Aplicação de um value stream map nos serviços após venda automóvel

O projeto desenvolvido tem como objetivo principal a melhoria da eficiência na prestação de serviços de reparação de chapa e pintura na Caetano Auto Colisão, através da aplicação de ferramentas associadas à filosofia Lean. Apesar das ferramentas e técnicas lean estarem bem exploradas nas empresas de produção e manufatura, o mesmo não se verifica em relação às empresas da área dos serviços. O Value Stream Mapping é uma ferramenta lean que consiste no mapeamento do fluxo de materiais e informação necessários para a realização das atividades (que acrescentam e não acrescentam valor), desempenhadas pelos colaboradores, fornecedores e distribuidores, desde a obtenção do pedido do cliente até à entrega final do serviço. Através desta ferramenta é possível identificar as atividades que não acrescentam valor para o processo e propor medidas de melhoria que resultem na eliminação ou redução das mesmas. Com base neste conceito, foi realizado o mapeamento do processo de prestação de serviços de chapa e pintura e identificados os focos de ineficiência. A partir desta análise foram sugeridas melhorias que têm como objetivo atingir o estado futuro proposto assim como tornar o processo mais eficiente. Duas destas melhorias passaram pela implementação dos 5S na sala das tintas e pela elaboração de um relatório A3 para o centro de lavagens. O projeto realizado permitiu o estudo de um problema real numa empresa de serviços, bem como a proposta de um conjunto de melhorias que a médio prazo se espera virem a contribuir para a melhoria da eficiência na prestação de serviços de chapa e pintura.

Seasonality Shows Evidence for Polygenic Architecture and Genetic Correlation With Schizophrenia and Bipolar Disorder

OBJECTIVE: To test common genetic variants for association with seasonality (seasonal changes in mood and behavior) and to investigate whether there are shared genetic risk factors between psychiatric disorders and seasonality. METHOD: Genome-wide association studies (GWASs) were conducted in Australian (between 1988 and 1990 and between 2010 and 2013) and Amish (between May 2010 and December 2011) samples in whom the Seasonal Pattern Assessment Questionnaire (SPAQ) had been administered, and the results were meta-analyzed in a total sample of 4,156 individuals. Genetic risk scores based on results from prior large GWAS studies of bipolar disorder, major depressive disorder (MDD), and schizophrenia were calculated to test for overlap in risk between psychiatric disorders and seasonality. RESULTS: The most significant association was with rs11825064 (P = 1.7 × 10⁻⁶, β = 0.64, standard error = 0.13), an intergenic single nucleotide polymorphism (SNP) found on chromosome 11. The evidence for overlap in risk factors was strongest for schizophrenia and seasonality, with the schizophrenia genetic profile scores explaining 3% of the variance in log-transformed global seasonality scores. Bipolar disorder genetic profile scores were also associated with seasonality, although at much weaker levels (minimum P value = 3.4 × 10⁻³), and no evidence for overlap in risk was detected between MDD and seasonality. CONCLUSIONS: Common SNPs of large effect most likely do not exist for seasonality in the populations examined. As expected, there were overlapping genetic risk factors for bipolar disorder (but not MDD) with seasonality. Unexpectedly, the risk for schizophrenia and seasonality had the largest overlap, an unprecedented finding that requires replication in other populations and has potential clinical implications considering overlapping cognitive deficits in seasonal affective disorders and schizophrenia.

Fungal contamination of sandpits from recreational parks and schools: a potential risk for human health

Sandpits used by children are frequently visited by wild life which constitutes a source of fungal pathogens and allergenic fungi. This study aimed to take an unannounced snapshot of the urban levels of fungal contaminants in sands, using for this purpose two public recreational parks, three elementary schools and two kindergartens. All samples were from Lisbon and neighboring municipalities and were tested for fungi of clinical interest. Potentially pathogenic fungi were isolated from all samples besides one. Fusarium dimerum (32.4%) was found to be the dominant species in one park and Chrysonilia spp. in the other (46.6%). Fourteen different species and genera were detected and no dermatophytes were found. Of a total of 14 species and genera, the fungi most isolated from the samples of the elementary schools were Penicillium spp. (74%), Cladophialophora spp. (38%) and Cladosporium spp. (90%). Five dominant species and genera were isolated from the kindergartens. Penicillium spp. was the only genus isolated in one, though with remarkably high counts (32500 colony forming units per gram). In the other kindergarten Penicillium spp. were also the most abundant species, occupying 69% of all the fungi found. All of the samples exceeded the Maximum Recommended Value (MRV) for beach sand defined by Brandão et al. 2011, which are currently the only quantitative guidelines available for the same matrix. The fungi found confirm the potential risk of exposure of children to keratinophilic fungi and demonstrates that regular cleaning or replacing of sand needs to be implemented in order to minimize contamination.

