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Funder: NIHR Great Ormond Street Hospital Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100019256, OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

Therapeutic options are limited for the management of extremely low-birth-weight infants with critical aortic coarctation despite high doses of prostaglandin infusion. We report successful hybrid, fluoroscopy-free, echocardiography-guided primary stenting of native aortic coarctation in a 920-grams premature infant.

Device-induced aortic obstruction is a known rare complication following transcatheter closure of patent ductus arteriosus in extremely low-birth-weight infants. Various mechanisms have been proposed. We report the first description of late aortic obstruction due to ductal vasoconstriction on pulmonic end causing device to be gradually pushed out of aortic end in a 980-gram premature infant.

In academic research and the pharmaceutical industry,in vitrosingle cell line cultures andin vivoanimal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have limitations, with incomplete reproduction of pathophysiological characteristics and absence of 3-dimensional architecture with cell lines or the use of live animals brings ethical considerations, limiting the experimental scale and design. The use of precision-cut tissue slices can bridge the gap between these mainstream models as this technique combines the advantages of studying all cell sub-types whilst preserving the tissue-matrix architecture, thereby closely mimicking a mini-organ. Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers. 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 citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. 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.

OBJECTIVES The antiarrhythmic effects of dexmedetomidine (DEX) have been suggested, but there are controversial reports on the effectiveness of intraoperative use of DEX to reduce the incidence of postoperative tachyarrhythmia (POT). METHODS From a local European Congenital Heart Surgery Association database, we included patients operated for congenital heart diseases under cardiopulmonary bypass within a 5-year period (2017–2021), during which intraoperative use of high dose of DEX (1–1.4 µg/kg/h) was implemented. A doubly robust matching estimation of the causal effect of DEX on the incidence of POT was conducted. We combined a multimodal estimation model in patients not exposed to DEX (disease risk score) as well as a regression analysis in a matched cohort for patients exposured to DEX. RESULTS From a cohort of 593 surgeries (514 patients) occurring during the study period, doubly matched analysis consisted of the analysis of 426 surgeries conducted under DEX or not (213 per group). The probability of developing POT in patients exposed to DEX was 6.6% (95% confidence interval 0.032–0.099) vs 14.5% (95% confidence interval 0.098–0.193) in the group of patients not exposed to DEX. The doubly robust matched estimation method showed a mean reduction of 8.8% (95% confidence interval −0.137 to −0.023) of POT when DEX is used for intraoperative anaesthesia. CONCLUSIONS The use of high doses of DEX during anaesthesia for congenital heart surgery in neonates and infants is associated with a moderate but significant reduction of POT.

IntroductionThis study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).MethodsClinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.ResultsThe clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.ConclusionThis study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

[abridged] We analyzed mid-infrared high-contrast coronagraphic images of the beta Pictoris system, taking advantage of the NEAR experiment using the VLT/VISIR instrument. The goal of our analysis is to investigate both the detection of the planet beta Pictoris b and of the disk features at mid-IR wavelengths. In addition, by combining several epochs of observation, we expect to constrain the position of the known clumps and improve our knowledge on the dynamics of the disk. To evaluate the planet b flux contribution, we extracted the photometry and compared it to the flux published in the literature. In addition, we used previous data from T-ReCS and VISIR, to study the evolution of the position of the southwest clump that was initially observed in the planetary disk back in 2003. While we did not detect the planet b, we were able to put constraints on the presence of circumplanetary material, ruling out the equivalent of a Saturn-like planetary ring around the planet. The disk presents several noticeable structures, including the known southwest clump. Using a 16-year baseline, sampled with five epochs of observations, we were able to examine the evolution of the clump: the clump orbits in a Keplerian motion with an sma of 56.1+-0.4 au. In addition to the known clump, the images clearly show the presence of a second clump on the northeast side of the disk and fainter and closer structures that are yet to be confirmed. We found correlations between the CO clumps detected with ALMA and the mid-IR images. If the circumplanetary material were located at the Roche radius, the maximum amount of dust determined from the flux upper limit around beta Pictoris b would correspond to the mass of an asteroid of 5 km in diameter. Finally, the Keplerian motion of the southwestern clump is possibly indicative of a yet-to-be-detected planet or signals the presence of a vortex., Comment: Accepted in Astronomy and Astrophysics

