As trocas complexas de água salgada, água subterrânea e água de superfície que ocorrem na região costeira afetam diretamente os ciclos biogeoquímicos globais e a aplicação de traçadores isotópicos, dentre eles radionuclídeos naturais das séries radioativas do U e do Th, se apresenta como uma ferramenta poderosa para se rastrear fontes e sumidouros de elementos-traço e nutrientes nestes ecossistemas. O comportamento único do Ra utilizado para estimar a contribuição destes fluxos é observado no estuário subterrâneo, uma zona de mistura entre a água doce subterrânea e a água salgada nos aqüíferos costeiros. Nas séries naturais de decaimento radioativo do U e do Th há quatro isótopos naturais de Ra: 223Ra (t1/2 = 11,4 d), 224Ra (t1/2 = 3,7 d), 228Ra (t1/2 = 5,7 a) e 226Ra (t1/2 = 1.600 a). As meias-vidas destes isótopos correspondem bem com a duração de muitos processos costeiros. Todos estes isótopos derivam do decaimento de um isótopo de Th precursor, que está fortemente ligado ao material particulado. Devido ao Ra ser mobilizado no ambiente marinho, os sedimentos constituem uma fonte contínua dos isótopos de Ra para as águas estuarinas em taxas estabelecidas por suas constantes de decaimento. As atividades dos isótopos de Th nos sedimentos e o coeficiente de distribuição do Ra entre os sedimentos e a água, determinam a entrada potencial de cada isótopo de Ra para um dado ambiente aquático. Como o 228Ra é regenerado mais rapidamente do que o 226Ra, estuários com altas taxas de atividade 228Ra/226Ra na água devem ter um alto grau de troca com os sedimentos na região costeira ou com a água subterrânea drenando próximo a ela. Esta informação é útil para elucidar a contribuição de sistemas estuarinos para a troca de elementos-traço, N, P e C na zona de mistura. As funções fonte combinadas para o Ra na área costeira incluem a sua entrada a partir dos rios nas formas dissolvida e particulada, das suas concentrações dissolvidas no oceano, da dessorção dos sedimentos costeiros e da água subterrânea. A importância relativa de cada uma destas fontes é geralmente uma função da hidrogeologia específica de cada local e do ambiente no qual as amostras foram coletadas em relação ao gradiente de salinidade (extensão da mistura de água doce/ água salgada). Desta forma, os isótopos de Ra fornecem informações fundamentais a respeito da interação dos sedimentos, água subterrânea e águas estuarinas. Neste projeto, a distribuição de isótopos naturais de Ra foi estudada em amostras de águas de superfície, subterrâneas e estuarinas coletadas nas estações seca e chuvosa (2009 - 2010) na região do Vale do Ribeira, litoral sul do Estado de São Paulo. O inventário permitiu utilizá-los como traçadores de descargas fluvial e subterrânea para o complexo estuarino-lagunar de Cananéia/Iguape. As trocas complexas da água subterrânea/água de superfície na bacia do Rio Ribeira de Iguape, assim como os fluxos de vários constituintes para o complexo estuarino-lagunar de Cananéia/Iguape ainda são ainda componentes pouco conhecidos nos balanços hídrico e de materiais no cenário de interesse. Os resultados obtidos mostraram que há uma predominância do isótopo de 228Ra em todas as amostras analisadas, embora as concentrações detectadas tanto no Alto Vale do Ribeira como ao longo da Planície Costeira indiquem que estes resultados representam níveis naturais de fundo, denotando pequena ou mínima intervenção humana. Nas amostras coletadas ao longo do Rio Ribeira de Iguape e nos estuários de Cananéia e de Iguape, as maiores concentrações dos isótopos de Ra foram observadas nas águas de fundo, indicando a difusão do 228Ra dos sedimentos recentemente depositados como uma fonte potencial das concentrações aumentadas deste isótopo em relação aos demais. As concentrações dos isótopos de meias-vidas curtas foram negligenciáveis, em sua maior parte menores que o limite inferior de detecção do método. Os fluxos de Ra para o sistema na Barra de Cananéia é fortemente influenciado pelas correntes e canais de maré, que modulam o aumento ou diminuição das concentrações de Ra em resposta direta ao respectivo aumento e diminuição da salinidade das águas. No estuário de Iguape e nas estações hidroquímicas realizadas no Rio Ribeira do Iguape observou-se uma correlação linear entre a quantidade de material em suspensão (MES) e o aumento da concentração de 228Ra. Quando se avaliam qualitativamente as diferenças entre o comportamento dos dois isótopos de Ra de meias-vidas longas, as concentrações de 226Ra não apresentaram distribuição idêntica aquelas do 228Ra. Isto demonstra um