Neurochemical differences in core regions of the autistic brain: a multivoxel 1H-MRS study in children.

Autism spectrum disorder (ASD) is a neurodevelopmental condition which compromises various cognitive and behavioural domains. The understanding of the pathophysiology and molecular neurobiology of ASD is still an open critical research question. Here, we aimed to address ASD neurochemistry in the same time point at key regions that have been associated with its pathophysiology: the insula, hippocampus, putamen and thalamus. We conducted a multivoxel proton magnetic resonance spectroscopy (1H-MRS) study to non-invasively estimate the concentrations of total choline (GPC + PCh, tCho), total N-acetyl-aspartate (NAA + NAAG, tNAA) and Glx (Glu + Gln), presenting the results as ratios to total creatine while investigating replication for ratios to total choline as a secondary analysis. Twenty-two male children aged between 10 and 18 years diagnosed with ASD (none with intellectual disability, in spite of the expected lower IQ) and 22 age- and gender-matched typically developing (TD) controls were included. Aspartate ratios were significantly lower in the insula (tNAA/tCr: p = 0.010; tNAA/tCho: p = 0.012) and putamen (tNAA/tCr: p = 0.015) of ASD individuals in comparison with TD controls. The Glx ratios were significantly higher in the hippocampus of the ASD group (Glx/tCr: p = 0.027; Glx/tCho: p = 0.011). Differences in tNAA and Glx indices suggest that these metabolites might be neurochemical markers of region-specific atypical metabolism in ASD children, with a potential contribution for future advances in clinical monitoring and treatment.

Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein-protein interactions, and the network's biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the PDE11A and SYTL3 genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.

Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase III studies.

The efficacy and safety of bumetanide oral solution for the treatment of autism spectrum disorder (ASD) in children and adolescents was evaluated in two international, multi-center, randomized, double-blind, placebo-controlled phase III trials; one enrolled patients aged 7-17 years (SIGN 1 trial) and the other enrolled younger patients aged 2-6 years (SIGN 2). In both studies, patients were randomized to receive bumetanide oral solution twice daily (BID) or placebo BID during a 6-month double-blind treatment period. The primary endpoint was change in Childhood Autism Rating Scale 2 (CARS2) total raw score from baseline to Week 26. Key secondary endpoints included changes in Social Responsiveness Scale-2, Clinical Global Impression Scale, and Vineland Adaptive Behavior Scale. Each study enrolled 211 patients (bumetanide, n = 107; placebo, n = 104). Both studies were terminated early due to absence of any significant difference between bumetanide and placebo in the overall studied populations. In both studies, CARS2 total raw score decreased from baseline to Week 26 in the bumetanide and placebo groups, with no statistically significant difference between groups. No differences were observed between treatment groups for any of the secondary efficacy endpoints in either study. In both studies, treatment-emergent adverse events that occurred more frequently with bumetanide than placebo included thirst, polyuria, hypokalemia, and dry mouth. These large phase III trials failed to demonstrate a benefit of bumetanide for the treatment of pediatric ASD compared with placebo. Consequently, the sponsor has discontinued the development of bumetanide for the treatment of this condition. Trial registration: https://clinicaltrials.gov: SIGN 1: NCT03715166; SIGN 2: NCT03715153.

Functional neuroimaging of responses to multiple sensory stimulations in newborns with perinatal asphyxia.

