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Abstract Background Effective physician-patient communication is crucial to compassionate healthcare, particularly when conveying life-altering diagnoses such as those associated with congenital heart diseases. Despite its importance, medical practitioners often face challenges in communicating effectively. Because of these gaps, we aim to introduce a simulation-based training protocol to improve pediatric cardiology trainee’s communication skills. This study will be conducted in collaboration with associations supporting caregivers of children with congenital heart disease. It strives to demonstrate how specific training programs can efficiently foster humanistic, patient-centered care in standard medical practice. Methods This multicenter, open-label randomized controlled trial will be conducted in pediatric cardiac units and simulation centers of across 10 universities in France. The study population comprises pediatric cardiologists in training (including pediatric cardiac fellows or specialist assistants). The SIMUL-CHD intervention will consist of simulation-based training with standardized patients, focusing on improving communication skills for pediatric cardiology trainees during diagnostic counselling. Patients and caregivers have been recruited from a National Patient Association named “Petit Cœur de Beurre”. The primary outcome is the quality of physicians’ communication skills. The evaluation committee, which will review video recordings of the sessions, will be blinded to which participants received simulation-based training (group of interest) and which received theory-based training (control group). Secondary outcomes are the effect of SIMUL-CHD on empathy and anxiety levels in young pediatric cardiologists. Baseline scores pre and post-intervention will be compared, and skill improvement resulting from the intervention measured. Discussion Simulation-based training has proven efficacy in teaching technical skills in various scenarios however its application to communication skills in pediatric cardiology remains unexplored. The involvement of experienced parents provides a unique perspective, incorporating their profound understanding of the emotional challenges and specific hurdles faced by families dealing with congenital heart disease. Trial registration This trial is registered with the OSF registry (registered https://osf.io/ed78q ).

Abstract S‐adenosylhomocysteine hydrolase deficiency is an autosomal recessive inborn error of metabolism affecting methylation by disrupting the methionine cycle. Its clinical spectrum spans from severe perinatal encephalomyopathy and liver failure to asymptomatic course in patients with isolated hypermethioninemia. We present two new cases of S‐adenosylhomocysteine hydrolase deficiency from Pakistani origin clinically asymptomatic at presentation. Both siblings showed mild chronic liver failure and elevation of creatine kinase. The older patient presented at 6 years of age with isolated verbal processing difficulty and mild diffuse leukodystrophy, reversible 12 months after introduction of methionine dietary restriction. The patient showed subtle atrophy in the muscle MRI at the age of 7 years. S‐adenosylhomocysteine hydrolase deficiency was confirmed with homozygous missense variant c.146G>A (p.Arg49His) in the AHCY gene, a genotype previously reported in Pakistani patients with mild presentation. Dietary methionine restriction decreased plasma methionine but not plasma S‐adenosylhomocysteine and S‐adenosylmethionine. This work expands the mild spectrum of S‐adenosylhomocysteine hydrolase deficiency with no noticeable clinical symptoms in children, highlighting a specific hotspot variant from South Asia. This mild form of the disease is likely underdiagnosed and raises the question of therapeutic management to prevent long‐term complications documented in the literature, such as hepatocellular carcinoma and myopathy in early adulthood.

The patent ductus arteriosus is a very common condition in preterm infants, and a hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. However, despite numerous randomized controlled trials, there is no consensus regarding management. Medical therapy is typically offered as first-line treatment, although it yields limited success and carries the potential for severe adverse events. In recent years, there has been rapid development in transcatheter patent ductus arteriosus closure primary with the use of the Amplatzer Piccolo Occluder, and this has gained widespread acceptance as a safe and effective alternative to surgical ligation in extremely low-birth-weight infants weighing over 700 g. This article aims to provide an appraisal of the patient selection process, a step-by-step procedural guide, and a comprehensive review of the outcomes associated with this approach.

Data on the safety and efficiency of perventricular device closure of complex ventricular septal defects (VSDs) are scarce. We report successful one-stage combined hybrid perventricular and percutaneous closure of the muscular VSDs in a critically ill 4-kg infant, using the new multifunctional occluder.

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations.

