The simple economics of risk-sharing agreements between the NHS and the pharmaceutical industry

The Janssen-Cilag proposal for a risk-sharing agreement regarding bortezomib received a welcome signal from NICE. The Office of Fair Trading report included risk-sharing agreements as an available tool for the National Health Service. Nonetheless, recent discussions have somewhat neglected the economic fundamentals underlying risk-sharing agreements. We argue here that risk-sharing agreements, although attractive due to the principle of paying by results, also entail risks. Too many patients may be put under treatment even with a low success probability. Prices are likely to be adjusted upward, in anticipation of future risk-sharing agreements between the pharmaceutical company and the third-party payer. An available instrument is a verification cost per patient treated, which allows obtaining the first-best allocation of patients to the new treatment, under the risk sharing agreement. Overall, the welfare effects of risk-sharing agreements are ambiguous, and care must be taken with their use.

A comparative review of risk based portfolio allocations: An empirical study throughout rising yields

Since the financial crisis, risk based portfolio allocations have gained a great deal in popularity. This increase in popularity is primarily due to the fact that they make no assumptions as to the expected return of the assets in the portfolio. These portfolios implicitly put risk management at the heart of asset allocation and thus their recent appeal. This paper will serve as a comparison of four well-known risk based portfolio allocation methods; minimum variance, maximum diversification, inverse volatility and equally weighted risk contribution. Empirical backtests will be performed throughout rising interest rate periods from 1953 to 2015. Additionally, I will compare these portfolios to more simple allocation methods, such as equally weighted and a 60/40 asset-allocation mix. This paper will help to answer the question if these portfolios can survive in a rising interest rate environment.

Understanding the internet banking adoption by Portuguese customers - a unified theory of acceptance and use of technology and perceived risk application.

Trabalho de Projeto apresentado como requisito parcial para obtenção do grau de Mestre em Estatística e Gestão de Informação

Development of web services to help risk management of construction projects

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia Electrotécnica e de Computadores

Determinants of mother-baby relationship evaluated during pregnancy

ABSTRACT Background Mental health promotion is supported by a strong body of knowledge and is a matter of public health with the potential of a large impact on society. Mental health promotion programs should be implemented as soon as possible in life, preferably starting during pregnancy. Programs should focus on malleable determinants, introducing strategies to reduce risk factors or their impact on mother and child, and also on strengthening protective factors to increase resilience. The ambition of early detecting risk situations requires the development and use of tools to assess risk, and the creation of a responsive network of services based in primary health care, especially maternal consultation during pregnancy and the first months of the born child. The number of risk factors and the way they interact and are buffered by protective factors are relevant for the final impact. Maternal-fetal attachment (MFA) is not yet a totally understood and well operationalized concept. Methodological problems limit the comparison of data as many studies used small size samples, had an exploratory character or used different selection criteria and different measures. There is still a lack of studies in high risk populations evaluating the consequences of a weak MFA. Instead, the available studies are not very conclusive, but suggest that social support, anxiety and depression, self-esteem and self-control and sense of coherence are correlated with MFA. MFA is also correlated with health practices during pregnancy, that influence pregnancy and baby outcomes. MFA seems a relevant concept for the future mother baby interaction, but more studies are needed to clarify the concept and its operationalization. Attachment is a strong scientific concept with multiple implications for future child development, personality and relationship with others. Secure attachment is considered an essential basis of good mental health, and promoting mother-baby interaction offers an excellent opportunity to intervention programmes targeted at enhancing mental health and well-being. Understanding the process of attachment and intervening to improve attachment requires a comprehension of more proximal factors, but also a broader approach that assesses the impact of more distal social conditions on attachment and how this social impact is mediated by family functioning and mother-baby interaction. Finally, it is essential to understand how this knowledge could be translated in effective mental health promoting interventions and measures that could reach large populations of pregnant mothers and families. Strengthening emotional availability (EA) seems to be a relevant approach to improve the mother-baby relationship. In this review we have offered evidence suggesting a range of determinants of mother-infant relationship, including age, marital relationship, social disadvantages, migration, parental psychiatric disorders and the situations of abuse or neglect. Based on this theoretical background we constructed a theoretical model that included proximal and distal factors, risk and protective factors, including variables related to the mother, the father, their social support and mother baby interaction from early pregnancy until six months after birth. We selected the Antenatal Psychosocial Health Assessment (ALPHA) for use as an instrument to detect psychosocial risk during pregnancy. Method Ninety two pregnant women were recruited from the Maternal Health Consultation in Primary Health Care (PHC) at Amadora. They had three moments of assessment: at T1 (until 12 weeks of pregnancy) they filed out a questionnaire that included socio-demographic data, ALPHA, Edinburgh post-natal Depression Scale (EDPS), General Health Questionnaire (GHQ) and Sense of Coherence (SOC); at T2 (after the 20th weeks of pregnancy) they answered EDPS, SOC and MFA Scale (MFAS), and finally at T3 (6 months after birth), they repeated EDPS and SOC, and their interaction with their babies was videotaped and later evaluated using EA Scales. A statistical analysis has been done using descriptive statistics, correlation analysis, univariate logistic regression and multiple linear regression. Results The study has increased our knowledge on this particular population living in a multicultural, suburb community. It allow us to identify specific groups with a higher level of psychosocial risk, such as single or divorced women, young couples, mothers with a low level of education and those who are depressed or have a low SOC. The hypothesis that psychosocial risk is directly correlated with MFAS and that MFA is directly correlated with EA was not confirmed, neither the correlation between prenatal psychosocial risk and mother-baby EA. The study identified depression as a relevant risk factor in pregnancy and its higher prevalence in single or divorced women, immigrants and in those who have a higher global psychosocial risk. Depressed women have a poor MFA, and a lower structuring capacity and a higher hostility to their babies. In average, depression seems to reduce among pregnant women in the second part of their pregnancy. The children of immigrant mothers show a lower level of responsiveness to their mothers what could be transmitted through depression, as immigrant mothers have a higher risk of depression in the beginning of pregnancy and six months after birth. Young mothers have a low MFA and are more intrusive. Women who have a higher level of education are more sensitive and their babies showed to be more responsive. Women who are or have been submitted to abuse were found to have a higher level of MFA but their babies are less responsive to them. The study highlights the relevance of SOC as a potential protective factor while it is strongly and negatively related with a wide range of risk factors and mental health outcomes especially depression before, during and after pregnancy. Conclusions ALPHA proved to be a valid, feasible and reliable instrument to Primary Health Care (PHC) that can be used as a total sum score. We could not prove the association between psychosocial risk factors and MFA, neither between MFA and EA, or between psychosocial risk and EA. Depression and SOC seems to have a clear and opposite relevance on this process. Pregnancy can be considered as a maturational process and an opportunity to change, where adaptation processes occur, buffering risk, decreasing depression and increasing SOC. Further research is necessary to better understand interactions between variables and also to clarify a better operationalization of MFA. We recommend the use of ALPHA, SOC and EDPS in early pregnancy as a way of identifying more vulnerable women that will require additional interventions and support in order to decrease risk. At political level we recommend the reinforcement of Immigrant integration and the increment of education in women. We recommend more focus in health care and public health in mental health condition and psychosocial risk of specific groups at high risk. In PHC special attention should be paid to pregnant women who are single or divorced, very young, low educated and to immigrant mothers. This study provides the basis for an intervention programme for this population, that aims to reduce broad spectrum risk factors and to promote Mental Health in women who become pregnant. Health and mental health policies should facilitate the implementation of the suggested measures.

