Search

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Nirsevimab, an RSV-neutralising monoclonal antibody, was approved for use in the EU in 2022, and a national immunisation campaign began in France in September, 2023. We aimed to assess the effectiveness of nirsevimab in reducing paediatric emergency department visits (and subsequent hospitalisations) for all-cause bronchiolitis and RSV-associated bronchiolitis.

L’urticaire au froid (UF) correspond à une éruption papuleuse, érythémateuse et prurigineuse superficielle et/ou profonde (angiœdème) survenant lors des expositions au froid et régressant en moins de deux heures après éviction de la source froide. C’est une pathologie rare, d’évolution habituellement chronique, pouvant avoir un impact important sur la qualité de vie et dans certaines situations être responsable de réactions systémiques sévères. L’ensemble des éléments rapportés dans ce texte émane d’un travail mené par le Centre de preuves et le Groupe urticaire de la Société française de dermatologie dont l’objectif était d’établir des recommandations françaises sur la prise en charge de l’urticaire au froid. L’objectif de ces recommandations était d’apporter des éléments de précision quant à la prise en charge diagnostique (test au glaçon, bilan biologique) et thérapeutique de l’UF, mais également de spécifier les situations à risque de réactions systémiques sévères, nécessitant la prescription d’adrénaline auto-injectable. C’est au sein de ce travail qu’ont été établis l’algorithme de prise en charge de l’UF et une fiche d’information sur l’UF à remettre aux patients (cf. annexes). L’ensemble de ces recommandations est disponible sur le site de la Société française de dermatologie (https://reco.sfdermato.org/).

In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N-linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to facilitate infection. As such, STT3A/B, the catalytic domain of the OST complex, became an intriguing drug target with broad-spectrum antiviral potential. However, due to the critical role N-linked glycosylation plays in a number of fundamental human processes, the toxicological ramifications of STT3A/B inhibition required attention commensurate to that given to antiviral efficacy. Herein, we describe how known STT3A/B inhibitor NGI-1 inspired the discovery of superior tool compounds which were evaluated in in vitroefficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating N-linked glycosylation as well as the broader scientific community.

Nonlinear photoluminescence (N-PL) is a broadband photon emission arising from a nonequilibrium heated electron distribution generated at the surface of metallic nanostructures by ultrafast pulsed laser illumination. N-PL is sensitive to surface morphology, local electromagnetic field strength, and electronic band structure, making it relevant to probe optically excited nanoscale plasmonic systems. It also has been key to accessing the complex multiscale time dynamics ruling electron thermalization. Here, we show that plasmon-mediated N-PL emitted by a gold nanowire can be modified by an electrical architecture featuring a nanogap. Upon voltage activation, we observe that N-PL becomes dependent on the electrical transport dynamics and can thus be locally modulated. This finding brings an electrical leverage to externally control the photoluminescence generated from metal nanostructures and constitutes an asset for the development of emerging nanoscale interface devices managing photons and electrons.

AbstractObjectives:Monitoring antibiotic consumption is a key component to steer antimicrobial stewardship programs, including in nursing homes. We analyzed changes in antibiotic consumption in French nursing homes during 5 years, including the COVID-19 pandemic, to identify potential priorities for improvement.Design:A multicenter survey was conducted between 2018 and 2022.Setting:The study was conducted across 220 French nursing homes with on-site pharmacies.Method:Antibiotic consumption data were collected from pharmacy records and are expressed as defined daily doses per 1,000 resident days. Antibiotic indicators promoted by health authorities were calculated from quantitative data to evaluate the quality of prescribing.Results:Antibiotic consumption significantly decreased between 2018 and 2022, particularly during the coronavirus disease 2019 (COVID-19) pandemic, despite a slight increase in 2022. During the study period, the most used antibiotic classes were penicillins (61.9% in 2022) followed by cephalosporins (10.5%), macrolides–lincosamides–streptogramins (7.3%) then fluoroquinolones (7.0%). Amoxicillin–clavulanic acid was the most consumed antibiotic; amoxicillin and ceftriaxone ranked second and third. Azithromycin consumption increased from 2020, as did the indicator regarding broad-spectrum antibiotics.Conclusions:The decreasing trend in antibiotic use and control of fluoroquinolone use over the study period suggest compliance with antibiotic use guidelines. However, changes in the use of broad-spectrum antibiotics and the substantial use of amoxicillin-clavulanic acid, although it is rarely a first-line antibiotic, highlight the need for antimicrobial stewardship activities and the usefulness of antibiotic consumption surveillance to identify priorities.

