Stem Cell Res

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of the liver metabolism due to functional deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in overproduction of oxalate which complexes with calcium to form insoluble calcium-oxalate salts in urinary tracts, ultimately leading to end-stage renal disease. Currently, the only curative treatment for PH1 is combined liver-kidney transplantation, which is limited by donor organ shortage and lifelong requirement for immunosuppression. Transplantation of genetically modified autologous hepatocytes is an attractive therapeutic option for PH1. However, the use of fresh primary hepatocytes suffers from limitations such as organ availability, insufficient cell proliferation, loss of function, and the risk of immune rejection. We developed patient-specific induced pluripotent stem cells (PH1-iPSCs) free of reprogramming factors as a source of renewable and genetically defined autologous PH1-hepatocytes. We then investigated additive gene therapy using a lentiviral vector encoding wild-type AGT under the control of the liver-specific transthyretin promoter. Genetically modified PH1-iPSCs successfully provided hepatocyte-like cells (HLCs) that exhibited significant AGT expression at both RNA and protein levels after liver-specific differentiation process. These results pave the way for cell-based therapy of PH1 by transplantation of genetically modified autologous HLCs derived from patient-specific iPSCs

CD63-GPC1-Positive Exosomes Coupled with CA19-9 Offer Good Diagnostic Potential for Resectable Pancreatic Ductal Adenocarcinoma

Tumor-released extracellular vesicles (EVs) contain tumor-specific cargo distinguishing them from healthy EVs, and making them eligible as circulating biomarkers. Glypican 1 (GPC1)-positive exosome relevance as liquid biopsy elements is still debated. We carried out a prospective study to quantify GPC1-positive exosomes in sera from pancreatic ductal adenocarcinoma (PDAC) patients undergoing up-front surgery, as compared to controls including patients without cancer history and patients displaying pancreatic preneoplasic lesions. Sera were enriched in EVs, and exosomes were pulled down with anti-CD63 coupled magnetic beads. GPC1-positive bead percentages determined by flow cytometry were significantly higher in PDAC than in the control group. Diagnosis accuracy reached 78% (sensitivity 64% and specificity 90%), when results from peripheral and portal blood were combined. In association with echo-guided-ultrasound-fine-needle-aspiration (EUS-FNA) negative predictive value was 80% as compared to 33% for EUS-FNA only. This approach is clinically relevant as a companion test to the already available diagnostic tools, since patients with GPC1-positive exosomes in peripheral blood showed decreased tumor free survival

Covichem: A biochemical severity risk score of COVID-19 upon hospital admission

Clinical and laboratory predictors of COVID-19 severity are now well described and combined to propose mortality or severity scores. However, they all necessitate saturable equipment such as scanners, or procedures difficult to implement such as blood gas measures. To provide an easy and fast COVID-19 severity risk score upon hospital admission, and keeping in mind the above limits, we sought for a scoring system needing limited invasive data such as a simple blood test and co-morbidity assessment by anamnesis. A retrospective study of 303 patients (203 from Bordeaux University hospital and an external independent cohort of 100 patients from Paris Pitié-Salpêtrière hospital) collected clinical and biochemical parameters at admission. Using stepwise model selection by Akaike Information Criterion (AIC), we built the severity score Covichem. Among 26 tested variables, 7: obesity, cardiovascular conditions, plasma sodium, albumin, ferritin, LDH and CK were the independent predictors of severity used in Covichem (accuracy 0.87, AUROC 0.91). Accuracy was 0.92 in the external validation cohort (89% sensitivity and 95% specificity). Covichem score could be useful as a rapid, costless and easy to implement severity assessment tool during acute COVID-19 pandemic waves

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631

Reuse of medical face masks in domestic and community settings without sacrificing safety: Ecological and economical lessons from the Covid-19 pandemic

