RCAAP Repository

Background and purpose: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system with an undetermined etiology. Retinoids may have immunomodulatory effects that favorably influence MS progression. We aimed to explore the yet unknown relationship between exposure to retinoids and the risk of acquiring MS. Methods: We performed a nationwide cohort study in the Danish population in the period 1998-2016, comparing MS incidence in three groups: users of systemic retinoids; users of topical retinoids (negative control group); and users of non-retinoid acne drugs (control group). We used data from the Danish Multiple Sclerosis Registry (DMSR), the Danish National Prescription Registry and the Danish National Patient Registry. Linkage was obtained through the personal identification number (CPR number). We addressed confounding by three-way propensity score (PS)-matching weights. Additionally, to evaluate a cumulative dose-response effect for systemic retinoids on MS incidence, we conducted a case-control study, nested within the cohort. Results: A total of 257,193 users of non-retinoid acne drugs, 130,560 users of topical retinoids, and 75,610 users of systemic retinoids were included. Systemic retinoid use was not associated with a reduced risk of MS compared to non-retinoid acne drug use in crude (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61 to 1.05]) and weighted analyses (HR 0.89, 95% CI 0.67 to 1.20). There was no evidence of a cumulative dose-response association between systemic retinoids and MS incidence. Conclusions: Use of systemic retinoids was not associated with a reduced incidence of MS compared to use of non-retinoid acne drugs in this study.

Background: Cognitive impairment, anxiety and depression are common in heart failure (HF) patients and its evolution is not fully understood. Objectives: To assess the cognitive status of HF patients over time, its relation to anxiety and depression, and its prognostic impact. Methods: Prospective, longitudinal, single center study including patients enrolled in a structured program for follow-up after hospital admission for HF decompensation. Cognitive function, anxiety/depression state, HF-related quality of life (QoL) were assessed before discharge and during follow-up (between 6th and 12th month) using Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS) and Kansas City Cardiomyopathy Questionnaire, respectively. HF related outcomes were all cause readmissions, HF readmissions and the composite endpoint of all-cause readmissions or death. Results: 43 patients included (67±11.3 years, 69% male); followed-up for 8.2±2.1 months. 25.6% had an abnormal MoCA score that remained stable during follow-up (22.6±4.2 vs. 22.2±5.5; p=NS). MoCA score <22 at discharge conferred a sixfold greater risk of HF readmission [HR=6.42 (1.26-32.61); p=0.025], also predicting all-cause readmissions [HR=4.00 (1.15-13.95); p=0.03] and death or all-cause readmissions [HR=4.63 (1.37-15.67); p=0.014]. Patients with higher MoCA score showed a greater ability to deal with their disease (p=0.038). At discharge, 14% and 18.6% had an abnormal HADS score for depression and anxiety, respectively, which remained stable during follow-up and was not related to MoCA. Conclusions: Cognitive function, anxiety and depressive status remain stable in HF patients despite optimized HF therapy. Cognitive status shall be routinely screened to adopt attitudes that improve management as it has an impact on HF-related QoL and prognosis.

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The aims of this research on burnout among physicians were threefold, (1) to characterize the burnout symptoms’ prevalence among Portuguese physicians, (2) to test the hypothesis that organizational demands and resources add, on top of other factors, to the explanatory level of burnout; and (3) to explore the predictors of organizational demands and resources. Data collection was conducted online at the national level in Portugal, with 9,176 complete replies and a response rate of 21%. Predictors stemming from theoretical models of an intra-individual, occupational, organizational, and socio-psychological nature were measured using an online/paper survey. Results were analyzed through a significantly modified version of the Maslach Burnout Inventory (MBI) after transformations to address the fit of this measure in this sample. Results show that 66% of physicians have high levels of emotional exhaustion, 33% high levels of depersonalization, and 39% high levels of decrease of personal accomplishment. Moreover, a first set of hierarchical multiple regression models with burnout symptoms reveals that organizational resources, demands of the relationship with the patients and of work schedule are consistently important predictors of emotional exhaustion and depersonalization on top of other theoretically relevant predictors. A second set of regression models with the organizational-level variables shows that, aside from organizational variables, other context variables, like procedural justice and teamwork, have the most substantial predictive value. These results highlight the importance of recognizing physicians’ burnout as a phenomenon that is predicted by a wide variety of factors, but also the importance of attending to the particular role of circumstancial factors that may be addressed in future interventions.

