Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

'If we take the engine out, how will the car go?': beliefs, understanding and access to vasectomy services in Timor-Leste.

Vasectomy is a safe, highly effective and affordable method of permanent contraception, and one of the few currently available contraceptive methods for men. Despite this, vasectomy uptake remains overall low, making up just 2% of the global contraceptive method mix. To better understand access to vasectomy in a country with negligible uptake, we conducted participatory and operational research in the Democratic Republic of Timor-Leste (Timor-Leste). We held 14 participatory group discussions with 175 community participants (84 men, 91 women; aged 18-72) across seven municipalities (Ainaro, Baucau, Bobonaro, Dili, Lautem, Manufahi, and Oecusse), and individual in-depth interviews with 24 healthcare providers (16 women, 8 men; aged 25-56 years). Data were analysed using reflexive thematic analysis. Community awareness and understanding about vasectomy were limited, with concerns expressed about physical and social side effects. Healthcare providers had limited experience and knowledge about vasectomy, and about male sexual and reproductive health more generally. However, our findings also indicate a small but existing demand for vasectomy services that could be grown and better met through health systems strengthening initiatives. Insights from our research have informed programmatic decision-making in Timor-Leste and can be further used to inform national health policy and practice.

Anti-dementia drugs: what is the evidence in advanced stages?

Dementia is a major public health concern due to its increasing prevalence, substantial caregiver burden, and high financial costs. Currently, the anti-dementia drugs aim only at a symptomatic effect. The subject of prescribing these drugs in advanced stages is a matter of considerable debate, with different countries making distinct recommendations. In this review article, we analyzed the evidence regarding cognitive and functional outcomes, adverse events, health-related costs, and caregiver burden in patients with advanced Alzheimer disease (AD) and mixed dementia. We included 35 studies. Most studies are heterogeneous, focus exclusively on AD, and show small benefits in terms of cognitive and functional scales. The overall evidence seems to suggest a benefit in introducing or maintaining anti-dementia drugs in patients with advanced dementia, but clinical meaningfulness is difficult to ascertain. The issue of costs and caregiver burden is significantly underexplored in this field but also seems to favor treatment continuation, despite a reduced overall effect. The decision of introducing or withdrawing anti-dementia drugs in advanced stages of dementia should be individualized. Future studies with homogeneous designs and outcomes are warranted.

A simple protocol for the synthesis of perylene bisimides from perylene tetracarboxylic dianhydride.

Perylene bisimides are highly attractive polycyclic aromatic hydrocarbons due to their photostability associated to unique and characteristic photochemical properties. They have been widely used for analytical purposes, despite the hydrophobicity of most of these compounds. The ring substitution pattern plays an important role in fine-tuning the physicochemical properties that govern solubility and aggregation. In this work, a selection of perylene bisimides were prepared from the reaction of perylenetetracarboxylic dianhydride with α-amino acids or primary aliphatic and aromatic amines. These molecules were obtained in good yield by a simple synthetic protocol based on the use of imidazole as a green solvent and avoiding the need for complex purification methods, a major advantage for future applications. Functionalization of the exocyclic substituent can also be performed and was exemplified by the incorporation of the maleimide and anthraquinone moieties.

The sound of Parkinson's disease: A model of audible bradykinesia.

INTRODUCTION: Evaluation of bradykinesia is based on five motor tasks from the MDS-UPDRS. Visually scoring these motor tasks is subjective, resulting in significant interrater variability. Recent observations suggest that it may be easier to hear the characteristic features of bradykinesia, such as the decrement in sound intensity or force of repetitive movements. The objective is to evaluate whether audio signals derived during four MDS-UPDRS tasks can be used to detect and grade bradykinesia, using two machine learning models. METHODS: 54 patients with Parkinson's disease and 28 healthy controls were filmed while executing the bradykinesia motor tasks. Several features were extracted from the audio signal, including number of taps, speed, sound intensity, decrement and freezes. For each motor task, two supervised machine learning models were trained, Logistic Regression (LR) and Support Vector Machine (SVM). RESULTS: Both classifiers were able to separate patients from controls reasonably well for the leg agility task, area under the receiver operating characteristic curve (AUC): 0.92 (95%CI: 0.78-0.99) for LR and 0.93 (0.81-1.00) for SVM. Also, models were able to differentiate less severe bradykinesia from severe bradykinesia, particularly for the pronation-supination motor task, with AUC: 0.90 (0.62-1.00) for LR and 0.82 (0.45-0.97) for SVM. CONCLUSION: This audio-based approach discriminates PD from healthy controls with moderate-high accuracy and separated individuals with less severe bradykinesia from those with severe bradykinesia. Sound analysis may contribute to the identification and monitoring of bradykinesia.

