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Aims Acute decompensated heart failure (ADHF), a live‐threatening complication of heart failure (HF), associates a further decrease of the already by HF‐impaired cardiac function with an increase in heart rate. We evaluated, using a new model of ADHF, whether heart rate reduction (HRR) opposes the acute decompensation‐related aggravation of cardiovascular dysfunction. Methods and results Cardiac output (echocardiography), cardiac tissue perfusion (magnetic resonance imaging), pulmonary wet weight, and in vitro coronary artery relaxation (Mulvany) were assessed 1 and 14 days after acute decompensation induced by salt‐loading (1.8 g/kg, PO) in rats with well‐established HF due to coronary ligation. HRR was induced by administration of the If current inhibitor S38844, 12 mg/kg PO twice daily for 2.5 days initiated 12 h or 6 days after salt‐loading (early or delayed treatment, respectively). After 24 h, salt‐loading resulted in acute decompensation, characterized by a reduction in cardiac output (HF: 130 ± 5 mL/min, ADHF: 105 ± 8 mL/min; P

ObjectiveTo evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.MethodsFrench patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.ResultsEighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved (p< 0.0001 andp= 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved (p= 0.0007). Severe sepsis (p= 0.011) and intensive care unit admission (p= 0.001) before LT were significantly associated with death.ConclusionsLT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.Classification of evidenceThis study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.

Background Congenital chloride diarrhoea [CLD] is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 [SLC26A3] gene. Patients suffer from life-long watery diarrhoea and chloride loss. Inflammatory bowel disease [IBD] has been reported in individual patients with CLD and in scl26a3-deficient mice. Methods We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD. Results In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients [17%] diagnosed with IBD. Nine patients had Crohn’s disease, two ulcerative colitis and one IBD-unclassified [IBD-U]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5–23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 12 patients had required surgery [ileostomy formation n = 2, ileocaecal resection due to ileocaecal valve stenosis n = 1 and colectomy due to stage II transverse colon cancer n = 1]. At last follow-up, 5/12 were on biologics [adalimumab, infliximab or vedolizumab], 5/12 on immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment. Conclusions A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

Background/aim The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. Methods Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. Results Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1–18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p Conclusion p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.

OBJECTIVES To describe a cohort of Wilson disease (WD) pediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome. METHODS Clinical data of 182 pediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered. RESULTS Diagnosis of WD was made at a mean age of 10.7 ± 4.2 years (range 1-18 years). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least 1 year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2 μmol/24 hours (0.2-253). The first-line treatment was d-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33 of 39 patients or for neurological deterioration in 6 of 39 patients, mean Unified Wilson's Disease Rating Scale of the latter went from 90 ± 23.1 before liver transplantation (LT) to 26.8 ± 14.1 (P

Background & Aims A single point mutation in the Z-variant of alpha 1-antitrypsin (Z-AAT) alone can lead to both a protein folding and trafficking defect, preventing its exit from the endoplasmic reticulum (ER), and the formation of aggregates that are retained as inclusions within the ER of hepatocytes. These defects result in a systemic AAT deficiency (AATD) that causes lung disease, whereas the ER-retained aggregates can induce severe liver injury in patients with ZZ-AATD. Unfortunately, therapeutic approaches are still limited and liver transplantation represents the only curative treatment option. To overcome this limitation, a better understanding of the molecular basis of ER aggregate formation could provide new strategies for therapeutic intervention. Methods Our functional and omics approaches here based on human hepatocytes from patients with ZZ-AATD have enabled the identification and characterisation of the role of the protein disulfide isomerase (PDI) A4/ERP72 in features of AATD-mediated liver disease. Results We report that 4 members of the PDI family (PDIA4, PDIA3, P4HB, and TXNDC5) are specifically upregulated in ZZ-AATD liver samples from adult patients. Furthermore, we show that only PDIA4 knockdown or alteration of its activity by cysteamine treatment can promote Z-AAT secretion and lead to a marked decrease in Z aggregates. Finally, detailed analysis of the Z-AAT interactome shows that PDIA4 silencing provides a more conducive environment for folding of the Z mutant, accompanied by reduction of Z-AAT-mediated oxidative stress, a feature of AATD-mediated liver disease. Conclusions PDIA4 is involved in AATD-mediated liver disease and thus represents a therapeutic target for inhibition by drugs such as cysteamine. PDI inhibition therefore represents a potential therapeutic approach for treatment of AATD. Lay summary Protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. PDI inhibition upon cysteamine treatment leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease., Graphical abstract, Highlights • PDIA4 is upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. • Knockdown of PDIA4 by siRNA or inhibition upon cysteamine treatment leads to improvements in features of AATD. • RNA interference against PDIA4 or cysteamine represent approaches for treatment of AATD-mediated liver disease.

A gain-of-function missense variant in the CELA3B gene, p.Arg90Cys (c.268C>T), has recently been reported to cause pancreatitis in an extended pedigree. Herein, we sequenced the CELA3B gene in 644 genetically unexplained French chronic pancreatitis (CP) patients (all unrelated) and 566 controls. No predicted loss-of-function variants were identified. None of the six low frequency or common missense variants detected showed significant association with CP. Nor did the aggregate rare/very rare missense variants (n=14) show any significant association with CP. However, p.Arg90Leu (c.269G>T), which was found in 4 patients but no controls and affects the same amino acid as p.Arg90Cys, serves to revert p.Arg90 to the human elastase ancestral allele. Since p.Arg90Leu has previously been shown to exert a similar functional effect to p.Arg90Cys, our findings not only confirm the involvement of CELA3B in the etiology of CP but also pinpoint a new evolutionarily adaptive site in the human genome.