The molar composition 30TeO2–40B2O3–30Bi2O3doped with 0.5Er2O3is explored. Starting from a homogeneous glass, new borotellurite glass-ceramics were elaborated after a two-step heat treatment composed of both nucleation and growth processes. The crucial parameters, determined by differential scanning calorimetry, were the nucleation optimal temperature and duration. The structural modifications occurring while heating and the related microstructure evolution were followed by ex situ X-ray Diffraction and Scanning Electron Microscopy. Mechanisms of the partial crystallization were investigated through Transmission Electron Microscopy observations and local chemical analyses (Energy Dispersive Spectroscopy and Electron Energy Loss Spectroscopy). Thus, the employed heat treatments formed glass-ceramics composed of boron-free Bi2Te2O7polycrystalline entities dispersed in the boron-oxide-enriched glassy matrix. The partial crystallization happens, therefore, concomitantly with the observed chemical demixtion, where boron oxide separates from the bismuth tellurite phase. Additionally, Raman spectroscopy and Nuclear Magnetic Resonance data reveal that the overall BO4/BO3ratio of the glass network does not show significant evolution during the partial crystallization. Optical transmission and photoluminescence properties were also measured. For glass-ceramics, the optical transmission strongly drops. Both emission and excitation spectra of Er3+ions, as well as lifetime measurements, highlight the modified environment around the rare-earth ions occurring with partial crystallization.

Across biological systems, cells undergo coordinated changes in gene expression, resulting in transcriptome dynamics that unfold within a low-dimensional manifold. While low-dimensional dynamics can be extracted using RNA velocity, these algorithms can be fragile and rely on heuristics lacking statistical control. Moreover, the estimated vector field is not dynamically consistent with the traversed gene expression manifold. To address these challenges, we introduce a Bayesian model of RNA velocity that couples velocity field and manifold estimation in a reformulated, unified framework, identifying the parameters of an explicit dynamical system. Focusing on the cell cycle, we implement VeloCycle to study gene regulation dynamics on one-dimensional periodic manifolds and validate its ability to infer cell cycle periods using live imaging. We also apply VeloCycle to reveal speed differences in regionally defined progenitors and Perturb-seq gene knockdowns. Overall, VeloCycle expands the single-cell RNA sequencing analysis toolkit with a modular and statistically consistent RNA velocity inference framework.

Constitutional mismatch repair deficiency (CMMRD), first described 25 years ago, confers an extremely high and lifelong cancer risk, including haematologic, brain, and gastrointestinal tract malignancies, and is associated with several non-neoplastic features. Our understanding of this condition has improved and novel assays to assist CMMRD diagnosis have been developed. Surveillance protocols need adjustment taking into account recent observational prospective studies assessing their effectiveness. Response to immune checkpoint inhibitors and the effectiveness and toxicity of other treatments have been described. An update and merging of the different guidelines on diagnosis and clinical management of CMMRD into one comprehensive guideline was needed. Seventy-two expert members of the European Reference Network GENTURIS and/or the European care for CMMRD consortium and one patient representative developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management based on a systematic literature search and comprehensive literature review and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life. Based on existing guidelines and currently available data, we present 82 recommendations to improve and standardise the care of CMMRD patients in Europe. These recommendations are not meant to be prescriptive and may be adjusted based on individual decisions.

