The potential role of microbiota for controlling the spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) in neonatal population [version 1; referees: 2 approved]

The spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) in the hospital and also the community is worrisome. Neonates particularly are exposed to the risk of ESBL-PE acquisition and, owing to the immaturity of their immune system, to a higher secondary risk of ESBL-PE-related infection. Reducing the risk of acquisition in the hospital is usually based on a bundle of measures, including screening policies at admission, improving hand hygiene compliance, and decreasing antibiotic consumption. However, recent scientific data suggest new prevention opportunities based on microbiota modifications

GERMLINE GAIN-OF-FUNCTION MUTATIONS of ALK DISRUPT CENTRAL NERVOUS SYSTEM DEVELOPMENT

International audienceNeuroblastoma (NB) is a frequent embryonal tumour of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK, MIM 105590) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harbouring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes

A Mild Form of SLC29A3 Disorder: A Frameshift Deletion Leads to the Paradoxical Translation of an Otherwise Noncoding mRNA Splice Variant

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the ‘rescue’ role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic

Seasonal migration, site fidelity, and population structure of European seabass (Dicentrarchus labrax)

Large-scale electronic tagging is a very powerful tool to study how fish movements and migrations shape the internal dynamics of populations. This knowledge, crucial for improving fishery management, was still limited for the European seabass, whose stocks in the Northeast Atlantic have declined drastically over the last decade. To better understand the species ecology and the spatio-temporal structure of the population, we tagged seabass in the North Sea, the English Channel, and the Bay of Biscay, from 2014 to 2016. Out of 1220 deployed DSTs, 482 have been recovered by November 2022. Approximately half of them included a period of potential spawning migration. Reconstructed trajectories confirmed seabass to be a partial migratory species, as individuals exhibited either long-distance migrations or residence. Most migrants exhibited fidelity to summer feeding areas and winter spawning areas. Our dataset enriches the knowledge of seabass biological traits (e.g. temperature and depth ranges, vulnerability to predation and fishing). Our results suggest a spatial structure of the Atlantic population that differs from the stock structure currently considered for assessment and management. The consequences should be explored at both the European level and by regional managers involved in conservation outcomes

Young children returning from Irak and Syria to Europe : a challenge for clinicians and for society

International audienc

Projet Barfray. Montage d’une opération pilote de marquage conventionnel sur frayère

