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Background: Functional abnormalities of the ascending aorta (AA) have been mainly reported in young patients who underwent arterial switch operation (ASO) for transposition of the great arteries (TGA)., Objectives: To compare systolic, diastolic brachial and central blood pressures (bSBP, bDBP, cSBP, cDBP), aortic biomechanical parameters, and left ventricular (LV) afterload criteria in adult ASO patients with healthy controls and to assess their relationships with LV remodeling and aortic size., Materials and Methods: Forty-one prospectively enrolled patients (16.8 to 35.8 years) and 41 age- and sex-matched healthy volunteers underwent cardiac MRI to assess LV remodeling with simultaneous brachial BP estimation. After MRI, carotid-femoral tonometry was performed to measure pulse wave velocity (cfPWV), cSBP and cDBP for further calculation of pulse pressure (cPP), AA distensibility (AA D ), and AA and LV elastance (AA E , LV E )., Results: bSBP, bDBP, cSBP,cDBP and cPP were all significantly higher in ASO group than in controls: cSBP (116.5 ± 13.8 vs 106.1 ± 12.0, p < 0.001), cDBP (72.5 ± 6.9 vs 67.1 ± 9.4, p = 0.002), cPP (44.0 ± 12.1 vs 39.1 ± 8.9, p = 0.003) and not related to aortic size. AA D were decreased in ASO patients vs controls (4.70 ± 2.72 vs 6.69 ± 2.16, p < 0.001). LV mass was correlated with bSBP, cSBP, cPP (ρ = 0.48; p < 0.001), while concentric LV remodeling was correlated with AA E (ρ = 0.60, p < 0.001) and LV E (ρ = 0.32, p = 0.04), but not with distensibility., Conclusion: Even without reaching arterial hypertension, aortic sBP and PP are increased in the adult TGA population after ASO, altering the pulsatile components of afterload and contributing to LV concentric remodeling., (Copyright © 2023. Published by Elsevier B.V.)

Background: The treatment approach for coronary artery fistulas (CAFs) is debatable, and long-term outcomes are unknown., Methods: This was a retrospective institutional data review of children in whom echocardiographically suspected CAFs were confirmed during cardiac catheterisation from 1997 to 2023. Treatment approach and outcomes were assessed., Results: We identified 94 CAFs in 78 patients (42.3% male), median age 3.4 years (interquartile range [IQR] 0.9-6.6 y). Twenty-five patients (32%) had other congenital anomalies; 41 (78.8%) of the 52 patients with isolated CAFs were asymptomatic. The most common site of CAF origin and drainage was the left system (62.8%) and right cardiac cavities (80.8%). Overall median follow-up was 101 months (IQR 41-185 mo); 23 patients (29.5%) with 35 (37.2%) small or nonshunting CAFs had conservative management, and 20 (87%) of those 23 patients had an uneventful follow-up; 8 patients (10.2%) with 9 (9.6%) complex CAFs were directly sent for surgery; 1 patient had early surgical patch failure needing surgical reintervention; 47 patients (60.3%) had catheter closure of 50 (53.2%) medium- or large-sized CAFs with the use of coils (30%), vascular plugs (20%), nitinol duct occluders (40%), or material combination (10%). Six serious complications occurred. Two of the 3 patients with unsuccessful catheter procedures had subsequent surgeries. Two of the 3 patients with mild shunts had successful redo closures. One asymptomatic patient had recanalisation after 12 years and is under watchful observation., Conclusions: CAFs have various anatomies and clinical presentations. Transcatheter closure is effective in carefully selected patients but is not complication free. Surgery is a valuable up-front option in complex CAFs or bailout of unsuccessful transcatheter closures, although it is not frequently used., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preterm birth is common in children with congenital heart disease. However, data on how to manage low-birth-weight infants with aortic coarctation are scarce and outcomes are poorly reported. Surgery is often delayed in these infants because gaining weight is supposed to improve mortality and to reduce the risk for recoarctation., Methods: All infants weighing less than 2000 g who underwent repair for aortic coarctation at our institution between January 2017 and December 2020 were included in a retrospective study. Baseline characteristics, medical and surgical management, and outcomes, including recoarctation, death, and complications of preterm birth, were analyzed., Results: A total of 15 patients had coarctation repair at a median age of 15 days and at a median weight of 1585 g. Infants with a birth weight <1200 g were operated on later and did not have higher recoarctation rates compared to those with a birth weight >1200 g. The recoarctation rate was 26.6% and one infant died of an extracardiac cause. Concerning prematurity-related complications, we observed 40% of bronchopulmonary dysplasia, 40% of intraventricular hemorrhage, and 27% of retinopathy of prematurity. These complications were more prevalent in children with a birth weight of <1200 g., Conclusion: Delaying surgery beyond 15 days to gain weight does not appear to decrease the risk of recoarctation and may be deleterious in low-birth-weight infants who are exposed for a longer period to risk factors of prematurity-related complications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

The uprising interest in gelatinous zooplankton populations must cope with a lack of robust time series of direct abundance observations in most of the ecosystems because of the difficulties in sampling small, fragile organisms, and of the dismissal of jellyfish as a nuisance. Most of the hypotheses about their dynamics are built on a few species and ecosystems and extended to the whole group, but the blooms are registered mainly for the members of the Class Scyphozoa that dwell in temperate, shallow waters. Within the scyphozoans, our knowledge about their phenology relies mainly on laboratory experiences. Here we present a long-term analysis of the phenology and life cycle of three scyphozoan species in an ecosystem affected by eutrophication in a climate change context. We have found that the phenology is directed by temperature, but not modified by different thermal and ecological regimes., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ability to isolate and characterize