0491: Extracardiac or chromosomal anomalies strongly influence parental treatment decision and postnatal survival of neonates with prenatally diagnosed congenital heart diseases

ObjectivesThis study was design to assess the influence of extracardiac or chromosomal anomalies on parental decision of termination of pregnancy and on survival rates in newborns with prenatally diagnosed congenital heart diseases.Methods and results2057 consecutive foetuses with congenital heart disease diagnosed from January 2002 to December 2011 were included: 1258 (61%) in-born neonates and 799 (39%) terminations of pregnancy (TOP). The overall prevalence of major extracardiac or chromosomal anomalies was 18,6%. Of the 1258 newborns, 121 had a major associated anomaly but only 55 were identified before birth. Prenatally identified associated anomalies were significantly lower in the newborn group in comparison with the TOP group (4% vs 31%, p<0,0001). They were also lower in the surviving group at one year of follow up (7,5% vs 20,7%, p<0,0001). A 4-fold increase of death rate was observed if an associated anomaly was identified (IC95%[2,5-6,7], p<0,0001). These associations remained significant after multiple logistic regression analysis including the severity of the heart defect (univentricular or biventricular physiology).ConclusionWomen are more likely to terminate pregnancy if extracardiac or chromosomal anomalies are associated. Post natal survival is strongly influenced by these associated anomalies

Subcutaneous anakinra in the management of refractory MIS-C in France

IntroductionMultisystemic inflammatory syndrome in children (MIS-C) is a therapeutic emergency and can lead to myocardial dysfunction (17%–75%) and heart failure (52%–53%). Intravenous immunoglobulins (IVIG) and corticosteroids (CST) have been validated for the management of this condition. Recent reports suggest that an interleukin-1 (IL-1) receptor antagonist, namely anakinra, may be a valuable add-on to the 2019 novel coronavirus disease (COVID-19) treatment for refractory patients. The purpose of this study was to describe the clinico-biological characteristics of patients treated with anakinra as well as the efficacy and safety of subcutaneous anakinra therapy in this condition.MethodsThe prospective multicentre study of children hospitalized for MIS-C between March 2020 and September 2022, including 23 international paediatric centres, followed for a mean duration of 3.072 ± 3.508 months. The patient data were extracted from the Juvenile Inflammatory Rheumatism (JIR) cohort. The clinico-pathological characteristics, cardiac ultrasound data, and adverse events were reported in patients receiving anakinra.ResultsOf the 470 children admitted with MIS-C, 18 French patients (50% girls) with a mean age of 10.06 ± 3.9 years were treated with subcutaneous anakinra. Anakinra was used in two situations, macrophage activation syndrome (MAS) (4 patients) and heart failure (14 patients) with a median left ventricular ejection fraction (LVEF) of 39.5% (30%–45%). The average dose of anakinra received was 2.53 ± 1.3 mg/kg/day for a median duration of 3 days. Prior to introduction, 78% (n = 14/18) of the patients had received CST and 56% (n = 10/18) had received IVIG. Only two patients received IVIG alone and six received CST alone plus anakinra. In 10% of cases, IVIG was poorly tolerated from a cardiovascular point of view and was discontinued. Transient elevations in serum transaminases were noted in four patients on anakinra without the need for treatment or dose modification. In all patients, rapid (48 h) improvement in myocardial function was observed (LVEF &gt; 55%) with a concomitant significant decrease in myocardial enzymes (p &lt; 0.05). All patients survived with complete recovery of cardiac function without sequelae.ConclusionsSubcutaneous anakinra appears to be a safe and effective treatment for the management of heart failure or MAS in MIS-C patients. The value of IVIG in these two situations remains to be reviewed

Immunodeficiency, auto-inflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic auto-inflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1, a component the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin-1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyperresponsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of auto-inflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 nea

Complications coronaires tardives après traitement de la transposition des gros vaisseaux par détransposition artérielle

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Éducation thérapeutique du jeune patient, domaine spécifique de l’ETP et évolution du métier d’infirmière

Les demandes d’accompagnement au changement professionnel sont de plus en plus nombreuses. Dans le champ des métiers adressés à autrui, l’éducation thérapeutique (ET) demande à être étayée par de nouvelles approches sollicitant les Sciences Humaines et Sociales (Tourette-Turgis, 2015 ; Chalmel, 2015). Ces demandes conduisent à des transformations des pratiques professionnelles et à des changements dans les dispositifs d’éducation. Cet article présente une observation directe des pratiques effectives d’ET adressée à de jeunes patients et la formation d’une infirmière par la pratique. Il discute les formes de collaboration scientifique entre chercheures de domaines scientifiques différents et professionnelles du corps médical conduisant ces dernières à transformer leurs pratiques en créant des instruments pédagogiques ou des outils nouveaux de formation. Les conceptions inventives issues de ces échanges s’appuient sur les expériences et compétences construites antérieurement et s’articulent pour faire évoluer les dispositifs. Notre contribution présente et discute à travers ces analyses les transformations du métier de l’IDE vers des actions qui ne visent pas seulement le soin du corps, mais une forme d’enseignement d’une hygiène de vie. Le moment étudié est celui de la passation et de la transmission de l’expérience et de la responsabilité d’animer les séances d’éducation de la cardiologue vers l’infirmière d’éducation.Requests for support in professional changes are getting more and more numerous. Regarding jobs concerned with caring for others, therapeutic education needs to be spread into new approaches requiring social and human sciences (Tourette-Turgis, 2015 ; Chalmel, 2015). These requests lead to alterations in professional practices and changes in educational devices. This chapter deals with a direct observation of effective practices addressed to young patients and also implies the training of nurses through experiences. It also discusses ways of scientific collaboration between female researchers in different scientific fields of the medical body leading the latter to alter their practices by creating pedagogic instruments or new tools for training. This inventive conception deriving from these exchanges leaning on experiences and skills previously built up and linked together to help devices development. Our contribution deals with and discusses the transformation of state nurses functions through these analyses and towards actions which do not only concern body care but a way of teaching healthy life style. The themes under study concerns the passing on and transferring experiences and responsibility when directing cessions from cardiology education to the therapeutic education nurse