Chronic graft-versus-host disease : second line therapy review

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2017Graft-versus-Host disease (GVHD) is a complication of bone marrow transplant. It has two forms: acute and chronic. In this work we’ll only address the chronic one (cGVHD). cGVHD is a very frequent complication of the transplant (up to 50% of the patients) and a major one, given its high mortality rate, being the main cause of death in these patients, apart from the recurrence of the primary malignancy. Even thought our understanding of GVHD is far from complete, some progresses are being made. Firstly, the disease itself is being defined differently, being no longer just a temporal division between the acute GVHD (if occurred in the first 100 days after the transplant) and the chronic form (after the 100 day mark) but a more precise distinction based on the clinical manifestations, which are different between both forms. Even more, new criteria to evaluate the manifestations and the overall severity of the cGVHD have been developed, reflecting the advances in this area and enabling a better management of the patients. cGVHD treatment is very complex and far from perfect. Nowadays, the first approach relies on Corticosteroids plus a Calcineurin inhibitor. However, this treatment option has a limited efficacy (with 10% of the patients without any improvement and less than 50% only with a partial response). So, many of the patients will require second line therapy, however this isn´t perfect either. Even though there is a vast amount of options and in constant update, the number of studies is small and in many times the results aren´t satisfactory, making the clinical decision very hard and relying in a “trial and error” approach. So, with all this in mind, we develop this work in order to address every single one of these second line therapies and make some conclusions regarding them.A Doença de Enxerto-vs-Hospedeiro (DEVH) é uma complicação decorrente do transplante de medula óssea. A DEVH pode ser dividida em forma crónica e aguda sendo que neste trabalho apenas iremos desenvolver a apresentação crónica (DEVHc). Esta é uma complicação não só extremamente frequente (até 50% dos recetores de transplante) mas também muito importante, dada a sua grande mortalidade, sendo a principal causa de morte nestes doentes, excluindo a recorrência da doença de base. Apesar de o nosso conhecimento sobre a DEVH ainda estar incompleto, já estão a ser feitos avanços. Em primeiro lugar, a própria conceção da DEVH alterou-se, passando de uma mera divisão temporal entre a forma aguda (caso se manifestasse nos primeiros 100 dias após o transplante) e a forma crónica (após o centésimo dia) para uma divisão baseada nas manifestações clínicas, que são diferentes entre ambas. Ainda mais, surgiram recentemente novos critérios de avaliação das manifestações e gravidade da DEVHc que refletem este avanço na compreensão da doença e possibilitam uma melhor avaliação dos doentes. O tratamento da DEVHc é complexo e longe se ser o ideal. Atualmente, a terapêutica inicial consiste em Corticoterapia associada a um inibidor da Calcineurina, no entanto, esta opção apresenta apenas uma eficácia limitada (com 10% dos doentes sem qualquer resposta e menos de 50% apenas com melhoria parcial). Assim, muitos doentes necessitam de terapêutica de segunda linha. No entanto, esta também não é perfeita pois, embora exista uma variedade considerável de terapêuticas possíveis e em constante atualização, estas estão pouco estudadas e muitas vezes apresentam resultados pouco satisfatórios, sendo a escolha entre estas difícil e muitas vezes baseada numa abordagem de “tentativa e erro”. Assim, é neste contexto que é desenvolvido este trabalho, com o objetivo de desenvolver cada uma destas terapêuticas de segunda linha e tecer considerações sobre estas

Relatório de estágio pedagógico realizado na Escola Secundária 2, 3 Dona Filipa de Lencastre.