aporte negligenciável advectivo das águas intersticiais dos sedimentos e subterrâneas para o cenário de interesse. Os fluxos dominantes de elementos-traço, radionuclídeos e nutrientes tem suas maiores fontes centradas no compartimento fluvial, sedimentos e material em suspensão. / The complex exchange of fluvial, subsurface and seawater within a coastal area directly affects global biogeochemical cycles and the application of isotopic tracers, mainly natural radionuclides from U and Th series, is a powerful tool to track sources and sinks of trace elements and nutrients to this systems. The unique Ra signature applied to quantify the contribution of such fluxes is acquired within the subterranean estuary, a mixing zone between fresh groundwater and seawater in coastal aquifers. In the U and Th natural radioactive decay series there are four radium isotopes: 223Ra (t1/2 = 11.4 d), 224Ra (t1/2 = 3.7 d), 228Ra (t1/2 = 5.7 y) and 226Ra (t1/2 = 1,600 y). Their wide range in half-lives corresponds well with the duration of many coastal processes. All these Ra isotopes derive from decay of Th parents, which are tightly bound to particles. Because Ra is mobilized in the marine environment, sediments provide a continuous source of Ra isotopes to estuarine waters at rates set by its decay constants. The Th isotope activities in the sediments and the distribution coefficient of Ra between the sediments and water determine the potential input of each Ra isotope to the water. Because 228Ra is regenerated much faster than 226Ra, estuaries with high 228Ra/ 226Ra activity ratios in the water must have a high degree of exchange with sediments on the sea bed or with groundwater draining nearby. This information is useful to elucidate the contribution of estuarine systems to the exchange of trace elements, N, P and C in the mixing zone. The combined source functions for Ra in a coastal area include riverine particulates/ dissolved input, oceanic dissolved concentrations, input from sediments and groundwater. The relative significance of each of these sources is usually a function of the site-specific hydrogeology and where the samples are taken relative to the salinity gradient (extent of freshwater/saltwater mixing). Thus, the Ra isotopes provide fundamental information on the interaction of sediments, groundwater and estuarine waters. In this project, the distribution of natural Ra isotopes was studied in surface, groundwater and estuarine water samples collected from dry and wet seasons (2009 2010) campaigns performed in Ribeira Valley, Southern São Paulo State. The inventory allowed the application of Ra isotopes as tracers of fluvial and groundwater discharges to the Cananéia-Iguape estuarine complex. The exchange of groundwater/ surface water in Ribeira do Iguape River basin and related fluxes of several constituents for the Cananéia-Iguape estuarine complex mass balance is still not very well known. The results obtained in this research work evidenced that there is a prevalence of 228Ra isotope in all the set of samples analyzed. However, the activity concentrations of Ra isotopes determined from Higher Ribeira Valley through the Southern Coastal Plain of São Paulo are representative of natural background levels, showing low or minimal human intervention. In the set of samples collected along Ribeira do Iguape River, Cananéia and Iguape outlets, the higher concentrations of Ra were observed in bottom waters, indicating the diffusion of 228Ra from sediments recently deposited as a potential source of the increased concentrations of this isotope when compared with others. The activity concentrations of the short-lived Ra isotopes were negligible, lower than the limit of the detection. Fluxes of Ra for Cananéia outlet are strongly influenced by tidal oscillations, which modulate the increase and decrease of Ra concentrations in response of the respective increase and decrease of waters salinity. In Iguape outlet and in hydrochemical stations performed along Ribeira do Iguape River it was observed a linear relationship between the amount of suspended matter and the increase of 228Ra activity concentration. When we evaluate qualitatively the differences in behavior of both long-lived Ra isotopes, the concentrations of 226Ra have not shown similar distribution to 228Ra. This demonstrates negligible contribution from advective porewaters and groundwater to the studied scenario. Dominant fluxes of trace-elements, radionuclides and nutrients have their main sources centered on fluvial, sediments and suspended matter compartiments.