As expectativas têm sido consideradas um factor que se pensa influenciar o processo e os resultados psicoterapêuticos e podem ser definidas como crenças antecipatórias que os pacientes trazem consigo para o acompanhamento psicológico. As expectativas podem englobar crenças relativas aos procedimentos, resultados, terapeutas e outros aspectos do processo terapêutico e surgem relacionadas com a eficiência que o cliente espera (expectativas de resultado) e com os comportamentos esperados existir numa situação de acompanhamento psicológico (expectativas de papel). O presente estudo procura avaliar as expectativas dos jovens relativamente ao acompanhamento psicológico, comparando as opiniões de jovens expostos ao trabalho do psicólogo em contexto escolar com jovens cuja escola não tem Serviço de Psicologia e Orientação. Pretende-se avaliar se o facto do psicólogo se encontrar inserido no ambiente escolar proporciona alguma familiarização dos jovens com o papel e prática da Psicologia. Neste estudo participaram 31 jovens, com idades compreendidas entre os 12 e os 13 anos de idade, divididos em dois grupos. Em termos metodológicos, optou-se por recorrer a uma metodologia qualitativa, tendo sido aplicado um questionário de resposta aberta, adaptado da entrevista semi-estruturada de Surf e Lycnh (1999). Para analisar os dados recolhidos, recorreu-se à análise de conteúdo que permitiu concluir que as opiniões dos jovens apresentam pequenas diferenças. Embora a análise dos dados tenha verificado que, na sua maioria, os jovens revelam uma opinião positiva em relação ao acompanhamento psicológico, os jovens da escola com SPO apresentaram uma tendência para expressar expectativas mais adequadas relativamente ao papel do psicólogo e ao próprio processo terapêutico. Estes dados sugerem que a presença ou ausência do psicólogo em meio escolar pode contribuir para o conhecimento e familiarização dos jovens com a Psicologia.

Esta dissertação foi elaborada no âmbito do Mestrado em Tradução e tem como objetivo descrever a tradução para legendagem de referências culturais como problema de tradução. Reconhecendo que a tradução consiste também em aspetos socioculturais considerados como obstáculos na tradução, propôs-se aqui explorar esta temática na modalidade do fansubbing. Nesta vertente, procedeu-se à análise comparativa das estratégias de tradução para legendagem de referências culturais no fansubbing e na tradução para legendagem profissional. De forma a desenvolver-se uma análise bem fundamentada, foi estabelecido um enquadramento teórico focado na revisão dos conceitos a analisar de tradução profissional, fansubbing e referências culturais. A discussão teórica baseada em Díaz Cintas & Muñoz Sánchez (2006), Díaz Cintas & Remael (2007), Dwyer (2012), e Pedersen (2011; 2016), mais precisamente no contexto português, Pais (2015) e Rocha (2012), permitirá conceber um instrumento de contextualização do presente estudo. Parar responder à pergunta de investigação elaborou-se um corpus paralelo bilingue (inglês-português europeu), com base na observação dos dados no corpus não translato e translato. O corpus de partida e de chegada consistiu na temporada 13 da série norte-americana Family Guy devido à elevada frequência de referências culturais na mesma. Com base nesta metodologia foi possível apurar que a estratégia mais utilizada pelo fansubber e tradutor profissional foi a retenção. Todavia, as conclusões deste estudo são fundamentais para reconhecer a influência do conhecimento da CC, do público-alvo e dos condicionalismos da legendagem na frequência das estratégias de tradução para legendagem. Em suma, este estudo tem como intuito a busca de resultados que possam auxiliar investigações futuras sobre a Tradução Audiovisual, mais concretamente o fansubbing, e a tradução de referências culturais para legendagem, de forma a moldar o fansubbing como prática de tradução, bem como a descrição de uma manifestação de fãs que interagem em comunidades online.

Objective: Individuals with high levels of psychopathic traits are often characterized by aberrant reinforcement learning. This type of learning, which implicates making choices that maximize rewards and minimize punishments, may be affected by acute stress. However, how acute stress affects reinforcement learning in individuals with different levels of psychopathic traits is not well-understood. Here, we investigated whether and how individual differences in psychopathic traits modulated the impact of acute stress on reward and punishment learning. Method: Sixty-two male participants from a university sample completed the Self-Report Psychopathy-Short Form scale and performed a reinforcement-learning task involving monetary gains and losses whilst under acute stress and control conditions. Results: Individual differences in psychopathic traits modulated the impact of acute stress on behavioral performance toward obtaining gains, but not toward avoiding losses. As levels of psychopathic traits increased, the impairing effect of acute stress on reward learning decreased. Specifically, acute stress impaired performance toward seeking gains to a larger extent in individuals with lower levels of psychopathic traits than in individuals with higher levels of these traits. Conclusions: Our study indicates that psychopathic traits modulate the impact of acute stress on reward learning.

Neuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer’s disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124’s role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.

Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.

Monocytes are key modulators in acute viral infections, determining both inflammation and development of specific B- and T-cell responses. Recently, these cells were shown to be associated to different SARS-CoV-2 infection outcome. However, their role in acute HIV-1 infection remains unclear. We had the opportunity to evaluate the mononuclear cell compartment in an early hyper-acute HIV-1 patient in comparison with an untreated chronic HIV-1 and a cohort of SARS-CoV-2 infected patients, by high dimensional flow cytometry using an unsupervised approach. A distinct polarization of the monocyte phenotype was observed in the two viral infections, with maintenance of pro-inflammatory M1-like profile in HIV-1, in contrast to the M2-like immunosuppressive shift in SARS-CoV-2. Noticeably, both acute infections had reduced CD14low/-CD16+ non-classical monocytes, with depletion of the population expressing Slan (6-sulfo LacNac), which is thought to contribute to immune surveillance through pro-inflammatory properties. This depletion indicates a potential role of these cells in acute viral infection, which has not previously been explored. The inflammatory state accompanied by the depletion of Slan+ monocytes may provide new insights on the critical events that determine the rate of viral set-point in acute HIV-1 infection and subsequent impact on transmission and reservoir establishment.

Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly detail the multi-functional, protumoral, and antitumoral roles of macrophages in the tumor microenvironment. Our objective is to focus on the ever-growing therapeutic opportunities, with promising preclinical and clinical results developed in recent years, to modulate the contribution of macrophages in oncologic diseases. While the majority of cancer immunotherapies target T cells, we believe that macrophages have a promising therapeutic potential as tumoricidal effectors and in mobilizing their surroundings towards antitumor immunity to efficiently limit cancer progression.

Background: The COVID-19 pandemic continues to rage on, and clinical research has been promoted worldwide. We aimed to assess the clinical and methodological characteristics of treatment clinical trials that have been set forth as an early response to the COVID-19 pandemic. Methods: First, we reviewed all registered clinical trials on COVID-19. The World Health Organization International Trials Registry Platform and national trial registries were searched for COVID-19 trials through April 19th, 2020. For each record, independent researchers extracted interventions, participants, and methodological characteristics. Second, on September 14th, 2020 we evaluated the recruitment status and availability of the results of COVID-19 treatment trials previously identified. Results: In April 2020, a total of 580 trials evaluating COVID-19 treatment were registered. Reporting quality was poor (core participant information was missing in 24.1 to 92.7%). Between 54.0 and 93.8% of the trials did not plan to include older people or those with a higher baseline risk. Most studies were randomised (67.9%), single-centre (58.3%), non-industry-funded (81.1%), to be conducted in China (47.6%), with a median duration of 184 days and a median sample size of 100 participants. Core endpoints (mortality, clinical status, and hospitalization length) were planned to be assessed in 5.2 to 13.1% of the trials. Five months later, 66 trials (11.4%) were reported as "Completed", and only 46 (7.9%) had public results available. One hundred forty-four of 580 trials (24.8%) either had the status "Not yet recruiting" or "Suspended", and 18 (3.1%) trials were prematurely stopped ("Terminated" or "Withdrawn") The number of completed trials and trials with results are much lower than anticipated, considering the planned follow-up. Conclusions: Our results raise concerns about the success of the initial global research effort on COVID-19 treatment. The clinical and methodological characteristics of early COVID-19 treatment trials limit their capability to produce clear answers to critical questions in the shortest possible time.

