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A farmacogenómica (PGx) permite, com base no perfil genético do doente, selecionar o(s) fármaco(s) mais apropriado(s) para o seu tratamento e ajustar a dose terapêutica, maximizando o efeito e diminuindo a toxicidade e a ocorrência de reações adversas (RAMs). Estes testes são também chamados testes genéticos de seleção terapêutica e integram a farmacoterapia personalizada. Para aferir atitudes, opiniões, expectativas, práticas e preocupações dos farmacêuticos enquanto técnicos do medicamento, relativamente à farmacogenómica e identificar necessidades formativas e de desenvolvimento de competências em farmacogenómica, foi desenvolvido um questionário dirigido a farmacêuticos sobre farmacogenómica, o qual foi testado e ajustado recorrendo à técnica de grupo focal, e recebeu parecer favorável à implementação da Comissão de Ética para a Saúde do Instituto Nacional de Saúde Doutor Ricardo Jorge. O questionário foi disponibilizado em plataforma online para acesso e resposta, tendo sido divulgado pelas newsletters da Ordem dos Farmacêuticos e da Associação Nacional de Farmácias em janeiro de 2020, e partilhado também nas redes sociais Facebook, Linkdin e por email. Obtiveram-se respostas a 303 questionários: 64% completamente preenchidos e 36% incompletos. Os inquiridos são farmacêuticos com idades compreendidas entre os 23 e 77 anos, 77% do sexo feminino e 99% estão empregados. Há 46,1% de licenciados pré-Bolonha, 44,4% são mestres (38% com Mestrado Integrado em Ciências Farmacêutica, MICF ) e 9,5% são doutorados. Opiniões : 98% dos inquiridos considera que a farmacogenómica é uma área importante das ciências farmacêuticas, 97% que devia ser incluída na formação continua e 96% no currículo do MICF. Expectativas: 99% espera que a implementação da farmacogenómica evite a administração de medicamentos ineficazes e em doses inapropriadas e 98% que conduza a uma redução de RAMs. Preocupações: a venda dos testes de farmacogenómica diretamente ao utente através da internet (78%), 91% o acesso aos resultados por pessoa não autorizada e 58% que os resultados mostrem a inexistência de um tratamento apropriado. Prática: 11% sentem-se habilitados para recomendar a realização de um teste de farmacogómica, 10% já analisaram um relatório de farmacogenómica e 25,6% conhecem fontes fidedignas de informação sobre este tema. Identificamos a existência de opiniões e expectativas altamente favoráveis à utilização dos testes de farmacogenómica, e algumas preocupações a nível de regulamentação. Tal como noutros países, os farmacêuticos portugueses estão interessados em aprender mais sobre farmacogenómica, acham que esta pode trazer benefícios aos doentes, mas não se sentem preparados para sua aplicação imediata no seu local de trabalho. Há necessidades educativas em farmacogenómica que têm de ser colmatadas para que se torne uma prática comum de rotina do ato farmacêutico. Pharmacogenomics helps to select the most appropriate drug(s), based on the genetic profile of the patient and by adjusting the dose, maximizing the effect and reducing toxicity as well as adverse drug reactions (ADRs). These tests are part of personalized pharmacotherapy. A questionnaire for pharmacists was developed to assess the attitudes, opinions, expectations, practices, and concerns of pharmacists as health professionals specialised in clinical drugs, in relation to pharmacogenomics. Identification of training needs and skills development in pharmacogenomics. The questionnaire was tested and adjusted using the focus group technique and received a favorable opinion for the implementation of the Health Ethics Committee of the National Institute of Health Dr Ricardo Jorge of Portugal. The questionnaire was disseminated by the newsletters of the Pharmaceutical Society and the National Association Pharmacies of Portugal in January 2020, and it was also shared on the social networks Facebook, Linkedin and by email. It was available online for access and response. A total of 303 pharmacists answered to the questionnaire: 64% were completely filled in and 36% were incomplete. Respondents are pharmacists aged between 23 and 77 years, 77% are female and 99% are employed. There are 46.1% pre-Bologna graduates, 44.4% are masters (38% with an Integrated Masters in Pharmaceutical Sciences, MICF) and 9.5% are PhDs. Opinions: 98% of respondents consider that pharmacogenomics is an important area of pharmaceutical sciences, 97% that it should be included in continuing education and 96% in the MICF curricula. Expectations: 99% expect that the implementation of pharmacogenomics will avoid the administration of ineffective drugs and in inappropriate doses and 98% that it will lead to a reduction of ADRs. Concerns: the sale of pharmacogenomics tests directly to the consumer via the internet (78%), access to the results by an unauthorized person (91%) and that the results show the absence of an appropriate treatment (58%). Practice: 11% feel qualified to recommend a pharmacogenomics test, 10% have already analyzed a pharmacogenomics report and 25.6% know reliable sources of information on this topic. We identified the existence of highly favorable opinions and expectations regarding the use of pharmacogenomics tests, and some regulatory concerns. As in other countries, Portuguese pharmacists are interested in learning more about pharmacogenomics, they think that it can bring benefits to patients, but they do not feel prepared yet for its immediate application in their workplace. There are educational needs in pharmacogenomics that have to be met so that it becomes a common routine practice of the pharmaceutical practice. info:eu-repo/semantics/publishedVersion