Background: Patient safety in healthcare organisations received global attention following the Institute of Medicine’s release of its hallmark report “To Err Is Human: Building a Safer Health System”, where it was estimated that 44,000–98,000 patients die annually in US hospitals as a result of errors in care. Similar rates of error and avoidable harm have been reported in different research studies in many modern health systems across the world. “Safety Culture” has been identified as a key element of healthcare organisations’ ability to learn from errors and reduce preventable harm to patients resulting from health care. The perceived importance of safety culture in improving patient safety and its impact on patient outcomes has led to a growing interest in the assessment of safety culture in healthcare organisations. The use of safety climate questionnaires is one of the most popular methods for assessing safety culture. These questionnaires are thought to help in measuring healthcare workers' perceptions of the prevailing safety culture or “safety climate” in their organisations. Since no surveys of safety climate have been conducted at public hospitals in the state of Kuwait, nor are valid or reliable survey instruments available, this thesis aimed to investigate patient safety climate in public hospitals in Kuwait. The main objectives of the study were: 1. To identify an existing safety climate tools to be employed in my PhD thesis. 2. To test the psychometric properties of the identified tool in a sample of Kuwaiti public hospitals. 3. To provide a measure of the prevailing safety climate in Kuwaiti public hospitals. 4. To explore with key stakeholders the main findings of the safety climate survey and identify the potential barriers and facilitators to safety improvement initiatives in Kuwaiti public hospitals. Based on the overall findings, a series of recommendations are made for clinical leaders, policy makers and others to consider and a conceptual model informing a systems’ based approach to safety culture theory and practice is proposed for future research. Methods: A multi-method, triangulated approach including both quantitative and qualitative methods was adopted for the study. There were four phases of the research: A systematic review of published literature on safety climate tools used in acute hospital settings was carried out using seven electronic databases, with manual searches of bibliographies of included papers and key journals. A suitable tool was identified. A cross-sectional survey of 1,511 healthcare staff in three public hospitals was conducted for two purposes: Firstly, to assess the psychometric properties of the identified tool and develop an optimum model for assessing safety climate in Kuwaiti hospitals. Secondly, to provide an assessment of the current state of safety climate in Kuwaiti hospitals. Finally, interviews with key personnel were conducted to extend the examination of the survey findings and provide a rounded picture of the current state of safety climate in Kuwaiti public hospitals. Results: The search strategy identified 3,576 potential papers. Of these, eighty-eight papers were reviewed, with five studies meeting the inclusion criteria. Three out of five studies, covering three tools, were rated as ‘good’ quality papers and reported more robust psychometric properties. The Hospital Survey on Patient Safety Culture (HSOPSC) was selected as the most appropriate for my PhD thesis (in terms of usability, applicability and psychometric properties), and was pilot tested with minor modifications. A modified version of the HSOPSC was used to conduct the survey using a sample of healthcare staff with an 87% (n=1,310) response rate. Results of psychometric evaluation, including exploratory factor analysis, confirmatory factor analysis, reliability and correlation analysis, showed an optimal model of eight factors and 22 safety climate items. General evaluation of the prevailing safety climate amongst the workforce in acute hospital settings was conducted. The dimensions “Teamwork within units” (84%), “organisational learning-continuous improvement” (82%), “supervisor/manager expectations and actions promoting safety” (77%) and “management support for patient safety” (74%) were identified as strongly positive areas for the three hospitals. The dimensions “Non-punitive response to error” (34%), “communication openness” (47%) and “frequency of event reporting” (50%) were identified as areas in need of improvement. Building on the survey findings, interviews with key stakeholders added rich