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Abstract 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.

Introduction Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants’ genetic profiles.Methods and analysis EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms.Ethics and dissemination To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).

IntroductionAccurate 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.MethodsWe 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.ResultsThe 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).DiscussionThe 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.

Introduction: In home mechanical ventilated (HMV) children, treatment is not based on cure, but rather on preventing morbidity and mortality and promoting their well-being. This study aimed to evaluate the different dimensions of quality of life (QoL), of HMV children/adolescents of a tertiary pediatric hospital, according to children/adolescents and caregiver’s perspective, and relating it to sociodemographic and clinical characteristics. Methods: We studied families who integrated the home- ventilation program. The PedsQL™ questionnaire was answered by children/adolescents and their caregivers. Sociodemographic and clinical information was recorded. Results: 46 parents and 39 children/adolescents’ questionnaires were answered. The median of the average duration of ventilatory support was 3,5y. 60,9% attend full-time school. The average of general QoL, according to parents and children/adolescents, was 61,6 and 64,0, respectively, with a strong correlation between two groups (r = 0,691). Children/adolescents showed higher scores for all dimensions of QoL. In the physical dimension a very strong correlation between groups was verified. For both groups it was found that psychosocial dimension is the best predictor of QoL. Discussion/conclusion: Parents and children/adolescents shared the same perspective about QoL, with a good correlation between answers of both groups, concluding that home ventilation is an acceptable medical strategy and has impact in QoL for both.

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.

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.

Abstract 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.

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.

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.

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.

Executive functioning (EF) impairments in Autism Spectrum Disorder (ASD) impact on complex functions, such as social cognition. We assessed this link between EF, attentional cueing, and social cognition with a novel ecological task, “EcoSupermarketX.” Our task had three blocks of increasing executive load and incorporated social and non-social cues, with different degrees of saliency. Performance of ASD and typical neurodevelopment was compared. The ASD showed a significant performance dependence on the presence of contextual cues. Difficulties increased as a function of cognitive load. Between-group differences were found both for social and non-social salient cues. Eye-tracking measures showed significantly larger fixation time of more salient social cues in ASD. In sum, EcoSupermarketX is sensitive to detect EF and attentional cueing deficits in ASD.

Abstract Background High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). Results We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. Conclusions Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

Social attention deficits represent a central impairment of patients suffering from autism spectrum disorder (ASD), but the nature of such deficits remains controversial. We compared visual attention regarding social (faces) vs. non-social stimuli (objects), in an ecological diagnostic context, in 46 children and adolescents divided in two groups: ASD (N = 23) and typical neurodevelopment (TD) (N = 23), matched for chronological age and intellectual performance. Eye-tracking measures of visual scanning, while exploring and describing scenes from three different tasks from the Autism Diagnostic Observation Schedule (ADOS), were analyzed: “Description of a Picture,” “Cartoons,” and “Telling a Story from a Book.” Our analyses revealed a three-way interaction between Group, Task, and Social vs. Object Stimuli. We found a striking main effect of group and a task dependence of attentional allocation: while the TD attended first and longer to faces, ASD participants became similar to TD when they were asked to look at pictures while telling a story. Our results suggest that social attention allocation is task dependent, raising the question whether spontaneous attention deficits can be rescued by guiding goal-directed actions.

Introdução: As perturbações do neurodesenvolvimento são, nas sociedades modernas, as patologias crónicas mais frequentes da idade pediátrica. Muitas permanecem na vida adulta. A organização da rede de cuidados de saúde nacional carece de conhecimento fundamentado das necessidades assistenciais para lhes responder de um modo eficaz, eficiente e efetivo. Com o objetivo de conhecer a realidade assistencial hospitalar atual da Pediatria do Neurodesenvolvimento, a Sociedade de Pediatria do Neurodesenvolvimento da Sociedade Portuguesa de Pediatria procedeu a um levantamento nacional em 2007, repetindo-o dez anos depois. Material e Métodos: No biénio 2016-2017 procedeu-se a um inquérito dirigido ao universo de 45 unidades hospitalares abrangendo o movimento assistencial das consultas de Pediatria do Neurodesenvolvimento, a alocação de recursos humanos, e as necessidades de reforço de profissionais. Resultados: Obteve-se 100% de respostas. O número total de consultas de Pediatria do Neurodesenvolvimento subiu de 38 238 (2007) para 99 815 (2017). O número de profissionais também aumentou: os pediatras passaram de 82 a 156. Uma mediana de 101 crianças aguardavam primeira consulta, contra 185 em 2007. Discussão: Numa década, o movimento assistencial quase triplicou. O reforço de profissionais, apesar de positivo, não teve o mesmo incremento; ainda assim, o número de crianças em lista de espera para primeira consulta reduziu-se quase para metade, o que reflete o comprometimento dos profissionais. Conclusão: É de salientar a melhoria global da resposta nacional na área da Pediatria do Neurodesenvolvimento. Contudo, o reforço dos recursos humanos numa perspectiva pluridisciplinar não deve ser negligenciado, tendo em vista a melhoria contínua da prestação de cuidados numa área de grande cronicidade e complexidade.

