Search

Background. No device is yet available to effectively capture the attentional repercussions of hypersomnolence (HYP). The present study aimed to compare attentional performance of children with HYP, attention deficit hyperactivity disorder (ADHD), and controls using behavioral and electrophysiological (EEG) markers, and to assess their relationship with conventional sleepiness measurements. Methods. Children with HYP underwent a multiple sleep latency test (MSLT) and completed the adapted Epworth sleepiness scale (AESS). Along with age-matched children with ADHD, they were submitted to a resting EEG followed by the Bron–Lyon Attention Stability Test (BLAST). The control group only performed the BLAST. Multivariate models compared reaction time (RT), error percentage, BLAST-Intensity, BLAST-Stability, theta activity, and theta/beta ratio between groups. Correlations between these measures and conventional sleepiness measurements were conducted in children with HYP. Results. Children with HYP had lower RT and BLAST-Stability than controls but showed no significant difference in BLAST/EEG markers compared to children with ADHD. The AESS was positively correlated with the percentage of errors and negatively with BLAST-Intensity. Conclusions. Children with HYP showed impulsivity and attention fluctuations, without difference from children with ADHD for BLAST/EEG markers. The BLAST–EEG protocol could be relevant for the objective assessment of attentional fluctuations related to hypersomnolence. [ABSTRACT FROM AUTHOR]

Limb movement direction can be inferred from local field potentials in motor cortex during movement execution. Yet, it remains unclear to what extent intended hand movements can be predicted from brain activity recorded during movement planning. Here, we set out to probe the directional-tuning of oscillatory features during motor planning and execution, using a machine learning framework on multi-site local field potentials (LFPs) in humans. We recorded intracranial EEG data from implanted epilepsy patients as they performed a four-direction delayed center-out motor task. Fronto-parietal LFP low-frequency power predicted hand-movement direction during planning while execution was largely mediated by higher frequency power and low-frequency phase in motor areas. By contrast, Phase-Amplitude Coupling showed uniform modulations across directions. Finally, multivariate classification led to an increase in overall decoding accuracy (>80%). The novel insights revealed here extend our understanding of the role of neural oscillations in encoding motor plans. A study using intracranial recordings in humans suggests that upcoming hand movements can be predicted by oscillatory brain features of the LFP signal. [ABSTRACT FROM AUTHOR]

It has been suggested that cross-frequency coupling in cortico-hippocampal networks enables the maintenance of multiple visuo-spatial items in working memory. However, whether this mechanism acts as a global neural code for memory retention across sensory modalities remains to be demonstrated. Intracranial EEG data were recorded while drug-resistant patients with epilepsy performed a delayed matched-to-sample task with tone sequences. We manipulated task difficulty by varying the memory load and the duration of the silent retention period between the to-be-compared sequences. We show that the strength of theta-gamma phase amplitude coupling in the superior temporal sulcus, the inferior frontal gyrus, the inferior temporal gyrus, and the hippocampus (i) supports the short-term retention of auditory sequences; (ii) decodes correct and incorrect memory trials as revealed by machine learning analysis; and (iii) is positively correlated with individual short-term memory performance. Specifically, we show that successful task performance is associated with consistent phase coupling in these regions across participants, with gamma bursts restricted to specific theta phase ranges corresponding to higher levels of neural excitability. These findings highlight the role of cortico-hippocampal activity in auditory short-term memory and expand our knowledge about the role of cross-frequency coupling as a global biological mechanism for information processing, integration, and memory in the human brain. Cross-frequency coupling in cortico-hippocampal networks enables the maintenance of multiple visuo-spatial items in working memory. This study shows that cross-frequency coupling extends also to auditory information, pointing to a global biological mechanism of cross-frequency coupling for information processing in the human brain. [ABSTRACT FROM AUTHOR]

The Attentional Control Theory (ACT) posits that, while trait anxiety may not directly impact performance, it can influence processing efficiency by prompting the use of compensatory mechanisms. The specific nature of these mechanisms, which might be reflective, is not detailed by the ACT. In a study involving 110 students (M = 20.12; SD = 2.10), surveys were administered to assess the students' metacognitive beliefs, trait anxiety, and emotion regulation strategies (ERSs). The participants engaged in two working memory exercises: the digit span task from the WAIS-IV and an emotional n-back task. The findings indicated that anxiety, metacognitive beliefs, and maladaptive ERSs did not affect task performance but were correlated with increased response times. Several regression analyses demonstrated that a lack of confidence in one's cognitive abilities and maladaptive ERSs predict higher reaction times (RT) in the n-back task. Additionally, maladaptive ERSs also predict an increased use of strategies in the digit span task. Finally, two mediation analyses revealed that anxiety increases processing efficiency, and this relation is mediated by the use of maladaptive ERSs. These results underscore the importance of the reflective level in mediating the effects of trait anxiety on efficiency. They highlight the necessity of incorporating metacognitive beliefs and maladaptive emotion regulation strategies for a thorough comprehension of the Attentional Control Theory. Recognizing these factors offers valuable perspectives for enhancing cognitive capabilities and fostering academic achievement. [ABSTRACT FROM AUTHOR]