International audience; The presence of modifier genes is now well recognized in severe liver disease outcome associated with alpha-1-antitrypsin deficiency (A1ATD) but their identification remains to be fully elucidated. To address this goal, we performed a candidate gene study with the SORL1 gene, already identified as risk gene in early-onset Alzheimer Disease families. A particular SORL1 micro-haplotype constituted with 3 SNPs (wild-type form TTG) was genotyped on 86 ZZ A1ATD children issued from 66 families. Interestingly, the mutated forms of this micro-haplotype (CAT most of the time) were associated with lower occurrence of severe liver disease and in cellulo studies showed that SORL1 influences Z-A1ATD cellular toxicity and biogenesis. These data suggest that the mutated CAT form of SORL1 micro-haplotype may partly prevent from severe liver disease in A1ATD children. Overall, these findings support a replication study on an independent cohort and additional in cellulo studies to confirm these promising results.Trial registration: ClinicalTrials.gov NCT01862211.

International audience; Familial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result in a defect in the synthesis or secretion of lipoproteins containing apolipoprotein B.In children, these conditions present with diarrhoea and growth failure, whereas adults present with neuromuscular, ophthalmological, and hepatic symptoms. Simple laboratory investigations have shown that diagnosis can be made from findings of dramatically decreased cholesterol levels, deficiencies in fat-soluble vitamins (mostly vitamin E), endoscopic findings of the characteristic white intestinal mucosa, and fat-loaded enterocytes in biopsy samples. Genetic analysis is used to confirm the diagnosis. Treatment is based on a low-fat diet with essential fatty acid supplementation, high doses of fat-soluble vitamins, and regular and life-long follow-up.The present study examines cases and literature findings of these conditions, and emphasises the need to explore severe hypocholesterolemia and deficiencies in fat-soluble vitamins to not miss these rare, but easy to diagnose and treat, disorders.

International audience; Proprotein convertase 1 (PCSK1, PC1/3) deficiency is an uncommon cause of neonatal malabsorptive diarrhoea associated with endocrinopathies that are due to the disrupted processing of a large number of prohormones, including proinsulin. To date, only 26 cases have been reported. Herein, we describe two siblings with typical features including severe congenital diarrhoea, central diabetes insipidus, growth hormone deficiency, and hypoadrenalism. Next generation sequencing found a homozygous missense mutation in exon 5 of PCSK1 gene, c.500A\textgreaterC (p.Asp167Ala), located within the catalytic domain. Both patients presented a high level of proinsulin. In the first years of life they required parenteral nutrition and hormone replacement therapy. The patients, aged 3 and 1.5 years, experienced several infectious episodes associated with septic shocks. While the mechanism underlying intestinal failure remains poorly investigated, parenteral nutrition is essential in order to ensure normal growth in early childhood.

Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are rare indications for liver transplantation (LT) in children. The aim of the present retrospective multicenter study was to evaluate long-term outcome after LT for autoimmune liver disease in childhood.Retrospective data from 30 children who underwent a first LT from 1988 to 2018 were collected.The study population consisted of 18 girls and 12 boys, transplanted for AIH type 1 (n=14), AIH type 2 (n=7) or PSC (n=9). Mean age at LT was 11.8±5.2 years. The main indications for LT were acute (36.7%) or chronic end-stage liver failure (63.3%). Graft rejection occurred in 19 patients (63.3%); 6 pts required retransplantation for chronic rejection. Recurrence of initial disease was observed in 6 patients (20.0%), all of them with type 1 AIH, after a median time of 42 months, requiring retransplantation in 2 cases. Overall patient survival rates were 96.4%, 84.6%, 74.8%, 68.0%, 68.0%, 68.0% and 68.0% at 1, 5, 10, 15, 20, 25 and 30 years, respectively. Age at LT1year (p0.0001), LT for fulminant failure (p=0.023) and LT for type 2 AIH (p=0.049) were significant predictive factors of death.Long-term outcome after LT for pediatric autoimmune liver disease is impaired in patients with AIH because of consistent complications such as rejection and disease recurrence.

International audience; Introduction: Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with alpha1 antitrypsin (A1AT) deficiency. The aim of the present retrospective study was to report on long-term outcomes following LT for A1AT deficiency.Methods: The medical records of 90 pediatric and adult patients transplanted between 1982 and 2017 in France and Geneva (Switzerland) were reviewed.Results: The study population consisted of 32 adults and 58 children; median age at transplant was 13.0 years (range: 0.2-65.1), and 65 were male (72.2%). Eighty-two patients (94.8% of children and 84.4% of adults) had the PI*ZZ genotype/phenotype and eight patients (8.9%) had the Pi*SZ genotype/phenotype. Eighty-four patients (93.3%) were transplanted for end-stage liver disease and six (all Pi*ZZ adults) for HCC. Median follow-up after LT was 13.6 years (0.1-31.7). The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years respectively. The overall cumulative graft survival rates were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively.Conclusions: In a representative cohort of patients having presented with end-stage-liver disease or HCC secondary to A1AT, liver transplantation offered very good patient and graft survival rates.