Introduction: Common Variable Immunodeficiency (CVID) is characterized by defective antibody production and hypogammaglobulinemia. Flow cytometry immunophenotyping of blood lymphocytes has become of great relevance for the diagnosis and classification of CVID, due to an impaired differentiation of mature post-germinal-center (GC) class-switched memory B-cells (MBC) and severely decreased plasmablast/plasma cell (Pb) counts. Here, we investigated in detail the pre-GC B-cell maturation compartment in blood of CVID patients. Methods: In this collaborative multicentric study the EuroFlow PID 8-color Pre-GC B-cell tube, standardized sample preparation procedures (SOPs) and innovative data analysis tools, were used to characterize the maturation profile of pre-GC B-cells in 100 CVID patients, vs 62 age-matched healthy donors (HD). Results: The Pre-GC B-cell tube allowed identification within pre-GC B-cells of three subsets of maturation associated immature B-cells and three subpopulations of mature naïve B-lymphocytes. CVID patients showed overall reduced median absolute counts (vs HD) of the two more advanced stages of maturation of both CD5+ CD38+/++ CD21het CD24++ (2.7 vs 5.6 cells/µl, p=0.0004) and CD5+ CD38het CD21+ CD24+ (6.5 vs 17 cells/µl, p<0.0001) immature B cells (below normal HD levels in 22% and 37% of CVID patients). This was associated with an expansion of CD21-CD24- (6.1 vs 0.74 cells/µl, p<0.0001) and CD21-CD24++ (1.8 vs 0.4 cells/µl, p<0.0001) naïve B-cell counts above normal values in 73% and 94% cases, respectively. Additionally, reduced IgMD+ (21 vs 32 cells/µl, p=0.03) and IgMD- (4 vs 35 cells/µl, p<0.0001) MBC counts were found to be below normal values in 25% and 77% of CVID patients, respectively, always together with severely reduced/undetectable circulating blood pb. Comparison of the maturation pathway profile of pre-GC B cells in blood of CVID patients vs HD using EuroFlow software tools showed systematically altered patterns in CVID. These consisted of: i) a normally-appearing maturation pathway with altered levels of expression of >1 (CD38, CD5, CD19, CD21, CD24, and/or smIgM) phenotypic marker (57/88 patients; 65%) for a total of 3 distinct CVID patient profiles (group 1: 42/88 patients, 48%; group 2: 8/88, 9%; and group 3: 7/88, 8%) and ii) CVID patients with a clearly altered pre-GC B cell maturation pathway in blood (group 4: 31/88 cases, 35%). Conclusion: Our results show that maturation of pre-GC B-cells in blood of CVID is systematically altered with up to four distinctly altered maturation profiles. Further studies, are necessary to better understand the impact of such alterations on the post-GC defects and the clinical heterogeneity of CVID.

Background: The role of cardiovascular risk factors in amyotrophic lateral sclerosis (ALS) is controversial. A favourable profile has been found in ALS patients, but previous studies have not specifically considered the profile in different disease phenotypes. Methods: Demographic data, smoking habits, lifetime exercise, and medical history including diabetes mellitus, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, stroke, and cardiac events, were analysed in ALS patients and in controls with other neurological disorders, utilising a standardized questionnaire applied by the same neurologist. In ALS patients the results were analysed according to their different phenotypes. Univariate analyses and multinomial logistic models were applied to estimate the odds ratios (ORs) and confidence intervals (CIs) for covariates, to test potential modifiers and their effects. Results: 500 consecutively assessed adult ALS patients (mean age 65.6, 47% women, and 136 bulbar-onset) and 327 age and gender-matched controls were studied. Patients with spinal-onset ALS took more exercise (p = 0.012), reported less hypertension (p = 0.002) and had fewer cardiac events (p = 0.012). Multinomial regression analysis showed that men without hypertension have a higher risk of having spinal-onset ALS (p < 0.001) while female with hypertension have a higher risk of having bulbar-onset ALS (p = 0.033). Conclusions: Risk-factors in ALS can be influenced by gender and phenotype. This study suggests that men with spinal ALS are healthier, exercise more and have lower rate of hypertension, but females with bulbar-onset ALS are more prone to hypertension. The complex interplay between exercise, diet and comorbidities with ALS phenotype requires further investigation.

Thrombosis of the cerebral veins and sinuses (CVT) is a distinct cerebrovascular disorder that, unlike arterial stroke, most often affects children and young adults, especially women. In this review, we will summarize recent advances on the knowledge of patients with CVT.