This paper proposes new popularizing science activities based on artistic concepts, promoting diversity and inclusion among secondary and high-school learners. Two easily reproducible workshops are designed to arouse girls’ interest in Science, Technology, Engineering, and Mathematics through the Arts perspective. Therefore, basic scientific concepts in Mathematics and Automatic Control are proposed for young participants from the artistic standpoint of Architecture and Animation, respectively. The Maths workshop focuses on fractals and golden ratio, while the Control workshop explains the feedback-loop elements. A video containing the first Control Engineering animated cartoon explains basic concepts of Control in an artistic manner, highlighting the importance of the controller, actuator, and sensor, illustrated on a drone. Lessons learned and feedback from the workshops participants are discussed.

PurposeMosaic BRCA1promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed.PatientsBlood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATMand BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues.ConclusionsThe high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.

Differential diagnosis between constitutional mismatch repair deficiency (CMMRD)and neurofibromatosis type 1 (NF1) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.

Ce document est le fruit du travail d’un groupe d’experts, réunis à la demande de la Société française de recherche et médecine du sommeil, pour émettre des recommandations sur le parcours de soins de l’enfant (diagnostic et prise en charge thérapeutique) atteint d’un trouble respiratoire obstructif du sommeil (TROS) de type 1 (TROS1). Le partage d’expérience et les données de littérature ont permis d’élaborer ces recommandations. Le TROS est suspecté lorsque plusieurs symptômes respiratoires nocturnes, en relation avec une obstruction des voies aériennes supérieures, sont retrouvés à l’interrogatoire. L’examen oto-rhino-laryngologique (ORL) spécialisé, avec nasofibroscopie, est indispensable au cours de la démarche diagnostique. L’examen du sommeil, dans ce contexte de TROS1, n’est pas obligatoire lorsque au moins 2 symptômes nocturnes (dont les ronflements) sont présents. La prise en charge thérapeutique doit être individualisée selon les sites obstructifs. Elle repose, le plus souvent, sur une chirurgie ORL (la cause principale des TROS1 chez l’enfant est l’hypertrophie des tissus lymphoïdes), mais également, selon les constatations cliniques, sur un traitement orthodontique associé généralement à une rééducation spécialisée oro-maxillo-faciale. Quelle que soit la prise en charge, le suivi doit être continu et multidisciplinaire, intégré dans un réseau de spécialistes formés aux TROS de l’enfant.

Information visualization uses various types of representations to encode data into graphical formats. Prior work on visualization techniques has evaluated the accuracy of perceived numerical data values from visual data encodings such as graphical position, length, orientation, size, and color. Our work aims to extend the research of graphical perception to the use of motion as data encodings for quantitative values. We present two experiments implementing multiple fundamental aspects of motion such as type, speed, and synchronicity that can be used for numerical value encoding as well as comparing motion to static visual encodings in terms of user perception and accuracy. We studied how well users can assess the differences between several types of motion and static visual encodings and present an updated ranking of accuracy for quantitative judgments. Our results indicate that non-synchronized motion can be interpreted more quickly and more accurately than synchronized motion. Moreover, our ranking of static and motion visual representations shows that motion, especially expansion and translational types, has great potential as a data encoding technique for quantitative value. Finally, we discuss the implications for the use of animation and motion for numerical representations in data visualization.

The article reviews the art exhibition "Le Poème de l'âme", by Louis Janmot, at Musée d'Orsay, Esplanade Valéry-Giscard-d'Estaing, in Paris, France, from September 11, 2023, to January 7, 2024.