Background: Functional neuroimaging can provide pathophysiological information in perinatal asphyxia (PA). However, fundamental unresolved questions remain related to the influence of neurovascular coupling (NVC) maturation on functional responses in early development. We aimed to probe the feasibility and compare the responses to multiple sensory stimulations in newborns with PA using functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS). Methods: Responses to visual, auditory, and sensorimotor passive stimulation were measured with fMRI and fNIRS and compared in 18 term newborns with PA and six controls. Results: Most newborns exhibited a positive fMRI response during visual and sensorimotor stimulation, higher in the sensorimotor. An asymmetric pattern (negative in the left hemisphere) was observed in auditory stimulation. The fNIRS response most resembling the adult pattern (positive) in PA occurred during auditory stimulation, in which oxyhemoglobin (HbO) increased, and deoxyhemoglobin (HbR) decreased. Significative differences were found in the HbO and HbR profiles in newborns with PA compared to the controls, more evident in auditory stimulation. Positive correlations between the fMRI BOLD signal and at least one fNIRS channel (HbO) in all stimuli in newborns with PA were identified: the strongest was in the auditory (r=0.704) and the weakest in the sensorimotor (r=0.544); in more fNIRS channels, in the visual. Conclusions: Both techniques are feasible physiological assessment tools, suggesting a distinctive level of maturation in sensory and motor areas. Differences in fNIRS profiles in newborns with PA and controls and the fMRI-fNIRS relationship observed can encourage the fNIRS as a clinically emergent valuable tool.

Prevalence of Autism Spectrum Disorder in the Centro region of Portugal: a population based study of school age children within the ASDEU project.

Introduction: Accurate prevalence estimates for Autism Spectrum Disorder (ASD) are fundamental to adequately program medical and educational resources for children. However, estimates vary globally and across Europe, and it is therefore wise to conduct epidemiological studies in defined geo-cultural contexts. Methods: We used a population screening approach to estimate the prevalence of ASD in the Centro region of Portugal, using a harmonized protocol as part of the Autism Spectrum Disorders in the European Union (ASDEU) project. Results: The overall prevalence was estimated at 0.5% (95% CI 0.3-0.7), higher in schools with Autism Units (3.3%, 95%CI 2.7-3.9) than in regular schools (0.3%, 95% CI 0.1-0.5) or schools with Multiple Disability Units (0.3%, 95% CI 0.04-0.6). Discussion: The results indicate that the diagnosis of ASD is followed by the most effective educational policies in Centro Region. The variability in prevalence estimates across the different regions from the ASDEU project, and globally, is discussed.

A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.

Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.

Evidence for an association of prenatal exposure to particulate matter with clinical severity of Autism Spectrum Disorder.

Early-life exposure to air pollutants, including ozone (O3), particulate matter (PM2.5 or PM10, depending on diameter of particles), nitrogen dioxide (NO2) and sulfur dioxide (SO2) has been suggested to contribute to the etiology of Autism Spectrum Disorder (ASD). In this study, we used air quality monitoring data to examine whether mothers of children with ASD were exposed to high levels of air pollutants during critical periods of pregnancy, and if higher exposure levels may lead to a higher clinical severity in their offspring. We used public data from the Portuguese Environment Agency to estimate exposure to these pollutants during the first, second and third trimesters of pregnancy, full pregnancy and first year of life of the child, for 217 subjects with ASD born between 2003 and 2016. These subjects were stratified in two subgroups according to clinical severity, as defined by the Autism Diagnostic Observational Schedule (ADOS). For all time periods, the average levels of PM2.5, PM10 and NO2 to which the subjects were exposed were within the admissible levels defined by the European Union. However, a fraction of these subjects showed exposure to levels of PM2.5 and PM10 above the admissible threshold. A higher clinical severity was associated with higher exposure to PM2.5 (p = 0.001), NO2 (p = 0.011) and PM10 (p = 0.041) during the first trimester of pregnancy, when compared with milder clinical severity. After logistic regression, associations with higher clinical severity were identified for PM2.5 exposure during the first trimester (p = 0.002; OR = 1.14, 95%CI: 1.05-1.23) and full pregnancy (p = 0.04; OR = 1.07, 95%CI: 1.00-1.15) and for PM10 (p = 0.02; OR = 1.07, 95%CI: 1.01-1.14) exposure during the third trimester. Exposure to PM is known to elicit neuropathological mechanisms associated with ASD, including neuroinflammation, mitochondrial disruptions, oxidative stress and epigenetic changes. These results offer new insights on the impact of early-life exposure to PM in ASD clinical severity.

Design and Implementation of a Collaborative Clinical Practice and Research Documentation System Using SNOMED-CT and HL7-CDA in the Context of a Pediatric Neurodevelopmental Unit.

