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Background & Aims: Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC) that is difficult to diagnose and associated with high mortality. A lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis has hindered the development of novel treatments. Herein, we sought to develop a mouse model of PSC-associated CCA., Methods: Ten-week-old Mdr2 -/- mice with congenital PSC-like disease, and healthy wild-type littermates were subjected to either modified retrograde biliary instillation or hydrodynamic tail vein injection of a sleeping beauty transposon-transposase plasmid system with activated AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes (SB AKT/YAP1). The role of TGFβ was interrogated via ALK5 inhibitor (SB-525334) administration. Tumor phenotype, burden and desmoplastic reaction were analyzed histologically and via RNA sequencing., Results: While SB AKT/YAP1 plasmids administered via retrograde biliary injection caused tumors in Mdr2 -/- , only 26.67% (4/15) of these tumors were CCA. Alternatively, hydrodynamic tail vein injection of SB AKT/YAP1 resulted in robust tumorigenesis in all fibrotic Mdr2 -/- mice with high CCA burden compared to healthy mice. Tumors phenotypically resembled human CCA, expressed multiple CCA (but not hepatocellular carcinoma) markers, and exhibited a profound desmoplastic reaction. RNA sequencing analysis revealed profound transcriptional changes in CCA evolving in a PSC-like context, with specific alterations in multiple immune pathways. Pharmacological TGFβ inhibition led to enhanced immune cell tumor infiltration, reduced tumor burden and suppressed desmoplastic collagen accumulation compared to placebo., Conclusion: We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2 -/- , which recapitulates the increased susceptibility to CCA in the setting of biliary injury and fibrosis observed in PSC. Through transcriptomics and pharmacological studies, we show dysregulation of multiple immune pathways and TGFβ signaling as potential drivers of CCA in a PSC-like microenvironment., Impact and Implications: Animal models for primary sclerosing cholangitis (PSC)-related cholangiocarcinoma (PSC-CCA) are lacking. Thus, we have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2 -/- , which features reliable tumor induction on a PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal preclinical drug testing., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Antimicrobial resistance (AMR) is a major public health threat, affecting not only people but also animals and the environment. The One Health dimension of AMR is well known; however, data are lacking on the circulation of resistance-conferring genes, particularly in low-income countries. In 2017, WHO proposed a protocol called Tricycle, focusing on extended-spectrum β-lactamase (ESBL)-Escherichia coli surveillance in the three sectors (humans, animals, and the environment). We implemented Tricycle in Madagascar to assess ESBL-E coli prevalence and describe intrasector and intersector circulation of ESBL-E coli and plasmids., Methods: In this prospective study, we collected blood culture data from hospitalised patients with a suspected bloodstream infection processed from May 1, 2018, to April 30, 2019, and rectal swabs from healthy pregnant women from July 30, 2018, to April 27, 2019, both from three hospitals in Antananarivo, Madagascar; and caeca from farm chickens and surface waters from the Ikopa river, wastewater, and slaughterhouse effluents in the Antananarivo area, Madagascar, from April 9, 2018, to April 30, 2019. All samples were tested for ESBL-E coli. The genomes of all isolates were sequenced using a short-read method on NextSeq 500 and NovaSeq 6000 platforms (Illumina, San Diego, CA, USA) and those carrying plasmid replicons using an additional long-read method on a MinION platform (Oxford Nanopore Technologies, Oxford, UK). We characterised genomes of isolated strains (sequence type, resistance and virulence gene content, and plasmid replicons). We then compared isolates using the variant calling method (single-nucleotide polymorphism)., Findings: Data from 1056 blood cultures were collected and 289 pregnant women, 246 chickens, and 28 surface waters were sampled. Of the blood cultures, 18 contained E coli, of which seven (39%) were ESBL. ESBL-E coli was present in samples from 86 (30%) of 289 pregnant women, 140 (57%) of 246 chickens, and 28 (100%) of 28 surface water samples. The wet season (November to April) was associated with higher rates of carriage in humans (odds ratio 3·08 [1·81-5·27]) and chickens (2·79 [1·65-4·81]). Sequencing of 277 non-duplicated isolates (82 from pregnant women, 118 from chickens, and 77 from environmental samples) showed high genetic diversity (90 sequence types identified) with sector-specific genomic features. Single nucleotide polymorphism (SNP) analysis revealed that 169 (61%) of 277 isolates grouped into 44 clusters (two or more isolates) of closely related isolates (<40 SNPs), of which 24 clusters contained isolates from two sectors and five contained isolates from all three sectors. ESBL genes were all bla CTX-M variants (215 [78%] of 277 being bla CTX-M-15 ) and were located on a plasmid in 113 (41%) of 277 isolates. These ESBL-carrying plasmids were mainly IncF (63 [55%] of 114; one strain carried two plasmids) and IncY (42 [37%] of 114). The F31/36:A4:B1 (n=13) and F-:A-:B53 (n=8) pMLST subtypes, and the IncY plasmids, which were all highly conserved, were observed in isolates of differing genetic backgrounds from all sectors and were transferable in vitro by conjugation., Interpretation: Despite sector-specific population structures, both ESBL-E coli strains and plasmids are circulating among humans, chickens, and the environment in Antananarivo, Madagascar. The Tricycle protocol can be implemented in a low-income country and represents a powerful tool for investigating dissemination of AMR from a One Health perspective., Funding: Fondation Mérieux and INSERM, Université Paris Cité., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Antifibrotic trials rely on conventional pathology despite recognized limitations. We compared single-fiber digital image analysis with conventional pathology to quantify the antifibrotic effect of Aramchol, a stearoyl-CoA desaturase 1 inhibitor in development for metabolic dysfunction-associated steatohepatitis., Approach and Results: Fifty-one patients with metabolic dysfunction-associated steatohepatitis enrolled in the open-label part of the ARMOR trial received Aramchol 300 mg BID and had paired pre-post treatment liver biopsies scored by consensus among 3 hepatopathologists, and separately assessed by a digital image analysis platform (PharmaNest) that generates a continuous phenotypic Fibrosis Composite Severity (Ph-FCS) score. Fibrosis improvement was defined as: ≥1 NASH Clinical Research Network (NASH-CRN) stage reduction; "improved" by ranked pair assessment; reduction in Ph-FCS ("any" for ≥0.3 absolute reduction and "substantial" for ≥25% relative reduction). Fibrosis improved in 31% of patients (NASH-CRN), 51% (ranked pair assessment), 74.5% (any Ph-FCS reduction), and 41% (substantial Ph-FCS reduction). Most patients with stable fibrosis by NASH-CRN or ranked pair assessment had a Ph-FCS reduction (a third with substantial reduction). Fibrosis improvement increased with treatment duration: 25% for <48 weeks versus 39% for ≥48 weeks by NASH-CRN; 43% versus 61% by ranked pair assessment, mean Ph-FCS reduction -0.54 (SD: 1.22) versus -1.72 (SD: 1.02); Ph-FCS reduction (any in 54% vs. 100%, substantial in 21% vs. 65%). The antifibrotic effect of Aramchol was corroborated by reductions in liver stiffness, Pro-C3, and enhanced liver fibrosis. Changes in Ph-FCS were positively correlated with changes in liver stiffness., Conclusions: Continuous fibrosis scores generated in antifibrotic trials by digital image analysis quantify antifibrotic effects with greater sensitivity and a larger dynamic range than conventional pathology., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Fibrosis is an important complication in inflammatory bowel diseases. Previous studies suggest an important role of matrix Gla protein (MGP) and thrombospondin 2 (THBS2) in fibrosis in various organs. Our aim was to analyse their expression together with regulatory miRNAs in submucosal and subserosal fibroblasts in ulcerative colitis (UC) and Crohn's disease (CD) using immunohistochemistry and qPCR. Digital pathology was used to compare collagen fibre characteristics of submucosal and subserosal fibrosis. Immunohistochemistry showed expression of MGP, but not THBS2 in submucosa in UC and CD. In the subserosa, there was strong staining for both proteins in CD but not in UC. qPCR showed significant upregulation of THBS2 and MGP genes in CD subserosa compared to the submucosa. Digital pathology analysis revealed higher proportion of larger and thicker fibres that were more tortuous and reticulated in subserosal fibrosis compared to submucosal fibrosis. These results suggest distinct fibroblast populations in fibrostenosing CD, and are further supported by image analysis showing significant differences in the morphology and architecture of collagen fibres in submucosal fibrosis in comparison to subserosal fibrosis. Our study is the first to describe differences in submucosal and subserosal fibroblast populations, contributing to understanding of the pathogenesis of fibrostenosis in CD., (© 2024. The Author(s).)

