Homogneous time resolved fluorescence: a new technique for detection and quantifications of infliximab in autoimmune patients

RESUMO:As terapias biológicas revolucionaram o tratamento das doenças autoimunes nos últimos anos. Tipicamente têm como alvos mediadores importantes no mecanismo das doenças. Os antagonistas do fator de necrose tumoral-α (TNF-α) são um grupo de agentes biológicos muito prescrito, pois estão indicados no tratamento de doenças imuno-mediadas comuns, tais como artrite reumatoide, artrite idiopática juvenil, artrite psoriática, espondilite anquilosante, doença de Crohn e colite ulcerosa. Com o uso frequente de inibidores do TNF-α, tem-se tornado evidente que estes agentes têm um potencial imunogénico importante, que pode comprometer o prognóstico a longo prazo dos doentes cronicamente tratados. A produção de anticorpos anti-fármaco parece causar falência terapêutica secundária em muitos doentes. Um dos efeitos dos anticorpos anti-fármaco é o aumento da eliminação do fármaco. A eliminação do fármaco, por sua vez, varia entre indivíduos, refletindo diferentes perfis farmacocinéticos. A determinação dos níveis séricos mínimos do agente anti-TNF-α é assim muito informativa e pode auxiliar nas decisões terapêuticas. Contudo, os testes imunológicos para determinar as concentrações séricas do fármaco não estão facilmente disponíveis na prática clínica. De forma a investigar uma nova técnica potencialmente fidedigna e prática para a deteção e quantificação dos agentes biológicos anti-TNF-α, foi testada a técnica por HTRF (homogeneous time-resolved fluorescence resonance energy transfer) para a determinação de concentrações séricas de infliximab. Apesar de apresentar algumas limitações relacionadas com as condições de leitura da fluorescência, esta técnica provou obter resultados próximos das concentrações obtidas por ELISA (enzyme-linked immunosorbent assay) bridging. Adicionalmente, tem a vantagem de ser de execução muito mais fácil e rápida. Deste modo, a técnica por HTRF poderá ser otimizada e tornar-se uma valiosa ferramenta laboratorial para orientar as decisões terapêuticas em doentes autoimunes com falência da terapêutica anti-TNF-α.--------- ABSTRACT: Biologic therapies revolutionized the treatment of autoimmune diseases in the last years. Typically, they target important disease mediators. Tumor necrosis factor-alpha (TNF-α) antagonists constitute a very prescribed group of biologic agents as they are indicated for the treatment of common immune-mediated diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis. With the increasing use of TNF-α inhibitors it has been noticed that they have an important immunogenic potential that can compromise long-term outcomes in chronically treated patients. The production of anti-drug antibodies seems to cause secondary therapeutic failure in many patients. One of the effects of anti-drug antibodies is the enhancement of drug clearance. Drug clearance, in turn, varies among individuals, reflecting different pharmacokinetic profiles. Determination of serum anti-TNF-α drug trough levels is though very informative and could support treatment decisions. However, immunologic assays to determine drug serum concentrations are not readily available in clinical practice. In order to investigate a potentially reliable and practical new technique for detection and quantification of anti-TNF-α biologic agents, homogeneous time-resolved fluorescence resonance energy transfer (HTRF) technique was tested for determination of serum infliximab concentrations. Although presenting some limitations related with fluorescence reading conditions, this technique proved to give results close to the concentrations obtained by the widely used bridging enzyme-linked immunosorbent assay (ELISA). In addition, it has the advantage of being much easier and faster to perform. Thus, HTRF technique can be optimized and become a valuable laboratorial tool to guide treatment decisions in autoimmune patients with anti-TNF-α therapy failure.

Do hospitals react to random demand pressure by early discharges?

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA – School of Business and Economics

Facing unemployment after being at the top: impact, job search strategies and crucial competences

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

Hospital Efficiency: Directed internship: Deloitte & NOVA SBE

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA – School of Business and Economics

The impact of corporate social responsibility on consumer behavior: The role of profit-seeking and altruistic perceived motives

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

A proof system for lock-free concurrency

Dissertação para obtenção do Grau de Mestre em Engenharia Informática

Qualidade e satisfação do sistema de seguimento à distância de cardioversores-desfibrilhadores implantáveis

