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Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 10

Duration perception abilities seem to enhance reading skills, but the reason for this remains under debate. Some studies focused on the ability to perceive the length of sounds (speech-related duration perception), while others approached general time skills (using, e.g., beep stimuli), but a direct comparison between the two modalities has not been done so far. In the present study, we compared the relevance of domain-general (comparison of time intervals defined by beeps) vs. speech-specific duration perception (pre-attentive EEG responses to different consonants) as statistical predictors of reading in adults. Reading included word and pseudoword decoding, as well as reading comprehension. We made regression-based analyses with the two time-related predictors for each reading skill. Pseudoword decoding was the only reading skill that was significantly predicted by duration perception, and this happened for domain-general duration perception only. Our findings strengthen the idea that skilled duration perception enhances phonological coding and its impact on grapheme-to-phoneme conversion processes. They also suggest that the benefits to phonological encoding are not specifically related to better processing of speech sound durations. Instead, the impact of skilled duration perception may rely on its connection to entrainment-to-speech skills, and the enhanced encoding of speech units that comes with it.

It is known that dyslexics underperform controls in time perception tasks using visual stimuli. However, it remains undetermined whether this deficit is secondary to problems in visual, time-unrelated domains, such as luminance contrasts and/or motion processing. To address this gap, we asked adults with dyslexia and matched controls to perform an interval comparison task involving five different types of visual stimuli with different levels of challenge regarding luminance contrasts and motion. Results showed poorer time discrimination in adults with dyslexia, but this group-related disadvantage did not change according to stimulus type. Complementary analyses of oculomotor behavior during the task suggested that the poorer timing performance of dyslexics may relate to attention and/or engagement with the task. Our findings strengthen the evidence in favor of time perception deficits in dyslexia, but they do not support the hypothesis that these are secondary to visual problems.

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber’s congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new magnetic resonance imaging (MRI) technology for real-time reporting of gene-therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first time, we show reliable tracking of enzyme expression after a now in-human clinical trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (βgal) using a self-immolative βgal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1−/−) correlates with βgal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With >1,800 gene therapies in phase I/II clinical trials (ClinicalTrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of the gene-therapy field., Graphical abstract, We describe a bio-responsive contrast agent that informs on the biodistribution and durability of gene expression in the lysosomal storage disease, GM1 gangliosidosis. We illustrate the sensitivity of this contrast agent to detect β-galactosidase enzyme in the central nervous system and periphery of an AAV-GLB-1-treated mouse model of GM1.

Birds are potential carriers of pathogens affecting humans and agriculture. Aiming to evaluate the occurrence of the top three most important foodborne pathogens in free-living birds in Portugal, we investigated 108 individual fecal samples from free-living birds and one pooled sample of gull feces (

Human-wildlife coexistence may increase the potential risk of direct transmission of emergent or re-emergent zoonotic pathogens to humans. Intending to assess the occurrence of three important foodborne pathogens in wild animals of two wildlife conservation centers in Portugal, we investigated 132 fecal samples for the presence of