Tuberous sclerosis is an autosomal dominant disorder almost fully penetrant with highly variable expression. Most cases are de novo and this diagnosis is sometimes considered during prenatal life in case of cardiac tumor, unique or multiple. The couple should be referred to a specialized tertiary prenatal care center for expertise and information. Fetal molecular testing of the two genes TSC1 and TSC2 is often informative. Prognosis determination for Tuberous Sclerosis remains a difficult task. Cardiac tumors can be sometimes worrying but only a minority will have a pejorative issue and most cases are asymptomatic without any therapeutic intervention needed. Only few cases need surgical or medical treatment. Patients with Tuberous Sclerosis can develop skin, eye, kidney or lung lesions later on, but they are either of limited consequence or treatable. The crux of the matter is the neurological involvement with frequent intellectual deficiency and epilepsy that can be drug-resistant. The absence of lesion on fetal brain MRI is not predictive of any prognosis and does not rule out Tuberous Sclerosis. De novo TSC2 mutation is a negative prognosis factor and conversely, an inherited TSC1 mutation is a more favorable one, but with a severe issue still possible. Facing this cautious prognosis, some couple may opt for termination of pregnancy while others decide to pursue it. It is then fundamental to set cardiac and neurological regular follow-up for these newborns. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

IntroductionArgininosuccinate lyase is integral to the urea cycle, which enables nitrogen waste and biosynthesis of arginine, a precursor of nitric oxide. Inherited argininosuccinate lyase deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy and movement disorder. Here we aim to characterise epilepsy, a common and neurodebilitating complication in argininosuccinic aciduria.Patients and MethodsWe conducted a retrospective study in seven tertiary metabolic centres in the UK, Italy and Canada from 2020 to 2022 to assess the phenotype of epilepsy in ASA and correlate it with clinical, biochemical, radiological and electroencephalographic data.ResultsThirty-seven patients aged 1 to 31 years old were included. Twenty-two (60%) patients presented epilepsy. Median age at epilepsy-onset was 24 months. Generalized tonic clonic and focal seizures were most common in early-onset patients whilst atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and 6 (27%) had partially controlled or refractory epilepsy. Epileptic patients presented with a severe neurodebilitating disease with higher rates of speech delay (p=0.04) and autism spectrum disorders (p=0.01) and more frequent arginine supplementation (p=0.01) compared to non-epileptic patients. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy-onset in early infancy (p=0.05) and electroencephalographic background asymmetry (p=0.0007) were significant predictors of partially controlled or refractory epilepsy.ConclusionsEpilepsy in argininosuccinic aciduria is frequent, polymorphic, associated with more frequent neurodevelopmental complications. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests roles of arginine toxicity and central dopamine deficiency.Key PointsEpilepsy in ASA is frequent, polymorphic, occurring in early childhood and associated with a more severe neurodevelopmental phenotype.Early-onset epilepsy and electroencephalographic background asymmetry are prognostic for pharmaco-resistance of epilepsy in ASA.Hyperammonaemia is suggested not to be the primary pathophysiological mechanism for epileptogenesis in ASA.Central dopamine deficiency is suggested to have a role in pathophysiology of epilepsy in ASA.Arginine-related neurotoxicity is suggested to be associated with increased in frequency and severity of epilepsy in ASA.

