that long-term exposure to pAmo may induce significant lung damage and autoimmune effects, probably through an alteration of macrophage phenotype, supporting in vivo the higher toxicity of entire amosite (pAmo) with respect to grinded amosite. However, considering their impact on efferocytosis and co-stimulation markers, mAmo effects should not be neglected. Key messages Lung fibrosis and autoimmunity induced by amosite particles depend on their physicochemical characteristics (size and surface) Inhalation exposure of mice to pristine amosite fibers is associated with lung fibrosis and autoimmunity Anti-dsDNA antibody is a marker of autoimmunity in mice exposed to pristine amosite fibers Activation of lung mucosa-associated lymphoid tissue, characterized by IgA production, after exposure to pristine amosite fibers Pristine and milled amosite particle exposure reduced the efferocytosis capacity of human-derived macrophages

We report the catalytic transfer hydrogenation of urea derivatives using green hydrogen from methanol, which is the most ambitious effort in this hydrogenation world. On enlarging this methodology, selective N-methylated amines achieved from urea which are widely featured in drugs, natural products, paints etc. Moreover, this methodology making a sustain-able alternative pathway for the synthesis of selective methylated derivative from CO2 derived compound. The key to the success of this transformation is the use of a commercially available Pd/C heterogenous catalyst and Methanol which act as both H2 and C1 sources. In addition, several control experiments with the plausible intermediates were performed to analyze this novel pathway. This transformation proceeds in an environmentally friendly greener protocol and high at-om-economy.