RESUMO - Com o aumento da esperança de vida e das doenças crónicas, cada vez se tem implantado mais cardioversores-desfibrilhadores (CDI) para prevenção de morte súbita. O aumento exponencial no número de implantes aumenta o número de seguimentos dos dispositivos, sobrecarregando os profissionais de saúde e comprometendo a qualidade dos serviços prestados. Segundo as recomendações internacionais, um CDI deverá ser vigiado a cada 3 meses, o que perfaz 4 consultas por ano/doente no mínimo, se não existirem episódios de “choques” ou “descompensações” clínicas, e mensalmente quando é atingido o indicador de substituição electiva do gerador. A evolução da tecnologia, de algoritmos, visualização de episódios e terapias requer recursos técnicos e humanos diferenciados e um gasto de tempo considerável no seguimento. Em países como os Estados Unidos da América, em que os doentes têm de percorrer distâncias muito grandes para aceder aos cuidados de saúde, tornou-se preemente a necessidade de um sistema de vigilância alternativo. Nesse sentido, e usando o conceito da telemedicina, foi criado o seguimento/monitorização à distância de dispositivos cardíacos. Este reduz os custos em consultas, deslocações e recursos humanos, uma vez que contempla apenas uma consulta presencial por ano. Por outro lado, aumenta a segurança do doente com a monitorização periódica e a criação de alarmes, permitindo uma assistência de qualidade e intervenção adequada imediata. Aproveitando as vantagens que este tipo de sistema de transmissão remota oferece, procedeu-se no meu serviço, à distribuição inicial de 62 comunicadores a doentes portadores de CDI´s ou com Ressincronizadores Cardíacos (TRC´s1). Apesar de ser considerada uma melhoria na qualidade dos serviços prestados, é também uma mudança importante na metodologia da consulta feita até aqui. Segundo vários autores, a avaliação da qualidade dos cuidados em saúde está intrinsecamente ligada ao grau de satisfação dos doentes com esses serviços, ou seja, à relação entre as suas expectativas e os resultados percebidos por eles, sendo considerado um importante indicador de qualidade dos serviços. Com este trabalho, pretende-se avaliar a percepção dos doentes face ao novo seguimento em termos de aceitação, satisfação, validade, segurança e confiança no novo sistema. Se este mantém os mesmos padrões de qualidade que o seguimento presencial. Trata-se de um estudo transversal com uma componente retrospectiva de avaliação da nova metodologia de consulta à distância. Para tal, foi elaborado um questionário, que foi aplicado a 40 doentes (17,5% do género feminino e 82,5% do género masculino; média de idades de 65 anos) que constituíram a amostra do estudo. Verificou-se uma média de 5 anos de tempo de implante do CDI. Dos dados obtidos, é de realçar que 70% dos inquiridos estão satisfeitos e 30% estão muito satisfeitos com esta nova metodologia de consulta e cerca 67,4% prefere a consulta à distância. Quando solicitados para comparar a qualidade do serviço prestado entre as duas consultas, 65% respondeu igual e 27,5% melhor. Todos os inquiridos responderam ter confiança e segurança com o sistema de consulta à distância. Cerca de 87,5% dos inquiridos vê-se mesmo a continuar com este tipo de consulta. Os resultados obtidos são bastante satisfatórios no que diz respeito à transição do modo como a consulta de CDI´s é feita. Reflectem também que a tecnologia não é necessariamente uma barreira no acesso aos profissionais de saúde, desde que suportada por algum contacto directo (telefone e através de uma consulta presencial por ano). 1 TRC – Terapia de Ressincronização Cardíaca

Production of chitin-glucan complex by Pichia pastoris

Dissertation for the Degree of Master in Biotechnology

Optimization of ring oscillators

Dissertação para obtenção do Grau de Mestre em Engenharia Electrotécnica e de Computadores

Perspectives and approaches for the internet of things

Dissertação para obtenção do Grau de Mestre em Engenharia Electrotécnica e de Computadores

Predictive analytical and numerical modeling for orthogonal cutting

In this thesis, a predictive analytical and numerical modeling approach for the orthogonal cutting process is proposed to calculate temperature distributions and subsequently, forces and stress distributions. The models proposed include a constitutive model for the material being cut based on the work of Weber, a model for the shear plane based on Merchants model, a model describing the contribution of friction based on Zorev’s approach, a model for the effect of wear on the tool based on the work of Waldorf, and a thermal model based on the works of Komanduri and Hou, with a fraction heat partition for a non-uniform distribution of the heat in the interfaces, but extended to encompass a set of contributions to the global temperature rise of chip, tool and work piece. The models proposed in this work, try to avoid from experimental based values or expressions, and simplifying assumptions or suppositions, as much as possible. On a thermo-physical point of view, the results were affected not only by the mechanical or cutting parameters chosen, but also by their coupling effects, instead of the simplifying way of modeling which is to contemplate only the direct effect of the variation of a parameter. The implementation of these models was performed using the MATLAB environment. Since it was possible to find in the literature all the parameters for AISI 1045 and AISI O2, these materials were used to run the simulations in order to avoid arbitrary assumption.