Introduction: Gestational diabetes is one of the diseases associated with pregnancy with higher rate of complications. Despite being a transitory condition, short and long term complications related to gestational diabetes have been described. There is scientific evidence to say that good metabolic control decreases perinatal complications. In 2011, new criteria was proposed for its diagnosis, which made possible its diagnosis during the 1st trimester of pregnancy. The aim of this study is to compare neonatal morbidity in two groups of women with gestational diabetes diagnosis before and after the latest Portuguese guidelines for diabetes and pregnancy were published (February 2011). Material and Methods: We included all newborns born in Maternidade Bissaya Barreto whose mother, followed at our maternity between 2008 and 2013, had unifetal pregnancy complicated by diabetes. We used a perinatal database and analysed the impact of the new guidelines in perinatal morbidity over two periods of three years. Results: There were 774 women who met the inclusion criteria. We found that gestational diabetes was diagnosed earlier, insulin therapy was more frequent. Neonatal morbidity was increased, and there were more cases of neonatal hypoglycemia and congenital anomalies, and newborns became smaller for gestational age. Discussion: The increase in neonatal morbidity was associated with early diagnosis and rigorous metabolic control. Conclusion: To analyse national data will be fundamental to understand this unexpected increase in morbidity.

Imagery of facial expressions in Autism Spectrum Disorder (ASD) is likely impaired but has been very difficult to capture at a neurophysiological level. We developed an approach that allowed to directly link observation of emotional expressions and imagery in ASD, and to derive biomarkers that are able to classify abnormal imagery in ASD. To provide a handle between perception and action imagery cycles it is important to use visual stimuli exploring the dynamical nature of emotion representation. We conducted a case-control study providing a link between both visualization and mental imagery of dynamic facial expressions and investigated source responses to pure face-expression contrasts. We were able to replicate the same highly group discriminative neural signatures during action observation (dynamical face expressions) and imagery, in the precuneus. Larger activation in regions involved in imagery for the ASD group suggests that this effect is compensatory. We conducted a machine learning procedure to automatically identify these group differences, based on the EEG activity during mental imagery of facial expressions. We compared two classifiers and achieved an accuracy of 81% using 15 features (both linear and non-linear) of the signal from theta, high-beta and gamma bands extracted from right-parietal locations (matching the precuneus region), further confirming the findings regarding standard statistical analysis. This robust classification of signals resulting from imagery of dynamical expressions in ASD is surprising because it far and significantly exceeds the good classification already achieved with observation of neutral face expressions (74%). This novel neural correlate of emotional imagery in autism could potentially serve as a clinical interventional target for studies designed to improve facial expression recognition, or at least as an intervention biomarker.