insight into hospital employees' perceptions on safety and allowed exploration of emerging issues in more detail. The research findings of my PhD thesis, and of the literature informed the design of a preliminary framework that aims to extend the examination of the construct of safety climate beyond the domains and items that typically inform safety climate theory to include system wide factors which potentially influence the prevailing safety culture/climate. Conclusions: This is the first validation study of a Standardised safety climate measure in a Kuwaiti healthcare setting. The study assessed the psychometric properties of the HSOPSC questionnaire and constructed an optimal model for assessing patient safety climate in Kuwaiti hospitals. It highlighted important patient safety and staff wellbeing concerns to inform organisational and national learning, and provided a baseline for measuring patient safety climate in Kuwaiti hospitals. As such, my PhD thesis raises and emphasizes the critical importance of appropriate validation of safety climate questionnaires before extending their usage in different countries or healthcare contexts. It provided new knowledge about areas of strength and weakness in safety climate with the potential to drive local improvements in Kuwaiti public hospitals. It is recommended that future investigations of patient safety culture and climate combine both quantitative and qualitative approaches and adopt a system wide approach to inform safety climate theory and questionnaire development, leading to stronger frameworks guiding safety culture research and practice.

Background and aim: Accreditation is a process of evaluating an organisation. It comprises a self-assessment against a set of standards and an external evaluation followed by a report. The trend towards implementing healthcare accreditation has reached the Middle East, since the World Health Organisation reported, in 2003, a lack of accreditation programmes in this region. Many countries in the Middle East, including Kuwait, have been developing and implementing accreditation programmes since then. The aim of this research was to explore implementation of the accreditation programme in Kuwait general hospitals from the multiple perspectives of the healthcare professionals involved. Methods: The research employed a multiple methods approach with three inter-linked studies. The first study was a systematic review of the international literature that explored the implementation of accreditation programmes. Data analysis was guided by Normalisation Process Theory (NPT). The second study was a documentary analysis of the accreditation reports of six general Governmental hospitals. The third study involved interviews with twenty-five participants, from two general hospitals, who represented different professional backgrounds and were all self-assessment team members. The accreditation implementation process was explored in depth, focusing on the impact of the programme and the factors that influenced the process. Both the documentary analysis and the interviews were analysed by thematic analysis. The findings of the three studies were then synthesised, using Normalisation Process Theory. Results: The findings from the three studies identified four broad areas representing the process of accreditation implementation: understanding the accreditation process; engagement with the accreditation process; the work of accreditation; and monitoring the impact of accreditation. Within these themes, key factors were found to influence the successful implementation of the programme. These were: understanding the process; individuals’ engagement; communication and teamwork; leadership support; resources; infrastructure; adaptation of Standards; and education and training. The evidence for the impact of accreditation programmes on healthcare services in the systematic review was inconclusive. However, accreditation was perceived, in the interviews, to have a positive organisational impact. On the individual level, the findings identified the process of implementing accreditation to impact positively on the personal development; improve working relationships; and the morale of the teams. Conclusion: This thesis has contributed to the evidence for the implementation of accreditation in the hospital setting and its impact, from the perspective of accreditation self-assessment team members. Furthermore, it provides valuable insights for policy makers within the Kuwaiti healthcare context in future planning and monitoring of the National Accreditation Programme.