Summary Background Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. Methods ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1–18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0–4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. Findings Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference –117 μmol/L, 95% CI –232 to –2). From baseline to week 48, sBA (–96 μmol/L, –162 to –31) and pruritus (–1·6 pts, –2·1 to –1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. Interpretation In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Funding Mirum Pharmaceuticals.

Background Liver transplantation (LT) is a standard-of-care therapeutic modality for selected patients with life-threatening liver disease, including children. In addition to specific clinical characteristics of pediatric LT recipients due to initial liver disease (and related comorbidities) and level of liver failure, early postoperative outcome may be dependent on the surgical technique used, related to the type of organ donor and graft. Therefore, the aims of the present retrospective study from a large single centre cohort were to identify the prognostic factors for both 1-year patient and graft survival. Methods Between October 1990 and October 2010, 151 children underwent a first LT in our centre. Results The mean age was 5.3 ± 7.4 years, and the main indication was biliary atresia (BA) (49.0%). Living donor liver transplantation (LDLT) was performed in 39 cases (25.8%). Cadaveric liver graft was a whole liver in 50 cases (33.1%) and a partial liver (reduced or split) in 62 cases (41.1%). One-year patient and graft survival rates were 88.7% and 86.1%, respectively. Multivariate analysis disclosed that initial liver disease, location at time of LT, donor/recipient (D/R) delta age, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with patient survival and that D/R delta age, primary non-function, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with graft survival. Conclusion The results of our single-centre experience of pediatric LT emphasize that early patient and graft survivals depend on pre-operative/operative factors such as initial liver disease, D/R delta age and immunosuppressive regimen. Awareness of these factors can help in the decision making for children requiring LT.

SummaryWhether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across species and techniques, we recorded intracerebral activity from twenty patients with epilepsy while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlated positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA increased with both outcome (reward or punishment versus nothing) and surprise (how unexpected the outcome is). However, some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex) were more sensitive to reward PE, whereas others (such as the anterior insula and dorsolateral prefrontal cortex) were more sensitive to punishment PE. Thus, opponent systems in the human brain might mediate the repetition of rewarded choices and the avoidance of punished choices.

BACKGROUND Trichosporonosis is a rare invasive infection in humans mainly due to Trichosporon asahii, and especially recovered from patients having haematological malignancy. Since 2012, IGS1 region sequencing is used as a genotyping method to distinguish isolates, with high frequency of one haplotype worldwide and a geographic specificity for some haplotypes. OBJECTIVES We compared the IGS1 genotyping method and whole genome sequencing (WGS) to study the relationship between clinical isolates involved in two grouped cases in France. METHODS IGS1 sequencing and antifungal susceptibility testing were performed for 54 clinical isolates. Clinical data for 28 isolates included in surveillance programs were analysed. Whole genome was sequenced for 32 clinical isolates and the type strain. RESULTS All isolates were intrinsically resistant to flucytosine, while voriconazole had the most potent in vitro activity. The majority of the isolates was recovered from patients with haematological malignancies (42.86%), with a high proportion of children (

Introduction Imeglimin, a glucose‐lowering agent targeting mitochondrial bioenergetics, decreases reactive oxygen species (ROS) overproduction and improves glucose homeostasis. We investigated whether this is associated with protective effects on metabolic syndrome‐related left ventricular (LV) and vascular dysfunctions. Methods We used Zucker fa/fa rats to assess the effects on LV function, LV tissue perfusion, LV oxidative stress and vascular function induced by imeglimin administered orally for 9 or 90 days at a dose of 150 mg/kg twice daily. Results Compared to untreated animals, 9‐ and 90‐day imeglimin treatment decreased LV end‐diastolic pressure and LV end‐diastolic pressure‐volume relation, increased LV tissue perfusion and decreased LV ROS production. Simultaneously, imeglimin restored acetylcholine‐mediated coronary relaxation and mesenteric flow‐mediated dilation. One hour after imeglimin administration, when glucose plasma levels were not yet modified, imeglimin reduced LV mitochondrial ROS production and improved LV function. Ninety‐day imeglimin treatment reduced related LV and kidney fibrosis and improved kidney function. Conclusion In a rat model, mimicking Human metabolic syndrome, imeglimin immediately countered metabolic syndrome‐related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion and after 90‐day treatment myocardial and kidney structure, effects that are, at least in part, independent from glucose control., This study shows that imeglimin, the 1st representative of the new class of oral antidiabetic agents, glimins, immediately countered metabolic syndrome‐related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion, and over the long term by countering myocardial and kidney structural modifications, effects that are at least in part, independent from glucose control.

OBJECTIVE The authors assessed the clinical relevance of preoperative task-induced high-frequency activity (HFA) for language mapping in patients with refractory epilepsy during stereoelectroencephalography recording. Although HFA evaluation was described as a putative biomarker of cognition, its clinical relevance for mapping language networks was assessed predominantly by studies using electrocorticography (ECOG). METHODS Forty-two patients with epilepsy who underwent intracranial electrode implantation during both task-induced HFA and direct cortical stimulation (DCS) language mapping were evaluated. The spatial and functional relevance of each method in terms of specificity and sensitivity were evaluated. RESULTS The results showed that the two methods were able to map classic language regions, and a large and bilateral language network was obtained with induced HFA. At a regional level, differences were observed between methods for parietal and temporal lobes: HFA recruited a larger number of cortical parietal sites, while DCS involved more cortical temporal sites. Importantly, the results showed that HFA predicts language interference induced by DCS with high specificity (92.4%; negative predictive value 95.9%) and very low sensitivity (8.9%; positive predictive value 4.8%). CONCLUSIONS DCS language mapping appears to be more appropriate for an extensive temporal mapping than induced HFA mapping. Furthermore, induced HFA should be used as a complement to DCS to preselect the number of stimulated sites during DCS, by omitting those reported as HFA−. This may be a considerable advantage because it allows a reduction in the duration of the stimulation procedure. Several parameters to be used for each method are discussed and the results are interpreted in relation to previous results reported in ECOG studies.