The Barfray project aimed at improving the knowledge on the essential habitats of the European sea bass (Dicentrachus labrax) on the French Atlantic coast (English Channel and Bay of Biscay). One of the research need concerns the diversity of feeding areas contributing to the main spawning grounds. Here we present the setting up of a conventional tagging pilot operation on spawning ground, a prerequisite to carry out this research. The operation initially aimed to tag 2,000 adult sea bass by mobilising a pair of pelagic trawlers for 10 days of fishing on an offshore spawning ground in the Bay of Biscay. This operation had to be reorganised and reduced in duration as no pelagic trawlers agreed to participate. Ifremer therefore carried out a sea bass spawning tagging campaign with the help of two longliners from La Cotinière (Oléron Island) from 20 to 24 February 2019 off the Gironde. This campaign allowed the tagging of 321 adult sea bass with one or two external tags. The weather conditions did not allow the operation to start earlier in the sea bass fishing season on this spawning ground, when longline yields are usually better. Communication operations were set up to encourage the various stakeholders (e.g. professional and recreational fishermen) to return the tags to Ifremer in exchange for a reward. The expected results concern the analysis of the apparent movement of fish between the tagging area (the spawning ground) and their recapture locations in the following 6 months. The data should allow quantifying the contribution of the sampled spawning area to the coastal summer feeding grounds. The study area covers the whole Bay of Biscay and the Western English Channel. The project should ultimately enable the adaptation and/or reinforcement of the management measures implemented for this species, which is experiencing a decline in abundance, particularly in the Celtic Sea - Channel - North Sea, but also in the Bay of Biscay.Le projet Barfray visait à améliorer les connaissances sur les zones fonctionnelles du bar européen (Dicentrachus labrax) sur la façade Atlantique française (Manche et golfe de Gascogne). L’une des questions de recherche actuelles concerne la diversité des zones d'alimentation contribuant aux frayères principales. Ici nous présentons le montage d’une opération pilote de marquage conventionnel sur frayère, prérequis nécessaire pour mener à bien cette recherche. L’opération visait initialement l’objectif de marquage de 2000 bars adultes avec la mobilisation d’une paire de chalutiers pélagiques durant 10 jours de pêche sur une frayère au large dans le golfe de Gascogne. Cette opération a dû être réorganisée et réduite sur la durée, aucun chalutier pélagique n’ayant accepté d’y participer. L’Ifremer a donc réalisé une campagne de marquage de bars sur frayère avec l’aide de deux palangriers de La Cotinière (île d’Oléron) du 20 au 24 février 2019 au large de la Gironde. Cette campagne a permis le marquage de 321 bars adultes au moyen d’une ou deux marques externes. Les conditions météorologiques n’ont pas permis à l’action de débuter plus tôt dans la saison de pêche du bar sur cette frayère, lorsque les rendements à la palangre sont habituellement meilleurs. Des opérations de communication ont été mises en place pour inciter les différents acteurs (e.g. pêcheurs professionnels et récréatifs) à renvoyer les marques à l’Ifremer moyennant récompense. Les résultats attendus concernent l’analyse du déplacement apparent des poissons entre la zone de marquage (la frayère) et leur lieu de recapture dans les 6 mois suivants. Les données doivent permettre de quantifier la contribution de la frayère échantillonnée aux zones d’alimentation estivale côtières. L’aire d’étude englobe l’ensemble du golfe de Gascogne et de la Manche Ouest. Le projet devrait à terme permettre d’adapter et/ou renforcer les mesures de gestion mises en œuvre pour cette espèce qui connait une baisse d’abondance tout particulièrement, en mer Celtique – Manche - mer du Nord mais également dans le golfe de Gascogne

Dosage form suitability in vulnerable populations: A focus on paracetamol acceptability from infants to centenarians

International audienceIntroduction Medicine acceptability is a multi-faceted concept driven by both product and user characteristics. Although a key factor for treatment effectiveness, especially in vulnerable populations, knowledge of those medicine features that best promote individual user acceptability remains fragmented. Focusing on paracetamol, this study has explored the appropriateness of pharmaceutical products in different dosage forms to achieve adequate patient acceptability from infants to centenarians. Methods This observational, multicentre, prospective study was carried out in 10 hospitals, 8 nursing homes and over 150 community dispensaries. Observers reported several behaviours/events evaluating acceptability for 1016 different pharmaceutical product uses in paediatrics (= 65y.). Using mapping and clustering, a multivariate approach offered an intelligible reference framework for each population, providing comprehensive scores: positively or negatively accepted. Results Among all the evaluations supporting the acceptability reference frameworks, there were 502 reports on paracetamol products intake. Herein we focused on the 5 products with. 30 evaluations. Although oral suspension and powder for oral solution were positively-accepted in the paediatric group, the powder had a higher rate of negative patient reaction (p= 90y., capsule formulations appeared to be the best accepted product in patients without swallowing alterations, and thus could be a suitable alternative to the powder in this population. Conclusions By better integrating patient characteristics when choosing dosage forms, clinicians and caregivers may improve treatment acceptability and adherence. Moreover, hospitals and healthcare institutions could optimise purchasing to best suit their local population, disseminating information to help staff align specific dosage forms to targeted patients

Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome

International audiencePitt-Hopkins syndrome is a severe congenital encephalopathy recently ascribed to de novo heterozygous TCF4 gene mutations. We report a series of 13 novel PHS cases with a TCF4 mutation and show that EEG, brain magnetic resonance imagain (MRI), and immunological investigations provide valuable additional clues to the diagnosis. We confirm a mutational hot spot in the basic domain of the E-protein. Functional studies illustrate that heterodimerisation of mutant TCF4 proteins with a tissue-specific transcription factor is less effective than that homodimerisation in a luciferase reporter assay. We also show that the TCF4 expression pattern in human embryonic development is widespread but not ubiquitous. In summary, we further delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life

A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the"rescue" role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic