The Evolution of Function in the Rab family of Small GTPases

Dissertation presented to obtain the PhD degree in Computational Biology.

Report of a traineeship : audit of antidepressant prescribing in Primary and Mental Care: how to address appropriateness and keep a curb on costs. A tool suitable for all contexts?

RESUMO: Este é o relatório de um estágio realizado na Autoridade de Saúde Local de Bolonha com o objectivo de desenvolver capacidades e competências na área de projectos orientados para a avaliação com base epidemiológica. As prescrições de anti-depressivos aumentaram consideravelmente em todo o mundo durante as últimas décadas. O uso cada vez maior dos agentes mais dispendiosos desempenha um papel na subida do custo dos tratamentos. A Autoridade de Saúde Local de Bolonha implementou um processo de auditoria com o objectivo de melhorar a adequação das prescrições de pacientes externos, centrando-se em dois anti-depressivos de marca ainda protegidos por patente, Escitalopram e Duloxetine. Os Departamentos de Cuidados de Saúde Primários e de Cuidados de Saúde Mental, assim como o Departamento Farmacêutico e a Unidade de Gestão Clínica, estiveram envolvidos na fase de planeamento da auditoria. O grupo da auditoria, maioritariamente composto por médicos de clínica geral e psiquiatras, reuniu e analisou provas da eficácia e segurança dos anti-depressivos. Os dados sobre as prescrições das Unidades de Cuidados de Saúde Primários e dos Centros de Saúde Mental Comunitários da Autoridade de Saúde Local (866.294 habitantes) foram comparados, em particular as taxas de consumo de Escitalopram e Duloxetine. O grupo da auditoria definiu os standards a serem abordados, os indicadores a serem avaliados e as medidas a empreender para atingir os objectivos definidos. As directrizes do NICE sobre a depressão foram escolhidas como referência. O objectivo da auditoria foi definido como evitar o Escitalopram e Duloxetine como medicamentos de primeira escolha num tratamento anti-depressivo. De modo a verificar a eficácia das medidas empreendidas foi seleccionado um indicador, consistindo numa redução de 25% das prescrições de ambos os anti-depressivos na prática clínica de pacientes externos e numa redução de 20% da variabilidade nas Unidades de Cuidados de Saúde Primários. O relatório retrospectivo pré-auditoria (Janeiro a Abril de 2012) revelou que os tratamentos com anti-depressivos para pacientes externos eram prescritos pelos médicos de clínica geral em mais de90% dos casos. As medidas da auditoria foram implementadas entre Novembro de 2012 e Maio de 2013. Algumas medidas relevantes foram integradas com a revisão da auditoria, tais como reuniões educacionais de pequena escala com os médicos de clínica geral e psiquiatras, visitas de apoio do assessor de prescrições da Autoridade de Saúde Local aos médicos de clínica geral e Centros de Saúde Mental Comunitários, panfletos para profissionais com informação retirada das directrizes clínicas do NICE, implementação de um serviço de consulta na Web para médicos de clínica geral sobre provas relativas a anti-depressivos. O relatório de feedback é aguardado em Novembro de 2013 depois de se verificar nos standards atingidos a eficácia das medidas implementadas. Foi realizada uma análise SWOT para comprovar as forças e fraquezas, as oportunidades e ameaças do processo. Como identificação de fraquezas poderá ser útil identificar estratégias relevantes para melhoria interna, para que o conhecimento das ameaças possa amortizar factores que possam ter impactos adversos que fujam ao controlo do Departamento de Saúde Mental. Uma melhor compreensão das forças e das oportunidades facilita a consecução dos objectivos estabelecidos no projecto. O primeiro, mas não o último, resultado deste processo consistiu numa maior integração entre os Cuidados de Saúde Primários e de Saúde Mental, permitindo assim que a Autoridade de Saúde Local coloque as alterações em prática.------------ABSTRACT: This is the report of a traineeship held in the Local Health Authority of Bologna with the aim to develop skills and competencies in the field of epidemiogically based evaluation oriented projects. Antidepressants prescriptions have considerably increased all over the world in the last decades. The increasing use of the most expensive agents plays a part in the rising cost of treatments. The Local Health Authority of Bologna has implemented an audit process aimed at improving the appropriateness of outpatient prescriptions focusing on the two branded antidepressants still protected by patent, Escitalopram and Duloxetine. The Primary Care and the Mental Health Care Departments, as well as the Pharmaceutical Department and the Clinical Governance Unit, were involved in the planning phase of the audit. The audit group, mainly composed of general practitioners and psychiatrists, collected and analyzed scientific evidence on effectiveness and safety of antidepressants. Data on prescriptions of Primary Care Units and Community Mental Health Centers of the Local Health Authority (866.294 inhabitants) were compared, in particular consumption rates of Escitalopram and Duloxetine. The audit group defined the standards to be addressed, the indicators to be evaluated and the actions aimed at reaching the defined goals. NICE guidelines on depression were chosen as reference. The aim of the audit was settled as avoiding Escitalopram and Duloxetine as first choice drugs starting an AD treatment. In order to check the efficacy of the actions undertaken an indicator was selected, consisting in a reduction of 25% of prescriptions of both ADs in outpatient practice and in a 20% reduction of To develop skills and competencies across Primary Care Units. The pre-audit retrospective report (January-April 2012) showed that outpatient antidepressant treatments were prescribed by GPs in over 90% of cases. Audit actions were implemented between November 2012 and May 2013. Some relevant actions have been integrated with the audit review, such as small-scale educational meetings with GPs and psychiatrists, outreach visits of the LHA prescribing adviser to GPs and CMHCs,leaflets for professionals with information extracted from NICE clinical guidelines, implementation of a web consultation service for GPs about evidence on antidepressants. The feedback report is expected in November 2013 after checking through the standards attained the effectiveness of actions implemented. A SWOT Analysis was carried out to evidence the strengths and weaknesses, opportunities and threats of the process. As identification of weaknesses may be useful to identify relevant strategies for internal improvement, so the knowledge of threats can amortize factors that may have adverse impacts beyond the control of the Mental Health Department. Better understanding of the strengths and the opportunities facilitates the achievement of the goals set in the project. The first and not least upshot of this process has consisted in further integration between Primary and Mental Health Care, thus enabling the LHA to put the change into practice.