Argininosuccinate lyase (ASL) is a key enzyme integral to the hepatic urea cycle which is required for ammonia detoxification, and the citrulline-nitric oxide (NO) cycle for NO production. ASL deficient patients present with argininosuccinic aciduria (ASA), an inherited metabolic disease with hyperammonaemia and a chronic systemic phenotype with neurocognitive impairment and chronic liver disease. ASL deficiency as an inherited model of systemic NO deficiency, shows enhanced nitrosative and oxidative stress. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics andin vivopositron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-L-glutamate ([18F]FSPG). Upregulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways.hASLmRNA encapsulated in lipid nanoparticles corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis and glutathione metabolism and ameliorating chronic liver disease. We further present [18F]FSPG PET as a novel non-invasive diagnostic tool to assess liver disease and therapeutic efficacy in ASA. These findings support clinical translation of mRNA therapy for ASA.

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which model is the most relevant for the selection of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.

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.

With its large sub-mm continuum cavity, asymmetric clumps and spiral arms, the disc of MWC 758 is an ideal test laboratory to search for embedded planets at an early stage of formation and study their dynamical interplay with the disc. As such, two protoplanet candidates have been proposed in this disc by independent teams based on thermal IR high-contrast imaging data, which both require confirmation. In this contribution, I will compare three novel algorithms that we designed to alleviate current shortcomings stemming from the application of state-of-the-art Angular Differential Imaging (ADI)-based algorithms - namely geometric biases induced to azimuthally extended signals from the aggressive modeling and subtraction of the stellar halo. The first algorithm relies on an iterative approach, while the other two rely on an inverse-problem approach, with and without regularisation terms, respectively, to recover the unbiased circumstellar intensity distribution. I will show the images obtained from the application of these algorithms to the case of MWC 758, for which we considered the SPHERE (H23) and NIRC2 (L’) datasets obtained in the best observing conditions for this study. I will then compare these images to predictions from hydro-dynamical simulations testing the hypotheses of a single (internal) eccentric companion, and two giant (internal+external) planets on circular orbits, respectively, and will discuss the likelihood of each scenario based on the similarity to our new images.

Planet-disc interactions build up local pressure maxima that may halt the radial drift of protoplanetary dust, and pile it up in rings and crescents. ALMA observations of the HD135344B disc revealed two rings in the thermal continuum stemming from ~mm-sized dust. At higher frequencies the inner ring is brighter relative to the outer ring, which is also shaped as a crescent rather than a full ring. In near-IR scattered light images, the disc is modulated by a 2-armed grand-design spiral originating inside the ALMA inner ring. Such structures may be induced by a massive companion evacuating the central cavity, and by a giant planet in the gap separating both rings, that channels the accretion of small dust and gas through its filamentary wakes while stopping the larger dust from crossing the gap. Here we present ALMA observations in the J=(2-1)CO isotopologue lines and in the adjacent continuum, with up to 12km baselines. Angular resolutions of 0.03" reveal the tentative detection of a filament connecting both rings, and which coincides with a local discontinuity in the pitch angle of the IR spiral, proposed previously as the location of the protoplanet driving this spiral. Line diagnostics suggest that turbulence, or superposed velocity components, is particularly strong in the spirals. The 12CO(2-1) 3-D rotation curve points at stellocentric accretion at radii within the inner dust ring, with a radial velocity of up to ~6%+-0.5% Keplerian, which corresponds to an excessively large accretion rate of ~2E-6M_sun/yr if all of the CO layer follows the 12CO(2-1) kinematics. This suggests that only the surface layers of the disc are undergoing accretion, and that the line broadening is due to superposed laminar flows., accepted to MNRAS