Autonomous discovery and direct instruction are two distinct sources of learning in children but education sciences demonstrate that mixed approaches such as assisted discovery or guided play result in improved skill acquisition. In the field of artificial intelligence (AI), these extremes, respectively, map to autonomous agents learning from their own signals and interactive learning agents fully taught by their teachers. In between should stand teachable autonomous agents (TAA): agents that learn from both internal and teaching signals to benefit from the higher efficiency of assisted discovery. Designing such agents will enable real-world nonexpert users to orient the learning trajectories of agents toward their expectations. More fundamentally, this may also be a key step to build agents with human-level intelligence. This article presents a roadmap toward the design of teachable autonomous agents from a developmental AI perspective. Building on developmental psychology and education sciences, we start by identifying key features enabling assisted discovery processes in child–tutor interactions. This leads to the production of a checklist of features that future TAAs will need to demonstrate. The checklist allows us to precisely pinpoint the various limitations of current reinforcement learning agents and to identify the promising first steps toward TAAs. It also shows the way forward by highlighting key research directions toward the design or autonomous agents that can be taught by ordinary people via natural pedagogy.

While early introduction of food allergens is critical to prevent the development of food allergies, early introduction of food allergens can be challenging for families with food insecurity. Although validated screening measures for risk of food insecurity are available, such screening only occurs in a minority of allergy practices.

•Job satisfaction for residents was greater during COVID-19 than in 2016.•Residents report less regret in 2020 for specialty, residency, and career.•There is no difference in burnout scores between postgraduate years.•Residents exercised more, but ate similar fruits, vegetables, and fast food.

Ces recommandations détaillent les risques de la lobo-isthmectomie (LI) et de la thyroïdectomie totale (TT), et la place de ces deux procédures dans les principales situations cliniques. Elles sont basées sur les données actuelles de littérature médicale, ont été discutées jusqu’au consensus et examinées par l’Association francophone de chirurgie endocrinienne (AFCE), en concertation avec la Société française d’endocrinologie (SFE) et la Société française de mdecine nucléaire (SFMN). Le taux de complications est deux fois plus élevé après TT qu’après LI. La TT impose une supplémentation hormonale à vie, alors que celle-ci n’est nécessaire que dans 30 % des après LI. Face à un nodule Bethesda II, relevant d’une prise en charge chirurgicale, en l’absence de lésion relevant d’une indication chirurgicale sur le lobe controlatéral, la LI est à privilégier. Face à un cancer de la thyroïde (CDT)≤1cm relevant d’une prise en charge chirurgicale ou d’un CDT≤2cm, en l’absence de facteur prédisposant aux CDT et en l’absence d’identification en pré- ou en peropératoire d’une d’extension extra thyroïdienne, de métastases ganglionnaires (cN0) et de lésions suspectes controlatérales, la LI est l’intervention de choix si le patient accepte de subir une lobectomie de totalisation en présence de signes d’agressivité à l’examen anatomopathologique définitif (extension extra thyroïdienne, emboles vasculaire, histologie agressive). Pour les CDT de 2 à 4cm, la controverse entre LI et TT persistant à ce jour, l’option de la TT peut être préférée. En cas de CDT>4cm, d’adénopathies macroscopiques (cN1), de signes d’extension extra thyroïdienne ou de facteur prédisposant aux CDT, la thyroïdectomie est totale.

Thanks to their outstanding mechanical properties, Bulk Metallic Glasses (BMGs) are new alternatives to traditional crystalline metals for mechanical and micromechanical applications including power transmission. However, the tribological properties of BMGs are still poorly understood, mostly because their amorphous nature induces counter intuitive responses to friction and wear. In the present study, four different BMGs (Cu47Zr46Al7, Zr46Cu45Al7Nb2, Zr60Cu28Al12, and Zr61Cu25Al12Ti2) underwent ball-on-disc friction tests against 100Cr6 steel balls (American Iron and Steel Institute (AISI) 52100) at different relative humidities (RHs) ranging from 20% to 80%. Controlling humidity enabled to observe a high repeatability of the friction and wear responses of the BMG. Interestingly, the friction coefficient decreased by a factor of 2 when the humidity was increased, and the wear rate of BMGs was particularly low thanks to a 3rd-body tribolayer that forms on the BMG surface, composed of oxidized wear particles originating from the ball. The morphology of this tribolayer is highly correlated to humidity. The study also identifies how the tribolayer is built up from the initial contact until the steady state is achieved.