Enhancement of an implemented rating model and impact on existing risk management processes: A hands-on approach from financial supplier risk management within the automotive industry

The purpose of this paper is to conduct a methodical drawback analysis of a financial supplier risk management approach which is currently implemented in the automotive industry. Based on identified methodical flaws, the risk assessment model is further developed by introducing a malus system which incorporates hidden risks into the model and by revising the derivation of the most central risk measure in the current model. Both methodical changes lead to significant enhancements in terms of risk assessment accuracy, supplier identification and workload efficiency.

Anemia de células falciformes na idade pediátrica : contribuição para o estudo das suas principais complicações e indicadores de prognóstico

RESMO: Introdução: A anemia de células falciformes doença hereditária, com repercussão multi-orgânica, tem grande variabilidade na sua expressão clínica. Daí o interesse do estudo de indicadores de prognóstico. A investigação realizada foi precedida de um resumo histórico incidindo sobre a compreensão de aspectos fundamentais da doença ao longo dos tempos. Na primeira parte do estudo e após revisão bibliográfica, foram referidos dados da fisiopatologia como base para os estudos que integram a presente dissertação. Abordou-se o estado da arte relativamente às complicações, aos indicadores de prognóstico e à terapêutica utilizada. Objectivos: Constituíram objectivos deste estudo realizado numa amostra populacional representativa: identificar as lesões a nível dos sistemas cardio-respiratório e nervoso central, avaliando-se as respectivas repercussões; avaliar a presença de indicadores de prognóstico entre as variáveis seleccionadas; estudar a eficácia e toxicidade da HU nos doentes com as formas graves da ACF. Para a prossecução destes objectivos foram delineados para além do estudo global três estudos específicos: Estudo 1- repercussão no sistema cardio-respiratório; Estudo 2- repercussão no sistema nervoso central; Estudo 3- terapêutica com hidroxiureia. Doentes e métodos: Procedeu-se a um estudo prospectivo e multi-institucional durante um período de três anos tendo-se seleccionado para a amostra, e de acordo com critérios pré-definidos, 30 doentes com ACF na fase estável da doença, com idades compreendidas entre os sete e os 18 anos, todos de origem africana à excepção de um caucasiano. O diagnóstico baseou-se em técnicas de electroforese e estudo molecular que definiu o genotipo da doença e a presença da delecção da -talassémia assim como os haplotipos da amostra populacional. Foram utilizadas diferentes metodologias para avaliar a existência de lesão pulmonar e cerebral. Através do estudo estatístico foram seleccionadas diversas variáveis como hipotéticos indicadores de prognóstico. Estudo 1. Para determinar a existência de lesão a nível pulmonar usaram-se duas metodologias diferentes, a avaliação da função pulmonar com estudo da saturação da Hb em O2 no sangue arterial e a tomografia computadorizada de alta resolução. Estudou-se também a possível disfunção cardíaca como repercussão da lesão pulmonar, através do ecocardiograma, e os indicadores de prognóstico com significado estatístico para a lesão encontrada. Estudo 2. O desenho deste estudo foi sobreponível ao anterior, mas com metodologia adequada para o SNC. Procedeu-se ao estudo das lesões cerebrais por meio de exames imagiológicos, (RMN-CE e DTC) e de testes psicológicos. Correlacionaram-se as três metodologias utilizadas e a importância de cada uma para a decisão de atitudes terapêuticas preventivas. Estudo 3. Consistiu num estudo aberto prospectivo não controlado com nove crianças e adolescentes com formas graves de ACF, com o objectivo de avaliar a eficácia da terapêutica com hidroxiureia, durante um período de 24 meses. Todos os doentes completaram no mínimo 15 meses de terapêutica, com uma dose final média de 194 mg/K/dia. Resultados globais: Durante o período anterior à investigação caracterizou-se a amostra populacional estudada quanto ao fenotipo genético, clínico e hematológico de acordo com os critérios utilizados por outros investigadores. Verificou-se: predomínio do haplotipo Bantu na forma homozigótica em 53% dos doentes; número total de EVO ≥3/ano em 87,5% dos doentes; crises de sequestração em 18,75%; dactilites no primeiro ano de vida em 31,2%; quadro de sépsis grave apenas num doente; crises de hiper-hemólise em 50%; e STA em 59,38% dos doentes. Quanto ao fenotipo hematológico evidenciaram-se como factores de risco reticulocitose (13,1x103/l) e hiperbilirrubinémia (2,5 mg/dl) e como factores de bom prognóstico a presença de delecção de um gene da -talassémia em 46,9% dos doentes e valor médio de Hb 8,1 g/dl. Resultados dos estudos parcelares: Estudo 1. Deste estudo infere-se que a DPR ligeira foi diagnosticada em 70% dos doentes, uma vez que as alterações da difusão não foram estatisticamente significativas, o estudo dos gases no sangue não evidenciaram resultados anormais e a TCAR evidenciou alterações em 43,3% dos doentes. Apenas num doente se verificou doença pulmonar obstrutiva relacionada com maior número da STA.O estudo da disfunção cardíaca encontrada em 86,7% dos doentes não reflecte a repercussão da DPR a nível cardíaco, podendo estar associada às alterações fisiopatológicas da própria anemia crónica. Encontraram-se indicadores de prognóstico hematológicos e clínicos. Entre os primeiros, valores de Hb ≥8,5 g/dl e de HbF ≥13% foram considerados indicadores de bom prognóstico para a lesão pulmonar. Em relação aos parâmetros clínicos, as STA não foram consideradas indicadoras de prognóstico para a DPR ao contrário do que se verificou com o número de EVO. Pela análise dos parâmetros genéticos e socio-económicos provou-se a ausência de relação estatisticamente significativa com lesão pulmonar. Estudo 2. Pela RMN-CE foram diagnosticados ES em 33,3% com uma localização preferencial na substância branca profunda em 26,6% dos doentes. Relativamente aos parâmetros hematológicos seleccionados, o valor médio da HbF 8,6% constituíu um indicador de bom prognóstico para o aparecimento de ES, enquanto o valor médio de leucócitos 12.39x103/μl foi considerado um indicador de mau prognóstico. No estudo do DTC apenas um doente apresentou aumento da velocidade do fluxo cerebral na ACM igual a 196 cm/segundos, associado a vasculopatia grave. Os testes psicológicos alterados em 80% dos doentes mostraram ser o método mais sensível para detectar alterações do neurodesenvolvimento, mas sem correlação com os ES em 10% dos doentes. Realça-se a baixa percentagem de DTC patológicos encontrados neste estudo em relação ao número elevado de ES e de testes psicológicos alterados, não se verificando concordância entre os três exames. Dos indicadores de prognóstico estudados a -talassémia foi considerada um factor de protecção para o coeficiente de inteligência da escala de Wechsler. Em relação a parâmetros clínicos estudados os doentes com maior número de EVO, tem em média valores inferiores nos testes psicológicos. Estudo 3. Neste estudo verificou-se que o valor médio da HbF aumentou significativamente de 7,0±4% para 13,7±5,3% (p=0,028) ao fim de 15 meses de terapêutica com hidroxiureia. Clinicamente todos os doentes responderam significativamente com uma redução de 80% no número de EVO, 69% no número de internamentos, 76% no número de dias de hospitalização e 67% no número de transfusões. Deste modo comprovou-se não só a eficácia desta terapêutica neste grupo pediátrico como também a falta de efeitos secundários significativos. Considera-se a necessidade de estudos mais prolongados e em grande séries, para com segurança se usar a HU antes que a lesão orgânica se estabeleça, portanto logo nos primeiros anos de vida. Conclusão: Na amostra populacional estudada foram evidenciadas lesões pulmonares e cerebrais na grande maioria dos doentes que condicionaram a sua qualidade de vida. Foram identificados indicadores de prognóstico que poderão eventualmente ditar medidas terapêuticas precoces com o objectivo de diminuir a morbilidade e a mortalidade neste grupo etário. Demonstrou-se que a terapêutica com a HU foi eficaz e bem tolerada----------ABSTRACT: Background: Sickle cell