Mestrado em Ensino da Educação Física nos Ensinos Básico e SecundárioO presente relatório baseou-se no processo de estágio pedagógico, parte integrante do Mestrado em Ensino da Educação Física nos Ensinos Básico e Secundário. O estágio pedagógico realizou-se na Escola Secundária 2,3 Dona Filipa de Lencastre, durante o ano letivo 2014/2015. Pretendo descrever os principais desafios vividos durante o estágio, bem como as estratégias utilizadas para a sua superação. Alguns problemas sentidos ficam ainda como uma necessidade de formação no meu futuro profissional. Na área 1, saliento como principal dificuldade a motivação dos alunos para a prática e como ponto fraco a capacidade de organização das aulas, bem como a especificidade do feedback no acompanhamento dos Jogos Desportivos Coletivos (JDC). Na área 2, deverei melhorar o rigor na utilização de procedimentos científicos, como a construção e aplicação de instrumentos e o processamento dos dados recolhidos. Na área 3, saliento como principal dificuldade o recrutamento de alunos para participação nos treinos de Desporto Escolar (DE). Como principal qualidade nesta área realço a capacidade de intervenção no treino, numa modalidade na qual não tinha qualquer tipo de experiência. Por fim na área 4, destaco como principal ponto fraco a dificuldade em ter uma intervenção mais ativa junto do conselho de turma

Competitive coevolutionary algorithm for robust multi-objective optimization: the worst case minimization

Multi-Objective Optimization (MOO) problems might be subject to many modeling or manufacturing uncertainties that affect the performance of the solutions obtained by a multi-objective optimizer. The decision maker must perform an extra step of sensitivity analysis in which each solution should be verified for its robustness, but this post optimization procedure makes the optimization process expensive and inefficient. In order to avoid this situation, many researchers are developing Robust MOO, where uncertainties are incorporated in the optimization process, which seeks optimal robust solutions. We introduce a coevolutionary approach for robust MOO, without incorporating robustness measures neither in the objective function nor in the constraints. Two populations compete in the environment, one representing solutions and minimizing the objectives, another representing uncertainties and maximizing the objectives in a worst case scenario. The proposed coevolutionary method is a coevolutionary version of MOEA/D. The results clearly suggest that these competing co-evolving populations are able to identify robust solutions to multi-objective optimization problems.info:eu-repo/semantics/publishedVersio

A colecção de azulejos do Museu de Artes Decorativas Portuguesas: contributos para um projecto de comunicação expositiva

O presente trabalho de projecto de mestrado destina-se a dar um conjunto de contributos para um futuro projecto de comunicação expositiva da colecção de azulejos do Museu de Artes Decorativas Portuguesas da Fundação Ricardo do Espírito Santo Silva, em Lisboa. Esta ideia deve-se ao facto de o Museu em causa não comunicar, nem através da exposição permanente, nem de exposições temporárias, a história da colecção e o seu significado para a história da azulejaria portuguesa nos séculos XVII e XVIII. Para a realização deste trabalho aplicaram-se os princípios metodológicos da programação museológica. O trabalho é caracterizado por três partes distintas. Na primeira parte é feita uma caracterização e descrição do Museu e da colecção; na segunda parte procede-se a uma análise e diagnóstico da actual comunicação expositiva da colecção; na terceira parte avança-se com algumas ideias/contributos para um futuro projecto de comunicação expositiva. Estas ideias incidem essencialmente na elaboração de dois percursos interpretativos, mas também no restauro e conservação dos painéis de azulejos, na criação de recursos físicos que permitam uma maior acessibilidade do Museu e da exposição aos diversos tipos de público, e ainda na reformulação museográfica de alguns espaços expositivos.This master's project work is intended to give a set of contributions to a future draft expository communication Museum tile collection of Portuguese Decorative Arts of the Ricardo do Espírito Santo Silva Foundation, in Lisbon. This idea is due, to the fact that the museum in question does not communicate through either the permanent exhibition or temporary exhibitions, the history of the collection and its significance to the history of Portuguese azulejos/tiles in the seventeenth and eighteenth centuries. For this work, we have applied methodological principles of museum programming. The work is characterized by three distinct parts. The first part consists in the characterization and description of the museum and of its the collection. In the second part, we analyze and make the diagnosis of the current expository communication collection. The third part describes some ideas for a future draft expository communication. These ideas focus mainly on the development of two interpretive paths, but also the restoration and conservation of the tile panels, creating physical resources to enable greater accessibility Museum and exposure to various types of public and still in museographic reworking of some spaces expository