ResumoFrequentes dificuldades na compreensão probabilística exigem que se identifiquem crenças intuitivas das crianças para apoiar a promoção pedagógica dessas aprendizagens. O presente estudo versa analisar as compreensões de crianças brasileiras e portuguesas acerca de justiça em jogos, considerando demandas cognitivas da probabilidade referentes à aleatoriedade, ao espaço amostral e à comparação de probabilidades. A pesquisa envolveu a análise de seis jogos e foi realizada por meio de uma entrevista clínica com 15 crianças brasileiras e 15 portuguesas, com média de idade de 11 anos. Os resultados revelam que as crianças apresentaram facilidade em avaliar um jogo injusto quando envolvia aleatorizadores viciados e em perceber a justiça num jogo cujas regras mantinham equilíbrio, permitindo que houvesse chances iguais para os jogadores. No entanto, observou-se que apresentaram incompreensões acerca da independência de eventos, conduzindo a avaliações equivocadas sobre a justiça em jogos. Nenhuma criança conseguiu apresentar justificativa coerente quando necessário comparar probabilidades considerando eventos de espaços amostrais distintos. Também não conseguiram utilizar o raciocínio proporcional, e, portanto, não avaliaram corretamente a justiça nesses jogos. Finalmente, os resultados não apontam para diferenças substanciais nas compreensões dos dois grupos estudados. Só em termos de linguagem, as expressões mais utilizadas nas justificativas por ambos os grupos foi ‘chance’, mas as crianças brasileiras usaram mais a ‘sorte’ e as portuguesas os termos ‘possibilidade’ e ‘probabilidade’. Estes resultados implicam a necessidade de viabilizar ações pedagógicas interventivas realizadas com o apoio de jogos que se configuram num importante recurso para o redimensionamento das aprendizagens probabilísticas. Palavras-chave: Aleatoriedade. Espaço Amostral. Comparação de Probabilidades. Justiça em Jogos. Crianças. AbstractFrequent difficulties in probabilistic understanding require the identification of children's intuitive beliefs to support the pedagogical promotion of these learnings. The present study focuses on analyzing Brazilian and Portuguese children understandings about fairness in games, considering cognitive demands of probability regarding randomness, sample space and comparison of probabilities. The research involved the analysis of six games and was carried out through a clinical interview with 15 Brazilian and 15 Portuguese children, with an average age of 11 years. The results reveal that the children were able to evaluate an unfair game when it involved addicted randomizers and to perceive justice in a game whose rules maintained balance, allowing the players to have equal chances. However, it was observed that they presented misunderstandings about the independence of events, leading to mistaken assessments of fairness in games. No child was able to present a coherent justification when there was a need to compare probabilities considering events from different sample spaces. They were also unable to use proportional reasoning, and therefore did not correctly assess justice in these games. Finally, the results do not point to substantial differences in the understandings of the two groups studied. Only in the language, the most used expressions in the justifications by both groups was ‘chance’, although Brazilian children used more ‘luck’ and Portuguese used ‘possibility’ and ‘probability’. These results imply the need to make feasible interventional pedagogical actions carried out with the support of games which are an important resource for the resizing of probabilistic learning. Keywords: Randomness. Sample Space. Comparison of Probabilities. Fairness in Games. Children.

We explored whether a multi-component approach – using a digital health device, the easypod™ auto-injector, the ‘MySupport’ patient support programme (PSP) and a Patient Activation Measure® (PAM®) – could improve adherence in patients receiving recombinant human growth hormone (r-hGH). A 13-item PAM was used to assess caregiver self-reported knowledge, resulting in two PAM scores for 88 patients at four UK hospitals after an average of 5.6 months. Most patients improved their PAM score by ≥1 level (43%) or maintained it (>-1 and

Devido a incentivos ambientais e econômicos, o uso de veículos elétricos (VEs) tem aumentado em todo o mundo. Os carros elétricos são cargas do tipo resistiva devido à presença de baterias e, quando possuem o formato plug-in, o seu carregamento pode ser dado de duas formas: em postos de recarga e/ou residências. Esses veículos podem atuar tanto como fonte de carga (G2V) quanto fonte de energia (V2G). Neste sentido, são fundamentais análises para determinar problemas e soluções decorrentes da presença desses automóveis na rede elétrica. Assim, este trabalho analisa as consequências da presença da carga dos VEs no sistema elétrico, em situações que afetam as perdas elétricas do sistema. Para realização destas análises, um sistema real brasileiro é simulado no software OpenDSS e são analisados 3 cenários, considerando VEs na curva de carga típica residencial como fonte de energia e/ou fonte de carga. Como objeto de estudo será distribuído no sistema cargas de 4515 VEs e com os resultados obtidos nas simulações, buscou-se realizar análises a fim de verificar o comportamento da rede de forma geral, comparando as perdas de energia de todo o sistema de um dia sem VEs e o mesmo dia com os automóveis.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

The plasma confinement of the International Tokamak Experimental Rector (ITER) is provided by the magnetic field generated by 18 toroidal field (TF) coils while 6 poloidal field (PF) and 6 central solenoid coils have the function to drive, shape and pre-heat the plasma. Fusion for Energy (F4E), the European Domestic Agency for ITER, is responsible for the supply of 10 TF coils and 5 PF coils to the ITER project. The ITER Organization (IO) team is instead responsible for the design of such coils as well for the coordination of the activities of the different Domestic Agencies (DAs) producing the different components, and their assembly into the Tokamak. The PF coils utilize NbTi Cable-in-Conduit-Conductor and have different diameters between 8 and 24 meters and weights of up to 400 tons. Regarding the PF coils produced by F4E, so far one has been completed by the Institute of Plasma Physics Chinese Academy of Sciences (ASIPP) under a collaboration agreement with F4E. The other 4 PF coils are being produced at the ITER site in Saint Paul lez Durance, France, under F4E supervision. The first of these (PF5) will be completed by July 2020 while the last coil (PF3) will be ready be the end of 2023. The TF coils utilize Nb3Sn conductor and are manufactured with the “Wind, React & Transfer” method. The first TF coil is close to completion and will be delivered to the ITER site in early 2020. Subsequent TF coils will follow at a rate of about one every 3-4 months. In this article we will report on the production status of both PF and TF coils and, in particular, the different manufacturing strategies employed. The main challenges faced so far and the results obtained are also described.