Highlights • We investigated working memory in patients with ECTS and age-matched controls using a verbal working memory task. • Children with ECTS showed altered behavioral and fMRI responses to verbal working with increasing difficulty level. • Children with ECTS demonstrated reduced capacity to sustain high WM load., Background Previous functional magnetic resonance imaging (fMRI) studies have identified brain systems underlying different components of working memory (WM) in healthy subjects. The aim of this study was to compare the functional integrity of these neural networks in children with self-limited childhood epilepsy with centro-temporal spikes (ECTS) as compared to healthy controls, using a verbal working memory task (WMT). Methods Functional MRI of WM in seventeen 6-to-13 year-old children, diagnosed with ECTS, and 17 sex- and age-matched healthy controls were conducted at 3 T. To estimate BOLD responses during the maintenance of low, medium, and high WMT loads, we used a Sternberg verbal WMT. Neuropsychological testing prior to scanning and behavioral data during scanning were also acquired. Results Behavioral performances during WMT, in particular accuracy and response time, were poorer in children with ECTS than in controls. Increased WM load was associated with increased BOLD signal in all subjects, with significant clusters detected in frontal and parietal regions, predominantly in the left hemisphere. However, under the high load condition, patients showed reduced activation in the frontal, temporal and parietal regions as compared to controls. In brain regions where WM-triggered BOLD activation differed between groups, this activation correlated with neuropsychological performances in healthy controls but not in patients with ECTS, further suggesting WM network dysfunction in the latter. Conclusion Children with ECTS differ from healthy controls in how they control WM processes during tasks with increasing difficulty level, notably for high WM load where patients demonstrate both reduced BOLD activation and behavioral performances.

Background and study aims Eosinophilic esophagitis (EoE) is a chronic immune disease with increasing incidence. It is clinically defined by symptoms of esophageal dysfunction and histologically by eosinophilic polynuclear cell infiltration of the esophageal mucosa. Symptoms are not specific and include gastroesophageal reflux disease (GERD), dysphagia, vomiting or dietary blockages. Chronic inflammation of the mucosa may lead to narrowing of the esophageal lumen responsible for impactions. Extraction procedures can be complicated by dissection and perforation. Rare spontaneous ruptures of the esophagus known as Boerhaave syndrome are also possible. We report five cases of esophageal perforation in children with EoE, three with spontaneous rupture and two after an endoscopic procedure. The evolution was favorable under medical treatment.

International audience; No abstract available

International audience; Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency due to mutations of FOXP3, a master transcription factor of regulatory T cells (Treg). IPEX syndrome leads to fatal course in most cases during early childhood or severe multi-organ immune-mediated disorders in patients who survive. Currently hematopoietic stem cell transplantation represents the only known effective cure for IPEX syndrome. However, older patients with a mild disease not severe enough to justify transplantation, raise concerns regarding the appropriate therapeutic management, which is therefore based on supportive and replacement therapies combined with pharmacological immunosuppression. Herein, we report the case of a 22-year-old man with an incomplete IPEX syndrome without endocrine disorders having suffered from severe enteropathy since his birth treated with a combination of various immunosuppressant agents. He developed severe exacerbation of inflammatory low back pain in relation to sacroiliitis. Eventually, infliximab was initiated to control his back pain with rapid resolution as well as digestive improvement and also reduced biological inflammatory markers. In parallel, flow cytometry analysis revealed an increase in the frequency of circulating FOXP3+ CD4+ Treg cells. Altogether these data highlight that anti-TNF may represent a promising therapeutic option in patients with IPEX syndrome.

Background: Alagille syndrome (ALGS) is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical sodium-dependent bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in ALGS. Methods: ICONIC was a randomized, placebo-controlled, drug-withdrawal, Phase IIb study with open-label extension in children with ALGS (NCT02160782). Eligible participants had >3x normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once daily, participants were randomized 1:1 to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat to Week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice daily. The primary endpoint was the mean sBA change during the randomized withdrawal in participants with ≥50% sBA reduction by Week 18. Cholestasis was assessed using pruritus (observer-, patient- and clinician-rated; 0-4 scale), growth and liver function. Findings: Between October 2014 and August 2015, 31 participants (mean age: 5.4 years) were enrolled and 28 analyzed at Week 48. In the randomized-withdrawal period, participants switched to placebo experienced significant increases in sBA (+94 µmol/L; p=0.0130) and pruritus (+1.7 pts; p