different hematopoietic stem cell (HSC) or progenitor cell populations opens avenues to understand how hematopoiesis is regulated during development, homeostasis, and regeneration as well as in age-related conditions such as clonal hematopoiesis and leukemogenesis. Significant progress has been made in the past few decades in determining the composition of the cell types that exist in this system, but the most significant advances have come from mouse studies. However, recent breakthroughs have made significant strides that have enhanced the resolution of the human primitive hematopoietic compartment. Therefore, we aim to review this subject not only from a historical perspective but also to discuss the progress made in the characterization of the human postnatal CD34+ HSC-enriched populations. This approach will enable us to shed light on the potential future translational applicability of human HSCs., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Clinical and prognostic role of cardiac magnetic resonance (CMR) in adult population with hypertrophic cardiomyopathy (HCM) have been largely assessed. We sought to investigate the role of CMR for predicting cardiovascular events in children with HCM., Methods: CMR was performed in 116 patients with HCM (37 sarcomeric mutations, 31 other mutations, mean age 10.4 ± 4.3 yrs). CMR protocol included cine imaging for evaluation of morphology and function and late gadolinium enhancement (LGE). Hard cardiac events (sustained VT, resuscitated cardiac arrest, sudden cardiac death, end-stage heart failure, heart transplant and appropriate ICD intervention) were recorded through a median follow-up of 4 (1-7) years., Results: During follow-up 21 heart cardiac events occurred. At maximal-rank statistic the optimal cut-point for LGE extent for predicting events was ≥2%. Syncope, non-sustained ventricular tachycardia (NSVT) and LGE extent ≥2% were independent predictors of events. At Harrel's C statistic combination of LGE extent ≥2% and syncope was the strongest model for predicting events. HR of patients with LGE extent ≥2% and no history of syncope was 3.6 (1.1-12.2) that increased to 37.6 (5.4-161) in those with LGE extent ≥2% and syncope. The median time dependent AUC of LGE extent (0.88, 95% CI 0.86-0.89) was significantly higher than that of syncope (0.63, 95% CI 0.61-0.66, p < 0.0001) and NSVT (0.52, 95% CI 0.50-0.53, p < 0.0001)., Conclusions: In children with HCM, LGE and syncope were independent predictors of hard cardiac events at follow-up., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Since the COVID-19 pandemic began, a cohort of Multisystem inflammatory syndrome in children (MIS-C) patients has been described. Cardiac involvement is found in 80-85% patients, typically with cardiac dysfunction with or without cardiogenic shock. Here, three cardiac biomarkers, BNP, NT-proBNP and Galectin-3 were compared for the first time in MIS-C in a unique cohort of hospitalized French children., Methods: Fourteen children with MIS-C hospitalized at Necker-Enfants Malades for cardiac management during the first three COVID-19 waves (March 2020-March 2021) were included. All had positive SARS-CoV-2 serology and proven cardiac involvement assessed by transthoracic echocardiography. NT-proBNP, BNP and Galectin-3 were measured at admission, discharge and first follow-up clinic., Results: All admission Galectin-3 measurements were comprised within the reference interval, both in patients with and without cardiogenic shock, and did not vary between admission, discharge and first follow-up clinic. Both median admission BNP and NT-proBNP were higher in children with cardiogenic shock than without. Median admission NT-proBNP was higher than its predictive positive value in heart failure in both groups of children, while median BNP was below its negative predictive value in children without cardiogenic shock but with cardiac dysfunction., Conclusions: Galectin-3 does not seem affected by MIS-C. NT-proBNP seems to increase more precociously than BNP possibly making it a more sensitive marker for screening of heart failure in MIS-C., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Estrogens, such as the 17β-estradiol (E2) and the 17α-ethinylestradiol (EE2), have been regarded as a global threat to aquatic ecosystems due to their pseudo-persistence, their high estrogenic activity and their toxicity towards non-target species. Data regarding their ecotoxicological effects on marine calanoid copepods are very scarce. In this study, the calanoid copepod Acartia clausi was used as a model organism for estrogens exposure in marine pelagic ecosystems. Lethal effects of estrogens on A. clausi life-stages (Embryos, one day old nauplii: N1, three day old nauplii: N3, copepodites: C1-C3 and adults: C6) were investigated using 48 h acute tests. Copepods showed stage-specific responses against E2 and EE2 acute exposure. The most resistant life stage was N1 with LC 50 values > 1500 μg L -1 and >5000 μg L -1 , respectively for E2 and EE2. For N3, C1-C3, and C6, sensitivity to estrogens decreased with age and survival was affected at concentrations above those detected in the environment reflecting low estrogens acute toxicity for these life stages. In contrast, embryonic stage revealed high vulnerability to E2 and EE2 acute effects. Embryos showed non-monotonic dose-response and hatching success was significantly reduced at low realistic concentrations of E2 (0.005, 0.5, and 5 μg L -1 ) and EE2 (0.05 and 5 μg L -1 ). Survival, development and sex ratio of A. clausi to EE2 exposure at 1 and 100 μg L -1 were also determined during a life cycle experiment. Fitness of the females of the generation F0 was evaluated by measuring lifespan, prosome length and egg production. The main observed effects were the decrease of females' prosome length, the feminization of the population and the reduction of the egg production for the generation F0 at 100 μg L -1 of EE2. This concentration is above those reported in the environment indicating the tolerance of A. clausi to EE2 at environmentally relevant concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no financial interests or personal relationships that could influence the work reported in this article., (Copyright © 2021. Published by Elsevier B.V.)