Prosodic phrasing is the segmentation of utterances into prosodic words, phonological phrases (smaller units) and intonational phrases (larger units) based on acoustic cues—pauses, pitch changes and pre-boundary lengthening. The perception of prosodic boundaries is characterized by a positive event-related potential (ERP) component, temporally aligned with phrase boundaries—the Closure Positive Shift (CPS). The role of pre-boundary lengthening in boundary perception is still a matter of debate: while studies on phonological phrase boundaries indicate that all three cues contribute equally, approaches to intonational phrase boundaries highlight the pause as the most powerful cue. Moreover, all studies used explicit boundary recognition tasks, and it is unknown how pre-boundary lengthening works in implicit prosodic processing tasks, characteristic of real-life contexts. In this study, we examined the effects of pre-boundary lengthening (original, short, and long) on the EEG responses to intonational phrase boundaries (CPS effect) in European Portuguese, using an implicit task. Both original and short versions showed equivalent CPS effects, while the long set did not elicit the effect. This suggests that pre-boundary lengthening does not contribute to improved perception of boundaries in intonational phrases (longer units), possibly due to memory and attention-related constraints.

Multiple sclerosis (MS) is a demyelinating chronic disease that has had increasing prevalence over the last years. We have investigated whether the perceived quality of life is reduced in multiple sclerosis patients compared to control participants with a cross-sectional approach, and how it relates to sociodemographic, clinical, and psychosocial variables in MS with multiple regression. To that end, a group of MS patients (n = 50) and a control group (n = 50) that was matched for age and education level filled in the WHOQOL-BREF (perceived quality of life across four domains) and a sociodemographic questionnaire. The participants in the MS group also filled in a clinical questionnaire and three instruments measuring psychosocial variables (the DASS-21 for depression, anxiety, and stress, the Brief-COPE for coping skills, and the Meaning in Life Scale). The results showed that the perceived quality of life was lower in the MS group than in the control group. Multiple regression models incorporating the variables that showed significant correlations with the quality of life indicated that age, professional status, recovery from relapses, depression, active coping, and meaning in life predicted at least one domain of the quality of life. Meaning in life predicted the quality of life in all four of the domains. Although the quality of life in MS is linked to multiple biopsychosocial variables, meaning in life seems crucial.

Osteoporosis is characterized by a loss of bone mass along with alterations in its structure, with subsequent increase in bone fragility and susceptibility to fractures, ultimately reinforcing the importance of its prevention by the reduction of the risk of falling.

Adeno-associated virus (AAV) gene therapy for neurological diseases was revolutionized by the discovery that AAV9 crosses the blood–brain barrier (BBB) after systemic administration. Transformative...

OHEJP project DISCOVER

Tay-Sachs Disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Preclinical work demonstrated safety and efficacy of CNS gene therapy using AAVrh8-HEXA/HEXB. Here we describe an expanded access trial in two patients with infantile TSD (IND 18225). Case TSD-001 demonstrated neurodevelopmental regression by 8 months of age and severe seizures by 1 year was treated at 30 months. An equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB (now AXO-AAV-GM2) was administered intrathecally (IT), with 75% of the dose (1x1014vg) delivered to the cisterna magna and 25% at the thoraco-lumbar junction. The second patient (TSD-002) was treated at 7 months of age with 4.2x1013 vg by a combination of bilateral thalamic (0.18 mL; 1.5x1012vg per thalamus), and IT infusion (3.9x1013vg). Both patients underwent immunosuppression with sirolimus, corticosteroids, and rituximab. Injection procedures were well tolerated and have shown no vector-related adverse events to date. CSF HexA activity nearly doubled from baseline and remained stable. In TSD-002 (now 16 months of age), MRI showed stabilization of disease by 3 months post-injection and appeared to temporarily deviate from the natural history of infantile TSD but declined again 6 months post-treatment. TSD-001 (now 4.5 years of age remains seizure-free on the same anti-convulsant therapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months posttreatment (by 2 years of age). Administration of AXO-AAV-GM2 by IT and thalamic injections was safe, HexA activity increased in CSF and ongoing myelination was apparent in the younger patient treated at an early symptomatic stage. This study provides early safety and proof-of-concept in humans for treatment of TSD patients by AAV gene therapy.