Students' tactical understanding during a hybrid sport education/step-game approach model volleyball teaching unit / O conhecimento tático dos alunos durante uma unidade híbrida do modelo de educação desportiva e do modelo de abordagem progressiva ao jogo no voleibol / El conocimiento táctico de los alumnos durante una unidad de híbrida del modelo de educación deportiva y del modelo de aproximación progresiva al juego en el voleibol

Abstract: Model-based research has been enhancing the positive effectiveness of both Sport Education and Step-Game Approach on students' technical, tactical and game-play improvements. Nevertheless, the analysis of students' declarative understanding on the game in this area was scarce. This study examined their declarative understanding on the game during their participation in a hybrid Sport Education/Step-Game Approach teaching unit. Ninety-six students with no previous experience in either model participated in a 24-lesson volleyball season. A video-based test was developed to assess students' declarative game understanding and applied before and after the teaching unit. Results showed that they improved in all tactical content taught during the unit. These results can find explanation on Sport Education features such as cooperative team practices and the possibility for being in roles other than players. Beyond that, instructional procedures considered by the Step-Game-Approach stimulated the development of students' tactical awareness.

Resumo: A investigação nos modelos instrucionais tem enaltecido o impacto positivo do Modelo de Educação Desportiva e do Modelo de Abordagem Progressiva ao Jogo no desenvolvimento técnico e tático dos alunos, assim como no desempenho geral no jogo. Todavia, a análise do conhecimento tático dos alunos neste âmbito tem sido escassa. O presente estudo tem como propósito analisar o conhecimento tático declarativo dos alunos durante uma unidade híbrida desses dois modelos na modalidade de voleibol. Noventa e seis alunos sem experiência prévia nos dois modelos participaram numa época desportiva com 24 aulas. Foi desenvolvido um teste de vídeo para analisar o desenvolvimento do conhecimento tático declarativo dos alunos, o qual foi aplicado antes e depois da unidade. Todos os alunos melhoraram nos conteúdos táticos ensinados, o que pode encontrar explicação no trabalho colaborativo em equipas, na possibilidade dos alunos participarem noutros papéis para além de jogadores e nos processos instrucionais, características dos dois modelos.

Resumen: La investigación en los modelos de instrucción ha enaltecido el impacto positivo del Modelo de Educación Deportiva y del Modelo de Aproximación Progresiva al Juego en el desarrollo técnico y táctico de los alumnos, así como también en el desempeño general en el juego. Sin embargo, el análisis del conocimiento táctico de los alumnos en este ámbito ha sido escaso. El presente estudio tiene como propósito analizar el conocimiento táctico declarado de los alumnos durante una unidad híbrida de estos dos modelos en la modalidad de Voleibol. 96 alumnos sin experiencia previa en los dos modelos participaron en una temporada deportiva con 24 clases. Se desarrolló un test de vídeo para analizar el desarrollo del conocimiento táctico declarado de los alumnos, que se aplicó antes y después de la unidad. Todos los alumnos mejoraron en los contenidos tácticos enseñados, lo que puede encontrar explicación en el trabajo colaborativo en equipos, en la posibilidad de que los alumnos participen en otros papeles además de como jugadores y en los procesos de instrucción, características de los dos modelos.

Falha na ativação da equipe de emergência intra-hospitalar: causas e consequências / Failure to activate the in-hospital emergency team: causes and outcomes

RESUMO Objetivo: Determinar a incidência de falha na ativação da via aferente da Equipe de Emergência Médica intra-hospitalar, caraterizando-a e comparando a mortalidade dessa população com a da população em que não se verificou falha na ativação da via aferente. Métodos: Entre janeiro de 2013 e julho de 2015, ocorreram 478 ativações da Equipe de Emergência Médica do Hospital Pedro Hispano. Após a exclusão de registos incompletos e ativações para doentes com menos de 6 horas de internamento hospitalar, obtivemos uma amostra de 285 ativações. A amostra foi dividida em dois grupos: o grupo com falha na ativação da via aferente e o grupo em que não ocorreu falha na ativação da via aferente da Equipe de Emergência Médica. As duas populações foram caracterizadas e comparadas. A significância estatística foi considerada para p ≤ 0,05. Resultado: Em 22,1% das ativações, verificou-se falha na ativação da via aferente. Relativamente ao estudo causal, verificamos existir diferença estatisticamente significativa quanto aos critérios de ativação da Equipe de Emergência Médica (p = 0,003) no grupo com falha na ativação da via aferente, encontrando taxa mais elevada de ativação da Equipe de Emergência Médica por paragem cardiorrespiratória e disfunção cardiovascular. Em relação às consequências, no grupo em que ocorreu falha na ativação da via aferente houve uma maior taxa de mortalidade imediata e à data de alta hospitalar, sem significado estatístico. Não encontramos diferenças significativas com relação aos outros parâmetros. Conclusão: Nos doentes em que houve falha da ativação da via aferente da Equipe de Emergência Médica, a incidência de paragem cardiorrespiratória e a taxa de mortalidade foram maiores. Este estudo reforça a necessidade de as unidades de saúde investirem na formação de todos os profissionais de saúde sobre os critérios de ativação da Equipe de Emergência Médica e o funcionamento do sistema de resposta a emergência médica.