INTRODUCTION AND OBJECTIVES: Eosinophilic esophagitis (EoE) is frequently miss-diagnosed or overlooked for several years because of the invasiveness of investigations and the non-specificity of symptoms in childhood. Due to the lack of specific recommendations in children, its management remains very heterogeneous, especially concerning allergy testing. The aim of this study is to analyze our population and practices, in comparison with the literature, with a focus on allergic management, to harmonize and optimize our practice. MATERIAL AND METHODS: We included all children with a diagnosis of EoE at the Hospital Femme Mere Enfant, Bron, France. Data were collected via retrospective chart review. RESULTS: 108 patients were included with an average age of 9.5 years. Average delay before diagnosis was 6.65 years. Symptoms varied with age, with a predominance of vomiting (60% of patients), feeding difficulties (72%) and growth difficulties (24%) in children \textless5 years, whereas older children often presented with feeding blockage (64%) and dysphagia (61%). Cough was frequent in our cohort (18.5%), especially in children \textless10 years (38.5% between three and five years). The allergic background was frequent (70.3%) and 80% of our patients benefited from allergy testing. Allergy testing was particularly useful to guide therapy as elimination diet represented an effective treatment in 60% of our patients CONCLUSIONS: Allergy testing has to be harmonized to include major allergens (egg, milk, peanut, fish, wheat, and soy), including prick and patch tests. Allergy-testing based diet seemed to be the best compromise between efficiency and constraints, especially in mono-sensitized patients.

Background Esophagogastroduodenoscopy (EGD) is the standard method for diagnosis of esophageal and gastric varices in children. In this prospective study we evaluated the use of PillCam esophageal capsule endoscopy (ECE) in pediatric patients. Methods Patients aged 7 to 18 years presenting with portal hypertension and/or cirrhosis underwent ECE (PillCam ESO 2, Given Imaging Ltd.) followed by EGD. Results 102 patients were screened, 81 (52 boys; mean age 13.96 ± 0.25 years) were included and 21 were excluded (16 for “candy test” failure). Esophageal varices were identified by EGD in 62 patients (77 %) and by ECE in 57 patients (70 %) using the de Franchis classification (DFC). The sensitivity of ECE for esophageal varices was 92 % and the specificity was 100 % using DFC. Based upon 57/81 patients with small, medium, and large varices on both ECE and EGD, using DFC, the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were 55 %, 92 %, 89 %, and 63 %, respectively, giving a total overall accuracy of 72 %. To improve sensitivity and specificity in classification of esophageal varices, we propose using a modified score. This score detected esophageal varices with 100 % sensitivity, 93 % specificity, 94 % PPV, and 100 % NPV, giving a total overall accuracy of 97 %. All patients preferred ECE over EGD. No capsule retention was recorded. Conclusions ECE is a well-tolerated and safe procedure in children. Using the modified score, the sensitivity of ECE is currently sufficient to detect esophageal varices and replace EGD in infants with suspicion of esophageal varices or when EGD is refused.

International audience; Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR-alpha-tocopherol) and alpha-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus alpha-tocopherol acetate by measuring the plasma concentrations of alpha-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and alpha-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; alpha-tocopherol acetate, 11.4%). Plasma concentrations of alpha-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options.

Objective Few data are available about the functionality of type II focal cortical dysplasia (FCD). Identification of high-frequency activities (HFAs) induced by cognitive tasks has been proposed as an additional way to map cognitive functions in patients undergoing presurgical evaluation using stereoelectroencephalography (SEEG). However, the repetitive subcontinuous spiking pattern which characterizes type II FCD might limit the reliability of this approach, and its feasibility in these patients remains to be evaluated. Methods Seven patients whose magnetic resonance imaging (MRI) data, SEEG data, and/or pathological data were consistent with the diagnosis of type II FCD were included. All patients performed standardized cognitive tasks specifically designed to map task-induced increase of HFA (50 Hz to 150 Hz) at the recorded sites. Electrode contacts which showed an interictal SEEG pattern typical of type II FCD were considered to be localized within the FCD. A site was considered responsive if it was significantly different from baseline in at least one cognitive task. Results Three of the seven patients (43%) had significant task-induced increase of HFA in the FCD for a total of 15 sites with an interictal SEEG pattern typical of type II FCD. These sites were always localized at the external border of the FCD whereas no HFA response was in the core of FCD. In three of the four other patients, a significant task-induced increase of HFA was observed in a cortical site immediately adjacent to the dysplastic cortex. Significance Detection of task-induced HFA remains feasible despite the repetitive subcontinuous spiking pattern which characterizes type II FCD. Depending on the localization of the FCD, some sites of the dysplastic cortex were included in large-scale functional networks. However, these sites were always those closest to the nondysplastic cortex suggesting that persistence of cortical functions might be restricted to a limited part of the FCD.

OBJECTIVES: Research on long-term use of mitomycin C (MC) for recurrent esophageal stenoses is limited. We assessed the long-term efficacy and safety of local application of MC for recurrent esophageal stenoses in children. METHODS: This was a retrospective study of 39 patients (17 girls) with a median age of 19.5 months (range: 2.4-196.0) at the time of MC application. The etiologies of stenosis were esophageal atresia (n = 25), caustic ingestion (n = 9), congenital esophageal stenosis (n = 3), and other causes (n = 2). Stenosis was single in 35 (90%) patients and multiple in 4 (10%). Before MC, patients underwent multiple repeated dilations (median: 3 dilations per child [range: 2-26]) over a median period of 7 months (range: 2.6-49.3). Treatment success was defined a priori as a reduction in the number of dilations over the same period from before to after the application of MC. RESULTS: For 26 (67%) patients, the application of MC was considered a success: 102 versus 17 dilatations (P

TTC7A mutations cause multiple neonatal intestinal atresias with early inflammatory bowel disease and severe combined immunodeficiency. There are no treatment protocols for this rare disease. Two new cases are described for which radical early treatment measures – total enterectomy, home parenteral nutrition, immunoglobulin therapy and intravenous antibiotic prophylaxis – have allowed both patients to develop optimally.