Dissertação de mestrado integrado em Engenharia e Gestão Industrial, A presente dissertação foi realizada no âmbito do projeto de conclusão do Mestrado Integrado em Engenharia e Gestão Industrial e desenvolvida numa empresa produtora de componentes estruturais para automóveis, a Lear Corporation. Esta, teve como principal objetivo a reconfiguração do sistema produtivo de uma secção utilizando Lean Thinking. A metodologia de investigação utilizada foi a “Investigação-Ação” e, após uma revisão bibliográfica de Lean Manufacturing, foi realizada uma caraterização e análise atual da secção, com o propósito de diagnosticar os potenciais problemas. Durante este diagnóstico, identificaram-se vários problemas, destacando-se o deficiente dimensionamento da secção, a falta de 5S, o material inadequado das mesas dos postos de trabalho, o elevado desperdício no embalamento e as ferramentas de montagem não funcionais. Estes problemas geravam diversos desperdícios, e.g., uma taxa de utilização dos postos de trabalho de apenas 14%, uma perda de tempo de ciclo de dois segundos por peça, etc. Ainda, foi realizada uma avaliação ergonómica através do método do EWA. Tendo em conta os problemas identificados, procedeu-se ao desenvolvimento de soluções. Assim, começou-se por desenvolver propostas de reorganização de todo o espaço de trabalho, tendo-se alterado de um sistema de produção fixo para um flexível, onde apenas é alocado o material de cada produto quando necessário. Implementaram-se diversas ferramentas, como 5S, gestão visual, SW e TPM e redimensionou-se o processo de um dos produtos. Posto isto, houve um aumento de 386% da taxa de utilização da secção, uma redução de 23% do WIP e do tempo de atravessamento de um dos produtos e um aumento do respetivo RVA de 25%. Seguidamente, alterou-se o material de revestimento das mesas, dimensionaram-se novas ferramentas de montagem, implementaram-se planos de manutenção, etc. Em suma, os resultados foram bastante satisfatórios, visto ter havido um ganho total de 100m2 e, ainda, um ganho anual superior a 12 775€ numa secção com baixo volume de produção e com pouco tempo de vida, que apenas existe para cumprir quantidades mínimas acordadas com clientes. Por fim, também foram realizadas propostas, que devido à contingência pandêmica e temporal, foi impossível implementar no horizonte do projeto, como a implementação de um quadro kanban, do qual se espera a eliminação das discrepâncias na eficiência de mais de 10 pontos percentuais entre o turno da manhã e da tarde., This dissertation was carried out within the scope of the project for the completion of the integrated master’s in Industrial Engineering and Management and developed in a company that produces structural components for automobiles, the Lear Corporation. This one, had as main objective the reconfiguration of the productive system of a section using Lean Thinking. The research methodology used was “Research-Action” and, after a literature review of Lean Manufacturing, a characterization and current analysis of the section was carried out, with the purpose of diagnosing potential problems. During the diagnosis, several problems were identified, highlighting the poor dimensioning of the section, the lack of 5S, the inadequate material on the workstation tables, the high waste in packaging and the non-functional assembly tools. These problems generated a lot of waste, e.g., a workstation utilization rate of only 14%, a lost-on cycle time of two seconds per part, etc. Besides, an ergonomic assessment was performed using the EWA method. Considering the problems identified, solutions were developed. Thus, firstly, proposals were developed for the reorganization of the entire workspace, having changed the production system from a fixed system to a flexible one, where only the material of each product is allocated when necessary. Several tools were implemented, such 5S, visual management SW and TPM and having resized the process of one of the products produced. That said, there was a 386% increase in the section’s utilization, a 23% reduction in WIP and in the transit time of one of the products and an increase in the respective VAR of 75%. Then, the working tables covering material was changed, new assembly tools were designed, maintenance plans were implemented, etc. In short, the results were quite satisfactory, as there was a total gain of 100m2 and a gain of more than €12 775 each year in a section with a low production volume and a short lifetime, which only exists to meet agreed minimum quantities with customers. Finally, proposals were also made, which due to the pandemic and temporal contingency, it was impossible to implement in the project horizon, such as the implementation of a kanban framework, which is expected to eliminate discrepancies in efficiency of more than 10 percentage points between the morning and afternoon shift.