Beta-lactamase-mediated degradation of beta-lactams is the most common mechanism of beta-lactam resistance in Gram-negative bacteria. Beta-lactamase-encoding genes can be transferred between closely related bacteria, but spontaneous inter-phylum transfers (between distantly related bacteria) have never been reported. Here, we describe an extended-spectrum beta-lactamase (ESBL)-encoding gene ( bla MUN-1 ) shared between the Pseudomonadota and Bacteroidota phyla. An Escherichia coli strain was isolated from a patient in Münster (Germany). Its genome was sequenced. The ESBL-encoding gene (named bla MUN-1 ) was cloned, and the corresponding enzyme was characterized. The distribution of the gene among bacteria was investigated using the RefSeq Genomes database. The frequency and relative abundance of its closest homolog in the global microbial gene catalog (GMGC) were analyzed. The E. coli strain exhibited two distinct morphotypes. Each morphotype possessed two chromosomal copies of the bla MUN-1 gene, with one morphotype having two additional copies located on a phage-plasmid p0111. Each copy was located within a 7.6-kb genomic island associated with mobility. bla MUN-1 encoded for an extended-spectrum Ambler subclass A2 beta-lactamase with 43.0% amino acid identity to TLA-1. bla MUN-1 was found in species among the Bacteroidales order and in Sutterella wadsworthensis (Pseudomonadota). Its closest homolog in GMGC was detected frequently in human fecal samples. This is, to our knowledge, the first reported instance of inter-phylum transfer of an ESBL-encoding gene, between the Bacteroidota and Pseudomonadota phyla. Although the gene was frequently detected in the human gut, inter-phylum transfer was rare, indicating that inter-phylum barriers are effective in impeding the spread of ESBL-encoding genes, but not entirely impenetrable., Competing Interests: The authors declare no conflict of interest.

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe liver disease characterized by lipid accumulation, inflammation and fibrosis. The development of MASH therapies has been hindered by the lack of human translational models and limitations of analysis techniques for fibrosis. The MASH three-dimensional (3D) InSight™ human liver microtissue (hLiMT) model recapitulates pathophysiological features of the disease. We established an algorithm for automated phenotypic quantification of fibrosis of Sirius Red stained histology sections of MASH hLiMTs model using a digital pathology quantitative single-fiber artificial intelligence (AI) FibroNest™ image analysis platform. The FibroNest™ algorithm for MASH hLiMTs was validated using anti-fibrotic reference compounds with different therapeutic modalities-ALK5i and anti-TGF-β antibody. The phenotypic quantification of fibrosis demonstrated that both reference compounds decreased the deposition of fibrillated collagens in alignment with effects on the secretion of pro-collagen type I/III, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-3 and pro-fibrotic gene expression. In contrast, clinical compounds, Firsocostat and Selonsertib, alone and in combination showed strong anti-fibrotic effects on the deposition of collagen fibers, however less pronounced on the secretion of pro-fibrotic biomarkers. In summary, the phenotypic quantification of fibrosis of MASH hLiMTs combined with secretion of pro-fibrotic biomarkers and transcriptomics represents a promising drug discovery tool for assessing anti-fibrotic compounds., (© 2024. The Author(s).)