International audience; Optimal molecular diagnosis of primary dyslipidemia is challenging to confirm the diagnosis, test and identify at risk relatives. The aim of this study was to test the application of a single targeted next-generation sequencing (NGS) panel for hypercholesterolemia, hypocholesterolemia, and hypertriglyceridemia molecular diagnosis. NGS workflow based on a custom AmpliSeq panel was designed for sequencing the most prevalent dyslipidemia-causing genes (ANGPTL3, APOA5, APOC2, APOB, GPIHBP1, LDLR, LMF1, LPL, PCSK9) on the Ion PGM Sequencer. One hundred and forty patients without molecular diagnosis were studied. In silico analyses were performed using the NextGENe software and homemade tools for detection of copy number variations (CNV). All mutations were confirmed using appropriate tools. Eighty seven variations and 4 CNV were identified, allowing a molecular diagnosis for 40/116 hypercholesterolemic patients, 5/13 hypocholesterolemic patients, and 2/11, hypertriglyceridemic patients respectively. This workflow allowed the detection of CNV contrary to our previous strategy. Some variations were found in previously unexplored regions providing an added value for genotype-phenotype correlation and familial screening. In conclusion, this new NGS process is an effective mutation detection method and allows better understanding of phenotype. Consequently this assay meets the medical need for individualized diagnosis of dyslipidemia.

The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population.The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate.The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (10,000) had a significant poorer long-term graft survival (p=0.03).In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss.

We analyzed the characteristics of the population with congenital portosystemic shunt diagnosed during the antenatal period and the organization of their perinatal care. This multicentric retrospective study included all the patients with a prenatal diagnosis of congenital portosystemic shunt. Between 1999 and 2015, 12 patients were included. Prenatal diagnosis was done at a median 26.5 weeks of gestation (21-34). All the patients presented intrahepatic CPSS, three of them had associated congenital cardiopathy, and one a Bannayan-Zonana syndrome. Ten patients had simple outcome on conservative treatment, eight of them having a spontaneous closure of their portosystemic shunt within the first 2 years of life. One patient had surgical treatment which failed and he developed a focal nodular hyperplasia. Another patient had radiological interventional closure of his shunt which was complicated by a venal portal thrombosis.Outcome of intrahepatic portosystemic shunt diagnosed prenatally is good in the majority of cases. What is known: • Multiples studies exist on congenital porto systemic shunt but when the diagnosis is done after birth. • The evolution, management, and complication are well known. What is new: • There is very few studies with only patients diagnosed in antenatal and it is a large series of cases. • Outcome of intrahepatic portosystemic shunt diagnosed prenatally is good in the majority of cases.

Small-bowel capsule endoscopy (CE) has recently been used in children. During the past few years, an intense research activity has defined the advantages and limitations of CE. Its uses have been established in several small-bowel pathologies such as obvious or obscure digestive bleeding, Crohn disease, and hereditary polyposis. Although the absence of biopsy reduces the specificity of CE findings, small-bowel exploration using CE achieves better accuracy in detecting lesions than most radiological examinations. In children, swallowing problems and the risk of retention due to stenosis are the main concerns when using CE: these problems can be solved using endoscopic delivery of the capsule and luminal diameter calibration, respectively. This review focuses on the evidence making CE indispensable to small-bowel exploration.

We report on the case of a young infant with chronic diarrhea that worsened and turned into hypovolemic shock with methemoglobinemia. We underline and discuss the main features of food protein-induced enterocolitis syndrome (FPIES). FPIES is a non-IgE-mediated food allergy involving tumor necrosis factor-alpha (TNF-α). Many triggering foods exist but cow's milk, as in the case reported herein, is one of the most frequent. It can start early or be delayed and start around the average age of 5 months. Symptoms are nonspecific with diarrhea and vomiting, but in the presence of methemoglobinemia, the diagnosis must be seriously considered. The oral food challenge remains the gold standard to confirm the diagnosis if there is still a doubt. Treatment of FPIES associates emergency treatment of acute dehydration with the prevention of relapses by avoiding the suspected protein.

Background Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations. Objective/methods The recently developed Bron–Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition. Results In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores. Conclusions This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron–Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.

Objectives: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available. Methods: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed. Results: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin

Introduction Botulinum toxin injection is known to be efficient to treat achalasia. We conducted a randomized trial in order to evaluate its efficacy to treat symptomatic hypercontractile esophageal disorders as characterized by esophageal high-resolution manometry. Methods Patients with significant dysphagia and/or thoracic pain related to an hypercontractile esophageal motility disorder as defined by the Chicago Classification were randomized to receive an injection of botulinum toxin (100 U in 10 points in the distal part of the esophageal wall) or a sham procedure. Symptoms were assessed at 3 months with the Eckardt score. Patients could receive a first or second botulinum toxin injection 1 month later if symptoms persisted. Results Twenty-three patients (13 women, mean age 60 years) were included: 13 received botulinum toxin injection, and 10 a sham procedure. The improvement of symptoms at 3 months was significant compared to baseline, but similar in the active treatment and sham procedure arms. However, there was no change in quality of life scores. Seventeen patients received a second injection at 4 months. There was a significant trend toward improvement of symptoms up to the end of follow-up at 12 months, without a significant relationship with the administration of botulinum toxin. Discussion Botulinum toxin injection is not superior to a sham procedure to improve symptoms related to hypercontractile esophageal disorders, suggesting an important placebo effect in for this type of disease. This observation must be taken into account when evaluating more aggressive therapies such as endoscopic myotomy (clinicaltrials.gov: NCT01955174).