Background: Prestenting right ventricular outflow tracts (RVOTs) before transcatheter pulmonary valve replacement (TPVR) is essential. Optimus-XXL (AndraTec GmbH, Koblenz, Germany) is a new extra-large, balloon-expandable cobalt-chrome stent with promising technologies., Methods: From June 2020 to November 2020, 15 patients with congenital heart disease, dysfunctional RVOTs and target TPVR diameter ≥ 23 mm received Optimus-XXL stents before proceeding to TPVR using the SAPIEN valve (Edwards Lifesciences, Irvine, CA). Standard safety and outcomes were prospectively assessed., Results: Patients' median age and weight were 25.8 years (range: 10.5-63.1 years) and 58 kg (range: 43.8-101 kg), respectively. Underlying diagnosis was tetralogy of Fallot (66.7%), and RVOTs were patched (80%). Fifteen bare-metal stents were implanted using femoral (n = 14) and jugular approaches (n = 1). One conduit rupture was immediately controlled with a covered Optimus-XXL. Median stent length was 43 mm (range: 33-57 mm), and median target expansion diameter was 28 mm (range: 23-30 mm). Two procedural incidents occurred during stent delivery and were percutaneously treated. Stent stability was documented during TPVRs immediately performed in 14 patients. Median stent shortening was 13.7%, and median percentage of intended stent expansion was 95.9%. There was no stent fracture on the short-term follow-up (median: 4.5 months)., Conclusions: We report the first implantations of Optimus-XXL stents in dysfunctional RVOTs with excellent preliminary results. Optimus-XXL should be considered as a valuable adjunct in the armamentarium for routine and complex TPVR procedures., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the respiratory outcome in children with congenital heart disease (CHD), considering recent management procedures and the CHD pathophysiology., Design and Setting: Clinical and functional respiratory outcome were evaluated in 8-year-old children with isolated CHD followed up from birth in the prospective population-based EPICARD cohort., Patients: Children were assigned to two groups, based on the pathophysiology of the CHD: CHDs with left-to-right shunt (n = 212) and CHDs with right outflow tract obstruction (n = 113)., Results: Current wheezing episodes were observed in 15% of the children with isolated CHD and left-to-right shunt, and 11% of the children with isolated CHD and right outflow tract obstruction (not significant). Total lung capacity (TLC) was the only respiratory function parameter that significantly differed between the two groups. It was lower in children with left-to-right shunt (88.72 ± 0.65% predicted) than in those with right outflow tract obstruction (91.84 ± 0.96, p = 0.006). In multivariate analysis, CHD with left-to-right shunt (coeff. [95% CI]: -3.17 [-5.45; -0.89]) and surgery before the age of 2 months (-6.52 [-10.90; -2.15]) were identified as independent factors associated with significantly lower TLC values., Conclusion: Lower TLC remains a long-term complication in CHD, particularly in cases with left-to-right shunt and in patients requiring early repair. These findings suggest that an increase in pulmonary blood flow may directly impair lung development., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Patients with end-stage pulmonary arterial hypertension due to congenital heart disease have limited access to heart-lung transplantation or double-lung transplantation. We aimed to assess the effects of a high-priority allocation program established in France in 2007. We conducted a retrospective study to compare waitlist and posttransplantation outcomes before versus after implementation of the high-priority allocation program. We included 67 consecutive patients (mean age at listing, 33.2 ± 10.5 years) with pulmonary arterial hypertension due to congenital heart disease listed for heart-lung transplantation or double-lung transplantation from 1997 to 2016. At one month, the incidences of transplantation and death before transplantation were 3.5% and 24.6% in 1997-2006, 4.8% and 4.9% for patients on the regular list in 2007-2016, and 41.2% and 7.4% for patients listed under the high-priority allocation program (p < .001 and p = .0001, respectively). Overall survival was higher in patients listed in 2007-2016 (84.2% and 61.2% at 1 and 10 years vs. 36.8% and 22.1%, p = .0001). Increased incidence of transplantation, decreased waiting list mortality, and improved early and long-term outcomes were observed in patients with pulmonary arterial hypertension due to congenital heart disease listed for transplantation in the recent era, characterized by implementation of a high-priority allocation program., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose: Pulmonary arterial hypertension (PAH) is rare but remains fatal in infants and children despite the advance of targeted therapies. Lung transplantation (LTx), first performed in pediatric patients in the 1980s, is, with the Potts shunt, the only potentially life-extending option in patients with end-stage PAH but is possible only in tightly selected patients. Size-matching challenges severely restrict the donor organ pool, resulting-together with peculiarities of PAH in infants-in