Res Publica: Citizenship and Political Representation in Portugal, 1820-1926

The term res publica (literally “thing of the people”) was coined by the Romans to translate the Greek word politeia, which, as we know, referred to a political community organised in accordance with certain principles, amongst which the notion of the “good life” (as against exclusively private interests) was paramount. This ideal also came to be known as political virtue. To achieve it, it was necessary to combine the best of each “constitutional” type and avoid their worst aspects (tyranny, oligarchy and ochlocracy). Hence, the term acquired from the Greeks a sense of being a “mixed” and “balanced” system. Anyone that was entitled to citizenship could participate in the governance of the “public thing”. This implied the institutionalization of open debate and confrontation between interested parties as a way of achieving the consensus necessary to ensure that man the political animal, who fought with words and reason, prevailed over his “natural” counterpart. These premises lie at the heart of the project which is now being presented under the title of Res Publica: Citizenship and Political Representation in Portugal, 1820-1926. The fact that it is integrated into the centenary commemorations of the establishment of the Republic in Portugal is significant, as it was the idea of revolution – with its promise of rupture and change – that inspired it. However, it has also sought to explore events that could be considered the precursor of democratization in the history of Portugal, namely the vintista, setembrista and patuleia revolutions. It is true that the republican regime was opposed to the monarchic. However, although the thesis that monarchy would inevitably lead to tyranny had held sway for centuries, it had also been long believed that the monarchic system could be as “politically virtuous” as a republic (in the strict sense of the word) provided that power was not concentrated in the hands of a single individual. Moreover, various historical experiments had shown that republics could also degenerate into Caesarism and different kinds of despotism. Thus, when absolutism began to be overturned in continental Europe in the name of the natural rights of man and the new social pact theories, initiating the difficult process of (written) constitutionalization, the monarchic principle began to be qualified as a “monarchy hedged by republican institutions”, a situation in which not even the king was exempt from isonomy. This context justifies the time frame chosen here, as it captures the various changes and continuities that run through it. Having rejected the imperative mandate and the reinstatement of the model of corporative representation (which did not mean that, in new contexts, this might not be revived, or that the second chamber established by the Constitutional Charter of 1826 might not be given another lease of life), a new power base was convened: national sovereignty, a precept that would be shared by the monarchic constitutions of 1822 and 1838, and by the republican one of 1911. This followed the French example (manifested in the monarchic constitution of 1791 and in the Spanish constitution of 1812), as not even republicans entertained a tradition of republicanism based upon popular sovereignty. This enables us to better understand the rejection of direct democracy and universal suffrage, and also the long incapacitation (concerning voting and standing for office) of the vast body of “passive” citizens, justified by “enlightened”, property- and gender-based criteria. Although the republicans had promised in the propaganda phase to alter this situation, they ultimately failed to do so. Indeed, throughout the whole period under analysis, the realisation of the potential of national sovereignty was mediated above all by the individual citizen through his choice of representatives. However, this representation was indirect and took place at national level, in the hope that action would be motivated not by particular local interests but by the common good, as dictated by reason. This was considered the only way for the law to be virtuous, a requirement that was also manifested in the separation and balance of powers. As sovereignty was postulated as single and indivisible, so would be the nation that gave it soul and the State that embodied it. Although these characteristics were common to foreign paradigms of reference, in Portugal, the constitutionalization process also sought to nationalise the idea of Empire. Indeed, this had been the overriding purpose of the 1822 Constitution, and it persisted, even after the loss of Brazil, until decolonization. Then, the dream of a single nation stretching from the Minho to Timor finally came to an end.

Context-based identification of energy consumption in industrial plants

Nowadays, reducing energy consumption is one of the highest priorities and biggest challenges faced worldwide and in particular in the industrial sector. Given the increasing trend of consumption and the current economical crisis, identifying cost reductions on the most energy-intensive sectors has become one of the main concerns among companies and researchers. Particularly in industrial environments, energy consumption is affected by several factors, namely production factors(e.g. equipments), human (e.g. operators experience), environmental (e.g. temperature), among others, which influence the way of how energy is used across the plant. Therefore, several approaches for identifying consumption causes have been suggested and discussed. However, the existing methods only provide guidelines for energy consumption and have shown difficulties in explaining certain energy consumption patterns due to the lack of structure to incorporate context influence, hence are not able to track down the causes of consumption to a process level, where optimization measures can actually take place. This dissertation proposes a new approach to tackle this issue, by on-line estimation of context-based energy consumption models, which are able to map operating context to consumption patterns. Context identification is performed by regression tree algorithms. Energy consumption estimation is achieved by means of a multi-model architecture using multiple RLS algorithms, locally estimated for each operating context. Lastly, the proposed approach is applied to a real cement plant grinding circuit. Experimental results prove the viability of the overall system, regarding both automatic context identification and energy consumption estimation.