Objetivo: Apresentar resultados do Projeto SM-COVID19 e integrar painel de discussão dedicado ao tema do impacto da pandemia COVID-19 na Saúde Mental. N/A

Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impairedsocial/communication skills and stereotyped/repetitive behaviors. Genetic factors account for 50-80% of the familialrisk of ASD, but genetic determinants are not fully understood and a role for regulatory processes is plausible. Inthis study, we explored the contribution to ASD etiology of genes involved in an important post-transcriptionalregulatory mechanism implicated in neurodevelopment, the Nonsense-Mediated Decay (NMD). Methods: We first compiled a group of 46 genes encoding NMD factors and regulators. In these genes wesearched for Single Nucleotide Variants (SNVs) and Copy Number Variants (CNVs) in two samples of ASD patients(N=1828 and N=3570, respectively). We observed the frequency of these variants in 60146 controls from gnomADv2.1.1 (for SNVs) and in 10355 controls from the Database of Genomic Variant ( for CNVs). In genes with rarevariants (MAF

Análise longitudinal em Portugal sobre o sofrimento psicológico e seus determinantes em contexto da pandemia na população geral e em profissionais de saúde. N/A

Equipa do projecto: Teresa Caldas de Almeida, Coordenadora (INSA); Maria João Heitor (SPPSM e HBA); Osvaldo Santos (ISAMB); Mónica Fialho (ISAMB); Alexandra Costa (INSA); Ana Virgolino (ISAMB); Célia Rasga (INSA); Hugo Martiniano (INSA); Astrid Vicente (INSA). Objetivos: Caracterizar indicadores de saúde mental e bem-estar psicológico da população adulta residente em Portugal e dos profissionais de saúde; Identificar fatores modificáveis de proteção e de eventual risco acrescido relativamente à saúde mental e bemestar psicológico N/A