The worldwide prevalence of non-alcoholic steatohepatitis (NASH) is increasing, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrolment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localise, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Digital pathology image analysis can phenotype liver fibrosis using histological traits that reflect collagen content, morphometry and architecture. Here, we aimed to calculate fibrosis severity scores to quantify these traits., Methods: Liver biopsy slides were categorised by Ishak stage and aetiology. We used a digital pathology technique to calculate four fibrosis severity scores: Architecture Composite Score (ACS), Collagen Composite Score (CCS), Morphometric Composite Score (MCS) and Phenotypic Fibrosis Composite Score (PH-FCS). We compared how these scores varied according to disease stage and aetiology., Results: We included 80 patients (40% female, mean age 59.0 years, mean collagen proportionate area 17.1%) with mild (F0-2, n = 28), moderate (F3-4, n = 17) or severe (F5-6, n = 35) fibrosis. All four aetiology independent scores corelated with collagen proportionate area (ACS: r p  = .512, CCS: r p  = .727, MCS: r p  = .777, PFCS: r = .772, p < .01 for all) with significant differences between moderate and severe fibrosis (p < .05). ACS increased primarily between moderate and severe fibrosis (by 95% to 226% depending on underlying aetiology), whereas MCS and CCS accumulation was more varied. We used 28 qFTs that distinguished between autoimmune- and alcohol-related liver disease to generate an MCS that significantly differed between mild and severe fibrosis for these aetiologies (p < .05)., Conclusions: We describe four aetiology-dependent and -independent severity scores that quantify fibrosis architecture, collagen content and fibre morphometry. This approach provides additional insight into how progression of architectural changes and accumulation of collagen may differ depending on underlying disease aetiology., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Metabolic dysfunction-associated steatohepatitis (MASH) can progress to cirrhosis and liver cancer. There are no approved medical therapies to prevent or reverse disease progression. Fructose and its metabolism in the liver play integral roles in MASH pathogenesis and progression. Here we focus on mannose, a simple sugar, which dampens hepatic stellate cell activation and mitigates alcoholic liver disease in vitro and in vivo . In the well-validated FAT-MASH murine model, oral mannose supplementation improved both liver steatosis and fibrosis at low and high doses, whether administered either at the onset of the model ("Prevention") or at week 6 of the 12-week MASH regimen ("Reversal"). The in vivo anti-fibrotic effects of mannose supplementation were validated in a second model of carbon tetrachloride-induced liver fibrosis. In vitro human and mouse primary hepatocytes revealed that the anti-steatotic effects of mannose are dependent on the presence of fructose, which attenuates expression of ketohexokinase (KHK), the main enzyme in fructolysis. KHK is decreased with mannose supplementation in vivo and in vitro, and overexpression of KHK abrogated the anti-steatotic effects of mannose. Our study identifies mannose as a simple, novel therapeutic candidate for MASH that mitigates metabolic dysregulation and exerts anti-fibrotic effects.

The profession of operating theater nurse in the French Armed Forces Medical Corps is often little-known. Called upon to serve in mainland France, but also deployed on overseas operations, they provide medical and surgical support to the French armed forces. Personal qualities - human, physical and technical - are essential to adapt to the environmental constraints of this isolated post., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Two-thirds of ballistic injuries result in severe limb damage. Damage Control Orthopaedic is a surgical strategy that makes it possible to save life, limb and function using simple mnemonic markers: 5minutes, 6hours, 7 days, 8 weeks and 9 months. The many players involved in this coherent care pathway, with its multiple surgical challenges, help to meet the challenge of comprehensive rehabilitation for orthopaedic ballistic injuries., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: "Do it yourself" (DIY) food-based fortification involves adding fortificants into everyday foods. It is a flexible solution that allows older people with reduced appetite to meet their nutritional needs., Objectives: The aims of the systematic review are (a) to describe DIY fortified recipes, (b) to evaluate their acceptability, and (c) to evaluate whether they are effective levers to improve nutritional outcomes in older people., Methods: A systematic search of 3 databases (Web of Science, PubMed, Scopus, last searched on January 2022) was undertaken. Main eligibility criteria include older adults aged ≥60 years living at home, in an institution or in hospital. Studies carried out for a specific medical condition or targeting only micronutrient fortification were excluded. After reviewing all titles/abstracts then full-text papers, key data were extracted and synthesized narratively. The quality of included studies was assessed using Kmet et al., Results: Of 21,493 papers extracted, 44 original studies were included (3,384 participants), with 31 reporting nutritional outcomes, 3 reporting acceptability outcomes and 10 reporting both nutritional and acceptability outcomes. The review highlighted a wide variety of DIY fortified recipes, with additional energy ranging from 23 to 850 kcal/d ( M  = 403; SE = 62) and/or protein ranging from 4 to 40 g/d ( M  = 19; SE = 2). Compared to a standard diet, DIY fortification seems to be a valuable strategy for increasing energy and protein intake in older people. However, no strong evidence was observed on the nutritional status., Implication for Future: Further acceptability studies are crucial to ensure that DIY fortified foods are palatable and thus have a significant impact on the nutritional status. In addition, it would be useful for studies to better describe DIY recipes. This information would result in a better understanding of the factors that maximize the impact of DIY fortification on nutritional outcomes. Study registration: PROSPERO no. CRD42021244689. Systematic review registration : PROSPERO: https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42021244689., Competing Interests: During the past 36 months, CSGA and CHU Dijon received research grants from OGUST, SAVEURS et VIE, and INSTITUT NUTRITION. CS-R received consulting fees from BEL FOOD and author fees from Correspondances en Métabolismes Hormones Diabètes et Nutrition. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Geny, Petitjean, Van Wymelbeke-Delannoy and Sulmont-Rossé.)

