Objective
Evaluation of relevance and feasibility of universal newborn congenital cytomegalovirus infection (cCMVI) screening in saliva.
Design
Retrospective, population‐based cohort study.
Setting
...Clamart, France, 2016–2020.
Population
All neonates born consecutively in our level III maternity unit.
Methods
CMV PCR in saliva for all neonates at birth, and, if positive, CMV PCR in urine to confirm or exclude cCMVI. Prospective and retrospective characterisation of maternal infections. ROC curve analysis to assess saliva PCR performances. Acceptability of screening among staff members evaluated by a survey.
Main outcome measures
Number of cCMVI neonates; number of expected and unexpected cCMVI.
Results
Among 15 341 tested neonates, 63 had cCMVI (birth prevalence of 0.4%, 95% CI 0.3–0.5). In 50% of cases, maternal infection was a non‐primary infection (NPI) during pregnancy. cCMVI was expected or suspected (maternal primary infection PI, antenatal or neonatal signs) in 24/63 neonates (38%), and unexpected in 39/63 neonates (62%). The best CMV saliva threshold to predict cCMVI was 356 (2.55 log) copies/ml 95% CI 2.52 log–3.18 log, with an area under the ROC curve of 0.97. Over 90% of the 72 surveyed staff members reported that the screening was easy and quick. No parent refused the screening.
Conclusions
Universal screening for cCMVI with CMV PCR on saliva samples is feasible and highly acceptable to parents and healthcare providers. Over half (62%) of the cases had no prenatal/neonatal signs of cCMVI or a maternal history of CMV infection during pregnancy and would probably not have been diagnosed without universal screening.
Tweetable
In 62% of congenital cytomegalovirus infection cases, only universal neonatal screening in saliva can detect infection.
Tweetable
In 62% of congenital cytomegalovirus infection cases, only universal neonatal screening in saliva can detect infection.
Essentials Nitric oxide synthesis controls protein disulfide isomerase (PDI) function. Nitric oxide (NO) modulation of PDI controls endothelial thrombogenicity. S-nitrosylated PDI inhibits platelet ...function and thrombosis. Nitric oxide maintains vascular quiescence in part through inhibition of PDI. SUMMARY: Background Protein disulfide isomerase (PDI) plays an essential role in thrombus formation, and PDI inhibition is being evaluated clinically as a novel anticoagulant strategy. However, little is known about the regulation of PDI in the vasculature. Thiols within the catalytic motif of PDI are essential for its role in thrombosis. These same thiols bind nitric oxide (NO), which is a potent regulator of vessel function. To determine whether regulation of PDI represents a mechanism by which NO controls vascular quiescence, we evaluated the effect of NO on PDI function in endothelial cells and platelets, and thrombus formation in vivo. Aim To assess the effect of S-nitrosylation on the regulation of PDI and other thiol isomerases in the vasculature. Methods and results The role of endogenous NO in PDI activity was evaluated by incubating endothelium with an NO scavenger, which resulted in exposure of free thiols, increased thiol isomerase activity, and enhanced thrombin generation on the cell membrane. Conversely, exposure of endothelium to NO
carriers or elevation of endogenous NO levels by induction of NO synthesis resulted in S-nitrosylation of PDI and decreased surface thiol reductase activity. S-nitrosylation of platelet PDI inhibited its reductase activity, and S-nitrosylated PDI interfered with platelet aggregation, α-granule release, and thrombin generation on platelets. S-nitrosylated PDI also blocked laser-induced thrombus formation when infused into mice. S-nitrosylated ERp5 and ERp57 were found to have similar inhibitory activity. Conclusions These studies identify NO as a critical regulator of vascular PDI, and show that regulation of PDI function is an important mechanism by which NO maintains vascular quiescence.
Résumé
Résumé
Aujourd’hui en France, près d’une personne sur 850 âgée de 20 à 45 ans a été soignée pour un cancer pendant l’enfance ou l’adolescence. Les perspectives actuelles doivent donc ...s’orienter vers la réduction des séquelles et des effets secondaires à long terme. L’hypofertilité ou la stérilité en font partie. Cette préoccupation a inspiré et motivé cette recherche. Elle concerne d’une part les pratiques médicales pédiatriques pour transmettre l’information au sujet des risques pour la fertilité et proposer une cryopréservation de sperme pour les adolescents pubères, et d’autre part, l’expérience subjective d’anciens patients concernant cette information et cette proposition.