A Medicina Personalizada é um modelo de prática médica que utiliza o perfil fenotípico e genotípico do indivíduo para melhorar a precisão do diagnóstico, a eficácia terapêutica ou a prevenção de doenças. Neste sentido, a enorme quantidade de dados gerados ao longo dos últimos anos na área biomédica tem contribuído para uma melhor compreensão dos determinantes genéticos de várias patologias e, consequentemente, para a implementação de práticas de Medicina Personalizada em várias áreas, por exemplo na Oncologia e no âmbito das doenças raras. No entanto, ainda subsistem desafios significativos, nomeadamente no que diz respeito à integração de dados biomédicos oriundos de fontes heterogéneas e na obtenção de informação clinicamente relevante. Este trabalho descreve uma abordagem que usa métodos de aprendizagem automática aplicados a um Grafo de Conhecimento (GC) biomédico como um meio para integrar informação armazenada em bases de dados diversas. Este GC contém relações entre genes, doenças e outras entidades biológicas, extraídas de três bases de dados: Ensembl, DisGeNET e Gene Ontology. Neste trabalho exploramos o potencial dos métodos de aprendizagem automática em grafos para produzir informação clinicamente relevante e descrevemos a aplicação desta metodologia à previsão de associações gene-doença. Mostramos ainda que as principais associações gene-doença previstas por esta abordagem podem ser confirmadas em bases de dados externas ou já foram previamente identificadas na literatura. Personalized Medicine is a model of medical practice that uses an individual's phenotypic and genotypic profile to improve diagnostic accuracy, therapeutic efficacy or disease prevention. The huge amount of data generated over the last few years in the biomedical area has contributed to a better understanding of the genetic determinants of various pathologies and, consequently, to the implementation of Personalized Medicine practices in various areas, for example in Oncology and in the field of rare diseases. However, significant challenges remain, namely with regard to the integration of biomedical data from heterogeneous sources to obtain clinically relevant information. This work describes an approach that uses machine learning methods applied to a biomedical Knowledge Graph (KG) as a means to integrate information stored in different databases. To build the KG, three databases were used: Ensembl, DisGeNET and Gene Ontology. This KG contains relationships between genes, diseases, and other biological entities. In this work, we explore the potential of automatic graph learning methods to produce clinically relevant information and describe the application of this methodology to the prediction of gene-disease associations. We show that the main gene-disease associations predicted by this approach can be confirmed in external databases or have been previously identified in the literature. info:eu-repo/semantics/publishedVersion

Objective: To identify neurotransmission and synaptic (NS) genes that play a role in ASD and address the impact of ultra-rare variants in these genes in ASD, linking these mutations to the biological pathways affected. N/A

Objective: To identify neurotransmission and synaptic (NS) genes that play a role in ASD and address the impact of ultra-rare variants in these genes in ASD, linking these mutations to the biological pathways affected. N/A

Heritability estimates indicate that genetic susceptibility does not fully explain Autism Spectrum Disorder (ASD) risk variance, and that environmental factors may play a role in this disease. To explore the impact of the environment in ASD etiology, we performed a systematic review of the literature on xenobiotics implicated in the disease, and their interactions with gene variants. We compiled 72 studies reporting associations between ASD and xenobiotic exposure, including air pollutants, persistent and non-persistent organic pollutants, heavy metals, pesticides, pharmaceutical drugs and nutrients. Additionally, 9 studies reported that interactions between some of these chemicals (eg. NO2, particulate matter, manganese, folic acid and vitamin D) and genetic risk factors (eg. variants in the CYP2R1, GSTM1, GSTP1, MET, MTHFR and VDR genes) modulate ASD risk. The chemicals highlighted in this review induce neuropathological mechanisms previously implicated in ASD, including oxidative stress and hypoxia, dysregulation of signaling pathways and endocrine disruption. Exposure to xenobiotics may be harmful during critical windows of neurodevelopment, particularly for individuals with variants in genes involved in xenobiotic metabolization or in widespread signaling pathways. We emphasize the importance of leveraging multilevel data collections and integrative approaches grounded on artificial intelligence to address gene–environment interactions and understand ASD etiology, towards prevention and treatment strategies. info:eu-repo/semantics/publishedVersion

Our objective is to develop variant prioritization methods using machine learning approaches to predict genotype-phenotype associations, that can detect the most likely causal variants associated to a given phenotype. N/A

The objective of this study is the identification of Single Nucleotide Variants (SNVs) in neurotransmission and synaptic genes (NS genes) that play a role in ASD etiology, and the biological processes and global networks affected. N/A

Objetivo: Auscultar a opinião, expectativas, preocupações e prática dos farmacêuticos portugueses relativamente à aplicação dos testes de farmacogenómica na sua prática profissional. N/A