anemia (SCA), a hereditary disease characterized by pain and lifetime multi-organic lesion, is a challenge for all that work with carriers of this disease. The clinical expression variability of SCA is a constant reality and a problem to be solved in the current world of investigation, for which the knowledge of prognostic indicators responsible for the different aspects of clinical evolution diversity wiil be an added value. The study is preceded by a historical summary of the most important factors in the evolution of SCA, which are in themselves, an incentive for future research. In the first part of the study, after an extensive bibliographical revision, physiopathology data is referred to in general and specifically regarding the target organs, that constituted the base for the studies presented in the dissertation. The state of the art for the complications to be studied, the choice of prognostic indicators and the therapeutics application, were approached for the renewed interest in the theme. Aims: In regard to the investigation, the objective was to study the lesions in the most affected organs of a chosen pediatric group, to investigate prognostic indicators for lung and cerebral lesions and to evaluate the protective effect of hydroxyurea in children with severe outcomes. Patients and methods: A prospective and multi-institutional study was carried out during a three-year period, February 1998 to March 2001, with children and adolescents followed up at a Immunohematology Outpatient Clinic of Dona Estefânia's Hospital, Lisbon. Based in predefined criteria, 30 children with SCA were selected in a stable phase of the disease, aged from seven to 18 years old, all of whom were of African origin with exception of one who was Caucasian. The diagnosis was based on electrophoresis techniques and molecular study that allowed to define the genotype, the presence of deletional alpha-thalassemia as well as haplotypes in the population. Different methodologies were used to evaluate the existence of lung and cerebral lesion. Statistical study of the different variables selected the prognostic indicators. In Study 1, to determine the existence of lung lesion two different methodologies were used: pulmonar function study with arterial blood gases determination; and high resolution computerized tomography. Heart dysfunction as a repercussion of lung lesion was also studied through echocardiography, and prognostic indicators were statistically significant for lesions found. The design of Study 2 was similar to Study 1, but with the appropriate methodology for CNS. After neurological examination, which was normal in all patients (control group), cerebral lesions were studied with imagiologic exams (MRN-CE and TCD) and psychological tests. These three methodologies were correlated and the importance of each one in the decision of the therapeutic profilactic attitudes. Study 3 consisted of a controlled prospective open study in children with severe forms of SCA, with the aim of the evaluating therapeutic effectiveness of hydroxyurea, during a period of 24 months. Results: In the global overall study preceding the Studies 1,2 and 3, there were a prevalence of haplotype Bantu (53%) and other risk factors, namely the number of VOC (87,5%), sequestration crisis (18,75%), dactilytis in first year of life(31,2%), hyperhemolysis crisis (50%) and ATC in more than half of the patients (59,38%). This group of bad prognostic indicators, associated with the population of the lower class according to the Graffar scale, demonstrates the importance of primary health care services, information provided to the children and their relatives, as well as the interest in prophylactic therapeutics, specific screening and prenatal diagnosis. Study 1. It was evident from this study that slight RPD was diagnosed in 70% of the patients, because alterations of the diffusion had no statistical significance and arterial blood gases determinations were normal. Only one patient had restrictive lung disease related with numerous ACS. However ACS was not considered a prognostic indicator for RPD, contrary to the number of EVO. HRTC revealed discreet fibrotic lines that could be related with slight RPD, but the lack of correlation of these two exams (33%) supports the value of lung function tests for precocious diagnosis of RPD. Heart dysfunction was found in 86,7% of patients, does not reflect the repercussion of RPD, but with the physiopathology of chronic anemia. Hematologic and clinical prognostic indicators were found. Good prognostic indicators for the non-evolution of RPD with average Hb values of ≥ 8,5 g/dl and average HbF values of ≥13%, respectively. The genetic and social-economic factors had no statistical significance; nevertheless, they were more prevalent among Bantu haplotype (53,3%) in patients with RPD. Study 2. RMN-CE detected SI in 33,3% of the patients, with preferential location in deep white substance in 26,6% and in front lobe in 20%. This distribution can be related to structural aspects of the brain and with the high sensibility of this organ to hypoxia. From the hematological parameters selected, average HbF value 8,6% and average leucocyte count 12.39x103/μl were prognostic indicators with different meaning to SI. The increase in the total bilirubin related to hyperhemolysis clinically explains the genesis of SI In the TCD study, only one patient had increased cerebral flow speed >196 cm/sec in CMA, which corresponded to serious vasculopathy in AngioMR. This patient never present previously neurological symptoms and had several hyperhemolysis crisis and VOC as risk factors. Low percentage of pathological TCD in this study, in relation to the high number of SI and altered tests, although without correlation among the three exams, is probably attributed to factors related to the methodology, aspects of cerebral physiopathology or perhaps a sign of good prognostic if the duration of study had not been so short. TCD should be used as a screening method in the age groups with higher risk of AVC and should never be considered separately in prophylactic therapeutics indication. Psychological tests were the most sensitive method to detect neurodevelopment impairment; in 80% of patients the neuropsychologics tests were altered, but without correlation with SI (10%). Since SI can become evident during the first two years of life and develop with time, the first psychological tests should be carried out between 3 and 5 years of age to timely be referred to special education and stimulation programs. Prognostic indicators to psychological tests were also found: alpha-thalassemia was found to be a protection factor of the IQ, just as other hematologic factors (hematocrit, MGCV and erythrocytes count). In relation to clinical parameters, although without statistical significance, patients with larger number of VOC had average lower scores versus the average in tests, except in TP. Results from different studies were conclusive as to the type of lesion found and the importance of prognostic indicators. Study 3. All the patients completed a minimum of 15 months therapeutic treatment with the final average daily dose of 19±4 mg/kg/day. The average value of the fetal hemoglobin increased significantly from 7,0±3,9% to 13,7±5,3% (p=0.028). The HbF average values increased from 6% to 15% after 15 months of therapeutic treatment. Clinically there was a reduction of 80% in the number of VOE , 69% in the number of hospitalization, 76% in the number of days of hospitalization and 67% in the number of transfusions. Once again the effectiveness of this treatment in this pediatric group, as well as the lack of any significant secondary effects, was evident. The study confirms the need for further detailed research in order to safely effect the appropriate treatment prior to the development of organic lesions, which ideally should be in the first year of life. Conclusions: These results allow us to clarify the importance of either pulmonary lesions or either nervous central system impairment among patients, children and adolescents, with sickle cell anemia. These lesions were demonstrated in most of the patients studied compromising their quality of life and the mortality. The treatment with HU is proved to be effective and having low toxicity.