Deficits in the interpretation of others' intentions from gaze-direction or other social attention cues are well-recognized in ASD. Here we investigated whether an EEG brain computer interface (BCI) can be used to train social cognition skills in ASD patients. We performed a single-arm feasibility clinical trial and enrolled 15 participants (mean age 22y 2m) with high-functioning ASD (mean full-scale IQ 103). Participants were submitted to a BCI training paradigm using a virtual reality interface over seven sessions spread over 4 months. The first four sessions occurred weekly, and the remainder monthly. In each session, the subject was asked to identify objects of interest based on the gaze direction of an avatar. Attentional responses were extracted from the EEG P300 component. A final follow-up assessment was performed 6-months after the last session. To analyze responses to joint attention cues participants were assessed pre and post intervention and in the follow-up, using an ecologic “Joint-attention task.” We used eye-tracking to identify the number of social attention items that a patient could accurately identify from an avatar's action cues (e.g., looking, pointing at). As secondary outcome measures we used the Autism Treatment Evaluation Checklist (ATEC) and the Vineland Adaptive Behavior Scale (VABS). Neuropsychological measures related to mood and depression were also assessed. In sum, we observed a decrease in total ATEC and rated autism symptoms (Sociability; Sensory/Cognitive Awareness; Health/Physical/Behavior); an evident improvement in Adapted Behavior Composite and in the DLS subarea from VABS; a decrease in Depression (from POMS) and in mood disturbance/depression (BDI). BCI online performance and tolerance were stable along the intervention. Average P300 amplitude and alpha power were also preserved across sessions. We have demonstrated the feasibility of BCI in this kind of intervention in ASD. Participants engage successfully and consistently in the task. Although the primary outcome (rate of automatic responses to joint attention cues) did not show changes, most secondary neuropsychological outcome measures showed improvement, yielding promise for a future efficacy trial.(clinical-trial ID: NCT02445625—clinicaltrials.gov).

RESUMO Analisa-se a participação das universidades estaduais no ensino superior do Brasil, comparando-as com as federais, municipais e privadas em termos do número de instituições, vagas, ingressantes, matrículas e concluintes antes e depois da Lei de Diretrizes e Bases da Educação Nacional. Pergunta-se: qual a contribuição para o ensino superior brasileiro e que efeitos as inovações da LDB provocaram no setor? Deseja-se dimensionar essa participação, comparando a parcela de contribuição das UEs com a dos demais segmentos antes das inovações da lei geral. Tomam-se por base os Censos do Ensino Superior realizados pelo INEP, analisando a proporção do segmento em relação ao total. Constatou-se que as estaduais são as primeiras instituições universitárias e que, salvo nas primeiras décadas, quando a federalização subtraiu algumas unidades, até 1996, ampliava sua participação com 20% das instituições, 15% dos ingressantes, 17% das matrículas, 19% de concluintes e 13% das vagas. Desde então, apesar dos acréscimos, tem reduzido sua fatia, tendo, em 2013, 19% das universidades, 5% das vagas, 8% dos ingressantes, 13% das matrículas e 14% dos concluintes, não acompanhando o crescimento das federais e, principalmente, das privadas que, favorecidas com as alterações na legislação, tornaram-se o maior segmento. Conclui-se, então, que a participação das universidades estaduais no ensino superior brasileiro tem experimentado ora ampliação, ora redução, mas sempre favorecendo o acesso ao ensino superior de grandes camadas da população brasileira. Palavras-chave: Ensino superior. Educação brasileira. Universidades estaduais. Ensino superior estadual.

Este texto analisa o Programa Nacional de Tecnologia Educacional (ProInfo), caracterizando sua engenharia institucional, em particular o modo como estabelece parceria entre a União e os entes federados. O objetivo é examinar os traços constitutivos do ProInfo, identificando, nessa engenharia institucional, a estratégia de indução do governo federal para atrair a adesão de estados e municípios. Para tanto, recorre-se à legislação que o instituiu, além da literatura relativa à descentralização das políticas sociais num Estado federativo. Constatou-se que o modelo do ProInfo assenta-se numa divisão do trabalho em que a União financia, coordena, acompanha e avalia, enquanto os demais entes federativos administram, executam e mantêm as ações, responsabilizando-se pelos custos de manutenção, inclusive de pessoal e instalações. É uma estratégia desenhada que favorece a montagem da infraestrutura, oferecendo os meios, complementando-os ou incentivando-os a desenvolver a introdução das novas tecnologias na educação, mas não estabelece qualquer vínculo entre a liberação de recursos e o cumprimento das atribuições pactuadas ou mesmo destas com novos aportes de recurso. Portando, a engenharia institucional, ainda que tenha patrocinado a instalação de laboratórios, isto é, tenha disponibilizado os meios para a inclusão digital desejada, não favoreceu, como objetivava o programa, o uso pedagógico das tecnologias de informação e comunicação nas redes públicas de educação básica.