Metagenomics can be used to monitor the spread of antibiotic resistance genes (ARGs). ARGs found in databases such as ResFinder and CARD primarily originate from culturable and pathogenic bacteria, while ARGs from non-culturable and non-pathogenic bacteria remain understudied. Functional metagenomics is based on phenotypic gene selection and can identify ARGs from non-culturable bacteria with a potentially low identity shared with known ARGs. In 2016, the ResFinderFG v1.0 database was created to collect ARGs from functional metagenomics studies. Here, we present the second version of the database, ResFinderFG v2.0, which is available on the Center of Genomic Epidemiology web server (https://cge.food.dtu.dk/services/ResFinderFG/). It comprises 3913 ARGs identified by functional metagenomics from 50 carefully curated datasets. We assessed its potential to detect ARGs in comparison to other popular databases in gut, soil and water (marine + freshwater) Global Microbial Gene Catalogues (https://gmgc.embl.de). ResFinderFG v2.0 allowed for the detection of ARGs that were not detected using other databases. These included ARGs conferring resistance to beta-lactams, cycline, phenicol, glycopeptide/cycloserine and trimethoprim/sulfonamide. Thus, ResFinderFG v2.0 can be used to identify ARGs differing from those found in conventional databases and therefore improve the description of resistomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for the treatment of obesity as well. Semaglutide is postulated to be a promising candidate for the treatment of non-alcoholic steatohepatitis (NASH). Here, Ldlr-/-.Leiden mice received a fast-food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneous injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined, and hepatic transcriptome analysis was performed. In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p < 0.001) and inflammation (-73%, p < 0.001) and completely abolished microvesicular steatosis (-100%, p < 0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p < 0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for the treatment of hepatic steatosis and inflammation, while for the reversal of advanced fibrosis, combinations with other NASH agents may be necessary.

Background: Colistin is an antibiotic of last resort in the management of highly drug-resistant Enterobacterales infections. Travel to some destinations presents a high risk of acquiring multidrug-resistant Enterobacterales, but little data are available on the risk of acquiring colistin-resistant strains. Here, we use the VOYAG-R sample collection (2012-2013) in order to evaluate the rate of acquisition of colistin-resistant Enterobacterales, excluding species with intrinsic resistance (CRE), following travel to tropical regions., Methods: A total of 574 frozen stool samples of travellers returning from tropical regions were screened for colistin-resistant strains using ChromID Colistin R agar (bioMerieux®) after pre-enrichment culture with 1 mg/L of colistin. Genomes were obtained by Illumina sequencing and genetic determinants of colistin resistance (mutational events and mcr genes) were searched., Results: A total of 22 travellers (3.8%) acquired colistin-resistant Enterobacterales carrying an mcr gene. Acquisition rates varied between visited regions: 9.2% (18/195) for Asia (southeast Asia: 17/18), 2.2% (4/184) for Latin America (Peru: 4/4) and 0% from Africa (0/195). Acquired strains were predominantly Escherichia coli (92%) and carried mostly the mcr-1 variant (83%). Escherichia coli strains belonged mainly to commensal phylogroups A and B1, and were genetically highly diverse (5 non-clonal sequence type (ST)10 and 17 ST singletons). Only four non mcr colistin-resistant strains (two E. coli and two Enterobacter cloacae complex) were identified. Among all the strains, two also carried extended-spectrum beta-lactamase genes., Conclusions: Travel to tropical regions, and particularly to Southeast Asia, is a risk factor for the acquisition of mcr-carrying Enterobacterales. This study highlights the community dissemination of mcr in humans as early as 2012, 4 years prior to its first published description., (© International Society of Travel Medicine 2022. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Cyclodextrins, cyclic oligosaccharides with a hydrophobic cavity that form inclusion complexes with nonpolar molecules, can be used to functionalize other polysaccharides. Xanthan gum, locust bean gum or chitosan can be crosslinked using citric acid in the presence of β-cyclodextrin to produce insoluble matrices. In this work, polymeric foams based on those polysaccharides and saponin have been prepared using a green synthesis method to increase the porosity of the matrices. The saponin of soapbark ( Quillaja saponaria ) has been used to obtain foams using different procedures. The influence of the synthesis path on the porosity of the materials and their corresponding sorption capacities in the aqueous phase were evaluated., (Copyright © 2023, Petitjean and Isasi.)

Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3-neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.

Locust bean gum (LBG), a vegetable galactomannan extracted from carob tree seeds, is extensively used in the food industry as a thickening agent (E410). Its molecular conformation in aqueous solutions determines its solubility and rheological performance. LBG is an interesting polysaccharide also because of its synergistic behavior with other biopolymers (xanthan gum, carrageenan, etc.). In addition, this hydrocolloid is easily modified by derivatization or crosslinking. These LBG-related products, besides their applications in the food industry, can be used as encapsulation and drug delivery devices, packaging materials, batteries, and catalyst supports, among other biopharmaceutical and industrial uses. As the new derivatized or crosslinked polymers based on LBG are mainly biodegradable and non-toxic, the use of this polysaccharide (by itself or combined with other biopolymers) will contribute to generating greener products, considering the origin of raw materials used, the modification procedures selected and the final destination of the products.

Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology., (© 2022. The Author(s).)

Background: The composition of the digestive microbiota may be associated with outcome and infections in patients admitted to the intensive care unit (ICU). The dominance by opportunistic pathogens (such as Enterococcus) has been associated with death. However, whether this association remains all throughout the hospitalization are lacking., Methods: We performed a single-center observational prospective cohort study in critically ill patients admitted with severe SARS-CoV-2 infection. Oropharyngeal and rectal swabs were collected at admission and then twice weekly until discharge or death. Quantitative cultures for opportunistic pathogens were performed on oropharyngeal and rectal swabs. The composition of the intestinal microbiota was assessed by 16S rDNA sequencing. Oropharyngeal and intestinal concentrations of opportunistic pathogens, intestinal richness and diversity were entered into a multivariable Cox model as time-dependent covariates. The primary outcome was death at day 90., Results: From March to September 2020, 95 patients (765 samples) were included. The Simplified Acute Physiology Score 2 (SAPS 2) at admission was 33 [24; 50] and a Sequential Organ Failure Assessment score (SOFA score) at 6 [4; 8]. Day 90 all-cause mortality was 44.2% (42/95). We observed that the oropharyngeal and rectal concentrations of Enterococcus spp., Staphylococcus aureus and Candida spp. were associated with a higher risk of death. This association remained significant after adjustment for prognostic covariates (age, chronic disease, daily antimicrobial agent use and daily SOFA score). A one-log increase in Enterococcus spp., S. aureus and Candida spp. in oropharyngeal or rectal swabs was associated with a 17% or greater increase in the risk of death., Conclusion: We found that elevated oropharyngeal/intestinal Enterococcus spp. S. aureus and Candida spp. concentrations, assessed by culture, are associated with mortality, independent of age, organ failure, and antibiotic therapy, opening prospects for simple and inexpensive microbiota-based markers for the prognosis of critically ill SARS-CoV-2 patients., (© 2022. The Author(s).)