high waitlist mortality. We aimed to investigate survival when using a high-priority allocation program (HPAP) in children with PAH listed for double-LTx or heart-LTx., Methods: We conducted a single-center, retrospective, before-after study of consecutive children with severe Group 1 PAH listed for double-LTx or heart-LTx between 1988 and 2019. The HPAP was implemented in France in 2006 and 2007 for heart-LTx and double-LTx, respectively., Results: Fifty-five children with PAH were listed for transplantation. Mean age at transplantation was 15.8±2.8 years and 72% had heart-lung transplantation. PAH was usually idiopathic (65%) or due to congenital heart disease (25%). HPAP implementation resulted in the following significant benefits: Decreased cumulative incidence of waitlist death within 1 and 2 years (p < 0.0001); increased cumulative incidence of transplantation within 6 months, from 44% to 67% (p < 0.01); and improved survival after listing (at 1, 3, and 5 years: 61%, 50%, and 44% vs. 92%, 84%, and 72% before and after HPAP implementation, respectively; p = 0.02)., Conclusion: HPAP implementation was associated with significant improvements in access to transplantation and in survival after listing in children with end-stage PAH., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.

Background: Cardiac Magnetic Resonance (CMR) data regarding myocarditis presentation and disease course is still lacking in pediatric patients. We evaluate baseline CMR and evolution of functional and tissue abnormalities in children with acute myocarditis., Methods: CMR was performed in 125 patients with clinical diagnosis of acute myocarditis. Clinical follow-up was performed for a median of 498 (214-923) days., Results: LVEF was depressed (<55%) in 56 cases (45%) upon baseline CMR. LGE was found in 93 patients (77%) of cases. LGE was exclusively subepicardial in 29 patients (23%), while other LGE patterns (midwall/mixed) were present in 64 (51%). CMR was repeated in 92 (74%) patients. 67% presented recover of function at a median of 170 (70-746) days after onset of symptoms. Midwall/mixed LGE pattern had a statistically significant correlation with absent recover of function (OR 0.20 p 0.036). Thirteen patients (16%) had recovery from LV dysfunction but with persistence of LGE. Sub-epicardial pattern of LGE (OR 3.33, 95% CI 1.08-10.2, p = 0.036) and the presence of fever at admission (OR 4.67, 95% CI 1.16-18.7, p = 0.03) were associated with a significantly higher likelihood of complete normalization while midwall/mixed LGE pattern was associated with non-recovery., Conclusions: In pediatric myocarditis, midwall/mixed LGE pattern is associated with absent recover of function. Patients with recover of function may still have persistence of LGE, while a complete recovery from functional and tissue abnormalities is found only in a third of patients. Midwall/mixed pattern of LGE at first MRI was associated to worse outcome., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Geleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to define the natural history of these disorders and to establish genotype-phenotype correlations., Methods: This monocentric retrospective study was conducted between January 2008 and December 2018 in a pediatric tertiary care center and included patients with AD or GD with identified variants (FBN1, LTBP3, or ADAMTSL2)., Results: Twenty-two patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3) and 16 patients with AD (15 FBN1, 1 LTBP3) were included. Early death occurred in eight GD and one AD. Among GD patients, 68% presented with heart valve disease and 25% developed upper airway obstruction. No AD patient developed life-threatening cardiorespiratory issues. A greater proportion of patients with either a FBN1 cysteine variant or ADAMTSL2 variants had a poor outcome., Conclusion: GD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.

MUTYH-associated polyposis (MAP) was first described in 2002. It is an autosomal recessive condition associated with germline pathogenic variants of both MUTYH alleles. In 2011, a group of French experts reviewed the available data on this syndrome and established recommendations concerning the indications and strategies for molecular analysis of the MUTYH gene in index cases and their relatives, as well as the clinical management of affected individuals under the auspices of the French Institut National du Cancer (INCa). Some of these recommendations have become obsolete as a result of recent progress, especially those concerning the molecular strategy for MUTYH testing, as this gene has recently been included in a consensus panel of 14 colorectal cancer predisposition genes, justifying revision of the previous report. We report here the revised version of this work, which successively considers the phenotype and tumor risks associated with this genotype, differential diagnoses, criteria and strategy for molecular genetic testing and recommendations for the management of affected individuals. We also discuss the phenotype and tumor risks associated with monoallelic pathogenic variants of MUTYH., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions., (© 2020 by The American Society of Hematology.)

Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy., (© 2020 by The American Society of Hematology.)

MUTYH-associated polyposis (MUTYH-associated polyposis, MAP) is an autosomal recessive inheritance disorder related to bi-allelic constitutional pathogenic variants of the MUTYH gene which was first described in 2002. In 2011, a group of French experts composed of clinicians and biologists, performed a summary of the available data on this condition and drew up recommendations concerning the indications and the modalities of molecular analysis of the MUTYH gene in index cases and their relatives, as well as the management of affected individuals. In view of recent developments, some recommendations have become obsolete, in particular with regard to the molecular analysis strategy since MUTYH gene has been recently included in a consensus panel of 14 genes predisposing to colorectal cancer. This led us to revise all the points of the previous expertise. We report here the revised version of this work which successively considers the phenotype and the tumor risks associated with this genotype, the differential diagnoses, the indication criteria and the strategy of the molecular analysis and the recommendations for the management of affected individuals. We also discuss the phenotype and the tumor risks associated with mono-allelic pathogenic variants of MUTYH gene., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Children with repaired congenital heart disease (CHD) have impaired maximal aerobic capacity (VO2max). Determining the causes of their VO2max alteration remains challenging. Cardiac output measure using thoracic impedancemetry during cardiopulmonary exercise tests (CPET) can help to understand the determinants of VO2max in children with open-heart repaired CHD., Method: We analyzed CPET in 77 children with repaired CHD. Among them, 55 patients had residual lesions. Patients with repaired CHD were compared with 44 age-matched healthy individuals. Maximal oxygen content brought to capillaries (QO2max) and oxygen muscle diffusion capacity (DO2) were assessed using cardiac output measure, Fick principle and simplified Fick law., Results: In the 55 patients with residual lesion, VO2max, QO2max and DO2 were lower than those of controls (76.1 vs 86% of theoretical value, p < 0.01; 2.15 vs 2.81 L/mn, p < 0.001; 24.7 vs 28.8 ml/min/mmHg, p < 0.05). Decrease in QO2max was due to both impaired stroke volume and chronotropic insufficiency (48 vs 53 ml/m 2 and p < 0.05; 171 vs 185/min p < 0.001). Patients without residual lesion (22/77) had normal VO2max with lower maximal heart rate compensated by higher SV (p < 0.05)., Conclusion: Aerobic capacity was normal in children without residual lesions after CHD repair. Patients with residual lesion have impaired VO2max due to both lower central and peripheral determinants. Measuring cardiac performance during CPET allowed a better selection of patients with altered cardiac reserve that can benefit from residual lesion treatment and find the good timing for intervention. Detection of peripheral deconditioning can lead to a rehabilitation program., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: After tetralogy of Fallot (TOF) repair, pulmonary regurgitation and right ventricular function must be monitored. Conventional (2D) cardiac magnetic resonance (CMR) is currently the clinical reference method for measuring pulmonary regurgitation. However, 4DFlow CMR has been reported to provide a more comprehensive flow analysis than 2D CMR. We aimed to compare 4DFlow CMR to 2D CMR for assessing pulmonary regurgitation and flow, as well as aortic flow, in children and adults after surgical repair of TOF., Methods: Retrospective analysis of patients with repaired TOF admitted for cardiac MRI with 4DFlow acquisition from 2016 to 2018. Linear regression was used to assess correlations and Bland-Altman analyses were performed., Results: The 60 included patients had a mean age of 18.2 ± 10.4 years (range, 2-54 years). Significant correlations between the two techniques were found for pulmonary regurgitant fraction (R [2] = 0.6642, p < 0.0001), net pulmonary flow (R [2] = 0.6782, p < 0.0001), forward pulmonary flow (R [2] = 0.6185, p < 0.0001), backward pulmonary flow (R [2] = 0.8192, p < 0.0001), and aortic valve flow (R [2] = 0.6494, p < 0.0001). The Bland-Altman analysis showed no significant bias, narrow limits of agreement, and few scattered points. The correlation between pulmonary and aortic flow was better with 4DFlow CMR than with 2D CMR (R [2] = 0.8564, p < 0.0001 versus R [2] = 0.4393, p < 0,0001, respectively). Interobserver reliability was good., Conclusion: These results establish the feasibility and reliability of 4DFlow CMR for assessing pulmonary flow in a large paediatric and adult population with repaired TOF. 4DFlow CMR may be more reliable than 2D MRI for pulmonary flow assessment after TOF repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Harmful invader ctenophore Mnemiopsis leidyi's expansions in the Eurasian Seas, its spatio-temporal population dynamics depending on environmental conditions in recipient habitats have been