Purpose: Once difficult ventilation and intubation are declared, guidelines suggest the use of a supraglottic airway (SGA) as a rescue device to ventilate and, if oxygenation is restored, subsequently as an intubation conduit. Nevertheless, few trials have formally studied recent SGA devices in patients. Our objective was to compare the efficacy of three second-generation SGA devices as conduits for bronchoscopy-guided endotracheal intubation. Methods: In this prospective, single-blinded three-arm randomized controlled trial, patients with an American Society of Anesthesiologists Physical Status of I–III undergoing general anesthesia were randomized to bronchoscopy-guided endotracheal intubation using AuraGain™, Air-Q® Blocker, or i-gel® devices. We excluded patients with contraindications to an SGA or drugs and who were pregnant or had a neck, spine, or respiratory anomaly. The primary outcome was intubation time, measured from SGA circuit disconnection to CO2measurement. Secondary outcomes included ease, time, and success of SGA insertion; success of intubation on first attempt; overall intubation success; number of attempts to intubate; ease of intubation; and ease of SGA removals. Results: One hundred and fifty patients were enrolled from March 2017 to January 2018. Median intubation times were similar across the three groups (Air-Q Blocker, 44 sec; AuraGain, 45 sec; i-gel, 36 sec; P= 0.08). The i-gel was faster to insert (i-gel: 10 sec; Air-Q Blocker, 16 sec; AuraGain, 16 sec; P< 0.001) and easier to insert (Air-Q Blocker vsi-gel, P= 0.001; AuraGain vsi-gel, P= 0.002). Success of SGA insertion, success of intubation, and number of attempts were similar. The Air-Q Blocker was easier to remove than the i-gel (P< 0.001). Conclusion: All three second-generation SGA devices performed similarly regarding intubation. Despite minor benefits of the i-gel, clinicians should select their SGA based on clinical experience. Study registration: ClinicalTrials.gov (NCT02975466); registered on 29 November 2016.

Although no known asteroid poses a threat to Earth for at least the next century, the catalogue of near-Earth asteroids is incomplete for objects whose impacts would produce regional devastation1,2. Several approaches have been proposed to potentially prevent an asteroid impact with Earth by deflecting or disrupting an asteroid1–3. A test of kinetic impact technology was identified as the highest-priority space mission related to asteroid mitigation1. NASA’s Double Asteroid Redirection Test (DART) mission is a full-scale test of kinetic impact technology. The mission’s target asteroid was Dimorphos, the secondary member of the S-type binary near-Earth asteroid (65803) Didymos. This binary asteroid system was chosen to enable ground-based telescopes to quantify the asteroid deflection caused by the impact of the DART spacecraft4. Although past missions have utilized impactors to investigate the properties of small bodies5,6, those earlier missions were not intended to deflect their targets and did not achieve measurable deflections. Here we report the DART spacecraft’s autonomous kinetic impact into Dimorphos and reconstruct the impact event, including the timeline leading to impact, the location and nature of the DART impact site, and the size and shape of Dimorphos. The successful impact of the DART spacecraft with Dimorphos and the resulting change in the orbit of Dimorphos7demonstrates that kinetic impactor technology is a viable technique to potentially defend Earth if necessary.

Depuis la pandémie, le Réseau Morphée anime ses groupes de thérapie comportementale et cognitive de l’insomnie par visioconférence. Le programme est basé essentiellement sur un travail de modifications comportementales. Notre objectif est d’évaluer une potentielle restructuration cognitive en lien avec l’amélioration du trouble insomnie.