Objectives This study sought to investigate patient intermediate-term outcomes after transcatheter pulmonary valve replacement (TPVR) with Edwards SAPIEN valve. Background The Edwards SAPIEN valve, initially designed for percutaneous aortic valve replacement, has been approved for TPVR in patients with dysfunctional right ventricular outflow tracts (RVOT), but only short-term follow-up has been reported. Methods From 2011 to 2016, 62 patients undergoing successful TPVR using the SAPIEN XT valve were consecutively included into the study. Primary efficacy and safety endpoints were defined as freedom from valve-reintervention and freedom from infective endocarditis at last follow-up, respectively. Results The primary efficacy outcome was met for 87.1% patients after a mean follow-up of 4.6 ± 1.8 years, corresponding to a freedom of reintervention at 5 years of 89% (95% CI 74.8-95.6%). Reinterventions were exclusively due to recurrent obstruction, no significant valvular regurgitation was observed. One case of infective endocarditis was reported, corresponding to a rate of 0.35% per patient-year (95% CI 0.01-2.00%). At 5 years, freedom from infective endocarditis was 98.4% (95% CI 89.1-99.8%). Six patients died or were transplanted due to advanced cardiac failure, without relationship with TPVR. In univariate analysis, reintervention was associated with young age, a smaller tube-graft, a higher pulmonary valve gradient after the procedure and a ratio of largest implanted stent diameter to invasive balloon conduit diameter over 1.35. Conclusions This study documents the mid-term safety and efficacy of the Edwards SAPIEN XT valve in patients with dysfunctional RVOT, and identifies a patient profile associated with an uncertain benefit-risk balance.

L’objectif de ce papier vise a montrer que Doctrine Sociale de l’Eglise et principes de l’Entreprise Liberee reposent sur certains fondements anthropologiques et sociaux communs, mais qu’ils presentent des divergences significatives. Une etude exploratoire analysant les discours de dirigeants catholiques ayant mene des transformations de leur entreprise, inspirees par les preceptes du management dit « libere », permet de mieux apprehender ce constat d’un point de vue empirique et d’interroger plus generalement les conceptions de la gouvernance qui en decoulent.

OBJECTIVES Diaphragmatic paralysis following congenital cardiac surgery is associated with significant morbidity and mortality. Spontaneous recovery of diaphragmatic function has been described, contrasting with centres providing early diaphragmatic plication. We aimed to describe the outcomes of a conservative approach, as well as to identify factors associated with a failure of the strategy. METHODS This is a retrospective study of patients admitted after cardiac surgery and suffering unilateral diaphragmatic paralysis within 2 French Paediatric Cardiac Surgery Centers. The conservative approach, defined by the prolonged use of ventilation until successful weaning from respiratory support, was the primary strategy adopted in both centres. In case of unsuccessful evolution, a diaphragmatic plication was scheduled. Total ventilation time included invasive and non-invasive ventilation. Diaphragm asymmetry was defined by the number of posterior rib segments counted between the 2 hemi-diaphragms on the chest X-ray after cardiac surgery. RESULTS Fifty-one neonates and infants were included in the analysis. Patients’ median age was 12.0 days at cardiac surgery (5.0–82.0), and median weight was 3.5 kg (2.8–4.9). The conservative approach was successful for 32/51 patients (63%), whereas 19/51 patients (37%) needed diaphragm plication. There was no difference in patients’ characteristics between groups. Respiratory support prolonged for 21 days or more and diaphragm asymmetry more than 2 rib segments were independently associated with the failure of the conservative strategy [odds ratio (OR) 6.9 (1.29–37.3); P = 0.024 and OR 6.0 (1.4–24.7); P = 0.013, respectively]. CONCLUSIONS The conservative approach was successful for 63% of the patients. We identified risk factors associated with the strategy’s failure.

We report the exceptional case of transcatheter treatment of a partial anomalous pulmonary venous drainage of the right lung to the innominate vein and dual drainage to the left atrium.