The need for personal protective equipment increased exponentially in response to the Covid-19 pandemic. To cope with the mask shortage during springtime 2020, a French consortium was created to find ways to reuse medical and respiratory masks in healthcare departments. The consortium addressed the complex context of the balance between cleaning medical masks in a way that maintains their safety and functionality for reuse, with the environmental advantage to manage medical disposable waste despite the current mask designation as single-use by the regulatory frameworks. We report a Workflow that provides a quantitative basis to determine the safety and efficacy of a medical mask that is decontaminated for reuse. The type IIR polypropylene medical masks can be washed up to 10 times, washed 5 times and autoclaved 5 times, or washed then sterilized with radiations or ethylene oxide, without any degradation of their filtration or breathability properties. There is loss of the antiprojection properties. The Workflow rendered the medical masks to comply to the AFNOR S76-001 standard as “type 1 non-sanitory usage masks”. This qualification gives a legal status to the Workflow-treated masks and allows recommendation for the reuse of washed medical masks by the general population, with the significant public health advantage of providing better protection than cloth-tissue masks. Additionally, such a legal status provides a basis to perform a clinical trial to test the masks in real conditions, with full compliance with EN 14683 norm, for collective reuse. The rational reuse of medical mask and their end-of-life management is critical, particularly in pandemic periods when decisive turns can be taken. The reuse of masks in the general population, in industries, or in hospitals (but not for surgery) has significant advantages for the management of waste without degrading the safety of individuals wearing reused masks

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Long-lasting Recovery from Permanent Homonymous Hemianopia after Migraine

Vision can occasionally improve spontaneously in patients suffering from homonymous hemianopia. However, this prognosis becomes poor after 3 months from injury

Pharmacocinétique de l'acétonide de triamcinolone dans le liquide synovial, le plasma et les urines chez le cheval de sport en vue du contrôle antidopage

Notre travail de thèse a permis d'étudier la pharmacocinétique de l'acétonide de triamcinolone dans le liquide synovial, le plasma et les urines après une administration intra-articulaire chez le cheval de sport. Cinq chevaux ont reçu une administration unique par voie intra-articulaire d'acétonide de triamcinolone (Kénacort 40 mg suspension injectable ®, Bristol-Myers Squibb) à la dose de 12 mg. Cet essai doit être considéré comme une étude pilote ayant permis de préciser les objectifs à atteindre en matière analytique et pour la réalisation des futurs plans expérimentaux à réaliser afin de déterminer les temps de détection pour un contrôle des effets pharmacologiques. Aucune recommandation ne peut être faite à partir de ce travail quant au temps de détection à proposer aux vétérinaires praticiens.TOULOUSE-EN Vétérinaire (315552301) / SudocTOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Performances de reproduction des juments en suivi dans le cadre d'une clientèle équine du Sud-Ouest de la France

L’objectif de cette étude est d’analyser les performances de reproduction de juments suivies dans le cadre d’une clientèle type chevaux de selle d’un cabinet vétérinaire équin pluridisciplinaire du Sud-Ouest de la France, sur la période de 2012 à 2016, de façon à mettre en évidence des facteurs de variation. Sur les 207 cycles utilisés au cours de 118 saisons de reproduction de 98 juments, le mode de reproduction le plus utilisé a été l’IA en semence congelée (55 %) et l’IA en semence réfrigérée (40 %). Le taux de gestation en fin de saison a été de 66,4% et la fertilité par cycle a été de 46 %, ce qui est comparable aux données françaises. Le nombre total de chaleurs exploitées par jument gravide en fin de saison a été de 2,7. Les juments subfertiles (nécessitant plus de deux cycles exploités sur la saison) représentent 19,6% des femelles mises à la reproduction. La gestion de la reproduction et le recours aux traitements de maîtrise des cycles sont globalement conformes aux recommandations usuelles et permettent de garantir une fertilité optimale. Cependant, l’intérêt de l’insémination profonde semble limité, ce qui pourrait remettre en cause son utilisation. Au contraire, l’IA post-ovulation pourrait être davantage utilisée car elle permet de réduire le nombre d’IA, même si elle nécessite un suivi régulier des juments. Dans notre étude, l’âge des juments et les endométrites ont constitué les causes majeures de dégradation des performances de reproduction. Ainsi, les juments atteintes d’endométrite ont eu deux fois moins de chance d’être gravides sur un cycle que les femelles saines. Dans le cadre d’un cabinet vétérinaire, une analyse annuelle simplifiée des performances de reproduction des juments pourrait permettre aux vétérinaires d’évaluer de manière objective les stratégies de gestion de la reproduction et, éventuellement de proposer des voies d’amélioration

Nitrates : De l'azote minéral à la matière organique

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