This paper introduces a prototype for clinical research documentation using the structured information model HL7 CDA and clinical terminology (SNOMED CT). The proposed solution was integrated with the current electronic health record system (EHR-S) and aimed to implement interoperability and structure information, and to create a collaborative platform between clinical and research teams. The framework also aims to overcome the limitations imposed by classical documentation strategies in real-time healthcare encounters that may require fast access to complex information. The solution was developed in the pediatric hospital (HP) of the University Hospital Center of Coimbra (CHUC), a national reference for neurodevelopmental disorders, particularly for autism spectrum disorder (ASD), which is very demanding in terms of longitudinal and cross-sectional data throughput. The platform uses a three-layer approach to reduce components' dependencies and facilitate maintenance, scalability, and security. The system was validated in a real-life context of the neurodevelopmental and autism unit (UNDA) in the HP and assessed based on the functionalities model of EHR-S (EHR-S FM) regarding their successful implementation and comparison with state-of-the-art alternative platforms. A global approach to the clinical history of neurodevelopmental disorders was worked out, providing transparent healthcare data coding and structuring while preserving information quality. Thus, the platform enabled the development of user-defined structured templates and the creation of structured documents with standardized clinical terminology that can be used in many healthcare contexts. Moreover, storing structured data associated with healthcare encounters supports a longitudinal view of the patient's healthcare data and health status over time, which is critical in routine and pediatric research contexts. Additionally, it enables queries on population statistics that are key to supporting the definition of local and global policies, whose importance was recently emphasized by the COVID pandemic.

The role of early functional neuroimaging in predicting neurodevelopmental outcomes in neonatal encephalopathy.

Reliably assessing the early neurodevelopmental outcomes in infants with neonatal encephalopathy (NE) is of utmost importance to advise parents and implement early and personalized interventions. We aimed to evaluate the accuracy of neuroimaging modalities, including functional magnetic resonance imaging (fMRI) in predicting neurodevelopmental outcomes in NE. Eighteen newborns with NE due to presumed perinatal asphyxia (PA) were included in the study, 16 of whom underwent therapeutic hypothermia. Structural magnetic resonance imaging (MRI), and fMRI during passive visual, auditory, and sensorimotor stimulation were acquired between the 10th and 14th day of age. Clinical follow-up protocol included visual and auditory evoked potentials and a detailed neurodevelopmental evaluation at 12 and 18 months of age. Infants were divided according to sensory and neurodevelopmental outcome: severe, moderate disability, or normal. Structural MRI findings were the best predictor of severe disability with an AUC close to 1.0. There were no good predictors to discriminate between moderate disability versus normal outcome. Nevertheless, structural MRI measures showed a significant correlation with the scores of neurodevelopmental assessments. During sensorimotor stimulation, the fMRI signal in the right hemisphere had an AUC of 0.9 to predict absence of cerebral palsy (CP). fMRI measures during auditory and visual stimulation did not predict sensorineural hearing loss or cerebral visual impairment. CONCLUSION: In addition to structural MRI, fMRI with sensorimotor stimulation may open the gate to improve the knowledge of neurodevelopmental/motor prognosis if proven in a larger cohort of newborns with NE. WHAT IS KNOWN: • Establishing an early, accurate neurodevelopmental prognosis in neonatal encephalopathy remains challenging. • Although structural MRI has a central role in neonatal encephalopathy, advanced MRI modalities are gradually being explored to optimize neurodevelopmental outcome knowledge. WHAT IS NEW: • Newborns who later developed cerebral palsy had a trend towards lower fMRI measures in the right sensorimotor area during sensorimotor stimulation. • These preliminary fMRI results may improve future early delineation of motor prognosis in neonatal encephalopathy.

A Phase III Study of Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents Aged Between 7 and 17 Years with Autism Spectrum Disorder (SIGN 1 Trial): Participant Baseline Characteristics.