Thermal desorption is a method of soil treatment that heats soil in order to vaporize and extract contaminants. It relies on temperature measurements to assess the progress of the remediation, but these measurements are generally not numerous because of cost constraints. This paper proposes a low-complexity method to interpolate sparse temperature data over the whole site to generate visual representations that ease the treatment follow-up. The temperatures of the points that are not monitored are approximated by a weighted average of the 3 closest measurements, then a third-degree polynomial is fitted to the data via a finite element method. The resulting approximations yield an overall Root Mean Square Error (RMSE) of the temperature estimation of 35 K, which allows for realistic representations of the temperature at each point of the map with reduced sensor deployment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Polysaccharides such as xanthan, locust bean gum or chitosan are easily crosslinked and purified using citric acid in an ecofriendly process. In order to achieve an improved sorption capability towards hydrophobic solutes, β-cyclodextrin, a cyclic oligosaccharide, and lignin, a natural aromatic polymer, are incorporated in the same process. Once crosslinked, the influence of these on the sorption capacities towards model solutes has been assessed by comparing the sorption isotherms of matrices with or without the hydrophobic modifications. The sorption capacities of these materials for different phenolic compounds have also been tested to ascertain their efficiencies as a function of their affinities to β-cyclodextrin cavities and/or their partition coefficients. In addition, these functionalized carbohydrate matrices were successfully characterized by principal component analysis, which is a useful tool to select the most appropriate polymers to interact with a specific molecule., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Characterizing the effect of mutations is key to understand the evolution of protein sequences and to separate neutral amino-acid changes from deleterious ones. Epistatic interactions between residues can lead to a context dependence of mutation effects. Context dependence constrains the amino-acid changes that can contribute to polymorphism in the short term, and the ones that can accumulate between species in the long term. We use computational approaches to accurately predict the polymorphisms segregating in a panel of 61,157 Escherichia coli genomes from the analysis of distant homologues. By comparing a context-aware Direct-Coupling Analysis modelling to a non-epistatic approach, we show that the genetic context strongly constrains the tolerable amino acids in 30% to 50% of amino-acid sites. The study of more distant species suggests the gradual build-up of genetic context over long evolutionary timescales by the accumulation of small epistatic contributions., (© 2022. The Author(s).)

Carbapenems are considered last-line beta-lactams for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, their activity is compromised by the rising prevalence of carbapenemase-producing Enterobacterales (CPE), which are especially marked in the Indian subcontinent. In Pakistan, previous reports have warned about the possible spread of CPE in the community, but data are still partial. This study was carried out to analyse the prevalence of CPE, the genetic characterisation, and phylogenetic links among the spreading CPE in the community. In this cohort study, we collected 306 rectal swabs from patients visiting Benazir Bhutto hospital, Rawalpindi. CPEs were screened by using ertapenem-supplemented MacConkey agar. Identification was performed by using conventional biochemical tests, and genomes were sequenced using Illumina chemistry. Antibiotic resistance genes, plasmid incompatibility groups, and Escherichia coli phylogroups were determined in silico. Sequence types were determined by using MLST tool. The prevalence of CPE carriage observed was 14.4% (44/306 samples). The most common carbapenemase-encoding gene was bla-NDM-5 (n = 58) followed by blaNDM-1 (n = 7), blaNDM (non-assigned variant, n = 4), blaOXA-181 (n = 3), blaOXA-232 (n = 3) and blaNDM-7 (n = 1). Most of the CPE were E. coli (55/64, 86%), and the genomic analysis revealed a pauciclonal diffusion of E. coli with ST167 (n = 14), 405 (n = 10), 940 (n = 8), 648 (n = 6) and 617 (n = 5). We obtained a second sample from 94 patients during their hospital stay in whom carriage was negative at admission and found that 7 (7.4%) acquired a CPE. Our results indicate that the prevalence of CPE carriage in the Pakistani urban community was high and driven by the dissemination of some E. coli clones, with ST167 being the most frequent. The high CPE carriage in the community poses a serious public health threat and calls for implementation of adequate preventive measures., Competing Interests: The authors have declared that no competing interests exist.

Background: The current context of Covid-19 pandemic has broadened mask use., Objectives: Evaluate the impact of wearing a surgical mask on sense of smell by comparing the results of sniffin' sticks test (SST) with and without a surgical mask and evaluate the feasibility of practicing SST with a mask., Material and Methods: A crossover prospective comparative study between two groups of volunteers. The results of SST with a mask were compared to the results without a mask: group 1 first performed SST with a surgical mask and then one week later performed SST without a mask, while group 2 started without a mask., Results: Twenty volunteers were included. In group 1 and 2, all the subjects, except one, had a significantly better total score (TDI) without a mask. The average TDI difference score with and without a mask, was inferior to 5. 8/20 (40%) subjects had a TDI difference superior to 5 with and without mask, while 4/20 (20%) were normosmic without a mask, while being recategorized as hyposmic with a mask., Conclusions and Significance: Wearing a surgical mask may reduce the sense of smell, in a cohort of normosmic patients. Further larger studies must be conducted in hyposmic subjects.