Parkinson’s is a common neurodegenerative disorder that can have a significant impact on an individual’s health, quality of life (QoL), and wellbeing, causing a substantial economic burden on patients, their caregivers, the health service, and broader social and community services. Whilst Parkinson’s wide range of QoL and financial impacts have been well documented relatively little research has explored to what extent such impacts have been appropriately incorporated into economic evaluations. Economic evaluation is used by the National Institute for Health and Care Excellence (NICE) in the UK to guide health-care resource allocation in the NHS. It uses preference-based outcome measures to measure and value the health outcomes of different interventions. These health utilities are combined with durations to estimate quality-adjusted life-years. The important role of the preference-based outcomes requires them to be accurately capturing the benefit of interventions, otherwise the estimation of cost-effectiveness of interventions will be not be reflecting true preference/choice between interventions. This may lead to mistakes in funding decisions and insufficient allocation of resources. Despite the importance of accurately capturing the benefit of interventions, the existing generic preference-based measures (e.g., the EQ-5D measure as recommended by NICE) are sometimes criticised for their ‘health-related’ nature as insufficient to capture all the QoL aspects that are affected by the disease or the intervention. This raises a question of “is the generic ‘prescribed’ measure appropriate for all disease areas and all interventions?” For diseases that have broad impact on people’s health and wellbeing such as Parkinson’s, a broadly scoped preference-based wellbeing instrument which could measure the impact of intervention beyond health may potentially fill the gap of the limited scope of the ‘health-related’ preference-based measures (if any). Meanwhile, there are concerns relating to their relevance and sensitivity to specific health aspects and their validity in general to be used in the healthcare context. Given this, the aim of this thesis is to examine the performance of the existing preference-based outcomes in people with Parkinson’s, and evaluate the potential of using a generic preference-based capability-wellbeing measure, ICECAP-O, in this population. This thesis conducted a systematic review of the existing preference-based measures to assess their construct validity and responsiveness in people with Parkinson’s. Two empirical studies explored these properties of the ICECAP-O measure in people with Parkinson’s. Construct validity and responsiveness are the two key psychometric properties relevant to preference-based measures for their use in economic evaluations. Data for both empirical analyses were obtained from the PD MED large-scale randomised controlled trial. This thesis has identified evidence of limited responsiveness of the existing preference-based measures in people with Parkinson’s and suggested that the current commonly used preference-based health-related QoL measures may underestimate the value placed on the mental and social wellbeing aspects that Parkinson’s populations are affected by. This limited ability of the utility values to differentiate health states may have an impact on resource allocation decisions. Especially as this relates to the cost-effectiveness of interventions that have the capacity to influence the mental and social wellbeing aspects of people’s lives. This highlights the need for consideration of a broadly scoped measure such as the ICECAP-O to incorporate such aspects in economic evaluations of diseases such as Parkinson’s. This thesis established the construct validity and responsiveness of the ICECAP-O instrument and demonstrated that there are valued capability wellbeing attributes in Parkinson’s beyond those quality of life attributes reflected by the EQ-5D instrument. It contributes to understanding the use of broadly scoped outcome measures for economic evaluations in Parkinson’s by showing that the ICECAP-O capability wellbeing instrument was able to provide a preference-based assessment of these under-represented aspects in the Parkinson’s population, without compromising its sensitivity to the clinical and specific physical QoL dimensions in this patient group. While further exploration of the role of ICECAP-O in economic evaluation and decision making through the work of assessing ‘sufficient capability’ is required, this thesis establishes initial foundations for the use of the ICECAP-O as a preference-based instrument to measure the impact of interventions in Parkinson’s populations.