Sequencing studies have yielded several candidate genes for Autism Spectrum Disorder (ASD). However, the biological mechanisms underlying its onset are still unclear. Environmental factors may modulate ASD risk, with heritability estimates of 50-80% supporting a role for gene-environment interactions in idiopathic cases. We hypothesize that ASD candidate genes interact with reported ubiquitous environmental risk factors. Thus, we interrogated the Comparative Toxicogenomics Database (CTD) for interactions between 1144 ASD candidate genes and 59 ASD-risk chemicals. A proportion analysis was performed to identify genes that selectively interact with ASD risk chemicals (and vice-versa). Genetic data from ASD-individuals was inspected to identify SNVs (n=2674) and CNVs (n=3570). Eleven genes, including genes encoding for sex hormone receptors (AR, ESR1 and ESR2), signaling kinases (MAPK1 and MAPK3) and xenobiotics-responding molecules (GSTM1 and SLC7A5) were found to selectively interact with ASD-chemicals. Meanwhile, heavy metals, endocrine disruptors (pesticides, benzo(a)pyrene and a phthalate) and valproic acid were found to selectively target ASD-candidate genes. In ASD-cases, we found 22 loss-of-function or deleterious missense SNVs in 8/11 genes, of which 3 (ESR1, ESR2, and MAPK3) were also targeted by CNVs. External cues may dysregulate the MAPK signaling cascade, leading to neurodevelopmental problems. Hormone-mimicking toxins act as agonist/antagonist ligands to hormone receptors, while SLC7A5 is a blood-brain barrier (BBB) transporter. Sex hormones and BBB are fundamental during early development. We highlight the need of considering genetics and environment as interacting entities. Efforts to collect early-life exposure data from genetically susceptible patients may accelerate the implementation of health management strategies for ASD. N/A

The objective of this study is the identification of Single Nucleotide Variants (SNVs) in neurotransmission and synaptic genes (NS genes) that play a role in ASD etiology, and the biological processes and global networks affected. N/A

A pandemia da COVID-19 provocou alterações profundas na forma de viver, individual e comunitária. Essas alterações, aliadas ao medo e incerteza crescentes de infetar ou ser infetado e ao medo de perder emprego ou rendimento decorrentes da imprevisibilidade na evolução da doença, têm sido apontadas como potenciais fatores de risco para a saúde mental (SM) e bem-estar psicológico (BE) das populações, em particular, para a ansiedade, depressão, perturbação de stress pós-traumático e burnout. Vários estudos identificaram os profissionais de saúde na linha da frente e os indivíduos infetados como grupos de risco de sofrimento psicológico. O projeto SM-COVID19 teve como principal objetivo caracterizar a SM e o BE psicológico no contexto da pandemia, na população residente em Portugal e, em particular, em grupos de risco acrescido. Este é um estudo observacional transversal, com uma componente longitudinal, com recolha de dados através de questionário online de base populacional. Foram selecionados como outcomes a avaliar várias dimensões de SM, nomeadamente BE psicológico, ansiedade, depressão, perturbação de stress pós-traumático, burnout, presentismo e resiliência, assim como determinantes de SM relevantes. No âmbito da divulgação e comunicação do estudo foram criados diversos produtos. O SM-COVID19 representa um contributo para o conhecimento sobre SM da população portuguesa no contexto da pandemia. Os resultados obtidos constituem uma evidência sólida para a elaboração de recomendações, visando mitigar os problemas de SM identificados, bem como promover o BE psicológico em tempos de pandemia. The COVID-19 pandemic brought about profound changes in the way of life for the individual and for communities. These changes, combined with the growing fear and uncertainty of infecting or being infected and the fear of losing employment or income due to the unpredictability of the disease's evolution, have been identified as potential risk factors for mental health (MH) and psychological well-being (WB) of populations as anxiety, depression, post-traumatic stress disorder and burnout. Several studies have identified health professionals at the forefront of medical care and infected individuals as risk groups for psychological distress. The SM-COVID19 project aimed to characterize MH and psychological BE in the context of the pandemic of the population residing in Portugal particular of the groups at greatest risk. This is a cross-sectional observational study, with a longitudinal component, with data collection through a population-based online survey. The following outcomes were selected for assessment namely psychological WB, anxiety, depression, post-traumatic stress disorder, burnout, presentism and resilience, as well as relevant determinants of MS. As part of the dissemination and communication of the study, several products were created. SM-COVID19 represents a contribution to the knowledge about MH of the Portuguese population in the context of the pandemic. The results obtained constitute solid evidence for the elaboration of recommendations, aiming to mitigate the identified MH problems, as well as to promote psychological WB in times of pandemic. O projeto SM-COVID19 (ref. 279_596885124) foi financiado pela Fundação para a Ciência e Tecnologia (FCT), no âmbito da 1ª edição do apoio especial RESEARCH 4 COVID-19. info:eu-repo/semantics/publishedVersion