Trait anxiety, emotion regulation strategies, and metacognitive beliefs influence executive functions (EFs) and academic achievement. This study examines their interplay and impact on academic success. In total, 275 adolescents (10–17 years) and parents completed an online questionnaire assessing trait anxiety, emotion regulation strategies, metacognition, parent-reported behaviors related to executive functioning, and overall school average. Preliminary analyses confirmed consistency with the existing literature for each variable and their interaction. Furthermore, we conducted a network analysis among the main variables. This analysis supports the need to pay more attention to reflective variables—maladaptive emotion regulation strategies and metacognitive beliefs about worry—when studying trait anxiety. These variables were linked to problematic executive functioning in adolescents, and the latter was negatively linked to academic achievement. This study offers innovative insights by investigating relationships less explored in the scientific literature. It reveals high and significant correlations between metacognitive beliefs, maladaptive emotion regulation strategies, and trait anxiety (r > 0.500, p < 0.001) but also between these variables and both executive functioning and academic achievement. These findings offer new perspectives for research and underscore the importance of holistically examining the psychological factors related to academic success. [ABSTRACT FROM AUTHOR]

Background/Objectives: The mainstay treatment of cow's milk allergy (CMA) is to remove cow's milk proteins from children's dietary intake. In this context, dietary intake of children with CMA should be particularly checked and monitored. The objective of this study was to assess the applicability, usability, and accuracy of a new dietary intake (DI) assessment online tool (Nutricate© online application) for managing CMA in children. Subjects/Methods: This study used a pre-existing database of DI from the Nutricate© online application. DIs from 30 CMA children were used to compare micro/macronutrients (energy, protein, calcium, and iron intakes) calculated by Nutricate© and NutriLog© as the reference method. Comparisons were performed using the Pearson correlation analysis and the Bland–Altman plot. The Nutricate© tool usability was assessed via a System Usability Scale questionnaire (SUSq). Results: Correlation coefficient between the levels of micro/macronutrients obtained by Nutrilog© and Nutricate© software were highly significant (p = 0.0001) and were well-correlated (R coefficient > 0.6), indicating a very good concordance between the two methods. This observation was reinforced by the Bland–Altman plot, indicating the absence of proportional or fixed bias for energy, protein, calcium, and iron intakes. The mean SUSq score obtained was 81 ± 14, which is considered to be an excellent score. Conclusions: Nutricate© online application is a reliable method to assess micro/macronutrient (energy, protein, calcium, and iron intakes) intake in CMA children. Applicability and usability of this new dietary intake assessment online tool is excellent. [ABSTRACT FROM AUTHOR]

Background: The role of protocol liver biopsies (PLB) in the follow‐up of pediatric liver transplant recipients remains questionable. This single‐center retrospective study aimed to evaluate their clinical impact on the long‐term management of pediatric liver transplant recipients. Methods: We described histopathological lesions and clinical consequences for patient management of PLB performed 1, 5, 10, 15, 20, and 25 years after pediatric liver transplantation (LT). Results: A total of 351 PLB performed on 133 patients between 1992 and 2021 were reviewed. PLB found signs of rejection in 21.7% of cases (76/351), and moderate to severe fibrosis in 26.5% of cases (93/351). Overall, 264 PLB (75.2%) did not cause any changes to patient care. Immunosuppression was enhanced after 63 PLB, including 23 cases of occult rejection. The 1‐year PLB triggered significantly more changes, while biopsies at 15, 20, and 25 years produced the lowest rates of subsequent modifications. PLB had a significantly higher probability of inducing therapeutic changes if the patient had abnormal biological or imaging results (odds ratio [OR] 2.82 and 2.06), or a recent history of rejection or bacterial infection (OR 2.22 and 2.03). Conclusion: Our results suggest that, although it often does not prompt any treatment changes, PLB could be performed because of its ability to detect silent rejection requiring an increase in immunosuppression. PLB could be carried out 1, 5, and 10 years after LT and then every 10 years in patients with normal biological and imaging results and no recent complications, while other patients could be kept on a 5‐year protocol. [ABSTRACT FROM AUTHOR]