Indoor environment and the impact on the health of pre-exisiting asthmatics at work: the development of a risk management framework

This thesis examines the spatial and temporal variation in nitrogen dioxide (NO2) levels in Guernsey and the impacts on pre-existing asthmatics. Whilst air quality in Guernsey is generally good, the levels of NO2 exceed UK standards in several locations. The evidence indicates that people suffering from asthma have exacerbation of their symptoms if exposed to elevated levels of air pollutants including NO2, although this research has never been carried out in Guernsey before. In addition, exposure assessment of individuals is rarely carried out and research in this area is limited due to the complexity of undertaking such a study, which will include a combination of exposures in the home, the workplace and ambient exposures, which vary depending on the individual daily experience. For the first time in Guernsey, this research has examined NO2 levels in correlation with asthma patient admissions to hospital, assessment of NO2 exposures in typical homes and typical workplaces in Guernsey. The data showed a temporal correlation between NO2 levels and the number of hospital admissions and the trend from 2008-2012 was upwards. Statistical analysis of the data did not show a significant linear correlation due to the small size of the data sets. Exposure assessment of individuals showed a spatial variation in exposures in Guernsey and assessment in indoor environments showed that real-time analysis of NO2 levels needs to be undertaken if indoor micro environments for NO2 are the be assessed adequately. There was temporal and spatial variation in NO2 concentrations measured using diffusion tubes, which provide a monthly mean value, and analysers measuring NO2 concentrations in real time. The research shows that building layout and design are important factors for good air flow and ventilation and the dispersion of NO2 indoors. Environmental Health Officers have statutory responsibilities for ambient air quality, hygiene of buildings and workplace environments and this role needs to be co-ordinated with healthcare professionals to improve health outcomes for asthmatics. The outcome of the thesis was the development of a risk management framework for pre-existing asthmatics at work for use by regulators of workplaces and an information leaflet to assist in improving health outcomes for asthmatics in Guernsey.

Estimating glomerular filtration rate in acute coronary syndromes: Different equations, different mortality risk prediction

AIMS: Renal dysfunction is a powerful predictor of adverse outcomes in patients hospitalized for acute coronary syndrome. Three new glomerular filtration rate (GFR) estimating equations recently emerged, based on serum creatinine (CKD-EPIcreat), serum cystatin C (CKD-EPIcyst) or a combination of both (CKD-EPIcreat/cyst), and they are currently recommended to confirm the presence of renal dysfunction. Our aim was to analyse the predictive value of these new estimated GFR (eGFR) equations regarding mid-term mortality in patients with acute coronary syndrome, and compare them with the traditional Modification of Diet in Renal Disease (MDRD-4) formula. METHODS AND RESULTS: 801 patients admitted for acute coronary syndrome (age 67.3±13.3 years, 68.5% male) and followed for 23.6±9.8 months were included. For each equation, patient risk stratification was performed based on eGFR values: high-risk group (eGFR<60ml/min per 1.73m2) and low-risk group (eGFR⩾60ml/min per 1.73m2). The predictive performances of these equations were compared using area under each receiver operating characteristic curves (AUCs). Overall risk stratification improvement was assessed by the net reclassification improvement index. The incidence of the primary endpoint was 18.1%. The CKD-EPIcyst equation had the highest overall discriminate performance regarding mid-term mortality (AUC 0.782±0.20) and outperformed all other equations (ρ<0.001 in all comparisons). When compared with the MDRD-4 formula, the CKD-EPIcyst equation accurately reclassified a significant percentage of patients into more appropriate risk categories (net reclassification improvement index of 11.9% (p=0.003)). The CKD-EPIcyst equation added prognostic power to the Global Registry of Acute Coronary Events (GRACE) score in the prediction of mid-term mortality. CONCLUSION: The CKD-EPIcyst equation provides a novel and improved method for assessing the mid-term mortality risk in patients admitted for acute coronary syndrome, outperforming the most widely used formula (MDRD-4), and improving the predictive value of the GRACE score. These results reinforce the added value of cystatin C as a risk marker in these patients.