Background: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. Methods: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. Results: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. Conclusions: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Background Posterior fossa abnormalities (PFAs) are commonly identified within routine screening and are a frequent indication for fetal magnetic resonance imaging (MRI). Although biometric measurements of the posterior fossa (PF) are established on fetal ultrasound and MRI, qualitative visual assessments are predominantly used to differentiate PFAs. Objectives This systematic review aimed to assess 2-dimensional (2D) biometric measurements currently in use for assessing the PF on fetal MRI to delineate different PFAs. Methods The protocol was registered (PROSPERO ID CRD42019142162). Eligible studies included T2-weighted MRI PF measurements in fetuses with and without PFAs, including measurements of the PF, or other brain areas relevant to PFAs. Results 59 studies were included - 6859 fetuses had 62 2D PF and related measurements. These included linear, area and angular measurements, representing measures of PF size, cerebellum/vermis, brainstem, and supratentorial measurements. 11 measurements were used in 10 or more studies and at least 1200 fetuses. These dimensions were used to characterise normal for gestational age, diagnose a range of pathologies, and predict outcome. Conclusion A selection of validated 2D biometric measurements of the PF on fetal MRI may be useful for identification of PFA in different clinical settings. Consistent use of these measures, both clinically and for research, is recommended.

Summary Background Closure of patent foramen ovale is well-managed in adults, but is performed less frequently in children. Aim To analyse all patent foramen ovale closures performed in the past 20 years in French paediatric centres. Methods Retrospective study of patent foramen ovale closures in children without cardiopathy in nine centres between 2000 and 2019. Results Forty-one procedures were carried out in children (median age: 14.9 years). Thirty-one patent foramen ovales were closed after a transient ischaemic attack or stroke, six for a left-to-right shunt and four for other reasons. Transthoracic echocardiography was used for 72.2% of the diagnoses and transoesophageal echocardiography for 27.8%. A substantial degree of shunting was found in 42.9% of patients and an atrial septal aneurysm in 56.2%. General anaesthesia with transoesophageal echocardiography guidance was performed in 68.3% of the procedures; local anaesthesia and transthoracic echocardiography or intracardiac echocardiography was performed in 31.7%. The success rate was 100%. The median fluoroscopy time was 4.14 minutes: 3.55 minutes with transoesophageal echocardiography; and 4.38 minutes with transthoracic echocardiography (P = 0.67). There was only one periprocedural complication (2.4%). Postoperatively, 80,5% of patients were treated with aspirin and 12,2% with an anticoagulant. The rate of complete occlusion was 56.8% immediately after the procedure, 68.6% at 1 year and 92.3% at the last follow-up. There were no delayed complications or cases of recurrent stroke during follow-up (median follow-up: 568 days). Conclusion Closure of patent foramen ovale in children appears to be safe and effective, as we noted a low rate of immediate complications, no delayed complications and no stroke recurrence in this indication.

ObjectivesTo evaluate bare-metal Optimus and polytetrafluoroethylene (PTFE)-covered Optimus-CVS balloon-expandable, cobalt–chromium, hybrid cell–designed stents in congenital heart disease (CHD) interventions.MethodsRetrospective multicentre review of patients with CHD receiving Optimus stents. Stent mechanical behaviour, clinical indications and outcomes were assessed.Results183 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) (pConclusionsOptimus stents are effective tools for transcatheter treatment of simple and complex CHD. Optimus stents’ reliable mechanical behaviour and particular covering design can promote widespread use.

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin‐1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell‐penetrating autophagy‐inducing Tat‐Beclin‐1 (TB‐1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB‐1 reduced urinary orotic acid and improved survival under protein‐rich diet in spf‐ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB‐1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin‐1‐dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle., Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle.

5 pags., 3 figs., AB Aur is a Herbig Ae star hosting a well-known transitional disk. Because of its proximity and low inclination angle, it is an excellent object to study planet formation. Our goal is to investigate the chemistry and dynamics of the molecular gas component in the AB Aur disk, and its relation with the prominent horseshoe shape observed in continuum mm emission. We used the Northern Extended Milimeter Array interferometer to map with high angular resolution the J = 3-2 lines of HCO and HCN. By combining both, we can gain insight into the AB Aur disk structure. Chemical segregation is observed in the AB Aur disk: HCO shows intense emission toward the star position, at least one bright molecular bridge within the dust cavity, and ring-like emission at larger radii, while HCN is only detected in an annular ring that is coincident with the dust ring and presents an intense peak close to the dust trap. We use HCO to investigate the gas dynamics inside the cavity. The observed bright HCO bridge connects the compact central source with the outer dusty ring. This bridge can be interpreted as an accretion flow from the outer ring to the inner disk/jet system proving gas accretion through the cavity., We thank the Spanish MINECO for funding support from AYA2016- 75066-C2-1/2-P, AYA2012-32032 and ERC under ERC- 2013-SyG, G. A. 610256 NANOCOSMOS. This work was supported by the Programme National “Physique et Chimie du Milieu Interstellaire” (PCMI) of CNRS/INSU with INC/INP co-funded by CEA and CNES. S.P.T.M. acknowledges to the European Union’s Horizon 2020 research and innovation program for funding support given under grant agreement No. 639459 (PROMISE).