Objectives: Sleepiness is associated with decreased cognitive abilities and remains one of the main causes of fatal road accidents. The tools currently available to assess sleepiness, such as questionnaires, are subject to intra- and inter-individual variability, while multiple sleep latency tests are only feasible in few sleep laboratories. The main objective of this study was to explore new potential markers (neurocognitive, biological) to objectively assess sleepiness in drivers. Methods: A total of 186 drivers (median age 44 years, range 20-74 years, 73% men, 14% obese) were included during a break at a highway service area, in the morning, while on the road for vacation. Questionnaires on sleepiness and sleep characteristics (habitual and on the night before travel), the Bron-Lyon Attention Stability Test (BLAST), and two salivary samples (α-amylase and oxalate) were collected. Associations between measures of sleepiness [Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS)], sleep characteristics, neurocognitive, and biological markers were tested using regression models adjusted for confounding factors. Results: The night before travel, 83% of the drivers reduced their sleep time and 30% slept 5 h or less. The higher the number of miles to be traveled, the higher the decrease, and the shorter the sleep time. The night before travel, 18 and 24% of the drivers complained of poor sleep quality and difficulty falling asleep. The sleep characteristics on the night before travel were associated with the habitual sleep characteristics. At the time of the test, 47% of the drivers scored pathologically on the SSS. Poor sleep quality and difficulty falling asleep the night before travel were associated with increased sleepiness as assessed by the SSS and decreased attentional ability as assessed by the BLAST. No association between salivary markers and acute sleepiness was observed. Conclusions: The sleep characteristics of the night before travel were associated with sleepiness and attentional performance. The SSS and the BLAST could be used by individual drivers in a self-evaluation context. Biological markers showed a high variability and limited association with sleep parameters across subjects, emphasizing the need for within-subject designs to assess their usefulness. [ABSTRACT FROM AUTHOR]

Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis–associated protein 1 (FIC1) deficiencies, suffer debilitating cholestatic pruritus that adversely affects growth and quality of life (QoL). Reliance on surgical interventions, including liver transplantation, highlights the unmet therapeutic need. INDIGO was an open‐label, Phase 2, international, long‐term study to assess the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiencies. Thirty‐three patients, ranging from 12 months to 18 years of age, were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency. Of the latter, 6 had biallelic, protein truncating mutations (t)‐BSEP, and 19 had ≥ 1 nontruncating mutation (nt)‐BSEP. Patients received maralixibat 266 μg/kg orally, once daily, from baseline to Week 72, with twice‐daily dosing permitted from Week 72. Long‐term efficacy was determined at Week 240. Serum bile acid (sBA) response (reduction in sBAs of > 75% from baseline or concentrations <102.0 μmol/L) was achieved in 7 patients with nt‐BSEP, 6 during once‐daily dosing, and 1 after switching to twice‐daily dosing. sBA responders also demonstrated marked reductions in sBAs and pruritus, and increases in height, weight, and QoL. All sBA responders remained liver transplant–free after > 5 years. No patients with FIC1 deficiency or t‐BSEP deficiency met the sBA responder criteria during the study. Maralixibat was generally well‐tolerated throughout the study. Conclusion: Response to maralixibat was dependent on progressive familial intrahepatic cholestasis subtype, and 6 of 19 patients with nt‐BSEP experienced rapid and sustained reductions in sBA levels. The 7 responders survived with native liver and experienced clinically significant reductions in pruritus and meaningful improvements in growth and QoL. Maralixibat may represent a well‐tolerated alternative to surgical intervention. [ABSTRACT FROM AUTHOR]

In the present paper, we report the synthesis of highly functionalized nanomaterials carefully nanoengineered to catalyze the semi‐hydrogenation of acetylene in ethylene‐rich mixtures. Surface functionalization and structure modification of a series of bimetallic PdAg nanoparticles was performed using HHDMA as stabilizer and alloying the active palladium phase with silver. Bimetallic PdAg NPs with adjustable Pd/Ag ratio were prepared in water through a novel one‐pot methodology using hydrogen gas as a benign reducing agent and cyanide as additive. UV‐Vis studies indicated the formation of the bimetallic nanostructures through a sequential displacement‐galvanic reduction process mediated by cyanide. The series of colloidal NPs were deposited onto alumina and successfully applied as catalysts in the selective hydrogenation of acetylene in ethylene rich mixtures. Geometric and electronic promotion of Ag over Pd based catalysts was evidenced by the increase of the ethylene selectivity with the Ag content. The reactivity of these materials demonstrated the applicability of HHDMA stabilized NPs in a gas phase reaction of industrial interest and the success of combining several strategies for the enhancement of the alkene selectivity. [ABSTRACT FROM AUTHOR]