Objectifs
État des lieux des pratiques médicales confrontées à l’expérience des patients afin de dégager des recommandations et de développer un livret d’information pour les adolescents.
Méthodes
Un questionnaire anonyme, portant les indications de sexe et d’âge, a été adressé aux 79 pédiatres seniors exerçant au sein des services d’oncohématologie pédiatrique. Cinquante-six observations de 27 centres ont pu être exploitées au niveau statistique, soit 70,9 % de taux de participation individuelle et 84,4 % de taux de participation des centres.
Résultats
Quatre-vingt-seize pour cent des praticiens interrogés proposent une cryoconservation de sperme dans plus de 50 % des cas aux patients atteints par la maladie de Hodgkin. En revanche, près de 62 % la proposent « jamais–rarement » ou « parfois » aux patients atteints de tumeurs du système nerveux central (SNC). Seuls 29 % feront cette proposition « très souvent–toujours » à ces patients. La grande majorité des pédiatres informe les parents en priorité et leur demande leur avis avant d’évoquer la question avec l’adolescent, alors que 85 % de ces médecins jugent que c’est à l’adolescent de prendre une décision. Peu de ressources semblent mobilisables pour les médecins en difficulté. En effet, seulement 24,1 % d’entre eux travaillent en collaboration avec une personne formée à la question de la préservation de la fertilité, et ce sont en grande majorité des pédiatres de sexe féminin. 85,2 % n’ont aucun document à remettre à l’adolescent en soutien à la consultation. Près de 60 % des médecins pensent qu’une consultation avec un psychologue ou un pédopsychiatre devrait être proposée de façon systématique.
Conclusion
Les enjeux se situent donc dans la formation continue des médecins-pédiatres ainsi que dans le travail pluridisciplinaire et transdisciplinaire pour optimiser les pratiques.
Efficient differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to a variety of lineages requires step-wise approaches replicating the key commitment stages found ...during embryonic development. Here we show that expression of PdgfR-α segregates mouse ESC-derived Flk-1 mesoderm into Flk-1
+PdgfR-α
+ cardiac and Flk-1
+PdgfR-α
− hematopoietic subpopulations. By monitoring Flk-1 and PdgfR-α expression, we found that specification of cardiac mesoderm and cardiomyocytes is determined by remarkably small changes in levels of Activin/Nodal and BMP signaling. Translation to human ESCs and iPSCs revealed that the emergence of cardiac mesoderm could also be monitored by coexpression of KDR and PDGFR-α and that this process was similarly dependent on optimal levels of Activin/Nodal and BMP signaling. Importantly, we found that individual mouse and human pluripotent stem cell lines require optimization of these signaling pathways for efficient cardiac differentiation, illustrating a principle that may well apply in other contexts.
► Expression of Flk1/KDR and PDGFR-α identify PSC-derived cardiac mesoderm ► Cardiac specification requires stage-specific Activin/Nodal and BMP signaling ► Individual PSC lines require optimization for efficient cardiac differentiation
Résumé
Avec l’augmentation croissante des taux de guérison des cancers de l’enfant et de l’adolescent, la question de la fertilité et de sa préservation représente aujourd’hui une préoccupation ...majeure pour les équipes d’oncohématologie. Le statut de la fertilité à l’âge adulte constitue un secteur important de la qualité de vie des anciens patients, et en ce sens, les recommandations préconisent qu’une cryopréservation de sperme soit proposée à tout adolescent pubère avant le début d’un traitement potentiellement gonadotoxique. Cette recherche possède deux volets. Le premier a permis de faire l’état des lieux des pratiques médicales pédiatriques en oncologie concernant la transmission des informations au sujet des risques pour la fertilité ainsi qu’au sujet de la proposition de cryopréservation de sperme. Le second vise à explorer l’expérience subjective d’anciens patients autour de ces questions. Notre étude a inclus les anciens patients âgés de 14 à 18 ans au moment du diagnostic, traités et en rémission complète depuis au moins un an. Dix-sept entretiens ont été réalisés avec ces adolescents et jeunes adultes. Les objectifs principaux étaient de pouvoir dégager des recommandations pour les équipes médicales et soignantes et de créer un livret d’information à destination des adolescents et jeunes adultes. L’analyse thématique des entretiens montre l’importance de l’annonce des risques, la prise de décision, la médicalisation de la préservation du sperme et les interactions parentales. L’expérience subjective des anciens patients permet une prise de conscience de la nécessité de certains aménagements. Les jeunes ont eux-mêmes participé à l’élaboration des projets d’amélioration issus de notre étude. Le désir d’être reçus seuls, en priorité et en dehors de la présence de leurs parents, l’aménagement d’un accueil spécifique dans la structure de recueil et de conservation du sperme, les échanges avec le médecin référent ou le médecin biologiste sur les résultats du recueil de sperme, afin de conserver des informations sur le statut de la fertilité, forment les demandes principales issues des entretiens avec les jeunes.