The efficacy of bumetanide (oral liquid formulation 0.5 mg bid) as a treatment for the core symptoms of autism spectrum disorders in children and adolescents aged 7-17 years is being investigated in an international, randomised, double-blind, placebo-controlled phase III study. The primary endpoint is the change in Childhood Autism Rating Scale 2 (CARS2) total raw score after 6 months of treatment. At baseline, the 211 participants analysed are broadly representative of autistic subjects in this age range: mean (SD) age, 10.4 (3.0) years; 82.5% male; 47.7% with intelligence quotient ≥ 70. Mean CARS2 score was 40.1 (4.9) and mean Social Responsiveness Scale score was 116.7 (23.4). Final study results will provide data on efficacy and safety of bumetanide in autistic children and adolescents.

Motor stereotypies in autism spectrum disorder: Clinical randomized study and classification proposal.

LAY ABSTRACT: Motor stereotypies are one of the most frequent features in children with a diagnosis of autism spectrum disorder. They may disrupt children's functioning and development and be a potential source of stress for families. Several factors, including sex, age, cognitive ability, and severity of autism spectrum disorder, may influence the presence and intensity of stereotypies. The present study aimed to identify the prevalence of motor stereotypies in a group of children with autism spectrum disorder. In addition, it sought to investigate whether sex, age, cognitive ability, verbal language, neurological comorbidities, and severity of autism spectrum disorder were associated with an increased probability and higher number, duration, and variability of stereotypies. A total of 134 participants aged 2.3-17.6 years underwent a clinical protocol with standardized video-recorded sessions. Stereotypies were identified and classified by two independent evaluators. The prevalence of stereotypies was 56.7%, and a total of 1198 motor stereotypies were captured. Children who were younger, nonverbal, and had higher severity of autism spectrum disorder had an increased probability of presenting stereotypies. Being nonverbal or having higher severity of autism spectrum disorder was also associated with presenting a higher number of stereotypies. Children with developmental delay, intellectual disability, or epilepsy displayed longer stereotypies, and children with developmental delay or intellectual disability additionally presented more diverse stereotypies. As part of the study, the authors present a clinical classification model, a glossary, and video samples of motor stereotypies. The findings of this study suggest that children who are younger, nonverbal, have lower cognitive ability, and have higher severity of autism spectrum disorder may have a higher burden of stereotypies. Earlier intervention and monitoring of these children have the potential to improve their long-term outcomes.

The prognostic value of delta-lactate in critically ill children.

AIM: This study aimed to test delta-lactate (ΔL) as a short-term risk stratification method in critically ill children. METHODS: An exploratory study of patients admitted to paediatric intensive care unit (PICU) was conducted. ΔL was calculated as the difference between the maximum lactate concentrations on Days 1 and 2. According to the ΔL cutoff, two groups were considered: low mortality risk (LMR) - ΔL ≥ 0.05 mmol/L - and high mortality risk (HMR) - ΔL < 0.05 mmol/L. RESULTS: Mortality, both during PICU stay and at 28 days, was statistically associated with elevated serum lactate on D1 and D2, per se. For the 93 cases with elevated lactate on Day 1, and a ΔL cutoff of 0.05 mmol/L, the area under the ROC curve was 0.698 (95% confidence interval, 0.47-0.93). HMR patients scored higher PIM3, were not discharged home until 28 days, counted fewer ventilation-free days and needed renal replacement therapy more often. CONCLUSION: Elevated lactate levels at admission, as well as applying the optimal cutoff for ΔL, allowed to predict short-term mortality: if an increase or minimal decrease in lactate maximum levels occurred from D1 to D2, death was almost eight times more probable. In critically ill children, delta-lactate predicts short-term outcome.

Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disorders.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.

Faecal calprotectin and rectal histological inflammatory markers in cystic fibrosis: a single-centre study.