Introdução: Estudos evidenciaram maior taxa de alterações do neurodesenvolvimento nos gémeos em relação aos recém-nascidos de gestação unifetal. O objetivo deste trabalho foi comparar alterações do neurodesenvolvimento em gémeos (monocoriónicos e bicoriónicos) grandes prematuros ou de muito baixo peso ao nascer, com recém-nascidos de gestação unifetal. Material e Métodos: Estudo retrospetivo de uma coorte de recém-nascidos com idade gestacional inferior a 32 semanas ou peso de nascimento inferior a 1500 g, internados na Unidade de Cuidados Intensivos Neonatais, numa maternidade de apoio perinatal diferenciado da Região Centro de Portugal, no período de 2006 a 2010. A avaliação do neurodesenvolvimento foi realizada aos 24 meses, com a escala de Growing Skills II. No diagnóstico de paralisia cerebral usou-se a classificação internacional de Surveillance of Cerebral Palsy in Europe. Foram comparados recém-nascidos de gestação unifetal com recém-nascidos de gravidez múltipla e com os subgrupos: monocoriónicos e bicoriónicos. Análise estatística pelo SPSS versão 20.0. Foi aplicado um modelo de regressão logística. Resultados: Foram avaliados 194 recém-nascidos do grupo gestação unifetal e 89 gémeos - 50 bicoriónicos e 39 monocoriónicos. Os gémeos monocoriónicos apresentaram maior risco, em relação ao grupo de gestação unifetal, de alterações moderadas a graves do neurodesenvolvimento global (OR ajustado 3,6) e nas subáreas: locomoção (OR ajustado 12,2) linguagem (OR ajustado 6,5) e autonomia (OR ajustado 7,2). A paralisia cerebral foi diagnosticada em 15,4% dos gémeos monocoriónicos e 4,1% de gestação unifetal (OR ajustado 4,2). Discussão: Este trabalho evidenciou taxa superior de alterações moderadas a graves do neurodesenvolvimento, incluindo a paralisia cerebral nos gémeos monocoriónicos em relação ao grupo de gestação unifetal. A análise por grupos estratificados em relação à idade gestacional e a comparação de monocoriónicos com bicoriónicos alertou para o papel da corionicidade na base destas sequelas. Conclusão: Podemos concluir que os gémeos monocoriónicos apresentaram, na população estudada, um risco significativo de sequelas moderadas a graves do neurodesenvolvimento.

Introdução: Determinar a incidência de infeções da corrente sanguínea associadas ao uso de cateter venoso central, após reforço de medidas multidisciplinares de boa prática e a sua comparação com a taxa de incidência de infeções da corrente sanguínea associadas ao uso de cateter venoso central prévia. Material e Métodos: Estudo observacional descritivo, com colheita prospetiva de dados, durante cinco meses, após implementação de medidas multidisciplinares. Foram incluídas todas as crianças admitidas na unidade de Cuidados Intensivos Pediátricos, submetidas à colocação de cateter venoso central e foi efetuada comparação com controlos históricos. Resultados: Incluíram-se 75 doentes com idade mediana de 23 meses: 22 (29,3%) recém-nascidos, 28 (37,3%) submetidos a cirurgia e 32 (43,8%) com patologia subjacente. Foram colocados 105 cateteres venosos centrais, com tempo médio de permanência de 6,8 ± 6,7 dias. O tipo de cateter venoso central mais comum foi de curta duração (45,7%), sendo os locais de inserção mais frequentes a veia subclávia e da flexura braquial (ambos 25,7%). Não ocorreu nenhuma infeção da corrente sanguínea associada ao uso de cateter venoso central durante o período do estudo. Comparando com os controlos históricos, ambos os grupos eram semelhantes relativamente à idade, género, proveniência dos doentes e local de colocação de cateter venoso central. No estudo atual, a duração mediana de internamento foi superior, com tempo de permanência de cateter venoso central (excluindo epicutâneo-cava) semelhante. Não se verificou diferença em relação ao calibre e número de lumens do cateter venoso central utilizado. A percentagem de crianças que colocou cateter venoso central em relação ao total de crianças admitidas no serviço no mesmo período foi menor no estudo atual, não existindo diferença significativa entre colocação de cateter venoso central único ou múltiplo. Discussão: Após implementação da estratégia multidimensional não se registou nos Cuidados Intensivos Pediátricos ocorrência de infeções da corrente sanguínea associadas ao uso de cateter venoso central. Conclusões: Devem ser encetados esforços para preservar o mesmo grau de prevenção multidimensional, para que se confirme a redução efetiva da taxa de incidência de infeções da corrente sanguínea associadas ao uso de cateter venoso central.