Background: Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial leaf blight, a devastating disease of rice. Among the type-3 effectors secreted by Xoo to support pathogen virulence, the Transcription Activator-Like Effector (TALE) family plays a critical role. Some TALEs are major virulence factors that activate susceptibility (S) genes, overexpression of which contributes to disease development. Host incompatibility can result from TALE-induced expression of so-called executor (E) genes leading to a strong and rapid resistance response that blocks disease development. In that context, the TALE functions as an avirulence (Avr) factor. To date no such avirulence factors have been identified in African strains of Xoo. Results: With respect to the importance of TALEs in the Rice-Xoo pathosystem, we aimed at identifying those that may act as Avr factor within African Xoo. We screened 86 rice accessions, and identified 12 that were resistant to two African strains while being susceptible to a well-studied Asian strain. In a gain of function approach based on the introduction of each of the nine tal genes of the avirulent African strain MAI1 into the virulent Asian strain PXO99A, four were found to trigger resistance on specific rice accessions. Loss-of-function mutational analysis further demonstrated the avr activity of two of them, talD and talI, on the rice varieties IR64 and CT13432 respectively. Further analysis of TalI demonstrated the requirement of its activation domain for triggering resistance in CT13432. Resistance in 9 of the 12 rice accessions that were resistant against African Xoo specifically, including CT13432, could be suppressed or largely suppressed by trans-expression of the truncTALE tal2h, similarly to resistance conferred by the Xa1 gene which recognizes TALEs generally independently of their activation domain. Conclusion: We identified and characterized TalD and TalI as two African Xoo TALEs with avirulence activity on IR64 and CT13432 respectively. Resistance of CT13432 against African Xoo results from the combination of two mechanisms, one relying on the TalI-mediated induction of an unknown executor gene and the other on an Xa1-like gene or allele. [ABSTRACT FROM AUTHOR]

The recent discovery of TRPV6 as a pancreatitis susceptibility gene served to identify a novel mechanism of chronic pancreatitis (CP) due to Ca2+ dysregulation. Herein, we analyzed TRPV6 in 81 probands with hereditary CP (HCP), 204 probands with familial CP (FCP), and 462 patients with idiopathic CP (ICP) by targeted next‐generation sequencing. We identified 25 rare nonsynonymous TRPV6 variants, 18 of which had not been previously reported. All 18 variants were characterized by a Ca2+ imaging assay, with 8 being identified as functionally deficient. Evaluation of functionally deficient variants in the three CP cohorts revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Our findings confirm that functionally deficient TRPV6 variants represent an important contributor to CP. Importantly, functionally deficient TRPV6 variants account for a significant proportion of cases of HCP/FCP. [ABSTRACT FROM AUTHOR]

Résumé: Il est désormais reconnu que l'environnement joue un rôle prépondérant dans le développement de l'inflammation observée dans les maladies inflammatoires chroniques de l'intestin (MICI). Parmi les facteurs environnementaux, le rôle de l'alimentation est établi. Les comités d'experts pédiatriques recommandent chez l'enfant la nutrition entérale exclusive (NEE) en traitement d'induction de la maladie de Crohn (MC) légère à sévère sans lésions anopérinéales. Récemment, des régimes d'exclusion moins contraignants ont été proposés, afin d'améliorer l'acceptabilité de la NEE. Si certains régimes demandent encore une évaluation à plus grande échelle, d'autres semblent déjà très prometteurs. La prise en charge nutritionnelle de la maladie de Crohn, validée en pédiatrie, doit pouvoir être proposée aux patients adultes. Ces nouvelles approches thérapeutiques nécessiteront ainsi de nouveaux moyens humains et financiers déployés dans la prise en charge diététique et dans l'éducation thérapeutique des patients atteints d'une MC. Environmental factors play a critical role as trigger of inflammation in inflammatory bowel disease (IBD) and nutritional factors contribute to pathology of IBD. Moreover, exclusive enteral nutrition (EEN) is now considered, as the first line induction therapy for mild to severe paediatric Crohn disease (CD) without anoperineal disease. Recently, new therapeutic nutrition protocols such as "Crohn disease exclusion diet" have been prospectively evaluated in paediatric CD patients. Some of them reported promissing results. Yet, these new therapeutic options, validated in paediatric, could also be proposed to adult patients. Overall, new nutritional approaches will require new financial resources for dietetician and therapeutic education founding. [ABSTRACT FROM AUTHOR]

We have developed and tested a novel microfluidic device for blood oxygenation, which exhibits a large surface area of gas exchange and can support long-term sustainable endothelialization of blood microcapillaries, enhancing its hemocompatibility for clinical applications. The architecture of the parallel stacking of the trilayers is based on a central injection for blood and a lateral injection/output for gas which allows significant reduction in shear stress, promoting sustainable endothelialization since cells can be maintained viable for up to 2 weeks after initial seeding in the blood microchannel network. The circular design of curved blood capillaries allows covering a maximal surface area at 4 inch wafer scale, producing high oxygen uptake and carbon dioxide release in each single unit. Since the conventional bonding process based on oxygen plasma cannot be used for surface areas larger than several cm2, a new "wet bonding" process based on soft microprinting has been developed and patented. Using this new protocol, each 4 inch trilayer unit can be sealed without a collapsed membrane even at reduced 15 μm thickness and can support a high blood flow rate. The height of the blood channels has been optimized to reduce pressure drop and enhance gas exchange at a high volumetric blood flow rate up to 15 ml min−1. The simplicity of connecting different units in the stacked architecture is demonstrated for 3- or 5-unit stacked devices that exhibit remarkable performance with low primary volume, high oxygen uptake and carbon dioxide release and high flow rate of up to 80 ml min−1. [ABSTRACT FROM AUTHOR]