International audience; OBJECTIVES: Per-Oral Endoscopic Myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children. METHODS: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes such as clinical response were assessed when available. Adverse events and factors associated with clinical failure were also investigated. RESULTS: A total of 117 patients (mean +/- SD age: 14.2 +/- 3.7 years) underwent POEM for achalasia (type I n=36, II n=66, III n=8). Among these, 30 (26%) were pre-treated (botulinum injection and/or pneumatic dilatation). Mean +/- SD baseline Eckardt score was 7.5 +/- 2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean +/- SD Eckardt score post-POEM was 0.9 +/- 1.2 (p\textless0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% versus 8%, p=0.069). CONCLUSION: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.

Background Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection. Objective The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients. Methods This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old). Results The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6–39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1–25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17–18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92–0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died. Conclusion The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.

BACKGROUND: Alpha-1-antitrypsin deficiency (A1ATD) is a common genetic condition which predisposes to emphysema and liver disorders. It is estimated that 10-15% of homozygous individuals for the Z allele (PiZZ) may develop liver fibrosis. The optimal modalities to detect liver disease in PiZZ adult patients need to be defined. The aim of this prospective study was to perform a systematic non-invasive evaluation of the liver fibrosis by elastometry using Fibroscan((R)) in a cohort of A1ATD patients with emphysema. METHODS: Patients followed in our respiratory unit were enrolled in this prospective study and underwent on the same day a physical examination, a biochemical profiling, an abdominal ultrasound (US) and a Fibroscan((R)). RESULTS: Twenty-nine PiZZ adults (19 male) were included. Median age was 50.4 yrs (21.5-67.2). Median serum A1AT level was 0.20 g/L (0.15-0.33). Liver Function Tests (LFT) were not normal in 2 patients and US was abnormal in 6 patients. Two patients had both abdnormal LFT and US. Fibroscan((R)) was technically feasible in 28/29 (97%) patients. Median liver stiffness was 4.5 kPa (2.8-32.8), and was \\textgreater 7.2 kPa in 5/28 (18%) and \\textgreater 14 kPa in 2/28 (7%) patients. Liver stiffness was increased in 2/2 (100%) patients with abnormal LFT and US, in 1/4 (25%) with abnormal LFT or US and in 2/22 (10%) patients with normal LFT and US. CONCLUSIONS: Fibroscan((R)) is an easy and repeatable tool which can be used in PiZZ patients to screen for the presence of significant liver fibrosis and to identify patients at higher risk to develop liver complications in the future and who may benefit from a closer surveillance.

International audience; BACKGROUND AND AIMS: Abetalipoproteinemia (ABL) is a rare recessive monogenic disease due to MTTP (microsomal triglyceride transfer protein) mutations leading to the absence of plasma apoB-containing lipoproteins. Here we characterize a new ABL case with usual clinical phenotype, hypocholesterolemia, hypotriglyceridemia but normal serum apolipoprotein B48 (apoB48) and red blood cell vitamin E concentrations. METHODS: Histology and MTP activity measurements were performed on intestinal biopsies. Mutations in MTTP were identified by Sanger sequencing, quantitative digital droplet and long-range PCR. Functional consequences of the variants were studied in vitro using a minigene splicing assay, measurement of MTP activity and apoB48 secretion. RESULTS: Intestinal steatosis and the absence of measurable lipid transfer activity in intestinal protein extract supported the diagnosis of ABL. A novel MTTP c.1868G\textgreaterT variant inherited from the patient's father was identified. This variant gives rise to three mRNA transcripts: one normally spliced, found at a low frequency in intestinal biopsy, carrying the p.(Arg623Leu) missense variant, producing in vitro 65% of normal MTP activity and apoB48 secretion, and two abnormally spliced transcripts resulting in a non-functional MTP protein. Digital droplet PCR and long-range sequencing revealed a previously described c.1067+1217\₁141del allele inherited from the mother, removing exon 10. Thus, the patient is compound heterozygous for two dysfunctional MTTP alleles. The p.(Arg623Leu) variant may maintain residual secretion of apoB48. CONCLUSIONS: Complex cases of primary dyslipidemia require the use of a cascade of different methodologies to establish the diagnosis in patients with non-classical biological phenotypes and provide better knowledge on the regulation of lipid metabolism.