Autism Spectrum Disorder (ASD) heritability estimates of 50-80% support the hypothesis that gene-environment interactions play a role in this pathology. ASD risk has been associated with early exposure to various xenobiotics that are cleared in the liver by Cytochrome P450 enzymes. We therefore explored the hypothesis that variants in CYP450 genes, which define the rapid or slow metabolizer status of their carriers, may render individuals exposed to certain toxicants more susceptible to brain disruption during early development. João Xavier Santos, Ana Rita Marques and Joana Vilela are fellows of the BioSys-PhD programme. Autism Genome Project (AGP), Simons Foundation Autism Research Initiative (SFARI) and Autism Sequencing Consortium (ASC). N/A

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder which affects the brain structure and the proper establishment of the neuronal connectivity. The criteria of diagnosis are the presence of social communication deficits and restricted, repetitive patterns of behavior. ASD has a strong genetic component but, despite the reports of putative risk genes, the genetics underlying the disease is still incompletely understood. One hypothesis supported by strong genomic and functional evidence is that neurotransmission and synaptic biological processes are altered in ASD. Objective: The main objective of this work is to identify Single Nucleotide Variants (SNVs) in neurotransmission and synaptic genes (NS genes) that may play a role in ASD etiology. Joana M. Vilela is a fellow of the BioSys PhD Programme and a recipient of a PhD grant, with reference PD/BD/131390/2017, funded by FCT –Fundação para a Ciência e a Tecnologia. N/A

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, which affects brain function. It is characterized by the presence of social communication deficits and restricted, repetitive patterns of behavior. ASD has a strong genetic component and there is evidence in support of many putative risk genes. However, the genetics and the biological processes underlying the disease are still incompletely understood and will require the integration of intermediate phenotypic analysis provided by direct observation tools such as brain imaging. Support for this work was provided by Fundação para a Ciência e a Tecnologia (Grant PD/BD/131390/2017 to Joana Vilela). info:eu-repo/semantics/draft

Joana M. Vilela is a fellow of the BioSys PhD Programme and a recipient of a PhD grant, with reference PD/BD/131390/2017, funded by FCT – Fundação para a Ciência e a Tecnologia. The main objective of this work is to identify Single Nucleotide Variants (SNVs) that play a role in ASD etiology in neurotransmission and synaptic genes since there is strong genomic and functional evidence that these biological processes are altered in ASD. N/A

Objectives: The global objective of the study is to improve the current knowledge on ASD prognosis and diagnosis by delineating the complex genotype-phenotype associations using an integrative systems biology approach. For this purpose three specific objectives were pursued: - To identify clinically similar subgroups of individuals with ASD; - To find biological processes disrupted by rare CNVs targeting brain genes in ASD subjects; - To train a machine learning classifier for the clinical prediction of disease progression from genetic information in very young children. MA is supported by the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/52485/2014). Patients and parents were genotyped in the context of the Autism Genome Project (AGP), funded by NIMH, HRB, MRC, Autism Speaks, Hilibrand Foundation, Genome Canada, OGI, CIHR. N/A

Objective; The main objective of this project is to identify molecular alterations in neurotransmission and synaptic genes that play a role in ASD etiology. Support for this work was provided by Fundação para a Ciência e a Tecnologia (grant PD/BD/131390/2017 to J. M. Vilela. Joana M. Vilela is a fellow of the BioSys PhD Programme and a recipient of a PhD grant, with reference PD/BD/131390/2017, funded by FCT – Fundação para a Ciência e a Tecnologia. N/A