Dual-tasking is extremely prominent nowadays, despite ample evidence that it comes with a performance cost: the Dual-Task (DT) cost. Neuroimaging studies have established that tasks are more likely to interfere if they rely on common brain regions, but the precise neural origin of the DT cost has proven elusive so far, mostly because fMRI does not record neural activity directly and cannot reveal the key effect of timing, and how the spatio-temporal neural dynamics of the tasks coincide. Recently, DT electrophysiological studies in monkeys have recorded neural populations shared by the two tasks with millisecond precision to provide a much finer understanding of the origin of the DT cost. We used a similar approach in humans, with intracranial EEG, to assess the neural origin of the DT cost in a particularly challenging naturalistic paradigm which required accurate motor responses to frequent visual stimuli (task T1) and the retrieval of information from long-term memory (task T2), as when answering passengers' questions while driving. We found that T2 elicited neuroelectric interferences in the gamma-band (>40 Hz), in key regions of the T1 network including the Multiple Demand Network. They reproduced the effect of disruptive electrocortical stimulations to create a situation of dynamical incompatibility, which might explain the DT cost. Yet, participants were able to flexibly adapt their strategy to minimize interference, and most surprisingly, reduce the reliance of T1 on key regions of the executive control network-the anterior insula and the dorsal anterior cingulate cortex-with no performance decrement. [ABSTRACT FROM AUTHOR]

Whether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, given inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across techniques, we recorded intracerebral activity from twenty participants while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlate positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA scaled positively with the outcome (reward or punishment versus nothing) and negatively with the expectation (predictability of reward or punishment). However, reward PE were better signaled in some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex), and punishment PE in other regions (such as the anterior insula and dorsolateral prefrontal cortex). These regions might therefore belong to brain systems that differentially contribute to the repetition of rewarded choices and the avoidance of punished choices. Whether maximizing rewards and minimizing punishments rely on distinct brain learning systems remains debated. Here, using intracerebral recordings in humans, the authors provide evidence for brain regions differentially engaged in signaling reward and punishment prediction errors that prescribe repetition versus avoidance of past choices. [ABSTRACT FROM AUTHOR]

Long-term parenteral nutrition (PN) may induce bone complications. Tridimensional bone imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) allow the assessment of both compartmental volumetric densities and microarchitecture. Our aim was to evaluate these parameters in children and teenagers receiving long-term PN. This cross-sectional, case–control study included children older than 9 years undergoing PN for at least 2 years. They were age-, gender- and puberty-matched with healthy controls (1:2). Evaluation included biological assessment of bone metabolism (serum calcium, phosphate, and albumin; urinary calcium and creatinine; 25-OH vitamin D, osteocalcin and PTH), dual X-ray absorptiometry (DXA) and HR-pQCT at the ultradistal tibia and radius. Results are presented as median [range]. Eleven patients (3 girls) with a median age of 16 [9–19] years were included. Bone parameters assessed by HR-pQCT at the ultradistal radius and tibia were similar in patients and controls. Parathyroid hormone (PTH) levels were higher (14 [7–115] vs 16 [12–27]) and osteocalcin levels were lower (44 [15–65] vs 65 [38–142]) in patients than in controls, although within the normal range. Conclusions: there were no differences for compartmental bone densities and microarchitecture in patients undergoing chronic PN. Further longitudinal studies are required to confirm these quite reassuring preliminary results. [ABSTRACT FROM AUTHOR]

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 < 0.01), associated with a decreased myocardial perfusion (HF: 6.41 ± 0.53 mL/min/g, ADHF: 4.20 ± 0.11 mL/min/g; P < 0.01), a slight increase in pulmonary weight (HF: 1.68 ± 0.09 g, ADHF: 1.81 ± 0.15 g), and impaired coronary relaxation (HF: 55 ± 1% of pre‐contraction at acetylcholine 4.5 10−5 M, ADHF: 27 ± 7 %; P < 0.01). Fourteen days after salt‐loading, cardiac output only partially recovered (117 ± 5 mL/min; P < 0.05), while myocardial tissue perfusion (4.51 ± 0.44 mL/min; P < 0.01) and coronary relaxation (28 ± 4%; P < 0.01) remained impaired, but pulmonary weight further increased (2.06 ± 0.15 g, P < 0.05). Compared with untreated ADHF, HRR induced by S38844 improved cardiac output (125 ± 1 mL/min; P < 0.05), myocardial tissue perfusion (6.46 ± 0.42 mL/min/g; P < 0.01), and coronary relaxation (79 ± 2%; P < 0.01) as soon as 12 h after S38844 administration. These effects persisted beyond S38844 administration, illustrated by the improvements in cardiac output (130 ± 6 mL/min; P < 0.05), myocardial tissue perfusion (6.38 ± 0.48 mL/min/g; P < 0.01), and coronary relaxation (71 ± 4%; P < 0.01) at Day 14. S38844 did not modify pulmonary weight at Day 1 (1.78 ± 0.04 g) but tended to decrease pulmonary weight at Day 14 (1.80 ± 0.18 g). While delayed HRR induced by S38844 never improved cardiac function, early HRR rendered less prone to a second acute decompensation. Conclusions: In a model mimicking human ADHF, early, but not delayed, transient HRR induced by the If current inhibitor S38844 opposes acute decompensation by preventing the decompensated‐related aggravation of cardiovascular dysfunction as well as the development of pulmonary congestion, and these protective effects persist beyond the transient treatment. Whether early transient HRR induced by If current inhibitors or other bradycardic agents, i.e. beta‐blockers, exerts beneficial effects in human ADHF warrants further investigation. [ABSTRACT FROM AUTHOR]