Genome-wide association studies (GWAS) for Autism Spectrum Disorder (ASD) thus far met limited success in the identification of common risk variants, consistent with the notion that variants with small individual effects cannot be detected individually in single SNP analysis. To further capture disease risk gene information from ASD association studies, we applied a network-based strategy to the Autism Genome Project (AGP) and the Autism Genetics Resource Exchange GWAS datasets, combining family-based association data with Human Protein-Protein interaction (PPI) data. Our analysis showed that autism-associated proteins at higher than conventional levels of significance (P

Introdução: Nos últimos anos tem-se assistido a um aumento das infeções por bactérias multirresistentes. Os dados pediátricos no global, e em particular em Portugal, são escassos. Objectivos: Avaliar a evolução das infeções por bactérias multirresistentes associadas aos cuidados de saúde num hospital pediátrico. Material e Métodos: Estudo retrospetivo de incidência efetuado nas enfermarias médicas, cirúrgicas e de cuidados intensivos num hospital pediátrico nível III, entre Janeiro de 2005 e Dezembro de 2009. As bactérias multirresistentes estudadas foram Staphylococcus aureus meticilino-resistente (SAMR), bacilos gram negativos produtores de β-lactamases de espectro expandido (ESBL), Enterococcus spp resistentes à vancomicina (ERV), Pseudomonas aeruginosa multirresistentes (PAMR) e Acinetobacter baumanii resistente aos carbapenems. Foram analisados dados demográficos, clínicos, laboratoriais, terapêuticos e presença de fatores de risco. Resultados: Durante o período de estudo foram identificadas 106 bactérias multirresistentes associadas, correspondentes a 72 crianças, com predomínio do sexo masculino (65,3%). As bactérias multirresistentes mais frequentemente identificadas foram SAMR (35,8%), PAMR (29,2%) e bacilos gram negativos com fenótipo ESBL (17,9%). Destas 106 bactérias multirresistentes, 45 (42,5%) foram identificadas em infeção. Ao longo do período de estudo, a proporção anual de infeções por bactérias multirresistentes variou entre 32,0% em 2006 e 55,6% em 2009 (p = 0,376). A taxa de incidência global de infeção por estas bactérias foi de 0,400 por 1 000 dias de internamento, correspondendo a 0,274 infeções por 100 internamentos, valor que se manteve estável ao longo dos cinco anos. Predominaram as infeções da corrente sanguínea (31,1%), intra-abdominais (20,0%), associadas a cateter venoso central (17,8%) e da pele e tecidos moles (11,1%). Todas as crianças tinham fatores de risco e os mais frequentemente identificados foram antibioticoterapia prévia e doença crónica de base (> 90%). Seis crianças (13,3%) faleceram durante o internamento. Conclusões: Ao longo do período de estudo, a proporção de bactérias multirresistentes apresentou uma tendência de aumento, embora sem significado estatístico. As taxas de incidência de infeção mantiveram-se estáveis. SAMR foram as bactérias mais frequentemente identificadas, seguidas por PAMR e bacilos gram negativos ESBL. O tipo de infeção mais frequente foi da corrente sanguínea, seguido pelas infeções intra-abdominais e as associadas a dispositivos invasivos. A totalidade das crianças apresentava fatores de risco, nomeadamente antibioticoterapia prévia e doença crónica de base.