Integrated landscape approaches that engage diverse stakeholder groups in landscape governance are increasingly promoted to address linked social–ecological challenges in tropical landscapes. Recent research suggests that a transdisciplinary approach to landscape management can help identify common research needs, enhance knowledge co-production, guide evidence-based policy development, and harmonize cross-sectorial integration. Meanwhile, guiding principles for landscape approaches suggest that identifying common concerns and negotiating a process of change are fundamental to implementation and evaluation efforts. As such, the use of decision support tools such as theory of change models that build ordered sequences of actions towards a desired, and agreed, future state are increasingly advocated. However, the application of the theory of change concept to integrated landscape approaches is limited thus far, particularly within the scientific literature. Here, we address this gap by applying the principles of landscape approaches and knowledge co-production to co-produce a theory of change to address current unsustainable landscape management and associated conflicts in the Kalomo Hills Local Forest Reserve No. P.13 (KFR13) of Zambia. The participatory process engaged a diverse range of stakeholders including village head people, local and international researchers, district councillors, and civil society representatives amongst others. Several pathways, actions, and interventions were developed around the themes of deforestation, biodiversity and wildlife conservation, socio-economic development, access rights, and law enforcement. To make the theory of change actionable, participants identified a need for enhanced cross-sector and multi-level communication, capacity development, and improved governance, while a lack of commitment towards coordinated knowledge exchange and access to information along with poor policy formulation and weak enforcement of rules were among potential impediments to action. Use of theory of change can both inform evidence-based policy design (by revealing place-based challenges and proposing solutions) and support policy mechanisms that promote integration between state and non-state actors (by clarifying actor rights, roles and responsibilities). Co-developing a theory of change for integrated landscape management is inherently context specific, but the process and outcomes of this study should hold relevance across a range of contexts faced with sustainability challenges related to reconciling both conservation and development objectives.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P< .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P= .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P= .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

APCgermline pathogenic variants result in predisposition to familial adenomatous polyposis and extraintestinal tumours such as desmoid fibromatosis, medulloblastomas and thyroid cancers. They have also been recently involved in ovarian microcystic stromal tumours. APCinactivation has been described at the tumour level in epithelial ovarian cancers (EOCs). Here, we report the identification of APCgermline pathogenic variants in two patients diagnosed with premenopausal EOC in early 30s, with no other pathogenic variant detected in the known ovarian cancer predisposing genes. Subsequent tumour analysis showed neither a second hit of APCinactivation nor β-catenin activation. Both tumours did not have a homologous recombination (HR) deficiency, pointing towards the implication of other genes than those involved in HR. APCmay contribute to the carcinogenesis of EOC in a multifactorial context. Further studies are required to clarify the role of APCin predisposition to EOC.

BackgroundConstitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessively inherited syndrome that is caused by biallelic pathogenic variants of the mismatch repair genes. It is characterised by the development of multiple tumours in the first and second decade of life including brain, gastrointestinal and haematological tumours often resulting in early death. In order to improve the prognosis of these patients, the European collaborative group ‘care for CMMRD’ developed a surveillance programme in 2014 and established a registry of patients with CMMRD in Paris. The aim of the study was to evaluate the outcome of this programme.MethodsTwenty-two patients with a definitive diagnosis of CMMRD and with at least one follow-up study were selected from the registry. Medical data on the outcome of surveillance were collected from these patients.ResultsDuring a mean follow-up of 4 years, the programme detected eight malignant tumours including three brain tumours, three upper gastrointestinal cancers and two colorectal cancers. Most tumours could successfully be treated. In addition, many adenomas were detected in the duodenum, and colorectum and subsequently removed. Seven patients developed a symptomatic malignancy, including two brain tumours, one small bowel cancer and four haematological malignancies. At the end of the follow-up, 16 out of 22 patients (73%) who participated in the surveillance programme were still alive.ConclusionThe study suggests a beneficial effect of surveillance of the digestive tract and brains.

Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01–5.06, pvalue = 0.04). Four EO cases stood out: two with POLE/POLD1variants in the key exonuclease domain, one with a BMPR1Aduplication and one with an EPCAMdeletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.