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 obvious 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 four patients but no controls, and affects the same amino acid as p.Arg90Cys, serves to revert p.Arg90 to the human elastase ancestral allele. As p.Arg90Leu has previously been shown to exert a similar functional effect to that of 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. [ABSTRACT FROM AUTHOR]

Background: The literature shows the negative psychological impact of the coronavirus disease 2019 (COVID-19) outbreak on frontline healthcare workers. However, few are known about the mental health of physicians and nurses working in general hospitals during the outbreak, caring for patients with COVID-19 or not. Objectives: This survey assessed differences in mental health in physicians and nurses working in COVID-19 or non-COVID-19 medical care units. Design: A cross-sectional mixed-mode survey was used to assess burnout, insomnia, depression, anxiety, and stress. Setting: A total of 1,244 physicians and nurses from five general hospitals in Belgium, working in COVID-19 care units (CCU), non-COVID-19 care units (NCCU), or both (CCU + NCCU) were informed of the study. Participants: Six hundred forty-seven healthcare workers participated in the survey (response rate = 52%). Measurements: Validated instruments were used to assess the outcomes: the PFI (burnout/professional fulfillment), the ISI (insomnia), and the DASS-21 (depression, anxiety, and stress). Results: Results showed high prevalence of burnout, insomnia, depression, and anxiety among participants. After adjusting for confounders, multivariate analysis of variance showed no differences between CCU, NCCU, and CCU + NCCU workers. Univariate general linear models showed higher level of burnout, insomnia, and anxiety among nurses in comparison to physicians. Being a nurse, young, isolated, with an increased workload were risk factors for worse mental health outcomes. Limitations: The mental health of the tested sample, before the outbreak, is unknown. Moreover, this cross-sectional design provides no information on the evolution of the mental health outcomes over time. Conclusion: Directly caring for patients with COVID-19 is not associated with worse mental health outcomes among healthcare workers in general hospitals. High prevalence of burnout, insomnia, depression, and anxiety among physicians and nurses requires special attention, and specific interventions need to be implemented. Protocol Registration: ClinicalTrials.gov, identifier NCT04344145. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Résumé: En France, on estime entre 1 000 et 1 500 le nombre de patients atteints de maladie de Wilson. La maladie de Wilson est une affection monogénique de transmission autosomique récessive dont le gène est localisé sur le chromosome 13. Elle entraîne une accumulation de cuivre dans le foie puis ensuite évolue vers une affection systémique. Les premières manifestations sont le plus souvent hépatiques chez l'enfant, neuropsychiatriques et hépatiques chez l'adulte. Le diagnostic peut être porté à tout âge et le dépistage doit être réalisé dans toute la famille. Une fois le diagnostic évoqué, le bilan cuprique et en particulier l'étude du ratio cuivre échangeable/cuivre total (REC) (test rapide et sensible) permet en règle une confirmation du diagnostic avec en parallèle une mise en évidence des mutations par biologie moléculaire dans 98 % des cas. Enfin, les nouveaux traitements par sels de trientine permettent d'adapter les prises en charge au plus près des besoins des patients. In France, the number of patients with Wilson's disease is estimated between 1,000 and 1,500. It is a monogenic disorder of autosomal recessive transmission whose gene is located on chromosome 13. Wilson's disease is linked to an accumulation of copper in the liver and then progresses to a systemic disorder. The first symptoms are most often hepatic in children and neuro psychiatric and hepatic in adults. The diagnosis can be made at any age and screening must be carried out in the whole family. Once the diagnosis has been mentioned, the copper balance and in particular the study of the ratio of exchangeable copper/total copper (REC) (rapid and sensitive test) allows, as a rule, confirmation of the diagnosis, while at the same time highlighting mutations by molecular biology in 98% of cases. Finally, the new trientine salt treatments make it possible to adapt the treatment as closely as possible to the needs of the patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inner speech has been shown to vary in form along several dimensions. Along condensation, condensed inner speech forms have been described, that are supposed to be deprived of acoustic, phonological and even syntactic qualities. Expanded forms, on the other extreme, display articulatory and auditory properties. Along dialogality, inner speech can be monologal, when we engage in internal soliloquy, or dialogal, when we recall past conversations or imagine future dialogs involving our own voice as well as that of others addressing us. Along intentionality, it can be intentional (when we deliberately rehearse material in short-term memory) or it can arise unintentionally (during mind wandering). We introduce the ConDialInt model, a neurocognitive predictive control model of inner speech that accounts for its varieties along these three dimensions. ConDialInt spells out the condensation dimension by including inhibitory control at the conceptualization, formulation or articulatory planning stage. It accounts for dialogality, by assuming internal model adaptations and by speculating on neural processes underlying perspective switching. It explains the differences between intentional and spontaneous varieties in terms of monitoring. We present an fMRI study in which we probed varieties of inner speech along dialogality and intentionality, to examine the validity of the neuroanatomical correlates posited in ConDialInt. Condensation was also informally tackled. Our data support the hypothesis that expanded inner speech recruits speech production processes down to articulatory planning, resulting in a predicted signal, the inner voice, with auditory qualities. Along dialogality, covertly using an avatar's voice resulted in the activation of right hemisphere homologs of the regions involved in internal own-voice soliloquy and in reduced cerebellar activation, consistent with internal model adaptation. Switching from first-person to third-person perspective resulted in activations in precuneus and parietal lobules. Along intentionality, compared with intentional inner speech, mind wandering with inner speech episodes was associated with greater bilateral inferior frontal activation and decreased activation in left temporal regions. This is consistent with the reported subjective evanescence and presumably reflects condensation processes. Our results provide neuroanatomical evidence compatible with predictive control and in favor of the assumptions made in the ConDialInt model. [ABSTRACT FROM AUTHOR]