Improving risk stratification in non-ST-segment elevation myocardial infarction with combined assessment of GRACE and CRUSADE risk scores

BACKGROUND: Risk assessment is fundamental in the management of acute coronary syndromes (ACS), enabling estimation of prognosis. AIMS: To evaluate whether the combined use of GRACE and CRUSADE risk stratification schemes in patients with myocardial infarction outperforms each of the scores individually in terms of mortality and haemorrhagic risk prediction. METHODS: Observational retrospective single-centre cohort study including 566 consecutive patients admitted for non-ST-segment elevation myocardial infarction. The CRUSADE model increased GRACE discriminatory performance in predicting all-cause mortality, ascertained by Cox regression, demonstrating CRUSADE independent and additive predictive value, which was sustained throughout follow-up. The cohort was divided into four different subgroups: G1 (GRACE<141; CRUSADE<41); G2 (GRACE<141; CRUSADE≥41); G3 (GRACE≥141; CRUSADE<41); G4 (GRACE≥141; CRUSADE≥41). RESULTS: Outcomes and variables estimating clinical severity, such as admission Killip-Kimbal class and left ventricular systolic dysfunction, deteriorated progressively throughout the subgroups (G1 to G4). Survival analysis differentiated three risk strata (G1, lowest risk; G2 and G3, intermediate risk; G4, highest risk). The GRACE+CRUSADE model revealed higher prognostic performance (area under the curve [AUC] 0.76) than GRACE alone (AUC 0.70) for mortality prediction, further confirmed by the integrated discrimination improvement index. Moreover, GRACE+CRUSADE combined risk assessment seemed to be valuable in delineating bleeding risk in this setting, identifying G4 as a very high-risk subgroup (hazard ratio 3.5; P<0.001). CONCLUSIONS: Combined risk stratification with GRACE and CRUSADE scores can improve the individual discriminatory power of GRACE and CRUSADE models in the prediction of all-cause mortality and bleeding. This combined assessment is a practical approach that is potentially advantageous in treatment decision-making.

Avaliação do potencial cancerigénico de microcistinas (cianotoxinas)

Tese de doutoramento em Farmácia (Toxicologia), apresentada à Faculdade de Farmácia da Universidade de Lisboa, 2009.

Uso del indicador del retorno total del negocio como alternativa para optimizar la inversión en unidades de negocio en condiciones de incertidumbre

En este articulo se hace un análisis sobre la validez de la TBR (Total Bussines return) como medida de rentabilidad de unidades de negocio que pertenecen a un portafolio corporativo. Se establecen cuales son sus debilidades y en que casos es posible aceptarla como medida de rentabilidad asociada con la creación de valor. Se expone, la coincidencia matemática entre la TBR y el WACC (costo promedio ponderado de capital) a partir del descuento de flujos de caja proyectados y entre el CAV (creación adicional de valor) y la diferencia entre el ingreso económico obtenido y el ingreso económico esperado en un periodo determinado. También se evidencia la equivalencia entre el CAV y la variación del valor de las operaciones más la variación del flujo de caja del periodo. Posteriormente se realiza una aplicación para mostrar como puede utilizar la TBR y la teoría moderna de portafolio para que un gerente corporativo pueda controlar la relación rendimiento-riesgo existente entre las distintas unidades de negocio a cargo de su corporación.