O presente trabalho pretende dar um conhecimento mais fino sobre uma problemática ainda pouco desenvolvida no contexto da Administração e Gestão Pública, designadamente os impactos e os desafios causados pelo novo paradigma do Governo Digital nas políticas de Recursos Humanos do setor público. A globalização, a emergência da sociedade de informação e do conhecimento, assim como alterações de paradigma no setor público acompanham, traduzem e favorecem a evolução do Governo Digital; tornando-se, desta forma, importante analisar as políticas e estratégias do paradigma do Governo Digital, nomeadamente, as ações e os programas que o estimulam, as etapas que o constituem, os intervenientes e os seus papéis e o conjunto de impactos e desafios que lhe são atribuídos, na área das políticas de gestão de Recursos Humanos ao nível da prestação de serviços aos cidadãos. Almeja-se fundamentalmente compreender em que consiste a estratégia de Recursos Humanos do Governo Digital para a criação de estruturas orgânicas que suportem o cumprimento dos seus objetivos. Para alcançar o objetivo proposto realizou-se um enquadramento teórico que ilustra aspetos e definições fundamentais, interligado com o tema aqui em análise. A metodologia aplicada para a investigação é o caso de estudo que, para além do recurso a fundamentos teóricos, inclui a análise de dados, provenientes da aplicação de dois instrumentos de recolha de informação, nomeadamente o questionário e a entrevista, procurando desta forma responder às questões de investigação. A recolha de informação realizada permitiu constatar que os funcionários públicos têm sido envolvidos no novo modelo de prestação de serviços públicos; no entanto, deve ainda haver um reforço das competências para evitar um desfasamento entre os vários profissionais, e que não comprometam o sucesso da estratégia do Governo Digital. This paper aims to provide a better understanding of a problem still underdeveloped in the context of Public Administration and Management, namely the impacts and challenges caused by the new paradigm of Digital Government in public sector Human Resources policies. Globalization, the emergence of the information and knowledge society, as well as paradigm shifts in the public sector keep up, translate and favour the evolution of Digital Government; thus, it is important to analyse the policies and strategies of the Digital Government paradigm, namely the actions and programs that stimulate it, the stages that constitute it, the actors and their roles and the set of impacts and challenges that are assigned to it in the area of Human Resource management policies at the level of service delivery to citizens. The main objective is to understand what the Digital Government’s strategy is in Human Resources for the creation of organic structures that support the accomplishment of its main goals. To achieve this objective a theoretical framework was built, illustrating the fundamental aspects and definitions, interconnecting with the theme under study. The methodology applied is the case study that besides defining theoretical basis uses the analysis of data that is collected using various tools, namely the questionnaire and the interview, thus seeking to answer object of this research. The collection of information has shown that civil servants have been involved in the new model of public service provision; however, there should still be a strengthening of the powers to avoid a gap between the various professionals, and that does not compromise the success of the Digital Government strategy. Mestrado em Administração e Gestão Pública

Dissertation presented as the partial requirement for obtaining a Master's degree in Statistics and Information Management, specialization in Risk Analysis and Management The development of technology and the way of doing business exchange sensitive information all over the world through IT resources. In consequence of such reality, cyber events are more likely to occur, being the banking sector one of the major targets. However, in parallel with these new perils from technological growth, awareness of cyber risk is also increasing among institutions, as well as the search for protection and measures to fight them. Cyber insurance is one of the possible protection options. The main goal of this work is to assess the supply of cyber insurance among the banking sector operating in Portugal. As empirical investigations of cyber insurance applied in the country are rarely reported in the literature, the results are novel. In order to get the main goal, the research is based on a literature review where will be presented the “state of the art” of cyber insurance market in the world and in the country. In addition, an empirical study will be made through the application of questionnaires to ascertain the specificities of cyber insurance suppliers or potential suppliers in the Portuguese market, their perception of market evolution and knowledge about cyber risk. There is also a specific questionnaire for the supervisor entity in order to know its point of view about the topic in discussion. The main conclusions of this study relate to the fact that there is still a long way to go in the Portuguese insurance sector for cyber risk. The sector in the country started to be developed by international companies and only after that the national ones started to have more awareness on the subject, as mentioned by the Autoridade de Supervisão de Seguros e Fundos de Pensões (ASF). However, awareness of the issue is not the only point that leads to the underdevelopment of this specific insurance. The difficulties in the product underwriting process, which on the part of those who sell as well as those who buy, the high and variable prices, the lack of historical data and the information asymmetries are examples of obstacles that still have to be overcome. Although the cyber risk insurance sector is taking its first steps, it is believed to have a large margin of expansion, as has already been the case in several other countries. The creation of information sharing platforms on cyber incidents and the design of insurance and reinsurance products for cyber incidents are considered by the participant insurers as the main measures to be taken to assist this market development. It therefore becomes an inevitable topic to be addressed by the insurance sector in Portugal.