Scalable and customizable benchmark problems for many-objective optimization

Solving many-objective problems (MaOPs) is still a significant challenge in the multi-objective optimization (MOO) field. One way to measure algorithm performance is through the use of benchmark functions (also called test functions or test suites), which are artificial problems with a well-defined mathematical formulation, known solutions and a variety of features and difficulties. In this paper we propose a parameterized generator of scalable and customizable benchmark problems for MaOPs. It is able to generate problems that reproduce features present in other benchmarks and also problems with some new features. We propose here the concept of generative benchmarking, in which one can generate an infinite number of MOO problems, by varying parameters that control specific features that the problem should have: scalability in the number of variables and objectives, bias, deceptiveness, multimodality, robust and non-robust solutions, shape of the Pareto front, and constraints. The proposed Generalized Position-Distance (GPD) tunable benchmark generator uses the position-distance paradigm, a basic approach to building test functions, used in other benchmarks such as Deb, Thiele, Laumanns and Zitzler (DTLZ), Walking Fish Group (WFG) and others. It includes scalable problems in any number of variables and objectives and it presents Pareto fronts with different characteristics. The resulting functions are easy to understand and visualize, easy to implement, fast to compute and their Pareto optimal solutions are known.This work has been supported by the Brazilian agencies (i) National Council for Scientific and Technological Development (CNPq); (ii) Coordination for the Improvement of Higher Education (CAPES) and (iii) Foundation for Research of the State of Minas Gerais (FAPEMIG, in Portuguese)

Information to the eye of the beholder: data visualization for many-objective optimization

The visualization gap is one of the important challenges posed by many-objective optimization problems (MaOPs). In this paper, we present an integrated data visualization method for MaOPs, called CAP-vis plot, combining the Chord diagram, the Angular mapping and the Parallel coordinates in the same visualization. The method follows the circular design layout, showing different levels of information. This new approach allows the spatial location of points in high dimensional spaces, the visualization of harmony and conflict between objectives, as well as the comparison of the approximation sets provided by different algorithms. With this work, we try to fill the visualization gap and bring information to the eye of the decision-maker and the optimizer, with an intuitive overview of the obtained results. Some experiments were performed using the Benchmark Functions proposed for the IEEE-CEC 2018 Competition on Many-Objective Optimization. We used the tool to visualize the results obtained by NSGA-III, HypE, RVEA, MOEA/DD, PICEA-g, using the PlatEMO MATLAB platform, with the same parameter settings of the competition. The results on the Benchmark Problems show the importance of the qualitative analysis of the data. The experiments show how visualization can help interpretation of the results and identification of strengths and drawbacks of MOEA.The authors would like to thank the Brazilian agencies CAPES, CNPq and FAPEMIG for the financial support

Incorporation of region of interest in a decomposition-based multi-objective evolutionary algorithm

Preference-based Multi-Objective Evolutionary Algorithm (MOEA) restrict the search to a given region of the Pareto front preferred by the Decision Maker (DM), called the Region of Interest (ROI). In this paper, a new preference-guided MOEA is proposed. In this method, we define the ROI as a preference cone in the objective space. The preferential direction and the aperture of the cone are parameters that the DM has to provide to define the ROI. Given the preference cone, we employ a weight vector generation method that is based on a steady-state evolutionary algorithm. The main idea of our method is to evolve a population of weight vectors towards the characteristics that are desirable for a set of weight vectors in a decomposition-based MOEA framework. The main advantage is that the DM can define the number of weight vectors and thus can control the population size. Once the ROI is defined and the set of weight vectors are generated within the preference cone, we start a decomposition-based MOEA using the provided set of weights in its initialization. Therefore, this enforces the algorithm to converge to the ROI. The results show the benefit and adequacy of the preference cone MOEA/D for preference-guided many-objective optimization.This work was supported by the Brazilian funding agencies CAPES and CNPq