Ocular Risk Factors for Exudative AMD: A Novel Semiautomated Grading System

Purpose. To evaluate the contribution of the ocular risk factors in the conversion of the fellow eye of patients with unilateral exudative AMD, using a novel semiautomated grading system. Materials and Methods. Single-center, retrospective study including 89 consecutive patients with unilateral exudative AMD and ≥3 years of followup. Baseline color fundus photographs were graded using an innovative grading software, RetmarkerAMD (Critical Health SA). Results. The follow-up period was 60.9 ± 31.3 months. The occurrence of CNV was confirmed in 42 eyes (47.2%). The cumulative incidence of CNV was 23.6% at 2 years, 33.7% at 3 years, 39.3% at 5 years, and 47.2% at 10 years, with a mean annual incidence of 12.0% (95% CI = 0.088-0.162). The absolute number of drusen in the central 1000 and 3000  μ m (P < 0.05) and the absolute number of drusen ≥125 µm in the central 3000 and 6000 µm (P < 0.05) proved to be significant risk factors for CNV. Conclusion. The use of quantitative variables in the determination of the OR of developing CNV allowed the establishment of significant risk factors for neovascularization. The long follow-up period and the innovative methodology reinforce the value of our results. This trial is registered with ClinicalTrials.gov NCT00801541.

An investigation of environmental conditions experienced during the life of high-value wood components and products

Australian forest industries have a long history of export trade of a wide range of products from woodchips (for paper manufacturing), sandalwood (essential oils, carving and incense) to high value musical instruments, flooring and outdoor furniture. For the high value group, fluctuating environmental conditions brought on by changes in temperature and relative humidity, can lead to performance problems due to consequential swelling, shrinkage and/or distortion of the wood elements. A survey determined the types of value-added products exported, including species and dimensions packaging used and export markets. Data loggers were installed with shipments to monitor temperature and relative humidity conditions. These data were converted to timber equilibrium moisture content values to provide an indication of the environment that the wood elements would be acclimatising to. The results of the initial survey indicated that primary high value wood export products included guitars, flooring, decking and outdoor furniture. The destination markets were mainly located in the northern hemisphere, particularly the United States of America, China, Hong Kong, Europe (including the United Kingdom), Japan, Korea and the Middle East. Other regions importing Australian-made wooden articles were south-east Asia, New Zealand and South Africa. Different timber species have differing rates of swelling and shrinkage, so the types of timber were also recorded during the survey. Results from this work determined that the major species were ash-type eucalypts from south-eastern Australia (commonly referred to in the market as Tasmanian oak), jarrah from Western Australia, spotted gum, hoop pine, white cypress, black butt, brush box and Sydney blue gum from Queensland and New South Wales. The environmental conditions data indicated that microclimates in shipping containers can fluctuate extensively during shipping. Conditions at the time of manufacturing were usually between 10 and 12% equilibrium moisture content, however conditions during shipping could range from 5 (very dry) to 20% (very humid). The packaging systems incorporated were reported to be efficient at protecting the wooden articles from damage during transit. The research highlighted the potential risk for wood components to ‘move’ in response to periods of drier or more humid conditions than those at the time of manufacturing, and the importance of engineering a packaging system that can account for the environmental conditions experienced in shipping containers. Examples of potential dimensional changes in wooden components were calculated based on published unit shrinkage data for key species and the climatic data returned from the logging equipment. The information highlighted the importance of good design to account for possible timber movement during shipping. A timber movement calculator was developed to allow designers to input component species, dimensions, site of manufacture and destination, to see validate their product design.

Identifying New Business Opportunities and Customer Value Creation: Case Vuosaari

Previously conducted research projects in the field of logistics services have emphasized the importance of value added services in customer value creation. Through value added services companies can extend their service portfolio and gain higher customer satisfaction and loyalty. In more general level service marketing has been recognized to be challenging due the intangible nature of services. This has caused issues in pricing and value perceptions. To tackle these issues scholars have suggested well–managed customer reference marketing practices. The main goal of this research work is to identify shortages in the current service offering. Additionally, the focus is on, how these shortages can be fixed. Due the low capacity utilization of warehouse premises, there is a need to find the main factors, which are causing or affecting on the current situation. The research aims to offer a set of alternatives how to come over these issues. All the potential business opportunities are evaluated and the promising prospects are discussed. The focus is on logistics value added services and how those effect on route decisions in logistics. Simultaneously the aim is to create a holistic understanding of how added value and offered services effect on logistics centralization. Moreover, customer value creation and customer references’ effectiveness in logistics service marketing are emphasized in this project. Logistics value added services have a minor effect on logistics decision. Routes are chosen on a low–cost basis. However, it is challenging to track down logistics costs and break those down into different phases. Customer value as such is a difficult concept. This causes challenges when services are sold with value–based principles. Customer references are useful for logistics service providers and this should be exploited in marketing. Those reduce the perceived risk and give credibility to the service provider.