Salmonella enterica serovars Heidelberg and Minnesota frequently display several genetic mobile elements making them potential spreaders of resistance genes. Here, we phenotypically determined the antibiotic resistance profile and subsequently performed whole-genome sequencing on 36 isolates recovered from samples of fresh poultry meat, within the Portuguese Official Inspection Plan for Imported Foodstuffs. Several isolates of both serovars showed high genetic relatedness either with isolates from raw poultry meat imported to the Netherlands from Brazil or with isolates from samples from the broiler production chain in Brazil. The multidrug-resistant (MDR) character was common to the vast majority (94.4%) of isolates from both serovars, and several isolates carried the plasmid IncA/C2 containing the β-lactamase gene blaCMY-2 and IncX1 containing a type IV secretion system. These results somehow mirror the scenario observed in the Netherlands, showing the introduction, through fresh imported poultry meat in compliance with European legislation, of MDR Salmonella enterica serovars Heidelberg and Minnesota in Europe, with the potential spread of resistance markers. These data suggest the need to revise the hygiene criteria for foodstuffs monitoring before its placement on the market, with the determination of the resistome being an invaluable contribute to limit the dissemination of resistance markers. info:eu-repo/semantics/publishedVersion

Goji berries’ bioactive compounds, which allowed classifying them as superfruits, led to an enormous increase of its consumption in western countries. However, the potential risk of allergy is a concern. In this study, we aimed to characterise the proteome of goji berries (Lycium barbarum) and identify proteins with putative role in the allergic reaction (IgE-binding proteins). We firstly used twodimensional (2D) gel electrophoresis followed by mass spectrometry (MS) to characterise goji berries’ proteome, and then Immunoblot reactivity with plasma from tomato and potato (same botanical family, Solanaceae) allergic individuals was assessed to characterise goji berries IgE-binding proteins. An inhibition assay was further performed to evaluate cross-reactivity among potato, tomato and goji berries. We significantly identified 93 out of the 180 MS analysed spots, corresponding to 29 protein functions. From these, 11 could be identified as goji berries IgE-binding proteins. We further demonstratedcross-reactivity between goji berries, tomato and potato. This work was supported by research unit GREEN-IT “Bioresources for Sustainability” (UID/Multi/04551/2013). IML acknowledges FCT for funding her PhD fellowship (PD/BD/113982/2015) under MolBioS PhD-Program (PD/00133/2012), and IAA acknowledges the FCT Investigator funding (POPH-QREN - IF/00764/2014). info:eu-repo/semantics/publishedVersion

GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline β-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg body weight to six GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane end point; and (ii) a short-term group, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included β-galactosidase and virus distribution, histological analysis and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. MRI and MRS showed partial preservation of the brain in treated animals, which was supported by post-mortem histological evaluation. β-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of β-galactosidase activity in the CNS and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.

Here in is reported the case of a 16-year-old female diagnosed with vitreous haemorrhage and hemangioblastoma of the retina, referred to the Emergency Department due to sudden vision loss. Brain and pelvic magnetic resonance imaging showed cerebellar hemangioblastomas and renal nodular lesions of suspicious nature. The patient was submitted to partial left nephrectomy and histological examination revealed papillary renal cell carcinoma with clear-cell predominance. Clinical diagnosis of Von Hippel-Lindau (VHL) disease was confirmed by genetic study.VHL disease is a hereditary, autosomal dominant syndrome of multiple neoplasms caused by germline mutations in VHL tumor-suppressor gene. Patients are predisposed to development of cysts and hypervascular neoplasms, the most common being hemangioblastomas of the central nervous system (CNS) and retina, cysts and renal cell carcinomas, and pheochromocytomas. VHL diagnosis should be suspected if an individual with family history of VHL presents with a characteristic disease lesion or, in absence of family history of VHL, with two CNS and/or retinal hemangioblastomas or a CNS/retinal hemangioblastoma associated with renal cell carcinoma, pheochromocytoma, pancreatic cysts or endocrine tumor, or epididymal cystadenoma. In VHL disease, imaging plays a key role in detection of abnormalities, follow-up, and screening of asymptomatic mutated gene carriers., É descrito o caso clínico de uma adolescente de 16 anos diagnosticada com hemovítreo e hemangioblastoma da retina em contexto de urgência por perda súbita de visão. O estudo por ressonância magnética encefálica e pélvica evidenciou a presença de hemangioblastomas cerebelosos e lesões nodulares renais de natureza neoplásica suspeita. A doente foi submetida a nefrectomia parcial do rim esquerdo e o exame histológico confirmou o diagnóstico de carcinoma papilar de células renais com predomínio de células claras. O diagnóstico clínico de doença de Von Hippel-Lindau (VHL) foi confirmado por estudo genético. A doença de VHL é uma síndrome hereditária autossómica dominante de neoplasias múltiplas causada por mutações germinativas no gene supressor tumoral VHL. Os doentes apresentam predisposição para o desenvolvimento de quistos e neoplasias hipervascularizadas, sendo as mais comuns hemangioblastomas do sistema nervoso central (SNC) e da retina, quistos e carcinomas de células renais e feocromocitomas. A suspeita de diagnóstico de doença de VHL deve ser considerada se um indivíduo com antecedentes familiares de VHL apresentar uma lesão característica da doença ou, em ausência de história familiar de VHL, dois hemangioblastomas do SNC e/ou retina ou um hemangioblastoma do SNC ou da retina associado a carcinoma de células renais, feocromocitoma, quistos ou tumor endócrino pancreáticos ou cistadenoma do epidídimo. A imagiologia tem um papel importante nesta condição, através do diagnóstico de anomalias, seguimento e rastreio de portadores assintomáticos.