International audience; BACKGROUND: Prolonged occupational agricultural exposure is associated with an increase in asthma diagnosis. This study aimed to identify the prevalence and risk factors for asthma in dairy farmers. METHODS: AIRBAg was a cross-sectional study including 1203 representative dairy farmers. They completed a self-administered questionnaire and underwent a health respiratory check-up. Referral to a pulmonologist was made for any participant with wheezing, dyspnoea, chronic bronchitis, a chronic cough or a FEV(1)/FEV(6) ratio

Gas giant planets are turbulent rotating magnetic objects that have strong and complex interactions with their environment. In such systems, the dissipation of tidal waves excited by tidal forces shape the orbital architecture and the rotational dynamics of the planets. During the last decade, a revolution has occurred for our understanding of tides in these systems and for our knowledge of the interiors of giant planets thanks to the space mission JUNO and the grand finale of the CASSINI mission. Our objective is thus to predict tidal dissipation using internal structure models, which agree with these latest observational constrains. To accomplish that, we build a new ab-initio model of tidal dissipation in giant planets that coherently takes into account the interactions of tidal waves with their complex structure. This model is a semi-global model in the planetary equatorial plane. We study the linear excitation of tidal (magneto-)gravito-inertial progressive waves and standing modes. We present here the general formalism and the potential regimes of parameters that should be explored. This will pave the way for full 3D numerical simulations that will take into account complex internal structure and dynamics of gasgiant (exo-)planets.

Isoproterenol stress test during cardiac catheterization unmasked dynamic bulbo-ventricular foramen restriction in a 5-year-old boy with bidirectional Glenn anastomosis for tricuspid atresia/transposed great arteries and unexplained syncope.

Differential diagnosis of isolated single neurocysticercosis can be difficult, and management is controversial. We report here an original surgical strategy, and review previous studies reporting misdiagnosis, using the PRISMA guidelines. A 24-year-old man was admitted to our hospital for recent memory impairment, hypoesthesia of the right hand, and recurrent focal seizures without loss of consciousness. Brain MRI revealed a single ring-enhancing parenchymal lesion in the left superior postcentral gyrus, with large perilesional edema. Since exhaustive systemic exploration was negative, surgical resection of the lesion was decided on in a multidisciplinary team meeting. To preserve eloquent brain areas, surgery was performed in awake condition. It allowed complete resolution of clinical manifestations. The diagnosis of neurocysticercosis was confirmed on pathology. This case illustrates the utility of awake surgery in degenerating neurocysticercosis in functional areas, and emphasizes the importance of including it in differential diagnosis of cystic ring-enhancing brain lesions.

The Solar System gas giants are each surrounded by many moons, with at least 50 prograde satellites thought to have formed from circumplanetary material. Just like the Sun is not the only star surrounded by planets, extrasolar gas giants are likely surrounded by satellite systems. Here, we report on ALMA observations of four, 6 pages, 3 figures, accepted for publication in MNRAS

For the shortest period exoplanets, star-planet tidal interactions are likely to have played a major role in the ultimate orbital evolution of the planets and on the spin evolution of the host stars. Although low-mass stars are magnetically active objects, the question of how the star’s magnetic field impacts the excitation, propagation and dissipation of tidal waves remains open. We have derived the magnetic contribution to the tidal interaction and estimated its amplitude throughout the structural and rotational evolution of low-mass stars (from K to F-type). We find that the star’s magnetic field has little influence on the excitation of tidal waves in nearly circular and coplanar Hot-Jupiter systems, but that it has a major impact on the way waves are dissipated.