Medical practitioners are entrusted with the pivotal task of making optimal decisions in healthcare delivery. Despite rigorous training, our confidence in reasoning can fail when faced with pressures, uncertainties, urgencies, difficulties, and occasional errors. Day-to-day decisions rely on swift, intuitive cognitive processes known as heuristic or type 1 decision-making, which, while efficient in most scenarios, harbor inherent vulnerabilities leading to systematic errors. Cognitive biases receive limited explicit discussion during our training as junior doctors in the domain of paediatric cardiology. As pediatric cardiologists, we frequently confront emergencies necessitating rapid decision-making, while contending with the pressures of stress, fatigue, an earnest interest in “doing the right thing” and the impact of parental involvement. This article aims to describe cognitive biases in pediatric cardiology, highlighting their influence on therapeutic interventions for congenital heart disease. Whether future pediatric cardiologists or experienced professionals, understanding and actively combating cognitive biases are essential components of our ongoing medical education. Furthermore, it is our responsibility to thoroughly examine our own practices in our unwavering commitment to providing high-quality care.

Background In academic research and the pharmaceutical industry, in vitro cell lines and in vivo animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have intrinsic limitations, whilst the use of precision-cut tissue slices can bridge the gap between these mainstream models. Precision-cut tissue slices combine the advantage of high reproducibility, studying all cell sub-types whilst preserving the tissue matrix and extracellular architecture, thereby closely mimicking a mini-organ. This approach can be used to replicate the biological phenotype of liver monogenic diseases using mouse models. Methods Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers, enabling its use as a reliable ex-vivo model to assess the therapeutic screening of inherited metabolic diseases Results We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects such as citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. Conclusions Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases.

Abstract Isolated remethylation defects are rare inherited diseases caused by a defective remethylation of homocysteine to methionine, preventing various essential methylation reactions to occur. Patients present with a systemic phenotype, which can especially affect the central and peripheral nervous systems leading to epileptic encephalopathy, developmental delay and peripheral neuropathy. Respiratory failure has been described in some cases, caused by both central and peripheral neurological involvement. In published cases, the genetic diagnosis and initiation of appropriate therapy were rapidly performed following respiratory failure and led to a rapid recovery of respiratory insufficiency within days. Here, we present two infantile‐onset cases of isolated remethylation defects, cobalamine (Cbl)G and methylenetetrahydrofolate reductase (MTHFR) deficiencies, which were diagnosed after several months of respiratory failure. Disease modifying therapy based on hydroxocobalamin and betaine was initiated and shows a progressive improvement and enabled weaning off respiratory support after 21 and 17 months in CblG and MTHFR patients respectively. We show that prolonged respiratory failure responds to conventional therapy in isolated remethylation defects, but can require a sustained period of time before observing a full response to therapy.

BackgroundAdvancements in cardiac imaging have revolutionized our understanding of ventricular contraction. While ejection fraction (EF) is still the gold standard parameter to assess left ventricle (LV) function, strain imaging (SI) has provided valuable insights into ventricular mechanics. The lack of an integrative method including SI parameters in a single, validated formula may limit its use. Our aim was to compare different methods for evaluating global circumferential strain (GCS) and their relationship with global longitudinal strain (GLS) and EF in CMR and how the different evaluations fit in the theoretical relationship between EF and global strain.MethodsRetrospective monocenter study. Inclusion of every patient who underwent a CMR during a 15 months period with various clinical indication (congenital heart defect, myocarditis, cardiomyopathy). A minimum of three LV long-axis planes and a stack of short-axis slices covering the LV using classical steady-state free precession cine sequences. A single assessment of GLS on long axis (LAX) slices and a double assessment of GCS and EF with both short axis (SAX) and LAX slices were made by a single experienced CMR investigator.ResultsGCS-SAX and GCS-LAX were correlated (r = 0.77, P

Background In academic research and the pharmaceutical industry, in vitro cell lines and in vivo animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have intrinsic limitations, whilst the use of precision-cut tissue slices can bridge the gap between these mainstream models. Precision-cut tissue slices combine the advantage of high reproducibility, studying all cell sub-types whilst preserving the tissue matrix and extracellular architecture, thereby closely mimicking a mini-organ. This approach can be used to replicate the biological phenotype of liver monogenic diseases using mouse models. Methods Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers, enabling its use as a reliable ex-vivo model to assess the therapeutic screening of inherited metabolic diseases Results We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects such as citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. Conclusions Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases.