Autism Spectrum Disorder – Background: Phenotypically heterogeneous neurodevelopmental disorder, with a global prevalence rate of 1% , characterized by deficits in social communication and interaction and stereotyped and repetitive behaviours. - Genetic factors, namely rare copy number variants (CNVs), are responsible for a considerable fraction of ASD cases . - The recent heritability estimates of approximately 50% suggest a role of nongenetic factors in ASD etiology. - Pre-, peri- and post-natal exposure to toxic environmental factors has been implicated in the development of the disorder[5][6] . - ASD is most probably explained by a polygenic and multifactorial mechanism that involves genetic, environmental and epigenetic interactions. Objectives: 1. To identify specific exposure patterns to environmental toxicants, potentially involved in ASD etiology, in a dataset of Portuguese children diagnosed with the disorder, aged 7-9 years old; 2. To identify variants of ASD-candidate genes interacting with environmental factors 3. To build a global mathematical model that integrates genetic and environmental biomarkers with clinical data for risk assessment in ASD. João Xavier Santos is a fellow of the BioSys-PhD programme and a recipient of a scholarship funded by FCT (PD/BD/114386/2016). Autism Genome Project (AGP) and Simons Foundation Autism Research Initiative (SFARI) N/A

A Perturbação do Espetro do Autismo (PEA) tem uma heritabilidade estimada de 50%, indicativa de uma componente genética que pode ser modulada por fatores ambientais. A evidência de associação com autismo de alguns compostos potencialmente tóxicos levou-nos a colocar a hipótese de que genes envolvidos em processos de destoxificação e regulação da permeabilidade de barreiras fisiológicas (p. ex. placenta, hematoencefálica) são candidatos para a PEA. Neste trabalho definimos uma lista de 519 genes de destoxificação e das barreiras de permeabilidade, e comparamos a frequência de Copy Number Variants (CNVs) nestes genes em 2446 crianças com PEA, recrutadas através do Autism Genome Project (AGP), com 10355 controlos sem patologia neuropsiquiátrica da Database of Genomic Variants. Como validação, foram avaliados indivíduos com PEA da Simons Foundation Autism Research Initiative (SFARI) (N=1124). Verificouse que 555 (22,7%) indivíduos com PEA apresentavam CNVs contendo 173 dos 519 genes de interesse, 31 dos quais foram encontrados exclusivamente em pacientes com PEA, enquanto 23 genes eram significativamente mais frequentes em CNVs de indivíduos com PEA do que em controlos. Múltiplos dos genes identificados estão envolvidos no transporte através de barreiras fisiológicas ou na destoxificação de toxinas relevantes para a PEA. Este estudo reforça a hipótese de que, em indivíduos geneticamente suscetíveis, a exposição a fatores ambientais potencialmente tóxicos pode contribuir para a PEA. Autism Spectrum Disorder (ASD) has an estimated heritability of 50%, indicating a genetic component that may be modulated by the environment. Recent studies implicate exposure to specific toxins in ASD etiology. We thus hypothesize that genes involved in detoxification and regulation of physiological barrier permeability processes (e.g. placenta, blood-brain barrier) are plausible candidates for ASD etiology. In this study we defined a candidate list of 519 detoxification and barrier permeability genes that may interact with toxicants relevant for ASD. We compared the frequency of Copy Number Variants (CNVs) targeting these genes in 2446 ASD patients, recruited through the Autism Genome Project, and 10355 controls without neuropsychiatric disease from the Database of Genomic Variants, and validated results in 1124 ASD subjects from the Simons Foundation Autism Research Initiative. We found that 173 of the 519 detoxification and barrier genes were targeted by CNVs from 555 (22.7%) individuals with ASD. Of these genes, 31 were exclusively targeted by CNVs in ASD subjects and 23 were significantly more frequent in ASD than in controls. Network analysis showed that many of these genes are involved in the transport through physiological barriers or the detoxification of potential toxicants relevant for ASD. This study reinforces the hypothesis that the exposure to environmental factors in genetically susceptible individuals may contribute to ASD risk. info:eu-repo/semantics/publishedVersion