The growing use of decision analytic modelling (DAM) to aid decision making in healthcare has triggered the need for increased scrutiny of the methods used and the assessment of compliance with these methods. The assessment of structural uncertainty surrounding the choice of model structure and model external validity represent some of most frequent challenges faced by researchers. This thesis used systematic reviews and two case studies focused on the self-management of hypertension in patients at high risk and thrombolysis in acute stroke to critically examine all available guidelines and statements of good practice and the adherence of current research to good practice guidelines. Two case studies were developed to assess structural uncertainty surrounding the choice of model structure and the impact of the exclusion of secondary events. The results here indicate that DAM guidelines lack practicality due to the extensive amount of information available and their complexity; furthermore, researchers are failing to identifY and correctly assess model structural uncertainty. This thesis makes an important contribution to current knowledge by developing and proposing the use of a practical five-dimension framework to improve the current standards of reporting results of DAM and by illustrating, through case studies, the assessment of structural uncertainty arising from the choice of model structure via scenario analysis and the use of extensive sensitivity analysis.

In this study, the biocatalytic production of methacrylic acid (MAA), a commodity chemical with a large global market, was investigated. The target was to develop MAA formation via enzymatic decarboxylation of itaconic, mesaconic, citraconic and citramalic acid. Several candidate enzymes were tested, but none catalysed the target reactions. Therefore, a novel high throughput screening method for decarboxylases was developed to enable protein engineering. The screening assay detected gaseous CO2 with a pH-dependent colorimetric reaction, in a 96-well format. Focused mutagenesis was then performed on the mevalonate diphosphate decarboxylases (MVD) from Saccharomyces cerevisiae and from Picrophilus torridus. However, MAA formation was not observed, even after screening over 3800 variants. Further investigation was then performed on some of the candidates to understand why MAA was not formed and to develop alternative strategies for enzyme selection. P. torridus MVD was discovered to belong to a new class of enzymes, mevalonate-3-kinase, and to be part of a novel archaeal mevalonate pathway. The enzyme also catalysed the formation of isobutene from 3-hydroxyisovalerate with unprecedented production rates. S. cerevisiae and Aspergillus niger phenylacrylic acid decarboxylases, previously believed to be cofactor-free enzymes, were proposed to require divalent metals and a novel organic cofactor. The enzymatic mechanism of Pseudomonas fluorescens α-amino-β-carboxymuconate-ε-semialdehyde (ACMS) decarboxylase was investigated. Through inhibition studies, it was demonstrated that the aldehyde and amino moieties of ACMS could be directly involved in catalysis, in contrast to the previously reported mechanism. This information partially explains why some of these candidates could not catalyse the target reaction, and provides insights into their potential future use for the bioproduction of MAA. Although this route does not seem feasible at present, this study gives foundation and guidance for future investigations.

As trocas complexas de água salgada, água subterrânea e água de superfície que ocorrem na região costeira afetam diretamente os ciclos biogeoquímicos globais e a aplicação de traçadores isotópicos, dentre eles radionuclídeos naturais das séries radioativas do U e do Th, se apresenta como uma ferramenta poderosa para se rastrear fontes e sumidouros de elementos-traço e nutrientes nestes ecossistemas. O comportamento único do Ra utilizado para estimar a contribuição destes fluxos é observado no estuário subterrâneo, uma zona de mistura entre a água doce subterrânea e a água salgada nos aqüíferos costeiros. Nas séries naturais de decaimento radioativo do U e do Th há quatro isótopos naturais de Ra: 223Ra (t1/2 = 11,4 d), 224Ra (t1/2 = 3,7 d), 228Ra (t1/2 = 5,7 a) e 226Ra (t1/2 = 1.600 a). As meias-vidas destes isótopos correspondem bem com a duração de muitos processos costeiros. Todos estes isótopos derivam do decaimento de um isótopo de Th precursor, que está fortemente ligado ao material