Aborto recorrente das causas na mulher às consequências para o casal

RESUMO: O aborto recorrente (AR) é um evento extremamente traumático com grande impacto na vida dos casais. Apesar de avanços significativos verificados na investigação médica, cerca de 50% dos casos continua sem uma causa identificada. Alguns aspectos como a caracterização inadequada das doentes e das perdas gestacionais, assim como diferentes metodologias utilizadas no seu estudo, têm influenciado a prevalência de alguns dos factores causais e dificultado a compreensão do AR. Da mesma forma, pouco se sabe sobre as diferenças de género na vivência psicológica do aborto recorrente e das suas eventuais repercussões para o relacionamento do casal, centrando-se os poucos estudos existentes preferencialmente na mulher. Por esta razão, o objectivo desta tese foi a caracterização dos factores médicos associados ao AR e das consequências psicológicas desta entidade, contribuindo para promover estratégias clínicas baseadas na evidência específica. Na primeira parte desta tese (capítulos 1 e 2), após uma breve introdução geral e através de uma revisão da literatura, efectua-se uma reflexão sobre o tema, abordando a epidemiologia do aborto recorrente, os factores médicos e os aspectos psicológicos associados. Nos capítulos 3 e 4 descrevemos três estudos efectuados em mulheres portuguesas com aborto recorrente. O primeiro estudo teve por objectivo caracterizar os factores médicos e determinar o padrão da perda recorrente de gravidez, numa coorte de mulheres submetidas a um protocolo de diagnóstico definido. As participantes foram agrupadas de acordo com a paridade (AR primário ou secundário) e a idade gestacional das perdas (embrionárias ou fetais). As anomalias da cavidade uterina, a SAAF e as translocações equilibradas parentais foram os factores mais prevalentes. 15,6% das participantes eram obesas. Em 55,5% dos casos não foi identificado nenhum factor. A história obstétrica materna influenciou significativamente os resultados encontrados: os factores anatómicos e a SAAF foram mais prevalentes em nulíparas e as perdas inexplicadas foram mais frequentes em mulheres com AR secundário. Assim, os nossos dados reforçam os resultados de pesquisas anteriores sobre a importância da obesidade, da síndrome de anticorpos antifosfolípidos e das anomalias uterinas estruturais como factores associados ao AR e mostram que os a paridade é um moderador da importância desses factores. Capítulo 6 94 A ausência de resultados consensuais na literatura sobre a etiologia do AR condiciona a pesquisa sistemática de alguns factores, envolvendo exames dispendiosos, muitas vezes sem que exista evidência que suporte a sua associação com esta entidade. A trombofilia hereditária é uma das condições frequentemente investigadas nestas doentes. O nosso segundo estudo pretende contribuir para clarificar o papel de duas mutações (factor V Leiden e protrombina G20210A) na perda recorrente de gravidez e esclarecer a necessidade do seu rastreio nestas situações. Foi efectuada a pesquisa destes polimorfismos em 100 mulheres com AR inexplicado e num grupo de controlo de multíparas sem história de perdas de gravidez. Na nossa amostra não se verificou uma associação entre perdas embrionárias recorrentes e estas mutações. Nas mulheres com este tipo de perdas, a prevalência do FLV foi inclusive menor do que a verificada nos controlos. Pelo contrário, nas participantes com perdas fetais a prevalência destes polimorfismos foi muito superior à verificada nos controlos, sugerindo uma possível associação entre estas duas entidades. A pequena dimensão deste último subgrupo de mulheres, não nos permitiu contudo tirar conclusões. Uma investigação prospectiva multicêntrica é necessária antes de recomendar a pesquisa da trombofilia hereditária na investigação do AR. Procurámos incluir também nesta tese uma dimensão psicológica e contribuir assim para o conhecimento dos processos relacionais originados pelo AR. No terceiro estudo foram investigadas as diferenças de género na vivência do AR e o seu impacto no relacionamento e sexualidade do casal. Participaram neste estudo 30 casais sem filhos, com pelo menos 3 abortos espontâneos consecutivos. Cada membro do casal respondeu a um conjunto de questionários (Impact of Events Scale, Perinatal Grief Scale, Partnership Questionnaire e Intimate Relationship Scale). Os resultados mostram que as mulheres sofrem mais intensamente do que os homens com o AR, relacionando-se a intensidade do seu sofrimento com a qualidade do relacionamento conjugal. A sexualidade do casal é também afectada pelo stress e pelo sofrimento associados ao AR. Uma avaliação e acompanhamento deste tipo de problemas são imprescindíveis para ajudar estes casais a manterem a qualidade afectiva e sexual da sua relação. Finalmente, no capítulo 5 sumariámos as conclusões de toda a contribuição pessoal para a investigação sobre os factores associados e repercussões para o casal da perda recorrente de gravidez.