Background & Aims: To identify prognostic factors for liver disease in children with alpha‐1 antitrypsin deficiency, irrespective of phenotype, using the DEFI‐ALPHA cohort. Methods: Retrospective, then prospective from 2010, multicentre study including children known to have alpha‐1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Clinical and biological data were collected. Liver disease was classified as "severe" (portal hypertension, liver failure, liver transplantation or death); "moderate" (persistent abnormal liver biology without portal hypertension); and "mild/none" (normal or almost normal liver biology and native liver). Prognostic factors for severe liver disease were evaluated using a Cox semiparametric model. Results: In January 2017, 153 patients from 19 centres had been included; genotypes were PIZZ in 81.9%, PISZ in 8.1%, other in 10.0%. Mean ± SD follow‐up was 4.7 ± 2.1 years. Half of patients had moderate liver disease. Twenty‐eight children (18.3%) had severe liver disease (mean age 2.5 years, range: 0‐11.6): diagnosis of alpha‐1 antitrypsin deficiency was made before two months of age in 65.4%, genotypes were PIZZ in 25 (89.3%), PISZ in 2, PIMlikeZ in 1, 15 children underwent liver transplantation, 1 child died at 3 years of age. Neonatal cholestasis was significantly associated with severe liver disease (P = 0.007). Conclusion: Alpha‐1 antitrypsin‐deficient patients presenting with neonatal cholestasis were likely to develop severe liver disease. Some patients with non‐homozygous ZZ genotype can develop severe liver disease, such as PISZ and M variants, when associated with predisposing factors. Further genetic studies will help to identify other factors involved in the development of liver complications. See Editorial on Page 1019 [ABSTRACT FROM AUTHOR]

Inosine monophosphate dehydrogenase (IMPDH) is considered as the limiting enzyme of thiopurine metabolism for the formation of 6‐thioguanine nucleotides (6‐TGN). No data are available on the influence of RBC IMPDH activity on the metabolism of thiopurine drugs in individuals with IBD. The aims of this study were as follows: (a) to carry out a phenotypic study of RBC IMPDH activity in adults and children treated or not with azathioprine (AZA) for autoimmune diseases, and (b) to investigate the relationship between the activities of IMPDH, thiopurine metabolites, inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT). IMPDH activity was determined in 97 adults and 67 children treated or not with AZA. 6‐Thioguanine nucleotides (6‐TGN), 6‐methylmercaptopurine nucleotide (6‐MeMPN) levels, and ITPA as well as TPMT activities were measured in RBCs by HPLC. Using the Gaussian mixture model, distribution of IMPDH activity was evaluated. Influence of age, sex and AZA treatment on IMPDH activity was also assessed. A bimodal distribution in IMPDH activity was found with 87% of patients exhibiting normal activity and 13% of patients with high activity. No influence of age, sex and AZA therapy was found. There is no relationship between TPMT, ITPA and IMPDH activities. A negative correlation between IMPDH activity and 6‐MeMPN was shown in adults and children (rs = −0.335 P = 0.014 and rs = −0.383 P = 0.012, respectively). Our results suggest that AZA‐treated patients exhibiting lower IMPDH activity could have higher Me‐6MPN levels with higher risk of hepatotoxicity. We demonstrated that RBC matrix could be an interesting alternative to lymphocyte matrix to monitor thiopurine metabolites and enzyme activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: To determine whether non‐steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome‐related end‐organ, i.e. cardiac, damage. Materials and methods: In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non‐steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods). Results: Long‐term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end‐diastolic pressure and LV end‐diastolic pressure‐volume relationship, without modifying LV end‐systolic pressure and LV end‐systolic pressure‐volume relationship. Simultaneously, long‐term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short‐term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short‐term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio‐availability, were increased. Conclusions: In rats with metabolic syndrome, the non‐steroidal MR antagonist finerenone opposed metabolic syndrome‐related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long‐term effects, such as modifications in the myocardial structure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ‐globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ‐globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result. [ABSTRACT FROM AUTHOR]