OBJECTIVE: To analyse the association of faecal calprotectin with the genetic and clinical characteristics of paediatric patients with cystic fibrosis (PwCF). In a subset of these patients, we aimed to associate histological inflammatory features of rectal mucosa to faecal calprotectin levels. METHODS: In a prospective study, faecal calprotectin levels were collected in all 23 PwCF attending our paediatric centre, together with demographic and clinical data. Associations between faecal calprotectin and clinical features were determined. In 11 of these patients, endoscopic rectal biopsies were obtained and the association between faecal calprotectin and histological inflammatory markers was analysed. Statistical analyses included Spearman's correlation coefficient, Mann-Whitney U test and Fisher's exact test. Sensitivity and specificity was calculated. RESULTS: Median age of PwCF was 12 years, 19 had pancreatic insufficiency (PI) (19/23). Seventeen (17/23) had elevated faecal calprotectin, and the median value was 88 µg/g (IQR=178 µg/g). Higher faecal calprotectin levels were observed in the PI group (101 vs 30 µg/g, p=0.027). No significant correlation between elevated faecal calprotectin level and body mass index z-score was found. Five patients (22%) reported abdominal pain, three (13%) complained of diarrhoea and three (13%) had constipation, but these symptoms were not associated with elevated faecal calprotectin.Unspecific focal rectal inflammation was found in four patients (4/11). An association between rectal mucosa inflammation and elevated faecal calprotectin was found (p=0.015). Sensitivity was 100% and specificity was 86%. CONCLUSIONS: In our PwCF, elevated faecal calprotectin was frequent, particularly if PI, and it was not related to gastrointestinal symptoms or malnutrition. Elevated faecal calprotectin was present in patients with histological evidence of rectal inflammation. Faecal calprotectin may be an indicator of asymptomatic rectal inflammation in PwCF.

Metabolically healthy obesity in a paediatric obesity clinic.

OBJECTIVES: Metabolically healthy obese (MHO) children is a described subgroup of obese children who do not exhibit traditional cardiometabolic risk factors. The aim of this study was to determine the prevalence and characterize patients with this phenotype. METHODS: Cross-sectional study, performed in a paediatric obesity clinic (tertiary university hospital) in 2019. Children were classified with "MHO" or "metabolically unhealthy obesity" according to the criteria proposed by Damanhoury based on HDL, triglycerides, systolic and diastolic blood pressure (DBP) and fasting glucose values. RESULTS: 241 participants were included, with ages between two and 17 years. The prevalence of the MHO phenotype was 61.8%. The body mass index (Z-score) in children aged five years or older was significantly lower in those with MHO (p=0.040). In the MHO group, mean total cholesterol levels were higher (p<0.001), due to the high value of HDL (p<0.001); triglyceride levels (p<0.001), systolic blood pressure (SBP) (p=0.036), DBP (p=0.029) and the homeostasis model assessment - insulin resistance (HOMA-IR) index (p=0.001) were significantly lower. HDL (OR=1.421; 95% CI 1.279-1.579; p<0.001) and SBP (OR=0.943; 95% CI 0.903-0.985; p=0.008) were the only independent predictors for the development of MHO. CONCLUSIONS: Almost two-thirds of the participants had an MHO phenotype. The high and low values of HDL and SBP, respectively, were the only variables that proved to be predictors of MHO.

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics.

Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

New drugs in cystic fibrosis: what has changed in the last decade?

Cystic fibrosis (CF), a life-limiting chronic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, affects more than 90,000 people worldwide. Until recently, the only available treatments were directed to symptom control, but they failed to change the course of the disease. New drugs developed in the last decade have the potential to change the expression, function, and stability of CFTR protein, targeting the basic molecular defect. The authors seek to provide an update on the new drugs, with a special focus on the most promising clinical trials that have been carried out to date. These newly approved drugs that target specific CFTR mutations are mainly divided into two main groups of CFTR modulators: potentiators and correctors. New therapies have opened the door for potentially disease-modifying, personalized treatments for patients with CF.