Trexit: Uma Saída “Limpa” das Biópsias Prostáticas Transretais – Resultados Prospetivos de Biópsias da Próstata “Mãos-Livres” no Consultório Sob Anestesia Local

Introduction: Prostate biopsy (PB) may be performed by either the transrectal (TR) or transperineal (TP) approach. Cancer detection rates seem to be comparable between the two approaches. However, evidence suggests a reduced infection risk and a higher detection of tumours localised in the anterior zone of the prostate with the TP route. TP-PB is currently recommended as a first-line procedure for the diagnosis of prostate cancer (PCa) whenever available. We sought to report the initial results of in-office freehand TP-PB under local anaesthesia in the outpatient setting.   Methods: We conducted a prospective study with consecutive sampling with data from men submitted to TP-PB from Sep/2019 to Sep/2021, in a tertiary care centre. A questionnaire was carried out to appraise the pain related to the procedure on a pain numerical rating scale from 0 to 10. Presenting PSA, biopsy result and characteristics and complications that motivated a visit to the emergency department–ED – until 1 month after the PB were analysed. Antibiotic (AB) prophylaxis was not provided to any of the patients undergoing TP-PB. TP-PB was performed under local anaesthesia by freehand method.   Results: A hundred and eight (108) patients underwent TP-PB. The mean age was 66±9 years old. The median presenting PSA was comparable in patients with positive and negative PB results (7.7 ng/mL, p=0.11). Overall, 67/108 (62%) patients had PCa diagnosed. Clinically significant (cs) PCa (ISUP=2) was diagnosed in 42/67 (63%) patients. The TP approach allowed the diagnosis of anterior zone PCa in 61% (41/67) of the patients (anterior zone csPCa in 63% of these), 7% (5/67) had exclusively anterior zone pathological findings. Complications leading to an ED visit were recorded in only one patient. Patients reported only mild levels of discomfort related to the anaesthesia infiltration (3±3) and to the introduction of the US transducer (3±3). Globally, the patients ascribed a pain of 3±3 to the entire procedure.   Conclusion: Freehand TP-PB under local anaesthesia, without AB prophylaxis, is a well-tolerated and safe procedure, feasible as an outpatient procedure. TP-PB provides an easy access to the anterior zone of the prostate allowing for the diagnosis of previously missed PCa.Introdução: A biópsia prostática (BxP) pode ser realizada por via transretal (TR) ou transperineal (TP). As taxas de deteção de neoplasia parecem comparáveis entre ambas as abordagens. Contudo, a evidência sugere um menor risco infeccioso e uma maior taxa de deteção de tumores localizados na porção anterior da próstata com a via TP. A BxP-TP é atualmente recomendada como procedimento de primeira linha no diagnóstico de cancro da próstata (CaP), sempre que disponível. O trabalho tem como objetivo reportar os resultados iniciais de BxP-TP “mãos-livres” sob anestesia local, em regime de ambulatório.   Métodos: Realizou-se um estudo prospetivo com amostragem consecutiva e dados de homens submetidos a BxP-TP entre set/2019 e set/2021, num centro hospitalar terciário. Disponibilizou-se um questionário para avaliar a dor associada ao procedimento numa escala numérica de 0 a 10. Analisaram-se os PSA inicial, resultado e características da biópsia e complicações que motivaram uma ida ao Serviço de Urgência (SU) até um mês após a realização da BxP-TP. Não se procedeu a administração de antibioterapia profilática em nenhumdosdoentessubmetidosaBxP-TP. A BxP-TP foi efetuada sob anestesia local pelo método de “mãos-livres”.   Resultados: Um total de 108 doentes foram submetidos a BxP-TP.Aidademédiafoi66±9anos. O PSA inicial mediano foi comparável em doentes com BxP-TP com resultados positivo e negativo (7,7 ng/mL, p=0,11). No total, 67/108 (62%) doentes foram diagnosticados com CaP, clinicamente significativo (CaPcs) (ISUP=2) em 42/67 (63%) destes. A via TP permitiu diagnosticar CaP da zona anterior em 61% (41/ /67) dos doentes (CaPcs da zona anterior em 63% dos mesmos), 7% (5/67) tinham apenas positividade na zona anterior da próstata. Apenas um doente teve complicações a condicionar necessidade de ida ao SU. O procedimento causou apenas níveis ligeiros de desconforto associado à instilação de anestesia (3±3) e à introdução da sonda ecográfica (3±3). Globalmente, os doentes atribuíram uma dor de 3±3 ao procedimento na sua íntegra.   Conclusão: A BxP-TP “mãos-livres” sob anestesia local, sem antibioterapia profilática, é um procedimento bem tolerado, seguro, exequível em regime ambulatorial. A via TP proporciona um acesso fácil à zona anterior da próstata, permitindo diagnosticar neoplasias cujo diagnóstico previamente se falhava