synthesized. M. leidyi found suitable temperature, salinity and productivity conditions in the temperate and subtropical environments of the semi-enclosed seas, in the coastal areas of open basins and in closed water bodies, where it created autonomous populations. M. leidyi changes its phenology depending on seasonal temperature regime in different environments. We assessed ranges of sea surface temperature, sea surface salinity and sea surface chlorophyll values, sufficient for M. leidyi general occurrence and reproduction based on comprehensive long-term datasets, contributed by co-authors. This assessment revealed that there are at least two eco-types (Southern and Northern) in the recipient seas of Eurasia with features specific for their donor areas. The range of thresholds for M. leidyi establishment, occurrence and life cycle in both eco-types depends on variability of environmental parameters in their native habitats., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Until recently, jellyfish have been ignored as an important source of food, due to their low nutritional value. Here, quantitative PCR was used to detect and quantify the DNA of the jellyfish Aurelia coerulea in the gut contents of commercially important fish species from the Thau Lagoon. Individuals from five fish species were collected during two different periods: the bloom period, when the pelagic stages of A. coerulea are abundant, and the post-bloom period, when only the benthic stage - polyps - is present in the lagoon. The DNA of A. coerulea was detected in the guts of 41.9% of the fish analysed, belonging to four different species. The eel Anguilla anguilla and the seabream Sparus aurata were important jellyfish consumers during the bloom and post-bloom periods, respectively. These results provide new insights on the potential control of jellyfish populations and on jellyfish importance as a food source for exploited fishes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Composite clinical worsening (cCW) outcomes might allow measurement of disease progression in paediatric pulmonary arterial hypertension (PAH). This TOPP registry analysis investigated three cCW outcomes and their predictive strength for lung transplantation/death., Methods: Patients ≤17 years with idiopathic/familial PAH or PAH-associated congenital heart disease diagnosed ≤3 months before enrolment were included. cCW outcomes included the following variables at enrolment and/or follow-up: all-cause death, PAH-related hospitalisation, lung transplantation, atrial septostomy (cCW1, 2 and 3), WHO FC deterioration, intravenous/subcutaneous prostanoids initiation, syncope (cCW2,3) and occurrence/worsening of ≥2 PAH symptoms (cCW3). The predictive value of CW (excluding transplantation and death) to transplantation or death was assessed. Predictive values of each cCW for lung transplantation/death were analysed by Cox proportional hazards models., Results: From 255 patients, first-event rate/100 person-years (95% CI) were cCW1: 23.1(19.3,27.6), cCW2: 43.6(37.6,50.6), and cCW3: 46.3(40.0,53.7) with PAH-related hospitalisation as the most frequent first event in each. The cCW definitions comprised from endpoints (excluding transplantation and death), were associated with higher risk [hazard ratio (95% CI)] for lung transplantation/death [4.23(2.27,7.91), 3.25(1.65,6.39), 2.74(1.41,5.34), respectively]; individual parameters with higher risks were WHO FC deterioration [3.49(1.47,8.29)], PAH-related hospitalisation [2.62(1.32,5.20)] and occurrence/worsening of ≥2 PAH symptoms [2.13(1.02,4.45)]., Conclusions: These data support the use of cCW outcomes in paediatric PAH research. WHO FC deterioration, PAH-related hospitalisation, occurrence/worsening of ≥2 PAH symptoms may be important for risk assessment during clinical management., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Advances in congenital heart disease (CHD) have transferred the mortality from childhood to adulthood. Exercise capacity in young patients with CHD remains lower than in the general population, resulting in deconditioning and impaired quality of life. Evidence based-medicine in cardiac rehabilitation in this age group with CHD remains limited. We present the QUALI-REHAB study rationale, design and methods., Methods: The QUALI-REHAB trial is a nationwide, multicentre, randomised, controlled study, aiming to assess the impact of a combined centre and home-based cardiac rehabilitation program on the quality of life of adolescents and young adults (13 to 25 years old) with CHD. Patients with a maximum oxygen uptake (VO2 max ) < 80% and/or a ventilatory anaerobic threshold (VAT) < 55% of predicted VO2 max , will be eligible. Patients will be randomised into 2 groups (12-week cardiac rehabilitation program vs. controls). The primary outcome is the change in the PedsQL quality of life score between baseline and 12-month follow-up. A total of 130 patients are required to observe a significant increase of 7 ± 13.5 points in the PedsQL, with a power of 80% and an alpha risk of 5%. The secondary outcomes are: VO2 max , VAT, stroke volume, clinical outcomes, physical and psychological