Men's experiences of receiving objective feedback on physical activity and other indicators of health risk, within the context of a gender-sensitised weight loss intervention

Receiving personalised feedback on body mass index and other health risk indicators may prompt behaviour change. Few studies have investigated men’s reactions to receiving objective feedback on such measures and detailed information on physical activity and sedentary time. The aim of my research was to understand the meanings different forms of objective feedback have for overweight/obese men, and to explore whether these varied between groups. Participants took part in Football Fans in Training, a gender-sensitised, weight loss programme delivered via Scottish Professional Football Clubs. Semi-structured interviews were conducted with 28 men, purposively sampled from four clubs to investigate the experiences of men who achieved and did not achieve their 5% weight loss target. Data were analysed using the principles of thematic analysis and interpreted through Self-Determination Theory and sociological understandings of masculinity. Several factors were vital in supporting a ‘motivational climate’ in which men could feel ‘at ease’ and adopt self-regulation strategies: the ‘place’ was described as motivating, whereas the ‘people’ (other men ‘like them’; fieldwork staff; community coaches) provided supportive and facilitative roles. Men who achieved greater weight loss were more likely to describe being motivated as a consequence of receiving information on their objective health risk indicators. They continued using self-monitoring technologies after the programme as it was enjoyable; or they had redefined themselves by integrating new-found activities into their lives and no longer relied on external technologies/feedback. They were more likely to see post-programme feedback as confirmation of success, so long as they could fully interpret the information. Men who did not achieve their 5% weight loss reported no longer being motivated to continue their activity levels or self-monitor them with a pedometer. Social support within the programme appeared more important. These men were also less positive about objective post-programme feedback which confirmed their lack of success and had less utility as a motivational tool. Providing different forms of objective feedback to men within an environment that has intrinsic value (e.g. football club setting) and congruent with common cultural constructions of masculinity, appears more conducive to health behaviour change.

Exploring the potential role of allostatic load biomarkers in risk assessment of patients presenting with depressive symptoms