The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are fatal lysosomal storage disorders caused by mutations in the HEXA and HEXB genes, respectively. These mutations cause dysfunction of the lysosomal enzyme β-N-acetylhexosaminidase A (HexA) and accumulation of GM2 ganglioside (GM2) with ensuing neurodegeneration, and death by 5 years of age. Until recently, the most successful therapy was achieved by intracranial co-delivery of monocistronic adeno-associated viral (AAV) vectors encoding Hex alpha and beta-subunits in animal models of SD. The blood-brain barrier crossing properties of AAV9 enables systemic gene therapy; however, the requirement of co-delivery of two monocistronic AAV vectors to overexpress the heterodimeric HexA protein has prevented the use of this approach. To address this need, we developed multiple AAV constructs encoding simultaneously HEXA and HEXB using AAV9 and AAV-PHP.B and tested their therapeutic efficacy in 4- to 6-week-old SD mice after systemic administration. Survival and biochemical outcomes revealed superiority of the AAV vector design using a bidirectional CBA promoter with equivalent dose-dependent outcomes for both capsids. AAV-treated mice performed normally in tests of motor function, CNS GM2 ganglioside levels were significantly reduced, and survival increased by >4-fold with some animals surviving past 2 years of age.

This study aims to analyse the reasoning that children and adults with the same school level use to assess and justify the fairness of games, considering aspects of probability such as randomness, sample space, and comparison of probabilities. Data collection included a Piagetian clinical interview based on games of chance. The results showed that the participants’ judgments about the fairness of the games depends mainly on the understanding about independence of events, analysis of the sample space, and perception of proportionality when comparing probabilities, and that they have misunderstandings about these ideas. The similar low performance of adults and children on probabilistic reasoning, indicates that the maturity and experience of these adults were not enough to properly develop probabilistic reasoning and to instrumentalize it to assess the fairness of a game consistently. Thus, teaching interventions to expand and consolidate students' learning in the field of probability are recommended and the activities presented in this study may serve as a basis for such interventions.

Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.

Relatório da Prática de Ensino Supervisionada apresentada no ISPA – Instituto Universitário/ESEI Maria Ulrich para obtenção de grau de Mestre em Educação Pré-Escolar O presente relatório surge no âmbito da unidade curricular de Prática Supervisionada em Jardim-de-infância, do Mestrado em Educação Pré-escolar. O mesmo pretende apresentar uma investigação, decorrente da prática supervisionada, que tem como principal objetivo articular as práticas educativas e os referenciais teóricos e deste modo construir um percurso de consolidação do conhecimento profissional da sua autora. A prática supervisionada decorreu numa instituição de cariz privado, em Lisboa, na valência de jardim-de-infância e contou com a colaboração de 26 crianças, dos 3 aos 5 anos de idade. Este relatório tem como título “Emergência da matemática em educação pré-escolar” e surgiu da necessidade de compreender como surge a matemática em contexto de jardimde- infância e como poderá ser promovida a sua aprendizagem. Para dar início aos trabalhos subjacentes a este relatório foram realizadas diversas leituras com o objetivo de compreender e desenvolver conhecimentos acerca da temática. Para tal, foi conduzido um estudo qualitativo, onde os dados foram recolhidos essencialmente através de observação direta bem como através da análise das propostas de intervenção realizadas em prática supervisionada em Jardim de Infância. As mesmas foram analisadas de acordo com indicadores de oportunidade de aprendizagem ao nível do domínio da matemática. São ainda apresentadas as considerações finais deste estudo, onde é dada resposta aos objetivos aos quais me proponho responder com a execução deste estudo, assim como o seu impacto para a minha formação pessoal e profissional e uma reflexão da forma como pretendo que o mesmo faça parte do meu percurso profissional que agora se inicia This report results in the context of the curricular unit of supervised practice in kindergarten, in the master in preschool education. The same report aims to present an investigation, resulting from the supervised practice, which has as main objective to articulate the educational practices and the theoretical frameworks and thus build a path of consolidation of the professional knowledge of the author. The supervised practice took place in a private institution, in Lisbon, in the section of kindergarten and counted on the collaboration of 26 children, from 3 to 5 years old. This report is titled "Emergence of Mathematics in preschool education" and developed from the need to understand how mathematics appears in the context of kindergarten and how it can be promoted to their learning. To initiate the work underlying this report, several readings were carried out in order to understand and develop knowledge about the theme. To this end, a qualitative study was conducted, where data were collected essentially through direct observation as well as through the analysis of intervention proposals performed in supervised practice in kindergarten. They were examined according to indicators of learning opportunities at the level of mathematics mastery. The final deliberations of this study are also presented, where answers are given to the objectives to which I propose to respond with the implementation of this study, as well as its impact on my personal and professional training and a reflection on how I intend it to be part of my professional career that now begins.