-------------------ABSTRACT: Recurrent miscarriage (RM), a rare condition, has been described as a traumatic event for couples. Parental chromosomal anomalies, maternal thrombophilic disorders and structural uterine anomalies have been directly associated with RM. However, despite significant advances in medical research, the vast majority of cases remain unexplained. Aspects as the ethnic diversity of the population with different expression of genes, the inappropriate characterization of patients and of pregnancy losses, as well as different methodologies used in their study, have influenced the prevalence of etiological factors and have hampered the understanding of this problem. Similarly, little is known about gender differences in psychological experience of RM and its implications for the relationship of the couple. The first objective of this thesis is the characterization of the medical factors and of the psychological consequences related with RM, in the Portuguese population, helping to promote specific evidence-based clinical strategies. In the first part of this thesis, and after a brief general introduction (Chapter 1), a critical review of literature on the definition, the epidemiology and the dimensions involved, with a special emphasis on associated medical and psychological aspects of recurrent miscarriage, is presented (Chapter 2). In Chapters 3 and 4 we describe three studies carried out in Portuguese couples with RM. The first study aimed to investigate the etiological factors and the pattern of pregnancy loss in a cohort of women with RM. Subjects were divided in groups according to their parity (primary or secondary RM) and time of pregnancy loss (embryonic or fetal). Parental chromosome anomalies, uterine anomalies and antiphospholipid syndrome were the most prevalent medical factors. 15.6% of the women were obese. In the majority of cases (55.5%) no identifiable cause was detected. Parity influenced significantly our results. There was a higher prevalence of anatomic factors and antiphospholipid syndrome in primary RM. On the other hand, unexplained losses were more frequent in secondary RM. Except for the parental chromosomal abnormalities; the frequency of risk factors was similar among women with fetal or embryonic losses. Our data emphasizes the results of previous research on the importance of obesity, antiphospholipid syndrome and structural uterine abnormalities as known risk factors for RM, and shows that parity is an important moderator of the weight of those risk factors. Our second study aims to clarify the role of two mutations (factor V Leiden and prothrombin G20210A) and elucidate the need for their screening in Portuguese women with RM. FVL and PT G20210A analysis was carried out in 100 women with three or more consecutive miscarriages and a control group of 100 parous controls with no history of pregnancy losses. Secondary analysis was made regarding gestational age at miscarriage (embryonic and fetal loss). Overall the prevalence of FVL and PT G20210A was similar in RM women compared with controls. In the RM embryonic subgroup of women, FVL prevalence was inclusively lower than that of controls. Conversely in women with fetal losses both polymorphisms were much more frequent, although statistical significance was not reached due to the small size of this subgroup of patients. These data indicate that inherited maternal thrombophilia is not associated with RM prior to 10 weeks of gestation. Therefore, its screening is not indicated as an initial approach in Portuguese women with RM and a negative personal history of thromboembolic.96 Our second study aims to clarify the role of two mutations (factor V Leiden and prothrombin G20210A) and elucidate the need for their screening in Portuguese women with RM. FVL and PT G20210A analysis was carried out in 100 women with three or more consecutive miscarriages and a control group of 100 parous controls with no history of pregnancy losses. Secondary analysis was made regarding gestational age at miscarriage (embryonic and fetal loss). Overall the prevalence of FVL and PT G20210A was similar in RM women compared with controls. In the RM embryonic subgroup of women, FVL prevalence was inclusively lower than that of controls. Conversely in women with fetal losses both polymorphisms were much more frequent, although statistical significance was not reached due to the small size of this subgroup of patients. These data indicate that inherited maternal thrombophilia is not associated with RM prior to 10 weeks of gestation. Therefore, its screening is not indicated as an initial approach in Portuguese women with RM and a negative personal history of thromboembolic. In our third study, we investigate gender differences in RM experience and its impact on the couple's relationship and sexuality. Each member of 30 couples with RM answered a set of questionnaires, including the Impact of Events Scale (Horowitz et al., 1979), the Perinatal Grief Scale (Toedter et al., 1988), the Partnership Questionnaire (Hahlweg, 1979) and the Intimate Relationship Scale (Hetherington e Soeken, 1990). Results showed that men do grieve, but less intensely than women. Although the quality of the couple‟s relationship seemed not to be adversely affected by RM, both partners described sexual changes after those events. Grief was related to the quality of communication in the couple for women, and to the quality of sex life for men. An understanding of such issues is critical in helping these couples to maintain sexual and affective quality of their relationship. Finally, in Chapter 5, conclusions and clinical implications of all personal contribution to the investigation on associated factors and relational consequences of recurrent miscarriage are presented.