Argininosuccinic aciduria (ASA) is a rare inherited metabolic disease caused by argininosuccinate lyase (ASL) deficiency. Patients with ASA present with hyperammonaemia due to an impaired urea cycle pathway in the liver, and systemic disease with epileptic encephalopathy, chronic liver disease, and arterial hypertension. A human induced pluripotent stem cell (iPSC) line from the fibroblasts of a patient with ASA with homozygous pathogenic c.437G > A mutation of hASL was generated. Characterization of the cell line demonstrated pluripotency, differentiation potential and normal karyotype. This cell line, called UCLi024-A, can be utilized for in vitro disease modelling of ASA, and design of novel therapeutics.

Abstract In urea cycle disorders (UCDs) ammonia scavenger drugs, usually sodium‐based, have been the mainstay of treatment. Increasingly, glycerol phenylbutyrate (GPB, Ravicti®) is being used but scant real‐world data exist regarding clinical outcomes. A retrospective study of UCD patients initiated on or switched to GPB was performed at a UK centre. Data on population characteristics, treatment aspects, laboratory measurements, and clinical outcomes were collected before and after patients started GPB with a sub‐group analysis undertaken for patients with ≥12 months of data before and after starting GPB. UCDs included arginosuccinate synthetase deficiency (n = 8), arginosuccinate lyase deficiency (n = 6), ornithine carbamoyltransferase deficiency (n = 3), and carbamoyl phosphate synthetase 1 deficiency (n = 3). In the sub‐group analysis (n = 11), GPB resulted in lower plasma ammonia (31 vs. 41 μmol/L, p = 0.037), glutamine (670 vs. 838 μmol/L, p = 0.002), annualised hyperammonaemic episodes (0.2 vs. 1.9, p = 0.020), hospitalisations (0.5 vs. 2.2, p = 0.010), and hyperammonaemic episodes resulting in hospitalisation (0.2 vs. 1.6, p = 0.035) reflecting changes seen in the whole group. Overall, patients exposed to sodium and propylene glycol levels above UK daily limits reduced by 78% and 83% respectively. Mean levels of branched chain amino acids, haemoglobin, and white cell count were unchanged. Two adverse drug reactions (pancytopenia, fatigue/appetite loss) resolved without GPB discontinuation. Patients/families preferred GPB for its lower volume, greater palatability and easier administration. GPB appeared to improve biochemical measures and clinical outcomes. The causes are multi‐factorial and are likely to include prolonged action of GPB and its good tolerability, even at higher doses, facilitating tighter control of ammonia.

BackgroundThe Occlutech Atrial Flow Regulator (AFR) is a self-expandable double-disc nitinol device with a central fenestration. Its use has been approved in the adult population with heart failure and described for pulmonary hypertension (PH). Only case reports and small series have been published about its use in the paediatric population and for congenital heart disease (CHD).ObjectivesThe authors sought to investigate the feasibility, safety, and short-term follow-up of AFR implantation in patients with CHD or children with PH or cardiomyopathy.MethodsThis is a multicenter retrospective study involving 10 centers worldwide. Patients of any age with CHD or patients aged

Background In academic research and the pharmaceutical industry, in vitro cell lines and in vivo animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have intrinsic limitations, whilst the use of precision-cut tissue slices can bridge the gap between these mainstream models. Precision-cut tissue slices combine the advantage of high reproducibility, studying all cell sub-types whilst preserving the tissue matrix and extracellular architecture, thereby closely mimicking a mini-organ. This approach can be used to replicate the biological phenotype of liver monogenic diseases using mouse models. Methods Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers, enabling its use as a reliable ex-vivo model to assess the therapeutic screening of inherited metabolic diseases Results We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects such as citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. Conclusions Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases.