Application of NMR RDC’s, relaxation and self-diffusion for the study of dynamic processes of small molecules in solution

Spin-lattice Relaxation, self-Diffusion coefficients and Residual Dipolar Couplings (RDC’s) are the basis of well established Nuclear Magnetic Resonance techniques for the physicochemical study of small molecules (typically organic compounds and natural products with MW < 1000 Da), as they proved to be a powerful and complementary source of information about structural dynamic processes in solution. The work developed in this thesis consists in the application of the earlier-mentioned NMR techniques to explore, analyze and systematize patterns of the molecular dynamic behavior of selected small molecules in particular experimental conditions. Two systems were chosen to investigate molecular dynamic behavior by these techniques: the dynamics of ion-pair formation and ion interaction in ionic liquids (IL) and the dynamics of molecular reorientation when molecules are placed in oriented phases (alignment media). The application of NMR spin-lattice relaxation and self-diffusion measurements was applied to study the rotational and translational molecular dynamics of the IL: 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4]. The study of the cation-anion dynamics in neat and IL-water mixtures was systematically investigated by a combination of multinuclear NMR relaxation techniques with diffusion data (using by H1, C13 and F19 NMR spectroscopy). Spin-lattice relaxation time (T1), self-diffusion coefficients and nuclear Overhauser effect experiments were combined to determine the conditions that favor the formation of long lived [BMIM][BF4] ion-pairs in water. For this purpose and using the self-diffusion coefficients of cation and anion as a probe, different IL-water compositions were screened (from neat IL to infinite dilution) to find the conditions where both cation and anion present equal diffusion coefficients (8% water fraction at 25 ºC). This condition as well as the neat IL and the infinite dilution were then further studied by 13C NMR relaxation in order to determine correlation times (c) for the molecular reorientational motion using a mathematical iterative procedure and experimental data obtained in a temperature range between 273 and 353 K. The behavior of self-diffusion and relaxation data obtained in our experiments point at the combining parameters of molar fraction 8 % and temperature 298 K as the most favorable condition for the formation of long lived ion-pairs. When molecules are subjected to soft anisotropic motion by being placed in some special media, Residual Dipolar Couplings (RDCs), can be measured, because of the partial alignment induced by this media. RDCs are emerging as a powerful routine tool employed in conformational analysis, as it complements and even outperforms the approaches based on the classical NMR NOE or J3 couplings. In this work, three different alignment media have been characterized and evaluated in terms of integrity using 2H and 1H 1D-NMR spectroscopy, namely the stretched and compressed gel PMMA, and the lyotropic liquid crystals CpCl/n-hexanol/brine and cromolyn/water. The influence that different media and degrees of alignment have on the dynamic properties of several molecules was explored. Different sized sugars were used and their self-diffusion was determined as well as conformation features using RDCs. The results obtained indicate that no influence is felt by the small molecules diffusion and conformational features studied within the alignment degree range studied, which was the 3, 5 and 6 % CpCl/n-hexanol/brine for diffusion, and 5 and 7.5 % CpCl/n-hexanol/brine for conformation. It was also possible to determine that the small molecules diffusion verified in the alignment media presented close values to the ones observed in water, reinforcing the idea of no conditioning of molecular properties in such media.