A domain specific language for domotic systems

To cope with modernity, the interesting of having a fully automated house has been increasing over the years, as technology evolves and as our lives become more stressful and overloaded. An automation system provides a way to simplify some daily tasks, allowing us to have more spare time to perform activities where we are really needed. There are some systems in this domain that try to implement these characteristics, but this kind of technology is at its early stages of evolution being that it is still far away of empowering the user with the desired control over a habitation. The reason is that the mentioned systems miss some important features such as adaptability, extension and evolution. These systems, developed from a bottom-up approach, are often tailored for programmers and domain experts, discarding most of the times the end users that remain with unfinished interfaces or products that they have difficulty to control. Moreover, complex behaviors are avoided, since they are extremely difficult to implement mostly due to the necessity of handling priorities, conflicts and device calibration. Besides, these solutions are only reachable at very high costs, yet they still have the limitation of being difficult to configure by non-technical people once in runtime operation. As a result, it is necessary to create a tool that allows the execution of several automated actions, with an interface that is easy to use but at the same time supports all the main features of this domain. It is also desirable that this tool is independent of the hardware so it can be reused, thus a Model Driven Development approach (MDD) is the ideal option, as it is a method that follows those principles. Since the automation domain has some very specific concepts, the use of models should be combined with a Domain Specific Language (DSL). With these two methods, it is possible to create a solution that is adapted to the end users, but also to domain experts and programmers due to the several levels of abstraction that can be added to diminish the complexity of use. The aim of this thesis is to design a Domain Specific Language (DSL) that uses the Model Driven Development approach (MDD), with the purpose of supporting Home Automation (HA) concepts. In this implementation, the development of simple and complex scenarios should be supported and will be one of the most important concerns. This DSL should also support other significant features in this domain, such as the ability to schedule tasks, which is something that is limited in the current existing solutions.

The brushstroke and materials of Amadeo de Souza-Cardoso combined in an authentication tool

Nowadays, authentication studies for paintings require a multidisciplinary approach, based on the contribution of visual features analysis but also on characterizations of materials and techniques. Moreover, it is important that the assessment of the authorship of a painting is supported by technical studies of a selected number of original artworks that cover the entire career of an artist. This dissertation is concerned about the work of modernist painter Amadeo de Souza-Cardoso. It is divided in three parts. In the first part, we propose a tool based on image processing that combines information obtained by brushstroke and materials analysis. The resulting tool provides qualitative and quantitative evaluation of the authorship of the paintings; the quantitative element is particularly relevant, as it could be crucial in solving authorship controversies, such as judicial disputes. The brushstroke analysis was performed by combining two algorithms for feature detection, namely Gabor filter and Scale Invariant Feature Transform. Thanks to this combination (and to the use of the Bag-of-Features model), the proposed method shows an accuracy higher than 90% in distinguishing between images of Amadeo’s paintings and images of artworks by other contemporary artists. For the molecular analysis, we implemented a semi-automatic system that uses hyperspectral imaging and elemental analysis. The system provides as output an image that depicts the mapping of the pigments present, together with the areas made using materials not coherent with Amadeo’s palette, if any. This visual output is a simple and effective way of assessing the results of the system. The tool proposed based on the combination of brushstroke and molecular information was tested in twelve paintings obtaining promising results. The second part of the thesis presents a systematic study of four selected paintings made by Amadeo in 1917. Although untitled, three of these paintings are commonly known as BRUT, Entrada and Coty; they are considered as his most successful and genuine works. The materials and techniques of these artworks have never been studied before. The paintings were studied with a multi-analytical approach using micro-Energy Dispersive X-ray Fluorescence spectroscopy, micro-Infrared and Raman Spectroscopy, micro-Spectrofluorimetry and Scanning Electron Microscopy. The characterization of Amadeo’s materials and techniques used on his last paintings, as well as the investigation of some of the conservation problems that affect these paintings, is essential to enrich the knowledge on this artist. Moreover, the study of the materials in the four paintings reveals commonalities between the paintings BRUT and Entrada. This observation is supported also by the analysis of the elements present in a photograph of a collage (conserved at the Art Library of the Calouste Gulbenkian Foundation), the only remaining evidence of a supposed maquete of these paintings. The final part of the thesis describes the application of the image processing tools developed in the first part of the thesis on a set of case studies; this experience demonstrates the potential of the tool to support painting analysis and authentication studies. The brushstroke analysis was used as additional analysis on the evaluation process of four paintings attributed to Amadeo, and the system based on hyperspectral analysis was applied on the painting dated 1917. The case studies therefore serve as a bridge between the first two parts of the dissertation.