Background: Stent implantation has become the preferred method of treatment for treating vessel stenosis in congenital heart diseases. The availability of covered stents may decrease complications and have an important role in the management of patients with complex anatomy. Aim: This study aims to evaluate the feasibility and safety of the pre-mounted cobalt–chromium stent-graft-covered ePTFE Aortic BeGraft in a broad spectrum of vascular lesions. Methods: This is a multicenter retrospective results analysis of 107 implanted BeGraft stents between 2016 and 2022 in six different European centers. Results: One hundred and four patients with a mean age of thirteen years (range 1–70 years) and with the body weight of 56.5 kg (range 11–115 kg) underwent the BeGraft stent implantation. Stents were implanted in the following conditions: aortic coarctation (74 patients), RVOT dysfunction (12 patients), Fontan circulation (7 patients), and miscellaneous (11 subjects with complex CHD). All the stents were implanted successfully. The median stent diameter was 16 mm (range 7–24 mm), and the median length was 39 mm (range 19–49 mm). Major complications occurred in five subjects (4.7%). During a median follow-up of fourteen (1–70) months, stents’ re-dilatation was performed in five patients. Conclusions: The BeGraft stent can be used safely and effectively in a wide spectrum of congenital heart diseases. Whether these good results will be stable in the longer term still needs to be investigated in a follow-up given its recent introduction into clinical practice, in particular regarding stent fracture or neointimal proliferation.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD.We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records.A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6–24) and 66 months (35–156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues.LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Abstract The urea cycle is a liver-based pathway enabling disposal of nitrogen waste. Urea cycle disorders (UCDs) are inherited metabolic diseases caused by deficiency of enzymes or transporters involved in the urea cycle and have a prevalence of 1:35,000 live births. Patients present recurrent acute hyperammonaemia, which causes high rate of death and neurological sequelae. Long-term therapy relies on a protein-restricted diet and ammonia scavenger drugs. Currently, liver transplantation is the only cure. Hence, high unmet needs require the identification of effective methods to model these diseases to generate innovative therapeutics. Advances in both induced pluripotent stem cells (iPSCs) and genome editing technologies have provided an invaluable opportunity to model patient-specific phenotypes in vitro by creating patients’ avatar models, to investigate the pathophysiology, uncover novel therapeutic targets and provide a platform for drug discovery. This review summarises the progress made thus far in generating 2- and 3-dimensional iPSCs models for UCDs, the challenges encountered and how iPSCs offer future avenues for innovation in developing the next-generation of therapies for UCDs.

Persistent patent ductus arteriosus is a very common condition in preterm infants. Although there is no management agreed by consensus, despite numerous randomized controlled trials, hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. Medical treatment is usually offered as first-line therapy, although it carries a limited success rate and potential severe adverse events. In recent years, transcatheter patent ductus arteriosus closure has fast developed and become widely accepted as a safe and efficient alternative to surgical ductal ligation in extremely low birth weight infants >700 g, using most often the dedicated Amplatzer Piccolo Occluder device. This article aims to provide an appraisal of the patients’ selection process, and a step-by-step description of the procedure as well as a comprehensive review of its outcomes.

Abstract Long‐term management of urea cycle disorders (UCDs) often involves unlicensed oral sodium benzoate (NaBz) which has a high volume and unpleasant taste. A more palatable treatment is licenced and available (glycerol phenylbutyrate [GPB], Ravicti) but guidance on how to transition patients from NaBz is lacking. A retrospective analysis of clinical and biochemical data was performed for eight children who transitioned from treatment with a single ammonia scavenger, NaBz, to GPB at a single metabolic centre; UCDs included arginosuccinic aciduria (ASA) (n = 5), citrullinaemia type 1 (n = 2) and carbamoyl phosphate synthetase I deficiency (CPS1) (n = 1). Patients transitioned either by gradual transition over 1–2 weeks (n = 3) or direct replacement of NaBz with GPB (n = 5). Median initial dose of GPB was 8.5 mL/m2/day based on published product information; doses were revisited subsequently in clinic and titrated individually (range 4.5–11 mL/m2/day). Pre‐transition and post‐transition mean ammonia levels were 37 μmol/L (SD 28 μmol/L) and 29 μmol/L (SD 22 μmol/L), respectively (p = 0.09), and mean glutamine levels were 664 μmol/L (SD 225 μmol/L) and 598 μmol/L (SD 185 μmol/L), respectively (p = 0.24). There were no reductions in levels of branched chain amino acids. No related adverse drug reactions were reported. Patients preferred GPB because of its lower volume and greater palatability. Direct replacement of NaBz with GPB maintained metabolic control and was simple for the health service and patients to manage. A more cautious approach with additional monitoring would be warranted in brittle patients and patients whose ammonia levels are difficult to control.