Development of integrated separation processes with green solvents

Dissertação para obtenção do Grau de Doutor em Química Sustentável

Gastric adenocarcinoma: contribute of computed tomography in preoperative T nad N staging

RESUMO:Os recentes progressos na imagiologia médica possibilitaram um papel de destaque para a Tomografia Axial Computorizada Multicorte no estadiamento do carcinoma do estômago (GA). Foi objetivo deste estudo avaliar a acuidade desta técnica no estadiamento T (invasão mural) e N (ganglionar) e avaliar fatores de prognóstico como fatores de representação/substituição para melhorar a referida acuidade. Sessenta e nove pacientes operados a carcinoma gástrico (GA) entre Janeiro de 2010 e Julho de 2012 e avaliados por Tomografia Computorizada, a maioria recorrendo a técnica de multicorte com distensão gástrica, foram estadiados retrospetivamente por três imagiologistas. Utilizaram-se critérios de avaliação referidos na literatura especializada e fatores de substituição/representação nos estadios menos eficazes. O estadiamento T revelou acuidade de 66,7% e sensibilidade de 92% e a acuidade, sensibilidade e especificidade obtidas para o estadiamento N foram respetivamente 49%, 40,9% e 64%. Usando um fator de substituição de estadiamento diagnóstico T4/N2 para mudar o estadiamento N2 obtido por MDCT para estadiamento N3A aumentaria a acuidade do estadiamento N para 59% e a sensibilidade para 58,1% e baixaria a especificidade para 61,5%, embora essa mudança não fosse estatisticamente significativa (Teste exato de Fisher 0,159). Em conclusão a acuidade de uma técnica simples de MDCT com distensão gástrica no estadiamento T e N do GA está dentro dos valores citados na literatura e fatores de substituição/representação como o estadiamento T4 e o tipo Difuso da classificação de Lauren podem melhorar a acuidade do estadiamento N.-------------- ABSTRACT: Recent innovations in medical sectional imaging have allowed a major role of multi-detector computed tomography (MDCT) in staging of gastric adenocarcinoma (GA). The purpose of this study was to evaluate the accuracy of this technique in depth of mural invasion (T) and nodal (N) staging of GA and to evaluate prognostic factors as surrogate factors to improve such accuracy. Sixty nine patients operated to GA between January 2010 and July 2012 that underwent Computed Tomography, the majority through Multidetector Computed Tomography (MDCT) with gastric distention, were staged retrospectively by three imagiologists with state-of-the-art criteria and surrogate prognostic factors were analyzed for less accurate stages. MDCT T-staging was 66,7 % accurate with a sensibility of 92 % and there was a 49 % accuracy, 40,9 % sensibility and 64 % specificity for N Staging. Using a surrogate factor of T4/N2 diagnostic staging to change diagnostic MDCT N2 disease to N3A disease would increase accuracy of N staging to 59% and sensibility to 58,1% and would decrease specificity to 61,5 %, although that change was not statistically significant (Fisher´s Exact Test 0,159)In conclusion the accuracy of a simple hydro-MDCT technique in T and N staging of GA is in the range of values cited in the literature and surrogate factors as diagnostic T4 disease and diffuse type of Lauren´s Classification may improve the accuracy of N staging.