Pediatric population with cystic fibrosis in the centre of Portugal: candidates for new therapies

Abstract Objectives: Cystic fibrosis (CF) is a severe autosomal recessive disease that results from mutations in a gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a chloride channel. This study aims to characterize the clinical and genetic features of a cohort of pediatric people with CF (PwCF) in the center of Portugal and to determine which ones are candidates for the new drugs modulating the CFTR channel. Methods: A review of the demographic, genetic and clinical characteristics of PwCF undergoing follow-up at a CF reference center was carried out. Results: Twenty-three PwCF (12 male), with a median age of 12 years, were followed up. All patients carry the F508del mutation in at least one allele. Fifteen PwCF were F508del-homozygous, median BMI z-score was -0.13, all are pancreatic insufficient and median FEV1 value was 78.1%. These PwCF are eligible for dual therapy (lumacaftor/tezacaftor+ivacaftor) and for triple therapy (tezacaftor+ivacaftor+elexacaftor). PwCF with 711 +1G->T (n = 2), 2184insA (n = 1) mutations and a novel mutation c.3321dup (n = 1) have minimal function mutation and patients with a residual function mutation: R334W (n = 3) and P5L (n = 1) have a less severe phenotype. All these patients, because they also carry F508del mutation, are elegible to triple therapy. Conclusions: Genetic and molecular characterization of PwCF poses an important step not just for CF diagnosis and prognosis which is tightly correlated with the clinical phenotype, but also for the eligibility of CFTR modulator drugs.

Parahippocampal deactivation and hyperactivation of central executive, saliency and social cognition networks in autism spectrum disorder.

BACKGROUND: The concomitant role of the Central Executive, the Saliency and the Social Cognition networks in autism spectrum disorder (ASD) in demanding ecological tasks remains unanswered. We addressed this question using a novel task-based fMRI virtual-reality task mimicking a challenging daily-life chore that may present some difficulties to individuals with ASD: the EcoSupermarketX. METHODS: Participants included 29 adolescents: 15 with ASD and 15 with typical neurodevelopment (TD). They performed the EcoSupermarketX (a shopping simulation with three goal-oriented sub-tasks including "no cue", "non-social" or "social" cues), during neuroimaging and eye-tracking. RESULTS: ASD differed from TD only in total time and distance to complete the "social cue" sub-task with matched eye-tracking measures. Neuroimaging revealed simultaneous hyperactivation across social, executive, and saliency circuits in ASD. In contrast, ASD showed reduced activation in the parahippocampal gyrus, involved in scene recognition. CONCLUSIONS: When performing a virtual shopping task matching the performance of controls, ASD adolescents hyperactivate three core networks: executive, saliency and social cognition. Parahippocampal hypoactivation is consistent with effortless eidetic scene processing, in line with the notion of peaks and valleys of neural recruitment in individuals with ASD. These hyperactivation/hypoactivation patterns in daily life tasks provide a circuit-level signature of neural diversity in ASD, a possible intervention target.

Pediatric population with cystic fibrosis in the centre of Portugal: candidates for new therapies.

OBJECTIVES: Cystic fibrosis (CF) is a severe autosomal recessive disease that results from mutations in a gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a chloride channel. This study aims to characterize the clinical and genetic features of a cohort of pediatric people with CF (PwCF) in the center of Portugal and to determine which ones are candidates for the new drugs modulating the CFTR channel. METHODS: A review of the demographic, genetic and clinical characteristics of PwCF undergoing follow-up at a CF reference center was carried out. RESULTS: Twenty-three PwCF (12 male), with a median age of 12 years, were followed up. All patients carry the F508del mutation in at least one allele. Fifteen PwCF were F508del-homozygous, median BMI z-score was -0.13, all are pancreatic insufficient and median FEV1 value was 78.1%. These PwCF are eligible for dual therapy (lumacaftor/tezacaftor+ivacaftor) and for triple therapy (tezacaftor+ivacaftor+elexacaftor). PwCF with 711 +1G->T (n = 2), 2184insA (n = 1) mutations and a novel mutation c.3321dup (n = 1) have minimal function mutation and patients with a residual function mutation: R334W (n = 3) and P5L (n = 1) have a less severe phenotype. All these patients, because they also carry F508del mutation, are elegible to triple therapy. CONCLUSIONS: Genetic and molecular characterization of PwCF poses an important step not just for CF diagnosis and prognosis which is tightly correlated with the clinical phenotype, but also for the eligibility of CFTR modulator drugs.