Objectives To evaluate bare-metal Optimus and polytetrafluoroethylene (PTFE)-covered Optimus-CVS balloon-expandable, cobalt–chromium, hybrid cell–designed stents in congenital heart disease (CHD) interventions.Methods Retrospective multicentre review of patients with CHD receiving Optimus stents. Stent mechanical behaviour, clinical indications and outcomes were assessed.Results 183 stents (49.2% XXL/15-ZIG, 33.3% XL/12-ZIG, 17.5% L/9-ZIG) were implanted (98.9% success rate, 2.3% serious procedural complication rate) in 170 patients (57.6% men, 64.1% adults), median age 23.6 years (IQR, 15.2–39.2) and weight 63.5 kg (IQR, 47–75.7). Indications were right ventricular outflow tract stand-alone stenting or before revalvulation (62.4%), aortic coarctation treatment (15.3%), Fontan-circuit fenestration closure (12.4%) and miscellaneous (10%). 86/170 (50.6%) patients had PTFE-covered stenting (50% prophylactic). In 86/170 (50.6%) patients with stenotic lesions, median percentage of achieved stent expansion was 93.4% (IQR, 85.5%–97.7%), median gradient decreased from 28 mm Hg (IQR, 19–41) to 5 mm Hg (IQR, 1–9) (p

X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting the liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite the best-accepted therapy based on ammonia scavengers and protein-restricted diet. Liver transplantation is curative but associated with procedure-related complications and lifelong immunosuppression. Adeno-associated viral (AAV) vectors have demonstrated safety and clinical benefits in a rapidly growing number of clinical trials for inherited metabolic liver diseases. Engineered AAV capsids have shown promising enhanced liver tropism. Here, we conducted a good-laboratory practice-compliant investigational new drug-enabling study to assess the safety of intravenous liver-tropic AAVLK03 gene transfer of a human codon-optimized OTC gene. Juvenile cynomolgus monkeys received vehicle and a low and high dose of vector (2 × 1012 and 2 × 1013 vector genome (vg)/kg, respectively) and were monitored for 26 weeks for in-life safety with sequential liver biopsies at 1 and 13 weeks post-vector administration. Upon completion of monitoring, animals were euthanized to study vector biodistribution, immune responses, and histopathology. The product was well tolerated with no adverse clinical events, predominant hepatic biodistribution, and sustained supra-physiological OTC overexpression. This study supports the clinical deployment of intravenous AAVLK03 for severe OTCD.

Abstract Background Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial. Methods The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease’s clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%. Discussion After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 ( https://clinicaltrials.gov/ct2/show/NCT04712136 ).

Vitamin B12 or cobalamin deficiency is a commonly encountered clinical scenario and most clinicians will have familiarity prescribing Vitamin B12 to treat their patients. Despite the high prevalence of this condition, there is widespread heterogeneity regarding routes, schedules and dosages of vitamin B12 administration. In this review, we summarise the complex metabolic pathway of Vitamin B12, the inherited and acquired causes of Vitamin B12 deficiency and subsequently highlight the disparate international practice of prescribing Vitamin B12 replacement therapy. We describe the evidence base underpinning the novel sublingual, intranasal and subcutaneous modes of B12 replacement in comparison to intramuscular and oral routes, with their respective benefits for patient compliance and cost-saving.