15 Background: Compared to observation, maintenance therapy with a fluoropyrimidine +/- bevacizumab showed significant improvement in progression-free survival (PFS) but not in overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC) and disease control after first-line doublet chemotherapy (CT) +/- bevacizumab. Few studies are available on the role of maintenance therapy after induction anti-EGFR-based CT, and the benefit from anti-EGFR maintenance monotherapy during CT-free intervals (CFI) in patients with RAS wild-type (wt) mCRC. Methods: RAS wt unresectable mCRC patients with controlled disease after FOLFIRI + cetuximab (8 cycles) were randomized (1:1) to receive maintenance with bi-weekly cetuximab alone (arm A) or observation (arm B) until disease progression (PD)/unacceptable toxicity/death. Randomization was stratified according to tumor response, center, baseline Köhne Score, CEA and platelet count. In case of tumor progression during the CFI, FOLFIRI + cetuximab was to be reintroduced for 8 cycles, followed by a new CFI. Tumor response was assessed per RECIST1.1 every 8 weeks. The primary objective of this multicenter non-comparative randomized phase II trial was 6-month PFS rate after initiation of maintenance therapy. A total of 134 randomized and evaluable patients (67 per arm) were required (Fleming’s one-step design, one-sided α=5%, β=20%, H0: 40%; H1: 55%). Secondary endpoints were overall response rate (ORR), time to strategy failure, PFS, OS, safety, quality of life, circulating tumor cells and circulating tumor DNA detection and dynamic changes during treatment. Results: From January 2014 to April 2019, 214 patients were included and 139 randomized (67 arm A/72 arm B) in 35 centers. Baseline characteristics were: males, 67%/69%; median age, 64/68 years; ECOG PS 0, 54%/46%; previous adjuvant therapy, 25%/14%; single metastatic site, 58%/47%; right-sided primary, 24%/18%. The ORR in the overall and the randomized population was 55% and 72%, respectively. The median follow-up was 30 months. The 6-month PFS rate after initiation of maintenance therapy was 30% 95%CI[19; 42] in the maintenance arm, and 6% 95%CI[2;14] in the observation arm, with a median PFS of 5.3 95%CI[3.7;6.5] and 2.0 95%CI[1.8;2.8] months, respectively. Any grade treatment-related toxicity, including skin rash (40%/4%), diarrhea (33%/8%), and hypomagnesemia (46%/10%) was more frequent in arm A. Conclusions: Based on the study hypothesis, the cetuximab maintenance arm did not meet the primary objective. However, the clinically meaningful difference in PFS without any overlap in the confidence intervals between the two arms warrants further investigation. Clinical trial information: NCT02404935.

How do we choose a particular action among equally valid alternatives? Nonhuman primate findings have shown that decision-making implicates modulations in unit firing rates and local field potentials (LFPs) across frontal and parietal cortices. Yet the electrophysiological brain mechanisms that underlie free choice in humans remain ill defined. Here, we address this question using rare intracerebral electroencephalography (EEG) recordings in surgical epilepsy patients performing a delayed oculomotor decision task. We find that the temporal dynamics of high-gamma (HG, 60–140 Hz) neural activity in distinct frontal and parietal brain areas robustly discriminate free choice from instructed saccade planning at the level of single trials. Classification analysis was applied to the LFP signals to isolate decision-related activity from sensory and motor planning processes. Compared with instructed saccades, free-choice trials exhibited delayed and longer-lasting HG activity during the delay period. The temporal dynamics of the decision-specific sustained HG activity indexed the unfolding of a deliberation process, rather than memory maintenance. Taken together, these findings provide the first direct electrophysiological evidence in humans for the role of sustained high-frequency neural activation in frontoparietal cortex in mediating the intrinsically driven process of freely choosing among competing behavioral alternatives., How do we choose a particular action among equally valid alternatives? Intracranial recordings in humans performing a delayed oculomotor decision task reveal that deliberating between competing alternatives during free choice is indexed by sustained high frequency neural activity in a network of parieto-frontal brain areas.

Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight-junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in-frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.

Introduction Metabolic syndrome (MetS) is associated with Heart Failure with Preserved Ejection Fraction (HFpEF), characterized by diastolic dysfunction, notably affecting elderly menopausal women. To improve treatment strategies, deepened pathophysiological understanding of potential gender-specific mechanisms contributing to ventricular stiffening is needed. Objective We hypothesized that lymphatic alterations in the heart may contribute to cardiac inflammation and edema promoting cardiac fibrosis and dysfunction in a gender-specific manner. Method We investigated cardiovascular function by echocardiography, hemodynamic analyses, MRI, ex vivo coronary arteriography, and cardiac remodeling and inflammation by immunohistochemistry and flow cytometry in male and ovariectomized (ovx.) female obese Zucker (fa/fa) rats and their lean controls up to 24-weeks of age. Results Whereas body weight gain, insulin resistance, and diastolic dysfunction were similar in 24-weeks-old obese animals of both genders, only male obese rats displayed coronary endothelial dysfunction and reduced cardiac perfusion as compared to lean animals. In contrast, only female ovx. obese rats displayed significant cardiac hypertrophy as well as remodeling and rarefaction of cardiac lymphatics accompanied by persistent low-grade cardiac inflammation at both 14- and 24-weeks of age. The cardiac infiltration was characterized by increased levels of B lymphocytes, and both pro-inflammatory (M1) and non-classical (M2-like) monocytes, as well as increased frequency of M1 type macrophages. The monocytosis was linked to increased cardiac expression of CCL2. Studies are ongoing to determine chemokine expression changes in coronary endothelial cells. Conclusion In conclusion, our data show that gender-specific mechanisms involving cardiac lymphatics may underlie development of MetS-related diastolic dysfunction, suggesting novel therapeutic targets to prevent HFpEF in patients with MetS.