particulado. Devido ao Ra ser mobilizado no ambiente marinho, os sedimentos constituem uma fonte contínua dos isótopos de Ra para as águas estuarinas em taxas estabelecidas por suas constantes de decaimento. As atividades dos isótopos de Th nos sedimentos e o coeficiente de distribuição do Ra entre os sedimentos e a água, determinam a entrada potencial de cada isótopo de Ra para um dado ambiente aquático. Como o 228Ra é regenerado mais rapidamente do que o 226Ra, estuários com altas taxas de atividade 228Ra/226Ra na água devem ter um alto grau de troca com os sedimentos na região costeira ou com a água subterrânea drenando próximo a ela. Esta informação é útil para elucidar a contribuição de sistemas estuarinos para a troca de elementos-traço, N, P e C na zona de mistura. As funções fonte combinadas para o Ra na área costeira incluem a sua entrada a partir dos rios nas formas dissolvida e particulada, das suas concentrações dissolvidas no oceano, da dessorção dos sedimentos costeiros e da água subterrânea. A importância relativa de cada uma destas fontes é geralmente uma função da hidrogeologia específica de cada local e do ambiente no qual as amostras foram coletadas em relação ao gradiente de salinidade (extensão da mistura de água doce/ água salgada). Desta forma, os isótopos de Ra fornecem informações fundamentais a respeito da interação dos sedimentos, água subterrânea e águas estuarinas. Neste projeto, a distribuição de isótopos naturais de Ra foi estudada em amostras de águas de superfície, subterrâneas e estuarinas coletadas nas estações seca e chuvosa (2009 - 2010) na região do Vale do Ribeira, litoral sul do Estado de São Paulo. O inventário permitiu utilizá-los como traçadores de descargas fluvial e subterrânea para o complexo estuarino-lagunar de Cananéia/Iguape. As trocas complexas da água subterrânea/água de superfície na bacia do Rio Ribeira de Iguape, assim como os fluxos de vários constituintes para o complexo estuarino-lagunar de Cananéia/Iguape ainda são ainda componentes pouco conhecidos nos balanços hídrico e de materiais no cenário de interesse. Os resultados obtidos mostraram que há uma predominância do isótopo de 228Ra em todas as amostras analisadas, embora as concentrações detectadas tanto no Alto Vale do Ribeira como ao longo da Planície Costeira indiquem que estes resultados representam níveis naturais de fundo, denotando pequena ou mínima intervenção humana. Nas amostras coletadas ao longo do Rio Ribeira de Iguape e nos estuários de Cananéia e de Iguape, as maiores concentrações dos isótopos de Ra foram observadas nas águas de fundo, indicando a difusão do 228Ra dos sedimentos recentemente depositados como uma fonte potencial das concentrações aumentadas deste isótopo em relação aos demais. As concentrações dos isótopos de meias-vidas curtas foram negligenciáveis, em sua maior parte menores que o limite inferior de detecção do método. Os fluxos de Ra para o sistema na Barra de Cananéia é fortemente influenciado pelas correntes e canais de maré, que modulam o aumento ou diminuição das concentrações de Ra em resposta direta ao respectivo aumento e diminuição da salinidade das águas. No estuário de Iguape e nas estações hidroquímicas realizadas no Rio Ribeira do Iguape observou-se uma correlação linear entre a quantidade de material em suspensão (MES) e o aumento da concentração de 228Ra. Quando se avaliam qualitativamente as diferenças entre o comportamento dos dois isótopos de Ra de meias-vidas longas, as concentrações de 226Ra não apresentaram distribuição idêntica aquelas do 228Ra. Isto demonstra um aporte negligenciável advectivo das águas intersticiais dos sedimentos e subterrâneas para o cenário de interesse. Os fluxos dominantes de elementos-traço, radionuclídeos e nutrientes tem suas maiores fontes centradas no compartimento fluvial, sedimentos e material em suspensão. / The complex exchange of fluvial, subsurface and seawater within a coastal area directly affects global biogeochemical cycles and the application of isotopic tracers, mainly natural radionuclides from U and Th series, is a powerful tool to track sources and sinks of trace elements and nutrients to this systems. The unique Ra signature applied to quantify the contribution of such fluxes is acquired within the subterranean estuary, a mixing zone between fresh groundwater and seawater in coastal aquifers. In the U and Th natural radioactive decay series there are four radium isotopes: 223Ra (t1/2 = 11.4 d), 224Ra (t1/2 = 3.7 d), 228Ra (t1/2 = 5.7 y) and 226Ra (t1/2 = 