Background and aims: The role of inflammation in atherosclerosis development and expression in different arterial territories is unclear. Soluble CD40 ligand (sCD40L) mediates inflammation and atherogenesis. Through a systematic review and meta-analysis, we assessed whether sCD40L was dysregulated in stable atherosclerosis, irrespective of the diseased arterial territory, and whether this dysregulation differed according to the specific territory. Methods: Systematic literature searches were performed in MEDLINE, Cochrane Library, Web of Science, and Embase for studies reporting circulating sCD40L levels in individuals with and without stable atherosclerosis. sCD40L levels were compared using random-effects meta-analysis, weighted by the inverse variance method (study protocol: PROSPERO CRD42020181392). Results: Fifty-four studies (59 estimates) including 7705 patients and 7841 controls were analyzed. sCD40L levels were found to be increased in patients with atherosclerosis, irrespective of the territory (standardized mean difference [SMD] 0.43, 95% CI 0.29-0.57; 59 estimates; χ2 heterogeneity p < 0.001; I2 = 92%). SMD was greatest in carotid atherosclerosis (SMD 0.58, 95% CI 0.30-0.86; 17 estimates), followed by coronary (SMD 0.43, 95% CI 0.24-0.62; 33 estimates), lower extremity (SMD 0.26, 95% CI -0.02-0.54; 7 estimates), and renal atherosclerosis (SMD -0.07, 95% CI -2.77-2.64; 2 estimates) (χ2 heterogeneity p < 0.001; I2 ≥ 80% for all). Subgroup analysis revealed that sCD40L levels were increased in clinical, but not subclinical, atherosclerosis. Conclusions: sCD40L levels were increased in stable atherosclerosis, particularly in the carotid and coronary territories. These novel data support sCD40L as a marker of systemic atherosclerosis, possibly with differential roles in specific territories.

A revista Gama parece agir como um revelador de imagens latentes: a sua ação é uma ativação social, sempre de reforço simbólico, que permite auxiliar a discernir, e a identificar, aquilo a que todos chamamos de arte. É um projeto de legitimação apoiado nos criadores: que sejam os artistas a apontar os caminhos da arte, onde eles se escondem, onde ela pode passar a ser. Como em Espinosa, na ‘Ética,’ a arte pode ser uma ‘qualia’ de uma substância potente, que ao ser percebida e reconhecida, nas páginas do número 14 da revista Gama, nos seus 16 artigos, se percebe como coisa, ocorrência valiosa, ou melhor, ‘valente.’

Entre Lisboa e a América, encontra-se o pretexto para o conhecimento mútuo, para descobrir autores e artistas: a viagem torna-nos diferentes. A revista GAMA galga os muros e procura o reconhecimanto. O resultado, um acervo de informação sobre a arte de cá e de lá do Atlântico, de ontem, ou de há pouco. A revista GAMA não ficou no Quintal: saltou muros, brincou com os novos vizinhos, esfolou os joelhos, roubou laranjas. O resultado, uma aventura de conhecimento. A liberdade está na possibilidade da viagem e do conhecimento. Tenho que saber quem sou, tenho de saber quem és.

Esta dissertação é sobre a experiência da pintura (a experiência de pintar) na era da pós-internet e estrutura-se nos resultados de pesquisas das sociedades educadas ocidentais. Como é que o acesso efetivo às tecnologias da informação afeta o trabalho artístico e criativo? Como é que interfere nas escolhas de cada indivíduo e no seu desenvolvimento artístico? E porque é que o processo de crescimento e de independência é tão importante para o auto-conhecimento (pessoal e artístico)? Para responder a estas perguntas e aos assuntos que lhes são inerentes é necessário contextualizar sobre qual foi a minha área de interesse pessoal nos últimos dois anos, que passei em Portugal. Portanto, minhas experiências pessoais e as respectivas pesquisas plásticas, teóricas e conceptuais sobre os vários temas que me interessam fundem-se e vêm sublinhar a investigação pela pintura como um campo de questionamento criativo e artístico. Para salientar o aspecto pessoal, tomo a liberdade de falar na primeira pessoa ao longo de todo o documento. A investigação que se segue está ligada a uma série de pinturas que vão ser expostas na Faculdade de Belas-Artes de Lisboa entre 8 e 18 de Junho de 2021. A selecção desta série de oito pinturas é especial porque mostra o resultado do meu desenvolvimento artístico durante os últimos 2 anos, em Lisboa; reflecte os meus interesses, o desenvolvimento técnico pictórico e a minha forte ligação à pintura figurativa nos dias de hoje. Um dos meus objectivos nesta investigação foi pensar sobre a pintura que desenvolvo e que vou apresentar. Neste sentido, apresento o leque de informações que é inerente ao meu projecto pictórico, primeiro, para documentar e reforçar as motivações pessoais que o originaram e, depois, para ajudar o leitor ou observador identificar-me como o autor destas pinturas, especificamente, e neste movimento compreender quais os temas e conceitos que me interessam.