Aim: Congenital portosystemic shunts (CPSS) are rare, congenital malformations that are increasingly often discovered during the fetal period, and for which, the manifestations and evolution are poorly understood. The objective of this review is to describe the phenotype and evolution of forms diagnosed in the antenatal period.Materials and Methods: We performed a systematic review of the literature cited in Pubmed between 1982 and 2016 for CPSS cases diagnosed during the fetal period.Results: We identified 123 cases. The median age at diagnosis was 25 GA (14-38 weeks GA). Eighty patients had 128 associated congenital anomalies. The congenital abnormalities most frequently associated with antenatal diagnosis of CPSS were congenital cardiac disease (30 cases), intrauterine growth restriction (21 cases), vascular anomalies (14 cases), and trisomy 21 (7 cases). Seventy-five complications were reported in the literature. The most frequent were antenatal hemodynamic abnormalities (27 cases), neonatal cholestasis (11 cases), and hyperammonemia (10 cases). Twenty-nine patients had no complications. The choice of treatment was conservative in 29/56 cases, interventional radiology in 15 cases and surgery in 15 cases (three of the latter after failure of embolization).Conclusion: From this review, we propose an algorithm for the perinatal management of this congenital abnormality. [ABSTRACT FROM AUTHOR]

Background: Metabolic bone disease is common in children receiving home parenteral nutrition (HPN) for intestinal failure (IF). Long-term evolution of bone mass in pediatric IF is poorly documented. The aims of this study were (1) to determine the prevalence of low bone mass (LBM) in children receiving HPN for IF, (2) to evaluate the evolution of total bone mineral content (TBMC) during HPN with dual-energy x-ray absorptiometry (DXA), and (3) to identify related factors.Methods: All children referred in our HPN center from 2004 to 2014 were eligible. Inclusion criteria were HPN dependence due to noninflammatory IF, at least 2 TBMC assessments, and HPN duration of at least 2 years at last DXA. TBMC was expressed in z score for ideal weight for height (WFH). LBM was defined by a TBMC WFH z score ≤-2 standard deviations (SD).Results: A total of 175 DXAs for 31 children were performed, mean of 5.6 ± 2.9 assessments per child. The median time between first and last DXA recorded was 6.2 years (0.7-16.6). At the first DXA, 14 children (45%) had a LBM. TBMC increased by +0.1 ± 0.04 SD per year of HPN (P = .012). The risk of LBM decreased with an odds ratio of 0.9 per year of HPN (95% confidence interval, 0.92-0.99; P = .018). Lean mass z score and calcium parenteral intakes were related to the TBMC improvement.Conclusion: LBM is common in pediatric IF, but bone status could improve during HPN in these children. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Measuring of the relative exchangeable copper seems to be a promising tool for the diagnosis of Wilson disease. The aim of our study is to determine the performance of REC for the diagnosis of Wilson disease in a population of patients with chronic liver diseases. Methods: Measuring of exchangeable serum copper levels and relative exchangeable copper was performed in a group of Wilson disease patients at diagnosis or at clinical deterioration because of non‐compliance (group 1, n=9), a group of stable WD patients (group 2, n=40), and two groups of patients (adult and paediatric) followed for non‐Wilsonian liver diseases (group 3, n=103 and group 4, n=49 respectively). Results: Exchangeable serum copper (N: 0.6‐1.1 μmol/L) was significantly higher in group 1 (mean 2.2±0.7 μmol/L) compared to the other three groups: group 2=0.9±0.4 μmol/L, group 3=1.2±0.4 μmol/L, group 4=1.1±0.3 μmol/L (P<0.05). Relative exchangeable copper was significantly higher in Wilson disease patients group 1 and 2 (mean 52.6% and 43.8%) compared to patients suffering from other liver diseases (mean 7.1% and 5.9%) (P<0.05). Conclusions: Our study confirms that the determination of relative exchangeable copper is a highly valuable tool for the diagnosis of Wilson disease. [ABSTRACT FROM AUTHOR]