Background: Depression is a major health problem worldwide and the majority of patients presenting with depressive symptoms are managed in primary care. Current approaches for assessing depressive symptoms in primary care are not accurate in predicting future clinical outcomes, which may potentially lead to over or under treatment. The Allostatic Load (AL) theory suggests that by measuring multi-system biomarker levels as a proxy of measuring multi-system physiological dysregulation, it is possible to identify individuals at risk of having adverse health outcomes at a prodromal stage. Allostatic Index (AI) score, calculated by applying statistical formulations to different multi-system biomarkers, have been associated with depressive symptoms. Aims and Objectives: To test the hypothesis, that a combination of allostatic load (AL) biomarkers will form a predictive algorithm in defining clinically meaningful outcomes in a population of patients presenting with depressive symptoms. The key objectives were: 1. To explore the relationship between various allostatic load biomarkers and prevalence of depressive symptoms in patients, especially in patients diagnosed with three common cardiometabolic diseases (Coronary Heart Disease (CHD), Diabetes and Stroke). 2 To explore whether allostatic load biomarkers predict clinical outcomes in patients with depressive symptoms, especially in patients with three common cardiometabolic diseases (CHD, Diabetes and Stroke). 3 To develop a predictive tool to identify individuals with depressive symptoms at highest risk of adverse clinical outcomes. Methods: Datasets used: ‘DepChron’ was a dataset of 35,537 patients with existing cardiometabolic disease collected as a part of routine clinical practice. ‘Psobid’ was a research data source containing health related information from 666 participants recruited from the general population. The clinical outcomes for 3 both datasets were studied using electronic data linkage to hospital and mortality health records, undertaken by Information Services Division, Scotland. Cross-sectional associations between allostatic load biomarkers calculated at baseline, with clinical severity of depression assessed by a symptom score, were assessed using logistic and linear regression models in both datasets. Cox’s proportional hazards survival analysis models were used to assess the relationship of allostatic load biomarkers at baseline and the risk of adverse physical health outcomes at follow-up, in patients with depressive symptoms. The possibility of interaction between depressive symptoms and allostatic load biomarkers in risk prediction of adverse clinical outcomes was studied using the analysis of variance (ANOVA) test. Finally, the value of constructing a risk scoring scale using patient demographics and allostatic load biomarkers for predicting adverse outcomes in depressed patients was investigated using clinical risk prediction modelling and Area Under Curve (AUC) statistics. Key Results: Literature Review Findings. The literature review showed that twelve blood based peripheral biomarkers were statistically significant in predicting six different clinical outcomes in participants with depressive symptoms. Outcomes related to both mental health (depressive symptoms) and physical health were statistically associated with pre-treatment levels of peripheral biomarkers; however only two studies investigated outcomes related to physical health. Cross-sectional Analysis Findings: In DepChron, dysregulation of individual allostatic biomarkers (mainly cardiometabolic) were found to have a non-linear association with increased probability of co-morbid depressive symptoms (as assessed by Hospital Anxiety and Depression Score HADS-D≥8). A composite AI score constructed using five biomarkers did not lead to any improvement in the observed strength of the association. In Psobid, BMI was found to have a significant cross-sectional association with the probability of depressive symptoms (assessed by General Health Questionnaire GHQ-28≥5). BMI, triglycerides, highly sensitive C - reactive 4 protein (CRP) and High Density Lipoprotein-HDL cholesterol were found to have a significant cross-sectional relationship with the continuous measure of GHQ-28. A composite AI score constructed using 12 biomarkers did not show a significant association with depressive symptoms among Psobid participants. Longitudinal Analysis Findings: In DepChron, three clinical outcomes were studied over four years: all-cause death, all-cause hospital admissions and composite major adverse cardiovascular outcome-MACE (cardiovascular death or admission due to MI/stroke/HF). Presence of depressive symptoms and composite AI score calculated using mainly peripheral cardiometabolic biomarkers was found to have a significant association with all three clinical outcomes over the following four years in DepChron patients. There was no evidence of an interaction between AI score and presence of depressive symptoms in risk prediction of any of the three clinical outcomes. There was a statistically significant interaction noted between SBP and depressive symptoms in risk prediction of major adverse cardiovascular outcome, and also between HbA1c and depressive symptoms in risk prediction of all-cause mortality for patients with diabetes. In Psobid, depressive symptoms (assessed by GHQ-28≥5) did not have a statistically significant association with any of the four outcomes under study at seven years: all cause death, all cause hospital admission, MACE and incidence of new cancer. A composite AI score at baseline had a significant association with the risk of MACE at seven years, after adjusting for confounders. A continuous measure of IL-6 observed at baseline had a significant association with the risk of three clinical outcomes- all-cause mortality, all-cause hospital admissions and major adverse cardiovascular event. Raised total cholesterol at baseline was associated with lower risk of all-cause death at seven years while raised waist hip ratio- WHR at baseline was associated with higher risk of MACE at seven years among Psobid participants. There was no significant interaction between depressive symptoms and peripheral biomarkers (individual or combined) in risk prediction of any of the four clinical outcomes under consideration. Risk Scoring System Development: In the DepChron cohort, a scoring system was constructed based on eight baseline demographic and clinical variables to predict the risk of MACE over four years. The AUC value for the risk scoring system was modest at 56.7% (95% CI 55.6 to 57.5%). In Psobid, it was not possible to perform this analysis due to the low event rate observed for the clinical outcomes. Conclusion: Individual peripheral biomarkers were found to have a cross-sectional association with depressive symptoms both in patients with cardiometabolic disease and middle-aged participants recruited from the general population. AI score calculated with different statistical formulations was of no greater benefit in predicting concurrent depressive symptoms or clinical outcomes at follow-up, over and above its individual constituent biomarkers, in either patient cohort. SBP had a significant interaction with depressive symptoms in predicting cardiovascular events in patients with cardiometabolic disease; HbA1c had a significant interaction with depressive symptoms in predicting all-cause mortality in patients with diabetes. Peripheral biomarkers may have a role in predicting clinical outcomes in patients with depressive symptoms, especially for those with existing cardiometabolic disease, and this merits further investigation.