status, safety and acceptability., Conclusion: After focusing on the survival in CHD, current research is opening on secondary prevention and patient-related outcomes. The QUALI-REHAB trial intends to assess if a combined centre and home-based rehabilitation program, could improve the quality of life and the exercise capacity in youth with CHD., Trial Registration: Clinicaltrials.gov (NCT03690518)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study aims at quantifying and characterising microplastics (MP) distribution in the water column of the NW Mediterranean Sea as well as MP ingestion by the 2 main planktivorous fish of the area, sardine and anchovy. Debris of similar sizes were found in all water column samples and in all but 2 fish guts (out of 169). MP were found in 93% of water column samples with an average concentration of 0.23 ± 0.20 MP·m -3 , but in only 12% of sardines (0.20 ± 0.69 MP·ind -1 ) and 11% of anchovies (0.11 ± 0.31 MP·ind -1 ). Fibres were the only shape of MP encountered and polyethylene terephthalate was the main polymer identified in water columns (61%), sardines (71%) and anchovies (89%). This study confirms the ubiquity of MP in the Mediterranean Sea and imparts low occurrence in fish digestive tracts., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Neo-aortic root dilatation and regurgitation are common progressive long-term complications of the arterial switch operation (ASO) for transposition of the great arteries (TGA) with increasing clinical burden. While several risk factors have been identified, most are constitutional. The acute aortic angle commonly seen after ASO might alter aortic dynamics and facilitate progression of the neo-aortic root dilatation and aortic regurgitation, but insufficient data is available. We intend to assess the effect of the aortic angle in the extent of neo-aortic root dilatation and presence of regurgitation., Methods: Retrospective analysis of TGA patients undergoing CMR after ASO at a single tertiary centre from November 2010 to July 2017., Results: 180 patients were analysed, 157 of which having adequate imaging of the aortic arch and root. Neo-aortic root Z score was normally distributed with 73% of patients having a Z score > 2. The aortic angle had a significant (p < 0,001) inverse relationship with the neo-aortic root Z score both in univariate and multivariate linear regression. Other significant associations were male gender and the concomitant presence of a VSD or a dysplastic neo-aortic valve. The presence of neo-aortic regurgitation was also inversely correlated with the aortic angle. The presence of a bicuspid neo-aortic valve was another significant association, further correlating with the more severe forms., Conclusions: Acute aortic angles associate more extensive neo-aortic root dilatation and higher incidence of regurgitation. We believe a surgical technique promoting less acute aortic angles has potential for ameliorating the long-term outcomes of TGA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease with an elusive association with myocardial inflammation. A myocarditis phenotype has been well established without systematic evidence of a viral trigger. We intend to study the relationship between myocardial inflammation detected by Cardiac magnetic resonance (CMR) and ARVC in a paediatric population., Methods: Retrospective case series of all patients <18 years admitted to two CMR units for clinical suspicion of myocarditis from March 2012 to June 2017 who had genetic testing for inherited cardiomyopathies including analysis for known ARVC genes., Results: Six patients were identified experiencing myocarditis-like episodes with chest pain and troponin elevation. All had CMR evidence of active myocardial inflammation often affecting the left ventricle without identification of an infectious trigger. These episodes were likely exercise-induced in 50% of our patients and were multiple in all but one., Conclusion: We provide evidence that ARVC can present as recurrent myocarditis-like episodes with CMR evidence of myocardial inflammation despite absent infectious trigger in children. We believe they represent an active hot phase of the disease and may lead to disease progression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10., Methods: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF., Results: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling., Conclusion: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Sustained fetal tachyarrhythmia can evolve into a life-threatening condition in 40% of cases when hydrops develops, with a 27% risk of perinatal death. Several antiarrhythmic drugs can be given solely or in combination to the mother to achieve therapeutic transplacental concentrations. Therapeutic failure could lead to progressive cardiac insufficiency and restrict therapeutic options to either elective delivery or direct fetal administration of antiarrhythmic drugs, which may increase the risk of death. We report for the first time successful fetal transesophageal pacing to treat a hydropic fetus with drug-resistant tachyarrhythmia., (Copyright © 2018. Published by Elsevier Inc.)