Multidrug-resistant Enterobacterales , including carbapenemase producers, are currently spreading in health care facilities and the community. The Bichat Claude Bernard hospital in Paris faced a prolonged NDM-producing Enterobacterales (NDM-CPE) outbreak. Whole-genome sequencing (WGS) was performed on all isolated NDM-CPE to evaluate its benefits for outbreak surveillance and comprehension. All NDM-CPE isolates collected during the outbreak period (August 2016 to January 2018) were sequenced using the Illumina NextSeq platform. Gene content and core genomes were compared. Genomics results underwent epidemiological analysis which classified NDM-CPE cases as imported (positive sample during the 48 h after admission), hospital acquired, or uncertain. Over the epidemic period, 61 patients were colonized or infected with 81 distinct NDM-CPE isolates. Klebsiella pneumoniae was the most common species ( n  = 52, 64%), followed by Escherichia coli (13.5%) and other species (22.5%). In all, 43/52 (83%) K. pneumoniae isolates were clonal (≤18 single nucleotide polymorphisms [SNPs] except for three isolates) and belonged to ST307. The IncFIIK [K2:A-/B-] plasmid carrying bla NDM-1 present in all ST307 K. pneumoniae isolates was also detected in 18 other NDM-CPE isolates. Additionally, eight clonal ST144 Klebsiella oxytoca (≤18 SNPs) isolates lacking the epidemic plasmid were observed. The WGS analyses confirmed the acquired and imported cases except for two patients and resolved uncertain cases, which all turned out to be hospital acquisitions. WGS coupled with epidemiological analysis unraveled three epidemic phenomena: mainly the spread of a clonal ST307 K. pneumoniae strain and its conjugative plasmid carrying bla NDM-1 but also the unexpected clonal spread of an ST144 K. oxytoca strain. IMPORTANCE Carbapenemase-producing Enterobacterales (CPE) can spread and cause outbreaks in health care facilities, resulting in increased lengths of stay and morbidity. Control of outbreaks requires epidemiological surveillance, usually based on microbiological screening and patient follow-up. These data are sometimes insufficient to identify the routes of dissemination. There is therefore a need for more accurate tools such as whole-genome sequencing (WGS), which allows comparison of isolates but also plasmids carrying resistance with a high definition. In this work, we retrospectively sequenced the genomes of all NDM-producing Enterobacterales isolated during a prolonged NDM outbreak in our hospital. We demonstrated the value of combining WGS with epidemiological data that unveiled the multiple mechanisms of dissemination involved in the outbreak and confirmed transmission cases. This work reinforces the potential of WGS in outbreak surveillance and suggests that it could improve outbreak control if used in real time by confirming transmission cases more rapidly.

Bone and joint infections (BJIs) are complex infections that require precise microbiological documentation to optimize antibiotic therapy. Currently, diagnosis is based on microbiological culture, sometimes complemented by amplification and sequencing of the 16S rDNA gene. Clinical metagenomics (CMg), that is, the sequencing of the entire nucleic acids in a sample, was previously shown to identify bacteria not detected by conventional methods, but its actual contribution to the diagnosis remains to be assessed, especially with regard to 16S rDNA sequencing. In the present study, we tested the performance of CMg in 34 patients (94 samples) with suspected BJIs, as compared to culture and 16S rDNA sequencing. A total of 94 samples from 34 patients with suspicion of BJIs, recruited from two sites, were analyzed by (i) conventional culture, (ii) 16S rDNA sequencing (Sanger method), and (iii) CMg (Illumina Technology). Two negative controls were also sequenced by CMg for contamination assessment. Based on the sequencing results of negative controls, 414 out of 539 (76.7%) bacterial species detected by CMg were considered as contaminants and 125 (23.2%) as truly present. For monomicrobial infections (13 patients), the sensitivity of CMg was 83.3% as compared to culture, and 100% as compared to 16S rDNA. For polymicrobial infections (13 patients), the sensitivity of CMg was 50% compared to culture, and 100% compared to 16S rDNA. For samples negative in culture (8 patients, 21 samples), CMg detected 11 bacteria in 10 samples from 5 different patients. In 5/34 patients, CMg brought a microbiological diagnosis where conventional methods failed, and in 16/34 patients, CMg provided additional information. Finally, 99 antibiotic resistance genes were detected in 24 patients (56 samples). Provided sufficient genome coverage (87.5%), a correct inference of antibiotic susceptibility was achieved in 8/8 bacteria (100%). In conclusion, our study demonstrated that the CMg provides complementary and potentially valuable data to conventional methods of BJIs diagnosis., Competing Interests: GGu and GGe were employed by bioMérieux SA. SF was employed by Genoscreen. ER received consulting fees from Illumina and Pathoquest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 d’Humières, Gaïa, Gueye, de Lastours, Leflon-Guibout, Maataoui, Duprilot, Lecronier, Rousseau, Gamany, Lescure, Senard, Deconinck, Dollat, Isernia, Le Hur, Petitjean, Nazimoudine, Le Gac, Chalal, Ferreira, Lazarevic, Guigon, Gervasi, Armand-Lefèvre, Schrenzel and Ruppé.)