An ontology for risk management of digital collections

Maintaining accessibility to and understanding of digital information over time is a complex challenge that often requires contributions and interventions from a variety of individuals and organizations. The processes of preservation planning and evaluation are fundamentally implicit and share similar complexity. Both demand comprehensive knowledge and understanding of every aspect of to-be-preserved content and the contexts within which preservation is undertaken. Consequently, means are required for the identification, documentation and association of those properties of data, representation and management mechanisms that in combination lend value, facilitate interaction and influence the preservation process. These properties may be almost limitless in terms of diversity, but are integral to the establishment of classes of risk exposure, and the planning and deployment of appropriate preservation strategies. We explore several research objectives within the course of this thesis. Our main objective is the conception of an ontology for risk management of digital collections. Incorporated within this are our aims to survey the contexts within which preservation has been undertaken successfully, the development of an appropriate methodology for risk management, the evaluation of existing preservation evaluation approaches and metrics, the structuring of best practice knowledge and lastly the demonstration of a range of tools that utilise our findings. We describe a mixed methodology that uses interview and survey, extensive content analysis, practical case study and iterative software and ontology development. We build on a robust foundation, the development of the Digital Repository Audit Method Based on Risk Assessment. We summarise the extent of the challenge facing the digital preservation community (and by extension users and creators of digital materials from many disciplines and operational contexts) and present the case for a comprehensive and extensible knowledge base of best practice. These challenges are manifested in the scale of data growth, the increasing complexity and the increasing onus on communities with no formal training to offer assurances of data management and sustainability. These collectively imply a challenge that demands an intuitive and adaptable means of evaluating digital preservation efforts. The need for individuals and organisations to validate the legitimacy of their own efforts is particularly prioritised. We introduce our approach, based on risk management. Risk is an expression of the likelihood of a negative outcome, and an expression of the impact of such an occurrence. We describe how risk management may be considered synonymous with preservation activity, a persistent effort to negate the dangers posed to information availability, usability and sustainability. Risk can be characterised according to associated goals, activities, responsibilities and policies in terms of both their manifestation and mitigation. They have the capacity to be deconstructed into their atomic units and responsibility for their resolution delegated appropriately. We continue to describe how the manifestation of risks typically spans an entire organisational environment, and as the focus of our analysis risk safeguards against omissions that may occur when pursuing functional, departmental or role-based assessment. We discuss the importance of relating risk-factors, through the risks themselves or associated system elements. To do so will yield the preservation best-practice knowledge base that is conspicuously lacking within the international digital preservation community. We present as research outcomes an encapsulation of preservation practice (and explicitly defined best practice) as a series of case studies, in turn distilled into atomic, related information elements. We conduct our analyses in the formal evaluation of memory institutions in the UK, US and continental Europe. Furthermore we showcase a series of applications that use the fruits of this research as their intellectual foundation. Finally we document our results in a range of technical reports and conference and journal articles. We present evidence of preservation approaches and infrastructures from a series of case studies conducted in a range of international preservation environments. We then aggregate this into a linked data structure entitled PORRO, an ontology relating preservation repository, object and risk characteristics, intended to support preservation decision making and evaluation. The methodology leading to this ontology is outlined, and lessons are exposed by revisiting legacy studies and exposing the resource and associated applications to evaluation by the digital preservation community.