The Centre for Medical Image Computing (CMIC) at University College London (UCL) hosted a two-day workshop on placenta imaging on April 12th and 13th 2018. The workshop consisted of 10 invited talks, 3 contributed talks, a poster session, a public interaction session and a panel discussion about the future direction of placental imaging. With approximately 50 placental researchers in attendance, the workshop was a platform for engineers, clinicians and medical experts in the field to network and exchange ideas. Attendees had the chance to explore over 20 posters with subjects ranging from the movement of blood within the placenta to the efficient segmentation of fetal MRI using deep learning tools. UCL public engagement specialists also presented a poster, encouraging attendees to learn more about how to engage patients and the public with their research, creating spaces for mutual learning and dialogue.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls.METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis.RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS.CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

The sulfur abundance is poorly known in most environments. Yet, deriving the sulfur abundance is key to understanding the evolution of the chemistry from molecular clouds to planetary atmospheres. We present observations of H$_2$S 110-101 at 168.763 GHz toward the Herbig Ae star AB Aur. We aim to study the abundance of sulfuretted species toward AB Aur and to constrain how different species and phases contribute to the sulfur budget. We present new NOrthern Extended Millimeter Array (NOEMA) interferometric observations of the continuum and H$_2$S 110-101 line at 168.763 GHz toward AB Aur. We derived radial and azimuthal profiles and used them to compare the geometrical distribution of different species in the disk. Assuming local thermodynamical equilibrium (LTE), we derived column density and abundance maps for H$_2$S, and we further used Nautilus to produce a more detailed model of the chemical abundances at different heights over the mid-plane at a distance of r=200 au. We have resolved H$_2$S emission in the AB Aur protoplanetary disk. The emission comes from a ring extending from 0.67 (109 au) to 1.69 (275 au). Under simple assumptions, we derived an abundance of (3.1$\pm$0.8)$\times$10$\rm ^{-10}$ with respect to H nuclei, which we compare with Nautilus models to deepen our understanding of the sulfur chemistry in protoplanetary disks. Chemical models indicate that H$-2$S is an important sulfur carrier in the solid and gas phase. We also find an important transition at a height of 12 au, where the sulfur budget moves from being dominated by ice species to being dominated by gas species. Studying sulfuretted species in detail in the different phases of the interstellar medium is key to solving the issue., 11 pages, 14 figures, 4 tables