Abstract The use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications. Video Abstract

Context. Pebbles drifting past a disk-embedded low-mass planet develop asymmetries in their distribution and exert a substantial gravitational torque on the planet, thus modifying its migration rate. Aims. Our aim is to assess how the distribution of pebbles and the resulting torque change in the presence of pebble accretion, focusing on its 2D regime. Methods. First, we performed 2D high-resolution multi-fluid simulations with FARGO3D but found that they are impractical for resolving pebble accretion due to the smoothing of the planetary gravitational potential. To remove the smoothing and directly trace pebbles accreted by the planet, we developed a new code, DENEB, which evolves an ensemble of pebbles, represented by Lagrangian superparticles, in a steady-state gaseous background. Results. For small and moderate Stokes numbers, St ≲ 0.1, pebble accretion creates two underdense regions with a front-rear asymmetry with respect to the planet. The underdensity trailing the planet is more extended. The resulting excess of pebble mass in front of the planet then makes the pebble torque positive and capable of outperforming the negative gas torque. Pebble accretion thus enables outward migration (previously thought to occur mainly for St ≳ 0.1) in a larger portion of the parameter space. It occurs for the planet mass Mpl ≲ 3 M⊕ and for all the Stokes numbers considered in our study, St ∈ [10−2, 0.785], assuming a pebble-to-gas mass ratio of Z = 0.01. Conclusions. If some of the observed planets underwent outward pebble-driven migration during their accretion, the formation sites of their progenitor embryos could have differed greatly from the usual predictions of planet formation models. To enable an update of the respective models, we provide a scaling law for the pebble torque that can be readily incorporated in N-body simulations. [ABSTRACT FROM AUTHOR]

This document is a collection of abstracts from the Journal of Neonatal - Perinatal Medicine. The abstracts cover various topics related to neonatal neurodevelopment and brain abnormalities in preterm infants. One study focuses on the use of MRI in predicting long-term outcomes in infants with Hypoxic Ischemic Encephalopathy. Another study explores the prediction of post-hemorrhagic ventricular dilatation in preterm infants with intraventricular hemorrhage. A third study examines the impact of cerebellar hemorrhage on the neurodevelopmental outcomes of extremely preterm infants. The fourth abstract compares the utility of early and late MRI in evaluating infants with Neonatal Encephalopathy. Additionally, there is a study investigating the impact of SARS-CoV-2 infection during pregnancy on neonatal neurological outcomes. Lastly, a study explores the hemodynamic responses associated with spontaneous neural activity in the early developing brain. These abstracts provide valuable insights into neonatal neurodevelopment and brain abnormalities in preterm infants. [Extracted from the article]

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-offunction variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations. [ABSTRACT FROM AUTHOR]

In this paper, we report near-infrared observations of the classical T Tauri star TW Hya with the SPIRou high-resolution spectropolarimeter and velocimeter at the 3.6-m Canada–France–Hawaii Telescope in 2019, 2020, 2021, and 2022. By applying Least-Squares Deconvolution (LSD) to our circularly polarized spectra, we derived longitudinal fields that vary from year to year from –200 to +100 G, and exhibit low-level modulation on the 3.6 d rotation period of TW Hya, despite the star being viewed almost pole-on. We then used Zeeman–Doppler Imaging to invert our sets of unpolarized and circularly polarized LSD profiles into brightness and magnetic maps of TW Hya in all four seasons, and obtain that the large-scale field of this T Tauri star mainly consists of a 1.0–1.2 kG dipole tilted at about 20° to the rotation axis, whereas the small-scale field reaches strengths of up to 3–4 kG. We find that the large-scale field is strong enough to allow TW Hya to accrete material from the disc on the polar regions at the stellar surface in a more or less geometrically stable accretion pattern, but not to succeed in spinning down the star. We also report the discovery of a radial velocity signal of semi-amplitude |$11.1^{+3.3}_{-2.6}$| m s−1 (detected at 4.3σ) at a period of 8.3 d in the spectrum of TW Hya, whose origin may be attributed to either a non-axisymmetric density structure in the inner accretion disc, or to a |$0.55^{+0.17}_{-0.13}$| MꝜ candidate close-in planet (if orbiting in the disc plane), at an orbital distance of 0.075 ± 0.001 au. [ABSTRACT FROM AUTHOR]