Eph kinases and their ligands ephrins act in concert with sex hormones in regulating blood pressure

Les Erythropoietin-producing hepatocyte (EPH) sont la plus grande famille de récepteurs tyrosine kinase. Leurs ligands, les éphrines (EFNs), sont aussi des molécules exprimées à la surface cellulaire. Les EPH/EFNs sont impliqués dans de nombreux processus biologiques. L'hypertension artérielle (PA) est une maladie chronique qui, aujourd'hui, est devenue un problème médical critique dans le monde entier et un enjeu de santé publique. La découverte de nouvelles thérapeutiques de l'hypertension sont d'une grande importance pour la santé publique. Jusqu’à tout récemment, il existe seulement quelques études concernant le rôle de l’axe EPH/EFNs sur la fonction des cellules musculaires lisses vasculaires (CMLV). Dans nos études précédentes, nous avons montré qu'EPHB6 et EFNB1, de concert avec les hormones sexuelles, régulent la PA. Dans la présente étude, nous avons constaté que les différents membres de la famille EPH/EFN peuvent réguler soit positivement, soit négativement, la contractilité des CMLV et la PA: tandis que EPHB4 et EFNB2 appartiennent à la première catégorie, EFNB1, EFNB3 et EPHB6 appartiennent à la deuxième. In vivo, des souris males, mais non pas des femelles, porteuses d’une mutation EPHB4 (KO) spécifique du muscle lisse présentent une PA diminuée, comparée aux souris témoins (WT). Les CMLV de souris EPHB4 KO, en présence de testostérone, ont montré une contractilité réduite lors de la stimulation par la phényléphrine (PE). Au niveau moléculaire, la phosphorylation de la protéine kinase II dépendante de Ca2+/calmoduline et de la kinase de la chaine légère de la myosine (CLM) est augmentée, tandis que la phosphorylation de la kinase de la CLM est réduite dans les CMLV KO lors de la stimulation par PE, par rapport au WT CMLV. Cela fournit une base moléculaire à la réduction de la PA et de la contractilité des CMLV chez les souris EPHB4 KO. EFNB2 est le ligand majeur de l’EPHB4. Comme attendu, les souris EFNB2 KO spécifique du muscle lisse avaient un phénotype de PA semblable, quoique non identique, aux souris EPHB4 KO. Les souris mâles EFNB2 KO, mais pas femelles, sous régime régulier ou riche en sel, présentent une PA réduite, par rapport à leurs homologues WT. Au niveau cellulaire, les CMLV des souris KO ont montré une contractilité réduite lors de la stimulation par PE par rapport aux témoins WT. Une région de l’acide aminé (aa) 313 à l’aa 331 dans la partie intracellulaire d’EFNB2 est essentielle pour la signalisation inverse qui régule la contractilité des CMLV, selon des études de mutation-délétion. Dans une étude de génétique humaine, nous avons identifié, dans le gène EFNB2, six SNP qui étaient associées significativement au risque d'hypertension artérielle, de façon dépendante du sexe, ce qui corrobore nos résultats chez les souris. En revanche, la délétion du gène EFNB3 (KO) chez les souris femelles aboutit à une PA élevée et à une augmentation des résistances des petites artères in vivo, améliore la contractilité des petites artères ex-vivo et augmente la contractilité des CMLV in vitro. Les souris mâles KO ont une PA normale, mais la castration conduit à une augmentation significative de la PA dans les souris KO, mais pas dans les souris WT. Les CMLV des souris KO femelles ont montré une phosphorylation accrue de la CLM et une phosphorylation réduite de la kinase de la CLM, ce qui fournit à nouveau une base moléculaire aux phénotypes de PA et de contractilité des CMLV observés. Ce changement de signalisation est attribuable à une protéine adaptatrice Grip1. En effet, dans une étude d'association pan génomique par le Consortium International pour la Pression Sanguine, un SNP dans le gène GRIP1 a approché le seuil de significativité de la valeur p pour son association avec la pression diastolique. Nos recherches, pour la première fois, ont révélé que EPH/EFNs sont de nouveaux composants dans le système de régulation de la PA. Les membres de la famille EPH/EFN peuvent agir comme des forces Yin et Yang pour régler finement le tonus des vaisseaux pour assurer l'homéostasie de la PA et de sa régulation. Ces effets de EPH/EFNs dépendent du sexe et des niveaux d’hormones sexuelles. À partir de ces nouvelles connaissances, nous pourrions développer une nouvelle thérapie personnalisée pour l’hypertension artérielle, utilisant des antagonistes d'hormones sexuelles ou des thérapies de remplacement d'hormones sexuelles, selon les niveaux d'hormones sexuelles des patients et les mutations dans les gènes de l'EPH/EFN.