Introdução: As síndromes de deficiência cerebral de creatina (OMIM 300036) são um grupo de patologias recentemente descritas,caracterizadas por defeitos congénitos no metabolismo da creatina. A apresentação clínica compreende um espectro variado deperturbações do neurodesenvolvimento. Os baixos níveis de creatina cerebral verificados nestes doentes devem-se a diferentesmutações nos genes que codificam as enzimas de síntese da creatina [arginina:glicina amidinotransferase (AGAT, EC 2.1.4.1), emetiltransferase do ácido guanidinoacético (GAMT, EC 2.1.1.2)], AGAT e GAMT, respectivamente, ambas de transmissão autossómicarecessiva, ou o seu transportador (CT1), SLC6A8, de transmissão ligada ao cromossoma X.Objectivo: Caracterizar o espectro de apresentação clínica e laboratorial dos doentes com o diagnóstico da síndrome de deficiênciade creatina cerebral seguidos no Hospital Pediátrico Carmona da Mota, bem como a sua orientação diagnóstica e terapêutica. Adivulgação destes erros inatos do metabolismo enquanto doenças neurológicas, nomeadamente do neurodesenvolvimento, entre acomunidade médica é outro dos propósitos almejados.Material e Métodos: Análise retrospectiva dos processos clínicos de doentes com o diagnóstico de deficiência cerebral da creatinaseguidos no Hospital Pediátrico.Resultados: Foram identificados doze doentes com défice cerebral da creatina pertencentes a sete famílias. Cinco apresentam deficiênciade metiltransferase do ácido guanidinoacético e sete do transportador de creatina. Têm actualmente entre dois e 38 anos.Os principais motivos de consulta foram: atraso global de desenvolvimento em sete doentes, dois dos quais também apresentavamepilepsia, e atraso da linguagem em outros dois. Apenas num caso o motivo de consulta foi défice de interacção social e de comunicação.Em todos os casos se registou um quociente de desenvolvimento global na faixa da deficiência intelectual. O estudo imagiológicodemonstrou o padrão patognomónico destas síndromes em oito doentes. No estudo genético foram identificadas mutações nos genesGAMT ou SLC6A8 nos doze casos.Conclusões: A suspeita de deficiência de creatina cerebral deve ser considerada em todos os casos de atraso de desenvolvimentopsicomotor sem outra causa evidente. A terapêutica pré-sintomática tem mostrado resultados promissores em algumas crianças comdéfice cerebral de creatina, sobretudo nos défices de GAMT. A elevada taxa de portadores de mutações do gene GAMT em Portugaltorna esta anomalia elegível para o rastreio neonatal no nosso País.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

The weak central coherence hypothesis represents one of the current explanatory models in Autism Spectrum Disorders (ASD). Several experimental paradigms based on hierarchical figures have been used to test this controversial account. We addressed this hypothesis by testing central coherence in ASD (n = 19 with intellectual disability and n = 20 without intellectual disability), Williams syndrome (WS, n = 18), matched controls with intellectual disability (n = 20) and chronological age-matched controls (n = 20). We predicted that central coherence should be most impaired in ASD for the weak central coherence account to hold true. An alternative account includes dorsal stream dysfunction which dominates in WS. Central coherence was first measured by requiring subjects to perform local/global preference judgments using hierarchical figures under 6 different experimental settings (memory and perception tasks with 3 distinct geometries with and without local/global manipulations). We replicated these experiments under 4 additional conditions (memory/perception*local/global) in which subjects reported the correct local or global configurations. Finally, we used a visuoconstructive task to measure local/global perceptual interference. WS participants were the most impaired in central coherence whereas ASD participants showed a pattern of coherence loss found in other studies only in four task conditions favoring local analysis but it tended to disappear when matching for intellectual disability. We conclude that abnormal central coherence does not provide a comprehensive explanation of ASD deficits and is more prominent in populations, namely WS, characterized by strongly impaired dorsal stream functioning and other phenotypic traits that contrast with the autistic phenotype. Taken together these findings suggest that other mechanisms such as dorsal stream deficits (largest in WS) may underlie impaired central coherence.