Dimensions of source credibility in the case of user-generated advertisements

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

Comparative analysis of multicriteria decision making methods

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

Caracterização do papel dos genes TYMS e MTR no desenvolvimento de Cancro Colo-Rectal

RESUMO: O cancro colo-rectal (CCR) é um dos cancros que possui maior taxa de mortalidade a nível mundial. Em Portugal esta patologia é responsável pela morte de cerca de 3700 pessoas por ano, sendo que estes números aumentam de ano para ano. Ao longo das últimas décadas o papel das alterações genéticas na etiologia das patologias oncológicas tem vindo a ter cada vez mais um maior destaque. O número de estudos que avaliam a importância de polimorfismos, mutações, alterações na regulação génica e interacções entre genes no desenvolvimento destas patologias tem aumentado exponencialmente. Com o aumento do conhecimento da forma como estas alterações influenciam o desenvolvimento do cancro surgiram os primeiros meios de diagnóstico genético, levando assim a uma alteração da forma como são encarados o diagnóstico e a prevenção destas doenças. No CCR as formas hereditárias com alterações genéticas inequivocamente identificadas representam apenas 5% dos casos. Existem cerca de 25% que representam formas hereditárias para as quais ainda não foram estabelecidos os padrões de alterações genéticas subjacentes. Desta forma, estudos que venham contribuir para um maior conhecimento dos mecanismos moleculares responsáveis pelo aumento da susceptibilidade dos indivíduos para o desenvolvimento de CCR são extremamente importantes. O CCR é uma patologia multifactorial, onde factores genéticos interagem com factores ambientais no surgimento e desenvolvimento da doença. Assim, torna-se essencial integrar o estudo das alterações genéticas no contexto ambiental onde os indivíduos em estudo se encontram. No caso desta patologia um dos principais factores ambientais estudado é a nutrição. Vários estudos têm sido realizados ao longo dos últimos anos de forma a compreender como pode a ingestão dos nutrientes influenciar o desenvolvimento de CCR e de que forma interage com as alterações genéticas individuais. O ciclo do folato é um dos processos metabólicos onde o papel da nutrição em interacção com alterações genéticas mais tem sido estudado nos últimos anos. Deste cruzamento entre o estudo das alterações genéticas e ambientais surge a Nutrigenética. O conjunto de estudos da presente tese tem como objectivo aumentar o conhecimento do papel das alterações em genes do ciclo do folato, em interacção com factores nutricionais e de estilo de vida, não só no desenvolvimento de CCR, mas também de outra patologia do tracto gastrointestinal, a Doença de Crohn (DC), uma doença inflamatória muitas vezes associada como factor de risco para o desenvolvimento de CCR. Este estudo debruçou-se essencialmente no estudo dos genes timidilato sintetase (TYMS) e metionina sintetase (MTR) em populações com CCR e DC, bem como no padrão nutricional destas populações com particular incidência nos nutrientes envolvidos no ciclo do folato (folato, metionina, vitamina B6, vitamina B12). Analisando o conjunto de resultados obtidos para os estudos do CCR podemos concluir que quer a TYMS quer a MTR possuem um papel relevante na susceptibilidade para desenvolver esta patologia, assim como têm destaque no funcionamento do ciclo celular durante o processo oncogénico. Os resultados demonstram que os factores que levam a uma menor disponibilidade de grupos metil no ciclo de folato (baixos níveis de folato, alteração da actividade de MTR, elevada expressão de TYMS) constituem factores de risco, muito provavelmente por contribuírem para uma desregulação dos níveis de metionina disponível para a metilação do DNA da célula. Demonstram ainda que em células tumorais ocorrem alterações na regulação do ciclo do folato de forma a favorecer a síntese de DNA em detrimento da metilação do mesmo, alterando para isso a expressão dos genes de forma a que o fluxo de grupos metil provenientes do folato sejam encaminhados para a enzima TYMS. O polimorfismo de deleção 6pb da TYMS surge como um factor de diagnóstico e de prognóstico de CCR para a população portuguesa. Dos factores nutricionais analisados apenas o folato aparenta ter um papel relevante na modelação do risco de desenvolver CCR. Na doença de Crohn (DC) podemos verificar que a homocisteína e o seu metabolismo poderão contribuir para o aparecimento e desenvolvimento da patologia. O aumento da homocisteína poderá ser o responsável por um aumento da resposta auto-imune do organismo, promovendo o aparecimento da DC. O polimorfismo A2756G MTR desempenha um papel preponderante como factor de diagnóstico da DC, tendo sido associado pela primeira vez a esta patologia. Tem também um papel importante no desenvolvimento da doença, uma vez que está associado a uma idade de diagnóstico mais baixa, sugerindo assim que o desenvolvimento da doença ocorre de forma mais precoce. Concluindo, com este estudo pensamos ter contribuído para um melhor entendimento do papel do ciclo do folato no desenvolvimento de CCR e DC, sendo um ponto de partida para futuras investigações que possam revelar cada vez melhor as complexas interacções metabólicas desta via e a sua influência nas patologias estudadas. Do nosso estudo destacamos a importância de uma análise global das várias etapas do ciclo do folato para que se possa compreender a dinâmica que se estabelece no desenvolvimento destas patologias, podendo diversas alterações, quer a nível genético quer a nível nutricional, exercerem efeitos diferentes consoante o estado dos restantes intervenientes do ciclo do folato. Acreditamos que no futuro este estudo permitirá que o conhecimento do ciclo do folato tenha cada vez mais uma relevância fundamental a nível de diagnóstico e terapêutica destas patologias.