A solution for estimates in software development projects

The Corporate world is becoming more and more competitive. This leads organisations to adapt to this reality, by adopting more efficient processes, which result in a decrease in cost as well as an increase of product quality. One of these processes consists in making proposals to clients, which necessarily include a cost estimation of the project. This estimation is the main focus of this project. In particular, one of the goals is to evaluate which estimation models fit the Altran Portugal software factory the most, the organization where the fieldwork of this thesis will be carried out. There is no broad agreement about which is the type of estimation model more suitable to be used in software projects. Concerning contexts where there is plenty of objective information available to be used as input to an estimation model, model-based methods usually yield better results than the expert judgment. However, what happens more frequently is not having this volume and quality of information, which has a negative impact in the model-based methods performance, favouring the usage of expert judgement. In practice, most organisations use expert judgment, making themselves dependent on the expert. A common problem found is that the performance of the expert’s estimation depends on his previous experience with identical projects. This means that when new types of projects arrive, the estimation will have an unpredictable accuracy. Moreover, different experts will make different estimates, based on their individual experience. As a result, the company will not directly attain a continuous growing knowledge about how the estimate should be carried. Estimation models depend on the input information collected from previous projects, the size of the project database and the resources available. Altran currently does not store the input information from previous projects in a systematic way. It has a small project database and a team of experts. Our work is targeted to companies that operate in similar contexts. We start by gathering information from the organisation in order to identify which estimation approaches can be applied considering the organization’s context. A gap analysis is used to understand what type of information the company would have to collect so that other approaches would become available. Based on our assessment, in our opinion, expert judgment is the most adequate approach for Altran Portugal, in the current context. We analysed past development and evolution projects from Altran Portugal and assessed their estimates. This resulted in the identification of common estimation deviations, errors, and patterns, which lead to the proposal of metrics to help estimators produce estimates leveraging past projects quantitative and qualitative information in a convenient way. This dissertation aims to contribute to more realistic estimates, by identifying shortcomings in the current estimation process and supporting the self-improvement of the process, by gathering as much relevant information as possible from each finished project.

The role of qualitative data and systems thinking in addressing service decline in market towns

Retail services are a main contributor to municipal budget and are an activity that affects perceived quality-of-life, especially for those with mobility difficulties (e.g. the elderly, low income citizens). However, there is evidence of a decline in some of the services market towns provide to their citizens. In market towns, this decline has been reported all over the western world, from North America to Australia. The aim of this research was to understand retail decline and enlighten on some ways of addressing this decline, using a case study, Thornbury, a small town in the Southwest of England. Data collected came from two participatory approaches: photo-surveys and multicriteria mapping. The interpretation of data came from using participants as analysts, but also, using systems thinking (systems diagramming and social trap theory) for theory building. This research moves away from mainstream economic and town planning perspectives by making use of different methods and concepts used in anthropology and visual sociology (photo-surveys), decision-making and ecological economics (multicriteria mapping and social trap theory). In sum, this research has experimented with different methods, out of their context, to analyse retail decline in a small town. This research developed a conceptual model for retail decline and identified the existence of conflicting goals and interests and their implications for retail decline, as well as causes for these. Most of the potential causes have had little attention in the literature. This research also identified that some of the measures commonly used for dealing with retail decline may be contributing to the causes of retail decline itself. Additionally, this research reviewed some of the measures that can be used to deal with retail decline, implications for policy-making and reflected on the use of the data collection and analysis methods in the context of small to medium towns.

Support in decision-making under uncertainty: a project risk assessment tool development and supplementary advances

A foremost dispute that persists on the contemporary world’s agenda is change. The on-going social/technological/economic changes create a competitive and challenging environment for companies to endure. To benefit from these changes, world economies partially depend on emerging Small and Medium Enterprises (SMEs) and their adaptability skills, and subsequently the development of an integrated capability to innovate has become the prime strategy for most of SMEs to subsist and grow. However, innovation and change are always somewhat bonded to an inherent risk development, which subsequently brings on the necessity of a revision of risk management approaches in innovative processes, whose importance SMEs tend to disregard. Additionally, little efforts have been made to improve and create empirical models, metrics and tools to assist SMEs managing latent risks in their innovative projects. This work seeks to present and discuss a solution to support SMEs in engaging on systematic risk management practices, which consists on an integrated risk assessment and response support web-based tool - Spotrisk® - designed for SMEs. On the other hand, an inherent subjectivity is linked with risk management and identification processes, due to uncertainty trait of its nature, for each individual perceives situations according to his own idiosyncrasy, which brings complications in normalizing risk profiles and procedures. This essay aims to bring insights concerning the support in decision-making processes under uncertainty, by addressing issues related with the risk behavior character among individuals. To address such issues, subjects of neuroscience or psychology are explored and models to identify such character are proposed, as well as models to improve presented tool. This work attempts to go beyond the restrictive aim of endeavoring on technical improvement dissertation, and in embraces an exploratory conceptualization concerning micro, small and medium businesses’ traits regarding risk characters and project risk assessment tools.