ABSTRACT Objective: To determine the incidence of afferent limb failure of the in-hospital Medical Emergency Team, characterizing it and comparing the mortality between the population experiencing afferent limb failure and the population not experiencing afferent limb failure. Methods: A total of 478 activations of the Medical Emergency Team of Hospital Pedro Hispano occurred from January 2013 to July 2015. A sample of 285 activations was obtained after excluding incomplete records and activations for patients with less than 6 hours of hospitalization. The sample was divided into two groups: the group experiencing afferent limb failure and the group not experiencing afferent limb failure of the Medical Emergency Team. Both populations were characterized and compared. Statistical significance was set at p ≤ 0.05. Result: Afferent limb failure was observed in 22.1% of activations. The causal analysis revealed significant differences in Medical Emergency Team activation criteria (p = 0.003) in the group experiencing afferent limb failure, with higher rates of Medical Emergency Team activation for cardiac arrest and cardiovascular dysfunction. Regarding patient outcomes, the group experiencing afferent limb failure had higher immediate mortality rates and higher mortality rates at hospital discharge, with no significant differences. No significant differences were found for the other parameters. Conclusion: The incidence of cardiac arrest and the mortality rate were higher in patients experiencing failure of the afferent limb of the Medical Emergency Team. This study highlights the need for health units to invest in the training of all healthcare professionals regarding the Medical Emergency Team activation criteria and emergency medical response system operations.

O desenvolvimento da compreensão holística do jogo por meio da criação do jogo / The development of games literacy with student-designed games intervention / El desarrollo de la comprensión holística mediante la creación de juego

Resumo O estudo examinou a compreensão holística do jogo (compreensão de regras, valores, distinção entre boas e más práticas) aprendida por alunos do ensino fundamental após uma intervenção de criação de jogos de alvo. A intervenção foi dividida em cinco momentos: introdução aos jogos de alvo, ensinar jogos a outros alunos, criar novos jogos, ensinar seus próprios jogos e praticá-los. A coleta de dados incluiu observações, questionários e entrevistas, que foram analisados por meio de uma triangulação. Concluiu-se que os alunos foram capazes de valorizar as regras dos jogos criados, mas tiveram dificuldade na apresentação dos jogos, uma tarefa normalmente atribuída ao professor.

Abstract The study examined the games literacy (understanding rules, games values, distinction between good and bad practices) learned by elementary school students after a student-designed games intervention with target games. The intervention was divided into four stages: target games introduction, teaching games to other students, creating new games, teaching their own games. Data collection included observations, questionnaires and interviews, which were analyzed by a triangulation. It was concluded that students were able to appreciate the rules of the games created, but had difficulty in presenting the game, a task normally assigned to the teacher.

Resumen El estudio examinó el nivel de comprensión holística (entender las reglas, figuras del deporte, la distinción entre buenas y malas prácticas deportivas) aprendidas por alumnos de primaria después de una intervención para crear juegos de diana móvil. La intervención se divide en cuatro etapas: introducción a los juegos de diana, enseñanza de juegos a otros estudiantes, crear nuevos juegos, enseñar sus propios juegos. La recolección de datos incluyó observaciones, cuestionarios y entrevistas, que fueron analizados mediante una triangulación. Se concluyó que los estudiantes pudieron aprender las reglas de los juegos creados, pero tuvieron dificultades en la presentación del juego, una tarea normalmente asignada a la maestra.

Modelo de educação esportiva: da aprendizagem à aplicação / Sport education model: from learning to teaching

Este estudo teve como objetivo examinar a perceção de estudantes de Educação Física sobre o valor educativo do Modelo de Educação Esportiva (MEE) pelo confronto entre a vivência do modelo enquanto alunos e como professores estagiários. Participaram no estudo 16 estudantes do Mestrado em Ensino da Educação Física da FADEUP. Aplicou-se uma entrevista semiestruturada e de resposta aberta após a validação de construção e de conteúdo. Os participantes percepcionaram potencial elevado do MEE no desenvolvimento da formação pessoal, social e desportiva de crianças e jovens. Não obstante, as suas elevadas exigências, ao nível da organização e gestão de alunos e atividades, foram reconhecidas pelos participantes na condição de professores estagiários. A investigação futura deve se centrar na análise do modo como os futuros professores aprendem a ensinar o currículo do MEE, fornecendo indicadores para o domínio de prática e contribuindo para a eficácia pedagógica na sua implementação.

This study examined the perceptions of pre-service teachers on the educational value of the Sport Education model (SEM) by contraposition of their experiences as students during the teacher education program and as pre-service teachers. The participants were 16 senior students of the Master in Teaching Physical Education in FADEUP. After construct and content validation a semi-structured interview containing open-ended questions was applied. The participants grasped the model as an extremely valuable educational experience that holds the potential for the young students' personal, social, and sports development. Notwithstanding, as pre-service teachers, the participants pictured SEM as highly demanding in the managerial organization of class, students and activities. In future, research should examine more thoroughly the manner by which upcoming teachers learn to teach the SEM curriculum in order to provide benchmarks for enhanced practice and pedagogical capability of novice teachers during early implementation of the model.