------------ ABSTRACT: Colorectal Cancer (CRC) is one of the cancers that have a higher rate of mortality worldwide. In Portugal this pathology is responsible for the deaths of about 3700 people per year, and these numbers increase each year. Over the past few decades the role of genetic changes in the etiology of oncological pathologies has had an increasingly greater emphasis. The number of studies that evaluate the importance of polymorphisms, mutations, changes in gene regulation and gene interactions in the development of these diseases has increased exponentially. With the increased knowledge of how these changes influence the development of cancer, appeared the first means for genetic diagnostic, leading to a change in the way diagnosis is seen and in the prevention of these diseases. In CRC the hereditary forms with clearly identified genetic changes represent only 5% of cases. There are about 25% representing hereditary forms for which the patterns of genetic changes haven’t been established. In this way, studies that will contribute to a greater understanding of the molecular mechanisms responsible for increased susceptibility of individuals to the CRC development are extremely important. CRC is a multifactorial pathology, where genetic factors interact with environmental factors in the emergence and development of the disease.Thus, it is essential to integrate the study of genetic changes in the environmental context of the individuals under study. In the case of this pathology one of the main environmental factors studied is nutrition. Several studies have been conducted over the past few years in order to understand how the intake of nutrients can influence the development of CRC and how nutrients interact with the individual genetic changes. The folate cycle is one of the metabolic processes where the role of nutrition in interaction with genetic alterations has been studied in recent years. This cross between the study of genetic and environmental changes developed Nutrigenetics. The set of studies of this thesis aims to increase awareness of the role of changes in genes of the folate cycle, in interaction with nutritional factors and lifestyle, not only in the development of CRC, but also of another pathology of the gastrointestinal tract, Crohn's disease (CD), an inflammatory disease often associated as a risk factor for the development of CRC. This study dealt mainly in the study of genes thymidylate synthase (TYMS) and methionine synthase (MTR) in populations with CRC and CD, as well as in the nutritional pattern of these populations with particular focus on nutrients involved in the folate cycle (folate, methionine, vitamin B6, vitamin B12). Analyzing the results obtained for the CRC studies we conclude that either the MTR TYMS have a relevant role in susceptibility to develop this pathology, and have an important role in the functioning of the cell cycle during oncogenesis. The results show that the factors that lead to a lower availability of methyl groups in folate cycle (low levels of folate, change the activity of MTR, high expression of TYMS) constitute risk factors, most likely by contribute to a dysregulation of methionine levels available for DNA methylation of the cell. Our results also demonstrate that in tumor cells occur changes in the regulation of the folate cycle in order to promote the synthesis of DNA, to the detriment of methylation of the same by changing the expression of genes so that the methyl groups from folate are forwarded to the TYMS enzyme reaction. The deletion polymorphism 6bp of TYMS emerges as a diagnostic and prognostic factor of CCR for the Portuguese population. Nutritional factors analyzed only folate appears to have a major role in modulating the risk of developing CCR.In Crohn’s disease (CD) we can check that homocysteine and its metabolism may contribute to the emergence and development of this pathology. Increased homocysteine may be responsible for an increase in the body's autoimmune response, promoting the emergence of CD. The polymorphism A2756G MTR plays a leading role as a factor of diagnosis of DC, having been associated with this pathology for the first time. It also has an important role in the development of the disease, since it is associated with a lower diagnostic age, suggesting that the development of the disease occurs earlier. In conclusion, our study has contributed to a better understanding of the role of folate cycle in the development of CRC and CD, being a starting point for future research that may prove increasingly complex metabolic interactions in this via and its influence on the pathologies studied. In our study we highlight the importance of a comprehensive analysis of the various steps of the folate cycle in order to understand the dynamics that settles in the development of these pathologies, and a number of amendments, whether at the genetic level or at the nutritional level, exercise different effects depending on the stage of the remaining participants in the folate cycle. We believe that in the future this study will allow the knowledge of folate cycle to have increasingly a fundamental relevance at the level of diagnosis and treatment of these diseases.

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.

Search-for-yield in Portuguese fixed-income mutual funds and monetary policy

This paper studies the effects of monetary policy on mutual fund risk taking using a sample of Portuguese fixed-income mutual funds in the 2000-2012 period. Firstly I estimate time-varying measures of risk exposure (betas) for the individual funds, for the benchmark portfolio, as well as for a representative equally-weighted portfolio, through 24-month rolling regressions of a two-factor model with two systematic risk factors: interest rate risk (TERM) and default risk (DEF). Next, in the second phase, using the estimated betas, I try to understand what portion of the risk exposure is in excess of the benchmark (active risk) and how it relates to monetary policy proxies (one-month rate, Taylor residual, real rate and first principal component of a cross-section of government yields and rates). Using this methodology, I provide empirical evidence that Portuguese fixed-income mutual funds respond to accommodative monetary policy by significantly increasing exposure, in excess of their benchmarks, to default risk rate and slightly to interest risk rate as well. I also find that the increase in funds’ risk exposure to gain a boost in return (search-for-yield) is more pronounced following the 2007-2009 global financial crisis, indicating that the current historic low interest rates may incentivize excessive risk taking. My results suggest that monetary policy affects the risk appetite of non-bank financial intermediaries.