A model to screen and improve business potential of micro and small enterprises in developing countries: Evidence from the Island of Mozambique

Programmes supporting micro and small enterprises in developing countries have been showing that capital is not enough to allow business success: survival and growth. Literature does not provide comprehensive and practical tool to support business development in this context, but allowed the collection of forty-nine success variables that were studied in a sample of successful and unsuccessful businesses in the Island of Mozambique to discover what were the key factors affecting those businesses’ performance. Empirical data gave the insights for the development of a model to screen and improve business potential of micro and small enterprises in this context.

A regulação da atividade espacial

The technological evolution of the past fifty years has provided Humanity the contact with the last frontier of knowledge: space. An unknown world, explored by a small group of nations, which has become crucial to understanding who we are and where we come from. Space assets in recent years have opened the way to a digital society, shaped by the rapid exchange of information, whose means are mostly in space. A place of fascination and curiosity, restricted to a few people in these decades, which may soon be changing. This essay addresses some legal issues concerning the private exploration of space. Liability on space tourism is the core of this investigation, focusing on the comprehension of the international legal framework and its connection with the states national law. In particular, the study of the main international treaties, the U.S. legal system of space law and the developments in Europe are the fundamental tools of the current analysis, not forgetting the point of view of a possible international harmonization. Besides the needed theoretical context on the evolution of space law and a brief approach of the technical matters of the current aerospace engineering, the goal is to examine the characteristics of international space law and its relation with the new private actors, responsible for providing suborbital flights, operating in a near future. Within these circumstances, given the economic potential of the growing private space industry, it is essential to discuss the legal aspects of a spatial regulation. Being liability, undoubtedly, the emerging issue in the legal debate on this topic, it is important to safeguard the interests of the operators, States and, above all, future space tourists.

The importance of succession planning in family-owned Small and Medium Enterprises in Portugal

This work project addresses the importance of succession planning in family-owned Small and Medium Enterprises (SMEs). This is directly related with Human Resources Management (HRM) given that there is an HRM long term vision in order for the succession to be planned on time and benefit the companies. This study focused on SMEs since these are the entities that have a minor focus on HRM practices. A total of 22 in-depth interviews were conducted and analyzed. Selected SMEs owners/managers and successors/antecessors were interviewed with the purpose of acquiring more insight on the level of succession planning, using a qualitative methodology from which the process of succession was derived. This study unveils that the first step in this process is related to the definition of criteria to be a good successor, followed by the choice of possible successors, being the children the natural successors, but also considering other potential ones, and finally some considerations on the future of these companies.

Differences and reasons in IASB accounting standards between small and large companies

This paper studies the main differences in accounting standards of the International Accounting Standards Board (IASB) between small and large companies, materialised in the dissimilarities between the International Financial Reporting Standard for Small and Medium-sized Entities and the full International Financial Reporting Standards, as of 2010. Another element of this project is the analysis of the reasons behind the differences between the two aforementioned frameworks, which intends to expose the rationale and the mindset that led to an adaptation of the full standards in a stand-alone document designed for small companies.

The determinants of mutual fund performance: A cross-country study

We use a new data set to study the determinants of the performance of open–end actively managed equity mutual funds in 27 countries. We find that mutual funds underperform the market overall. The results show important differences in the determinants of fund performance in the USA and elsewhere in the world. The US evidence of diminishing returns to scale is not a universal truth as the performance of funds located outside the USA and funds that invest overseas is not negatively affected by scale. Our findings suggest that the adverse scale effects in the USA are related to liquidity constraints faced by funds that, by virtue of their style, have to invest in small and domestic stocks. Country characteristics also explain fund performance. Funds located in countries with liquid stock markets and strong legal institutions display better performance.

The flow-performance relationship around the world

We use a new dataset to study how mutual fund flows depend on past performance across 28 countries. We show that there are marked differences in the flow-performance relationship across countries, suggesting that US findings concerning its shape do not apply universally. We find that mutual fund investors sell losers more and buy winners less in more developed countries. This is because investors in more developed countries are more sophisticated and face lower costs of participating in the mutual fund industry. Higher country-level convexity is positively associated with higher levels of risk taking by fund managers.