Gaseous giant planets (Jupiter and Saturn in our solar system and hot Jupiters around other stars) are turbulent rotating magnetic objects that have strong and complex interactions with their environment (their moons in the case of Jupiter and Saturn and their host stars in the case of hot Jupiters/Saturns). In such systems, the dissipation of tidal waves excited by tidal forces shape the orbital architecture and the rotational dynamics of the planets. During the last decade, a revolution has occurred for our understanding of tides in these systems. First, Lainey et al. (2009, 2012, 2017) have measured tidal dissipation stronger by one order of magnitude than expected in Jupiter and Saturn. Second, unexplained broad diversity of orbital architectures and large radius of some hot Jupiters are observed in exoplanetary systems. Finally, new constraints obtained thanks to Kepler/K2 and TESS indicate that tidal dissipation in gaseous giant exoplanets is weaker than in Jupiter and in Saturn (Ogilvie 2014, Van Eylen et al. 2018, Huber et al. 2019). Furthermore, the space mission JUNO and the grand finale of the CASSINI mission have revolutionized our knowledge of the interiors of giant planets. We now know, for example, that Jupiter is a very complex planet: it is a stratified planet with, from the surface to the core, a differentially rotating convective envelope, a first mixing zone (with stratified convection), a uniformly rotating magnetised convective zone, a second magnetized mixing zone (the diluted core, potentially in stratified convection) and a solid core (Debras & Chabrier 2019). So far, tides in these planets have been studied by assuming a simplified internal structure with a stable rocky and icy core (Remus et al. 2012, 2015) and a deep convective envelope surrounded by a thin stable atmosphere (Ogilvie & Lin 2004) where mixing processes, differential rotation and magnetic field were completely neglected. Our objective is thus to predict tidal dissipation using internal structure models, which agree with these last observational constrains. In this work, we build a new ab-initio model of tidal dissipation in giant planets that coherently takes into account the interactions of tidal waves with their complex stratification induced by the mixing of heavy elements, their zonal winds, and (dynamo) magnetic fields. This model is a semi-global model in the planetary equatorial plane. We study the linear excitation of tidal magneto-gravito-inertial progressive waves and standing modes. We take into account the buoyancy, the compressibility, the Coriolis acceleration (including differential rotation), and the Lorentz force. The tidal waves are submitted to the different potential dissipative processes: Ohmic, thermal, molecular diffusivities, and viscosity. We here present the general formalism and the potential regimes of parameters that should be explored. The quantities of interest such as tidal torque, dissipation, and heating are derived. This will pave the way for full 3D numerical simulations that will take into account complex internal structure and dynamics of gaseous giant (exo-)planets in spherical/spheroidal geometry.

The aim of this study was to assess the diagnostic performances ofPPVE is a major issue in the growing CHD population. Diagnosis is challenging, and usual imaging tools are not always efficient or validated in this specific population. Particularly, the diagnostic yield ofA retrospective multicenter study was conducted in 8 French tertiary centers. Children and adult CHD patients who underwentA total of 66 cases of PPVE suspicion involving 59 patients (median age 23 years, 73% men) were included. Sensitivity, specificity, positive predictive value, and negative predictive value ofUsing

Over 4000 exoplanets have been discovered in the past 25 years or so, most of which orbit cool stars. Star-planet tidal interactions are known to drive the late evolution of the shortest-period planetary systems via tidal dissipation. Such dissipation is known to vary considerably with the mass, age, rotation, and metallicity of the star. To quantify tidal dissipation as accurately as possible, two key physical mechanisms need to be further explored : stellar differential rotation and magnetism in convective regions, which have been constrained in cool stars by ground-based spectropolarimetric observations as well as space-based asteroseismic observations. In this contribution, we report our recent progress on the investigation of the impact of stellar differential rotation and magnetism on the dynamics and dissipation of tidal inertial waves, along the evolution of low-mass stars. First, we show that a large-scale magnetic field has a negligible effect on the excitation of tidal waves whereas it deeply impacts the dissipation mechanism of tidal waves in the convective envelope of all cool stars all along their evolution. Then, by developing a local shearing box model of a small patch of the convective shell, we demonstrate how tidal waves can be either fully transmitted, damped, or even amplified at the so-called critical layers (when the phase speed of the wave is equal to the local velocity of the fluid), that has potentially strong implications for angular momentum exchanges between tidal waves and zonal flows, and ultimately for the evolution of planetary systems., {"references":["Lin & Ogilvie (2019). DOI:10.1093/mnras/stx2764","Amard et al. (2019). DOI: 10.1051/0004-6361/201935160","See et al. (2019). DOI: 10.3847/1538-4357/ab46b2","Astoul et al. (2019). DOI: 10.1051/0004-6361/201936477","Brun et al. (2017). DOI: 10.3847/1538-4357/aa5c40","Astoul et al. (2021). DOI: 10.1051/0004-6361/202039148"]}

Isoproterenol stress test during cardiac catheterization unmasked dynamic bulbo-ventricular foramen restriction in a 5-year-old boy with bidirectional Glenn anastomosis for tricuspid atresia/transposed great arteries and unexplained syncope.