To identify cell-surface markers specific to human cardiomyocytes, we screened cardiovascular cell populations derived from human embryonic stem cells (hESCs) against a panel of 370 known CD ...antibodies. This screen identified the signal-regulatory protein alpha (SIRPA) as a marker expressed specifically on cardiomyocytes derived from hESCs and human induced pluripotent stem cells (hiPSCs), and PECAM, THY1, PDGFRB and ITGA1 as markers of the nonmyocyte population. Cell sorting with an antibody against SIRPA allowed for the enrichment of cardiac precursors and cardiomyocytes from hESC/hiPSC differentiation cultures, yielding populations of up to 98% cardiac troponin T-positive cells. When plated in culture, SIRPA-positive cells were contracting and could be maintained over extended periods of time. These findings provide a simple method for isolating populations of cardiomyocytes from human pluripotent stem cell cultures, and thereby establish a readily adaptable technology for generating large numbers of enriched cardiomyocytes for therapeutic applications.
The Mediterranean is expected to be one of the most prominent and vulnerable climate change “hotspots” of the twenty-first century, and the physical mechanisms underlying this finding are still not ...clear. Furthermore, complex interactions and feedbacks involving ocean–atmosphere–land–biogeochemical processes play a prominent role in modulating the climate and environment of the Mediterranean region on a range of spatial and temporal scales. Therefore, it is critical to provide robust climate change information for use in vulnerability–impact–adaptation assessment studies considering the Mediterranean as a fully coupled environmental system. The Mediterranean Coordinated Regional Downscaling Experiment (Med-CORDEX) initiative aims at coordinating the Mediterranean climate modeling community toward the development of fully coupled regional climate simulations, improving all relevant components of the system from atmosphere and ocean dynamics to land surface, hydrology, and biogeochemical processes. The primary goals of Med-CORDEX are to improve understanding of past climate variability and trends and to provide more accurate and reliable future projections, assessing in a quantitative and robust way the added value of using high-resolution and coupled regional climate models. The coordination activities and the scientific outcomes of Med-CORDEX can produce an important framework to foster the development of regional Earth system models in several key regions worldwide.
Markers of epithelial‐mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, ...open‐label, 12‐month trial, de novo kidney transplant patients received cyclosporine, enteric‐coated mycophenolate sodium (EC‐MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT− based on month 3 biopsy, then randomized to start everolimus with half‐dose EC‐MPS (720 mg/day) and cyclosporine withdrawal (CNI‐free) or continue cyclosporine with standard EC‐MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy IF/TA grade increase ≥1 between months 3–12) in EMT+ patients. 194 patients were randomized (96 CNI‐free, 98 CNI); 153 (69 CNI‐free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI‐free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy‐proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI‐free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI‐free protocol, in which everolimus exposure was relatively low and administered with half‐dose EC‐MPS, CNI‐free patients were overwhelmingly under‐immunosuppressed and experienced an increased risk of BPAR.
In a 12‐month trial of 194 de novo kidney transplant patients receiving cyclosporine, enteric‐coated mycophenolate sodium, and steroids, the cohort randomized at month three to start everolimus with halfdose EC‐MPS and no cyclosporine was underimmunosuppressed and did not experience a benefit in terms of the primary endpoint of the study, progression of graft fibrosis in patients positive for epithelial‐mesenchymal transition.
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