BackgroundThe MSH3gene is part of the DNA mismatch repair system, but has never been shown to be involved in Lynch syndrome. A first report of four patients from two families, bearing biallelic MSH3germline variants, with a phenotype of attenuated colorectal adenomatous polyposis raised the question of its involvement in hereditary cancer predisposition. The patients’ tumours exhibited elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a hallmark of MSH3deficiency.MethodsWe report five new unrelated patients with MSH3-associated polyposis. We describe their personal and familial history and study the EMAST phenotype in various normal and tumour samples, which are relevant findings based on the rarity of this polyposis subtype so far.ResultsAll patients had attenuated colorectal adenomatous polyposis, with duodenal polyposis in two cases. Both women had breast carcinomas. EMAST phenotype was present at various levels in different samples of the five patients, confirming the MSH3deficiency, with a gradient of instability in polyps depending on their degree of dysplasia. The negative EMAST phenotype ruled out the diagnosis of germline MSH3deficiency for two patients: one homozygous for a benign variant and one with a monoallelic large deletion.ConclusionThis report lends further credence to biallelic MSH3germline pathogenic variants being involved in colorectal and duodenal adenomatous polyposis. Large-scale studies may help clarify the tumour spectrum and associated risks. Ascertainment of EMAST may help with the interpretation of variants of unknown significance. We recommend adding MSH3to dedicated diagnostic gene panels.

BRCA1and BRCA2are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural variants, functional consequences can be difficult to assess using standard molecular methods, as the precise resolution of their sequence is often impossible with short-read next generation sequencing techniques. It has been recently demonstrated that Oxford Nanopore long-read sequencing technology can accurately and rapidly provide genetic diagnoses of Mendelian diseases, including those linked to pathogenic structural variants. Here, we report the accurate resolution of a germline duplication event of exons 18–20 of BRCA1using Nanopore sequencing with adaptive sampling target enrichment. This allowed us to classify this variant as pathogenic within a short timeframe of 10 days. This study provides a proof-of-concept that nanopore adaptive sampling is a highly efficient technique for the investigation of structural variants of tumour suppressor genes in a clinical context.

ABSTRACTNucleus, chromatin, and chromosome organization studies heavily rely on fluorescence microscopy imaging to elucidate the distribution and abundance of structural and regulatory components. Three-dimensional (3D) image stacks are a source of quantitative data on signal intensity level and distribution and on the type and shape of distribution patterns in space. Their analysis can lead to novel insights that are otherwise missed in qualitative-only analyses. Quantitative image analysis requires specific software and workflows for image rendering, processing, segmentation, setting measurement points and reference frames and exporting target data before further numerical processing and plotting. These tasks often call for the development of customized computational scripts and require an expertise that is not broadly available to the community of experimental biologists. Yet, the increasing accessibility of high- and super-resolution imaging methods fuels the demand for user-friendly image analysis workflows. Here, we provide a compendium of strategies developed by participants of a training school from the COST action INDEPTH to analyze the spatial distribution of nuclear and chromosomal signals from 3D image stacks, acquired by diffraction-limited confocal microscopy and super-resolution microscopy methods (SIM and STED). While the examples make use of one specific commercial software package, the workflows can easily be adapted to concurrent commercial and open-source software. The aim is to encourage biologists lacking custom-script-based expertise to venture into quantitative image analysis and to better exploit the discovery potential of their images.Abbreviations:3D FISH: three-dimensional fluorescence in situ hybridization; 3D: three-dimensional; ASY1: ASYNAPTIC 1; CC: chromocenters; CO: Crossover; DAPI: 4',6-diamidino-2-phenylindole; DMC1: DNA MEIOTIC RECOMBINASE 1; DSB: Double-Strand Break; FISH: fluorescence in situ hybridization; GFP: GREEN FLUORESCENT PROTEIN; HEI10: HUMAN ENHANCER OF INVASION 10; NCO: Non-Crossover; NE: Nuclear Envelope; Oligo-FISH: oligonucleotide fluorescence in situ hybridization; RNPII: RNA Polymerase II; SC: Synaptonemal Complex; SIM: structured illumination microscopy; ZMM (ZIP: MSH4: MSH5 and MER3 proteins); ZYP1: ZIPPER-LIKE PROTEIN 1.