Background Pharmacy-based interventions are complex public health endeavors which include, but are not restricted to, the conventional medication supply role. In diabetes, such interventions may improve patients’ outcomes. The aim of this study was to review relevant policies and research developed in Portugal directed at pharmacy-based diabetes interventions, and to inform future policies, practice and research in collaborative practice with primary care. Research method An exploratory review of diabetes legislation and policy papers, as well as a comprehensive review in Embase, MEDLINE (via Ovid and PubMed), Google Scholar, and grey literature until November 2017 was performed. Results Sixteen policy papers and 10 studies were included in the analysis. Positive evidence from pharmacy interventions was retrieved concerning screening individuals at risk, screening uncontrolled patients, managing diabetes, and supporting self-monitoring. Conclusions Some consistency in favorable findings, but also room for improvements in health policies, intervention design and research methods, were observed. Electronic supplementary material The online version of this article (10.1186/s40545-019-0166-1) contains supplementary material, which is available to authorized users.

Os videojogos motivam os utilizadores a assimilar os conteúdos mais facilmente, através da simulação e da experiência, e é possível aplicar as técnicas e os contextos utilizados no seu desenvolvimento à prática jornalística. A gamificação da informação é uma forma de narrativa que poderá trazer mudanças significativas para o jornalismo e contribuir para a sua sustentabilidade. Este trabalho de projeto procura promover a necessidade de investigação e de utilização dos jogos noticiosos (“newsgames”) e compreender as suas potencialidades, testando a viabilidade do seu desenvolvimento e da sua aplicação, e acrescentar conhecimento sobre o tema. Através do método de revisão de literatura, foram sistematizados os principais pareceres de investigadores internacionais, sobre os conceitos, os objetivos, as especificidades e as questões que os newsgames suscitam, com especial enfoque nas questões relacionadas com jogos editoriais sobre eventos atuais. Para perceber quais as ferramentas necessárias e as eventuais limitações com que um jornalista se poderá deparar ao desenvolver um newsgame, de forma autónoma e com recursos limitados, foi desenvolvido um projeto de gamificação de uma notícia sobre diplomacia e política internacional. Através da produção de um protótipo de jogo foi possível verificar quais as etapas do processo de construção desta aplicação e avaliar a viabilidade da sua utilização. O protótipo foi desenvolvido no editor Game Maker, uma ferramenta para criação de jogos que não obriga a conhecimentos prévios em programação ou em design de jogos digitais. Video games motivate users to assimilate content more easily, through simulation and experience, and it is possible to apply the techniques and contexts used in their development in journalistic practice. The gamification of information is a type of narrative which can bring significant changes to journalism and contribute to its sustainability. This project seeks to promote the need for research and use of “newsgames", as well as to understand its potential, testing the feasibility of its development and application, while adding knowledge about the topic. Through the literature review method, the main opinions of international researchers were systematised, with regards to their concepts, goals, specific features and the issues raised by newsgames, with a special focus on those related to editorial games concerning current events. In order to understand what are the necessary tools and the potential limitations that a journalist may encounter when developing a newsgame, independently and with limited resources, this work had developed a gamification project for a piece of news concerning diplomacy and international politics. By means of the production of a game prototype it was possible to observe what are the stages of this application’s construction process and to assess the feasibility of its use. The prototype was developed in the Game Maker editor, a tool for game creation which does not require prior knowledge in programming or in digital game design.