Enterobacteriaceae are a common cause of invasive disease in children. The production of extended-spectrum ß-lactamase (ESBL) by these bacteria and consequent resistance to several antibiotics has increased. The paediatric data are scarce.To identify children infected with ESBL-producing bacilli, determining their prevalence in health care related infection and community-acquired disease. To analyse demographic, clinical, laboratory, therapeutic and follow-up data. To identify potential risk factors for infection by ESBL-producing organisms.A case-control study, conducted in a level III paediatric hospital, from July 2007 to December 2009. All patients were identified from the microbiology database. Children infected by ESBL-producing bacilli were compared with a group with infection by non-ESBL producers, selected in a systematic way, given the bacteria, product and date of isolation. Statistical data analysis was performed using SPSS® 17.1.The ESBL-producing phenotype was detected in 0.5% of Escherichia coli and 16.4% of Klebsiella spp identified. These bacteria were isolated in 23 children: 7 Escherichia coli (30.4%), 15 Klebsiella pneumoniae (65.2%) and 1 Klebsiella oxytoca (4.3%). The most common diagnosis was urinary tract infection (39%). Hospital admission was required in 70% of the cases versus 50% controls (p=0.141), with mean duration stay of 69 days for cases and 36 days for controls (p=0.235). The mean time between admission and infection was 32 days in both (p=0.978). Health care related infections were identified in 70% of cases versus 25% of controls (p=0.001). Infections due to ESBL producing organisms occurred in the community setting particularly in the last year of the study (n=4). The presence of chronic disease (p=0.022) and previous hospitalization (p=0.025), antibiotic use (p=0.008) and invasive ventilation (p=0.002) were more common in infection caused by ESBL-producing bacteria. Surgery (p=0.175) and the presence of a central venous catheter (p=0.189) were not risk factors. In a multivariate analysis, only prior invasive ventilation was an independent risk factor for infection by ESBL-producing bacteria (p=0.002, OR=7).The ESBL-producing phenotype was detected in 0.5% Escherichia coli and 16.4% Klebsiella spp identified; mainly in health care related infections. The presence of chronic disease and previous hospitalization, invasive ventilation and antibiotic intake were more common in infections caused by these bacteria. Prior invasive ventilation was an independent risk factor.

Traumatic brain injury is a frequent reason for admission at pediatric emergency services. In severe cases, with basilar skull fracture, bacterial meningitis is a serious and potentially fatal complication to be considered.To describe clinical and laboratory features, bacteriology and outcome of children with post-traumatic meningitis, and evaluate the proportion of meningitis in the population who suffered head trauma.Retrospective review of medical records of children with this diagnosis admitted to a level 3 pediatric hospitals in the Central Region of Portugal, contextualized in the evaluation of the number of head injuries, fractures and cerebrospinal fluid leakages, during a 11-year period (January 1999 to December 2009).Four children were identified, corresponding to 0,7% of the children with skull fractures, 4,1% of children with basilar skull fractures and 13,8% of those with documented cerebrospinal fluid leakage. Three were boys, with a median age of 8 years (2-10 years). The median time between head trauma and meningitis was 1,1 years (3 days-3,4 years). In all cases a basilar skull fracture was identified and cerebrospinal fluid leakage documented. Two children required surgery. Streptococcus pneumonia was the pathogen identified in two cases with positive cerebrospinal fluid culture. One child died and other has post-traumatic peripheral facial palsy.Bacterial meningitis is a complication to be considered in head injury with basilar skull fracture, particularly when associated with cerebrospinal fluid leakage, even though the injury occurred several years earlier, and is usually a serious condition. One of our children died. Similar to what is described, S. pneumoniae was the most common bacteria, and this fact supports that children with head trauma and cerebrospinal fluid leakage should receive pneumococcal vaccine. The follow-up of these children requires constant vigilance and should include a multidisciplinary approach.

O autismo é uma perturbação complexa e crónica do neurodesenvolvimento, habitualmente grave e frequente. Pretende-se com este manuscrito, e à luz do conhecimento actual, dar orientações sobre como vigiar e rastrear os sinais patológicos que o caracterizam, os quais, na maioria dos casos, são evidentes antes dos dois anos de idade. Fazem parte da tríade semiológica específica do autismo as dificuldades nas relações sociais e na comunicação verbal e não verbal e um comportamento rígido e repetitivo. É proposta a aplicação de um teste de rastreio específico de autismo, The Modified Checklist for Autism in Toddlers (M-CHAT), aos 18 e 24 meses. Os casos suspeitos devem ser orientados para avaliação especializada multidisciplinar em Unidades ou Centros de Desenvolvimento.

A saúde (bem-estar bio-psico-social) e as experiências dos primeiros anos de vida são determinantes críticos para o desenvolvimento e percurso de vida do indivíduo. Apesar das últimas décadas no nosso país se caracterizarem pela melhoria franca dos cuidados de saúde infantis, incluindo o avanço do diagnóstico e aconselhamento prénatal com a consequente redução da morbilidade e mortalidade infantil, tem-se verificado um aumento da prevalência das patologias do neurodesenvolvimento.