Antimicrobial resistance is a major public health concern worldwide affecting humans, animals and the environment. However, data is lacking especially in developing countries. Thus, the World Health Organization developed a One-Health surveillance project called Tricycle focusing on the prevalence of ESBL-producing Escherichia co li in humans, animals, and the environment. Here we present the first results of the human community component of Tricycle in Madagascar. From July 2018 to April 2019, rectal swabs from 492 pregnant women from Antananarivo, Mahajanga, Ambatondrazaka, and Toamasina were tested for ESBL- E. coli carriage. Demographic, sociological and environmental risk factors were investigated, and E. coli isolates were characterized (antibiotic susceptibility, resistance and virulence genes, plasmids, and genomic diversity). ESBL- E. coli prevalence carriage in pregnant women was 34% varying from 12% (Toamasina) to 65% (Ambatondrazaka). The main risk factor associated with ESBL -E. coli carriage was the rainy season (OR = 2.9, 95% CI 1.3-5.6, p = 0.009). Whole genome sequencing was performed on 168 isolates from 144 participants. bla CTX-M-15 was the most frequent ESBL gene (86%). One isolate was resistant to carbapenems and carried the bla NDM- 5 gene. Most isolates belonged to commensalism associated phylogenetic groups A, B1, and C (90%) and marginally to extra-intestinal virulence associated phylogenetic groups B2, D and F (10%). Multi locus sequence typing showed 67 different sequence types gathered in 17 clonal complexes (STc), the most frequent being STc10/phylogroup A (35%), followed distantly by the emerging STc155/phylogroup B1 (7%), STc38/phylogroup D (4%) and STc131/phylogroup B2 (3%). While a wide diversity of clones has been observed, SNP analysis revealed several genetically close isolates ( n = 34/168) which suggests human-to-human transmissions. IncY plasmids were found with an unusual prevalence (23%), all carrying a bla CTX-M-15 . Most of them (85%) showed substantial homology (≥85%) suggesting a dissemination of IncY ESBL plasmids in Madagascar. This large-scale study reveals a high prevalence of ESBL- E. coli among pregnant women in four cities in Madagascar associated with warmth and rainfall. It shows the great diversity of E. coli disseminating throughout the country but also transmission of specific clones and spread of plasmids. This highlights the urgent need of public-health interventions to control antibiotic resistance in the country., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Milenkov, Rasoanandrasana, Rahajamanana, Rakotomalala, Razafindrakoto, Rafalimanana, Ravelomandranto, Ravaoarisaina, Westeel, Petitjean, Mullaert, Clermont, Raskine, Samison, Endtz, Andremont, Denamur, Komurian-Pradel and Armand-Lefevre.)

Repetitive transcranial magnetic stimulation (rTMS) is a promising, innovative, and non-invasive therapy used clinically. Efficacy of rTMS has been demonstrated to ameliorate psychiatric disorders and neuropathic pain through neuromodulation of affected neural circuits. However, little is known about the mechanisms and the specific neural circuits via which rTMS facilitates these functional effects. The aim of this study was to begin revealing the mechanisms by which rTMS may tap into existing neural circuits, by using a well characterized spinal motor circuit - the phrenic circuit. Here we hypothesized that rTMS can be used to enhance phrenic motoneuron excitability in anesthetized Sprague Dawley rats. Multiple acute rTMS protocols were used revealing 10 Hz rTMS protocol induced a robust, long-lasting increase in phrenic motoneuron excitability, functionally evaluated by diaphragm motor evoked potentials (59.1 ± 21.1 % of increase compared to baseline 60 min after 10 Hz protocol against 6.0 ± 5.8 % (p = 0.007) for Time Control, -5.8 ± 7.4 % (p < 0.001) for 3 Hz, and 5.2 ± 12.5 % (p = 0.008) for 30 Hz protocols). A deeper analyze allowed to discriminate "responder" and "non-responder" subgroups among 10 Hz rTMS treated animals. Intravenous injections of GABA A and GABA B receptor agonists prior to 10 Hz rTMS treatment, abolished the enhanced phrenic motoneuron excitability, suggesting GABAergic input plays a mechanistic role in rTMS-induced phrenic excitability. These data demonstrate that a single high frequency rTMS protocol at 10 Hz increases phrenic motoneuron excitability, mediated by a local GABAergic "disinhibition". By understanding how rTMS can be used to affect neural circuits non-invasively we can begin to harness the therapeutic potential of this neuromodulatory strategy to promote recovery after disease or injury to the central nervous system., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The biological features that allow a pathogen to survive in the hospital environment are mostly unknown. The extinction of bacterial epidemics in hospitals is mostly attributed to changes in medical practice, including infection control, but the role of bacterial adaptation has never been documented. We analysed a collection of Pseudomonas aeruginosa isolates belonging to the Besançon Epidemic Strain (BES), responsible for a 12year nosocomial outbreak, using a genotype-to-phenotype approach. Bayesian analysis estimated the emergence of the clone in the hospital 5 years before its opening, during the creation of its water distribution network made of copper. BES survived better than the reference strains PAO1 and PA14 in a copper solution due to a genomic island containing 13 metal-resistance genes and was specifically able to proliferate in the ubiquitous amoeba Vermamoeba vermiformis . Mutations affecting amino-acid metabolism, antibiotic resistance, lipopolysaccharide biosynthesis, and regulation were enriched during the spread of BES. Seven distinct regulatory mutations attenuated the overexpression of the genes encoding the efflux pump MexAB-OprM over time. The fitness of BES decreased over time in correlation with its genome size. Overall, the resistance to inhibitors and predators presumably aided the proliferation and propagation of BES in the plumbing system of the hospital. The pathogen further spread among patients via multiple routes of contamination. The decreased prevalence of patients infected by BES mirrored the parallel and convergent genomic evolution and reduction that affected bacterial fitness. Along with infection control measures, this may have participated in the extinction of BES in the hospital setting.

Escherichia coli is a ubiquitous bacterium that has been widely exposed to antibiotics over the last 70 years. It has adapted by acquiring different antibiotic-resistance genes (ARGs), the census of which we aim to characterize here. To do so, we analysed 70 301 E. coli genomes obtained from the EnteroBase database and detected 1 027 651 ARGs using the AMRFinder, Mustard and ResfinderFG ARG databases. We observed a strong phylogroup and clonal lineage specific distribution of some ARGs, supporting the argument for epistasis between ARGs and the strain genetic background. However, each phylogroup had ARGs conferring a similar antibiotic class resistance pattern, indicating phenotypic adaptive convergence. The G+C content or the type of ARG was not associated with the frequency of the ARG in the database. In addition, we identified ARGs from anaerobic, non- Proteobacteria bacteria in four genomes of E. coli , supporting the hypothesis that the transfer between anaerobic bacteria and E. coli can spontaneously occur but remains exceptional. In conclusion, we showed that phylum barrier and intra-species phylogenetic history are major drivers of the acquisition of a resistome in E. coli .

Travel to tropical regions is associated with high risk of acquiring extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) that are typically cleared in less than 3 months following return. The conditions leading to persistent carriage that exceeds 3 months in some travellers require investigation. Whole-genome sequencing (Illumina MiSeq) was performed on the 82 ESBL-E isolates detected upon return and 1, 2, 3, 6 and 12 months later from the stools of 11 long-term (>3 months) ESBL-E carriers following travel abroad. One to five different ESBL Escherichia coli strains were detected per traveller upon return, and this diminished to one after 3 months. Long-term carriage was due to the presence of the same ESBL E. coli strain, for more than 3 months, in 9 out of 11 travellers, belonging to epidemic sequence type complexes (STc 10, 14, 38, 69, 131 and 648). The mean carriage duration of strains belonging to phylogroups B2/D/F, associated with extra-intestinal virulence, was higher than that for commensal-associated A/B1/E phylogroups (3.5 vs 0.5 months, P =0.021). Genes encoding iron capture systems ( fyuA, irp ), toxins ( senB , sat ), adhesins ( flu, daaF, afa/nfaE , pap , ecpA ) and colicin ( cjrA ) were more often present in persistent strains than in transient ones. Single-nucleotide polymorphism (SNP) analysis in persistent strains showed a maximum divergence of eight SNPs over 12 months without signs of adaptation. Genomic plasticity was observed during the follow-up with the loss or gain of mobile genetic elements such as plasmids, integrons and/or transposons that may contain resistance genes at different points in the follow-up. Long-term colonization of ESBL-E following travel is primarily due to the acquisition of E. coli strains belonging to epidemic clones and harbouring 'virulence genes', allowing good adaptation to the intestinal microbiota.

Three different polysaccharides, xanthan gum, chitosan and locust bean gum, were crosslinked with or without β-cyclodextrin, using citric acid in different ratios, to create 'green' hydrogel matrices. The crosslinking of these polysaccharides was produced through an inexpensive and innocuous solvent-free synthesis process. A favorable swelling behavior of the hydrophilic matrices facilitates the sorption of the solutes tested. Interestingly, the amount of β-cyclodextrin groups is not the only factor to yield the best sorption capability for hydrophobic model molecules: polysaccharides themselves also influence the sorption depending on their characteristic functional groups, the conformation of their chains and, as mentioned above, their degrees of swelling. In order to ascertain the effect of the polysaccharides on the sorption capabilities of a model sorbate (1-naphthol), isotherms using a wide range of solute concentrations were analyzed, and the Hill equation yielded the best fitting results and provided some insight into the mechanisms of interaction., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We report a case of an infective endocarditis caused by a Thalassospira sp. in a 53-year-old man with pre-existing valvular lesions and living in French Polynesia as a fisherman. The strain was identified with DNA-sequecing methods while it was not by mass spectrometry., (© 2021 The Author(s).)

Obstructive sleep apnea (OSA) syndrome is a multi-factorial disorder. Recently identified pathophysiological contributing factors include airway collapsibility, poor pharyngeal muscle responsiveness, a low arousal threshold, and a high loop gain. Understanding the pathophysiology is of pivotal importance to select the most effective treatment option. It is well documented that conventional treatments (continuous positive airway pressure (CPAP), upper airway surgery, and dental appliance) may not always be successful in the presence of non-anatomical traits, especially in mild to moderate OSA. Orofacial myofunctional therapy (OMT) consists of isotonic and isometric exercises targeted to oral and oropharyngeal structures, with the aim of increasing muscle tone, endurance, and coordinated movements of pharyngeal and peripharyngeal muscles. Recent studies have demonstrated the efficacy of OMT in reducing snoring, apnea-hypopnea index, and daytime sleepiness, and improving oxygen saturations and sleep quality. Myofunctional therapy helps to reposition the tongue, improve nasal breathing, and increase muscle tone in pediatric and adult OSA patients. Studies have shown that OMT prevents residual OSA in children after adenotonsillectomy and helps adherence in CPAP-treated OSA patients. Randomized multi-institutional studies will be necessary in the future to determine the effectiveness of OMT in a single or combined modality targeted approach in the treatment of OSA. In this narrative review, we present up-to-date literature data, focusing on the role of OSA pathophysiology concepts concerning pharyngeal anatomical collapsibility and muscle responsiveness, underlying the response to OMT in OSA patients.

Background: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients., Methods: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks., Results: Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios., Conclusion: Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF., Competing Interests: Declaration of competing interest François Briand, Emmanuel Brousseau, Natalia Breyner, Mélanie Bouchet and Thierry Sulpice are employees of Physiogenex. Julie Maupoint, Caroline Dubroca, Clément Costard and Thierry Sulpice are employees of Cardiomedex. François Briand, Rémy Burcelin and Thierry Sulpice have shares in Physiogenex. Thierry Sulpice and Rémy Burcelin have shares in Cardiomedex. Audrey Chabrat and Virgile Richard are employees of Sciempath Labo. Mathieu Petitjean and Li Chen are employees of PharmaNest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pockets and interfaces to explore the impacts of these induced structural deformations on these two regions. Our results showed that one mutation could induce large structural rearrangements in side-chain and backbone atoms of mutated residue, in its vicinity or further. Structural deformations observed in side-chain atoms are frequent and of greater magnitude, that confirms that to fight drug resistance, interactions with backbone atoms should be favored. We showed that these observed structural deformations modify the conformation, volume, and hydrophobicity of the binding pocket and the composition and size of the PR2 interface. These results suggest that resistance mutations could alter ligand binding by modifying pocket properties and PR2 stability by impacting its interface. Our results reinforce the understanding of the effects of mutations that occurred in PR2 and the different mechanisms of PR2 resistance.