Liposomes as a nanoplatform to improve the delivery of antibiotics into Staphylococcus aureus biofilms

Research Areas: Pharmacology & PharmacyABSTRACT - Staphylococcus aureus biofilm-associated infections are a major public health concern. Current therapies are hampered by reduced penetration of antibiotics through biofilm and low accumulation levels at infected sites, requiring prolonged usage. To overcome these, repurposing antibiotics in combination with nanotechnological platforms is one of the most appealing fast-track and costeffective approaches. In the present work, we assessed the potential therapeutic benefit of three antibiotics, vancomycin, levofloxacin and rifabutin (RFB), through their incorporation in liposomes. Free RFB displayed the utmost antibacterial effect with MIC and MBIC50 below 0.006 µg/mL towards a methicillin susceptible S. aureus (MSSA). RFB was selected for further in vitro studies and the influence of different lipid compositions on bacterial biofilm interactions was evaluated. Although positively charged RFB liposomes displayed the highest interaction with MSSA biofilms, RFB incorporated in negatively charged liposomes displayed lower MBIC50 values in comparison to the antibiotic in the free form. Preliminary safety assessment on all RFB formulations towards osteoblast and fibroblast cell lines demonstrated that a reduction on cell viability was only observed for the positively charged liposomes. Overall, negatively charged RFB liposomes are a promising approach against biofilm S. aureus infections and further in vivo studies should be performed.info:eu-repo/semantics/publishedVersio

Novel peptides derived from dengue virus capsid protein translocate reversibly the blood−brain barrier through a receptor-free mechanism

© 2017 American Chemical SocietyThe delivery of therapeutic molecules to the central nervous system is hampered by poor delivery across the blood-brain barrier (BBB). Several strategies have been proposed to enhance transport into the brain, including invasive techniques and receptor-mediated transport (RMT). Both approaches have several drawbacks, such as BBB disruption, receptor saturation, and off-target effects, raising safety issues. Herein, we show that specific domains of Dengue virus type 2 capsid protein (DEN2C) can be used as trans-BBB peptide vectors. Their mechanism of translocation is receptor-independent and consistent with adsorptive-mediated transport (AMT). One peptide in particular, named PepH3, reaches equilibrium distribution concentrations across the BBB in less than 24 h in a cellular in vitro assay. Importantly, in vivo biodistribution data with radiolabeled peptide derivatives show high brain penetration. In addition, there is fast clearance from the brain and high levels of excretion, showing that PepH3 is a very good candidate to be used as a peptide shuttle taking cargo in and out of the brain.The authors thank the Portuguese Funding Agency, Fundação para a Ciência e a Tecnologia, FCT IP, for financial support (grants SFRH/BPD/94466/2013; SFRH/BPD/109010/2015; IF/01010/2013; PTDC/BBBNAN/1578/2014; HIVERA/ 0002/2013) and Marie Skłodowska-Curie Research and Innovation Staff Exchange (MSCA-RISE), call 20-MSCARISE-2014 (grant agreement H20 644167 − INPACT). M.M., L.G., C.F., and J.D.G.C. gratefully acknowledge FCT support through the UID/Multi/04349/2013 project.info:eu-repo/semantics/publishedVersio