Background: Continuous intravenous epoprostenol was the first treatment approved for pulmonary arterial hypertension (PAH) but administration through a central venous line carries risks of thrombosis and sepsis, particularly in children. We sought to evaluate the safety, efficacy and management of subcutaneous (SC) treprostinil in children with PAH., Methods: Fifty-six children (median age 65, range 1-200 months) were treated with SC treprostinil. Clinical status, echocardiography, NT-proBNP, and site pain and infection were evaluated. Right heart catheterization was performed in 54 patients before starting SC treprostinil infusion and was repeated at 6 months in 31 patients., Results: Treatment was well tolerated in 79% of patients. Site pain resistant to simple analgesics occurred in 12 patients (21%), but could be managed in 9/12 children. At 6 months, 3 patients had died, 4 had received a Potts shunt and 1 underwent lung transplantation. Among the 48 treated patients, 40 (83%) showed significant improvement in WHO functional class, 6 minute walk distance, NT-proBNP and pulmonary vascular resistance (p < 0.01 for all parameters). At last follow-up (median 37 months), ten patients had died, 2 underwent a lung transplantation and 8 underwent a Potts shunt. In 30 of the 36 remaining treated patients, improvement of clinical status was sustained. No children developed sepsis and 12 had minor site infections., Conclusion: Subcutaneous treprostinil infusion is an effective therapy without serious side effects in children with PAH. Site pain can be managed with simple analgesics in most children., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Neurodevelopmental impairments have frequently been described in children and adolescents with dextro-transposition of the great arteries (d-TGA). The arterial switch operation (ASO) to correct d-TGA has been used for more than 30 years, and more than 90% of these patients now reach adulthood. However, very little is known about their long-term functional outcomes. The present study investigated neurocognitive outcomes and the prevalence of psychiatric disorders in adults with d-TGA corrected by ASO., Methods: Neurocognitive functioning was comprehensively assessed (general intellectual functioning, language, attention, visual-spatial skills, executive functions, memory) in 67 adults (59.7% men) with d-TGA (aged 22.9 ± 3.4 years) and in 43 healthy individuals. The prevalence of psychiatric disorders, including depression and anxiety, was evaluated using a structured diagnostic interview. We also analyzed patient- and operative-related risk factors associated with outcomes., Results: Compared with the general population and the control group, adults with d-TGA displayed reduced performance in tasks assessing attention, visual-spatial skills, executive functions, and memory (all p < 0.05). Compared with controls, patients had also a higher lifetime prevalence of depression (43% vs 19%, p = 0.008) and anxiety disorders (54% vs 33%, p = 0.025). Predictors of long-term outcomes included gender and parental socioeconomic and educational status (all p < 0.05)., Conclusions: Adults who have undergone a neonatal ASO to correct d-TGA have an increased risk of cognitive deficits and psychiatric disorders. Evaluation of long-term neuropsychological and psychosocial outcomes in early adulthood is a crucial step to anticipate for adapted treatment strategies in adults with congenital heart disease., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Dilated cardiomyopathy (DCM), a well-known complication of cardiac neonatal lupus, is associated with high mortality rate. Its risk factors remain unclear., Methods: We analyzed occurrence of postnatal DCM among children with high-degree congenital heart block (CHB) and mothers with anti-SSA and/or anti-SSB antibodies., Results: Among 187 neonates with CHB, 35 (18.8%, one missing data) had DCM and 22 (11.8%) died during a median follow-up of 7years [range: birth-36years]. On multivariate analysis, factors associated with postnatal DCM were in utero DCM (P=0.0199; HR=3.13 [95% CI: 1.20-8.16]), non-European origin (P=0.0052; HR=4.10 [95% CI: 1.81-9.28]) and pacemaker implantation (P=0.0013; HR=5.48 [95% CI: 1.94-15.47]). Postnatal DCM could be categorized in two subgroups: neonatal DCM (n=13, diagnosed at a median age of 0day [birth-4days]) and late-onset DCM (n=22, diagnosed at a median age of 15.2months [3.6months-22.8years]). Factors associated with neonatal DCM were in utero DCM, hydrops, endocardial fibroelastosis and pericardial effusion, whereas those associated with late-onset DCM were non-European origin, in utero mitral valve insufficiency, and pacemaker implantation. Fluorinated steroids showed no protective effect against late-onset DCM (P=0.27; HR=1.65 [95% CI: 0.63-4.25]). Probability of survival at 10years was 23.1% for newborns diagnosed neonatally with DCM, 53.9% for those who developed late-onset DCM, and 98.6% for those without DCM., Conclusion: Neonatal and late-onset DCM appear to be two different entities. None of the known risk factors associated with neonatal DCM predicted late-onset DCM. Long-term follow-up of cardiac function is warranted in all children with CHB., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The reversed Potts shunt improves right ventricular (RV) function in patients with suprasystemic pulmonary arterial hypertension (PAH). The proximity of the left pulmonary artery (LPA) to the descending aorta (DAo) permits the creation of a transcatheter connection. We sought to assess the safety, feasibility, and hemodynamic efficacy of the transcatheter Potts shunt (TPS) in children., Methods: The TPS procedure was performed using radiofrequency energy for vessel perforation and deployment of a covered stent to connect the DAo and LPA. Procedural details and clinical follow-up data were collected prospectively., Results: A TPS was successfully created in 6 children (mean age, 11.0 ± 4.2 years) with drug-refractory suprasystemic PAH and deteriorating RV function. All patients exhibited nearly complete equalization of aortic and pulmonary pressures and improvement in RV contractility within days after TPS placement. Two patients with pre-existing severe biventricular dysfunction and pericardial effusion experienced acute low-output states immediately after shunt creation because of sudden reductions in left ventricular (LV) preload, resulting in cardiac arrest, irreversible brain damage, and death. Stent dislodgement and embolization into the iliac artery occurred in 1 patient. The stent was successfully secured and followed by placement of a second stent at the target location. The procedure was uncomplicated in 4 patients, who remain alive after a mean follow-up of 10 ± 2.6 months. Intravenous vasodilator therapy was weaned uneventfully after TPS in 3 patients., Conclusions: TPS creation in children is feasible and results in hemodynamic improvement. Further insights into high-risk markers, such as reduced preprocedural LV function and preload reserves, are important for guiding patient selection., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin β1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins., (© 2017 by The American Society of Hematology.)