1,600 y). Their wide range in half-lives corresponds well with the duration of many coastal processes. All these Ra isotopes derive from decay of Th parents, which are tightly bound to particles. Because Ra is mobilized in the marine environment, sediments provide a continuous source of Ra isotopes to estuarine waters at rates set by its decay constants. The Th isotope activities in the sediments and the distribution coefficient of Ra between the sediments and water determine the potential input of each Ra isotope to the water. Because 228Ra is regenerated much faster than 226Ra, estuaries with high 228Ra/ 226Ra activity ratios in the water must have a high degree of exchange with sediments on the sea bed or with groundwater draining nearby. This information is useful to elucidate the contribution of estuarine systems to the exchange of trace elements, N, P and C in the mixing zone. The combined source functions for Ra in a coastal area include riverine particulates/ dissolved input, oceanic dissolved concentrations, input from sediments and groundwater. The relative significance of each of these sources is usually a function of the site-specific hydrogeology and where the samples are taken relative to the salinity gradient (extent of freshwater/saltwater mixing). Thus, the Ra isotopes provide fundamental information on the interaction of sediments, groundwater and estuarine waters. In this project, the distribution of natural Ra isotopes was studied in surface, groundwater and estuarine water samples collected from dry and wet seasons (2009 2010) campaigns performed in Ribeira Valley, Southern São Paulo State. The inventory allowed the application of Ra isotopes as tracers of fluvial and groundwater discharges to the Cananéia-Iguape estuarine complex. The exchange of groundwater/ surface water in Ribeira do Iguape River basin and related fluxes of several constituents for the Cananéia-Iguape estuarine complex mass balance is still not very well known. The results obtained in this research work evidenced that there is a prevalence of 228Ra isotope in all the set of samples analyzed. However, the activity concentrations of Ra isotopes determined from Higher Ribeira Valley through the Southern Coastal Plain of São Paulo are representative of natural background levels, showing low or minimal human intervention. In the set of samples collected along Ribeira do Iguape River, Cananéia and Iguape outlets, the higher concentrations of Ra were observed in bottom waters, indicating the diffusion of 228Ra from sediments recently deposited as a potential source of the increased concentrations of this isotope when compared with others. The activity concentrations of the short-lived Ra isotopes were negligible, lower than the limit of the detection. Fluxes of Ra for Cananéia outlet are strongly influenced by tidal oscillations, which modulate the increase and decrease of Ra concentrations in response of the respective increase and decrease of waters salinity. In Iguape outlet and in hydrochemical stations performed along Ribeira do Iguape River it was observed a linear relationship between the amount of suspended matter and the increase of 228Ra activity concentration. When we evaluate qualitatively the differences in behavior of both long-lived Ra isotopes, the concentrations of 226Ra have not shown similar distribution to 228Ra. This demonstrates negligible contribution from advective porewaters and groundwater to the studied scenario. Dominant fluxes of trace-elements, radionuclides and nutrients have their main sources centered on fluvial, sediments and suspended matter compartiments.

Background/aim: In the Western world, the emergence of historical research on the effects of the social determinants of health has provided the discipline of public health with new insight into this aspect of population health complementing the more traditional focus on the history of medicine. The Islamic Caliphate was a dominant power in its time and little is known about its public health history. This thesis aims to provide a chronologically historical account of the policies taken in this period and analyse them in the light of modern theories of public health. Materials and Methods: This thesis employed a qualitative research technique. Known primary and secondary historical sources were examined and data translated and presented in a chronological order. Modern historical sources analysing the historical accounts of that era were also used. Policies affecting health were retrieved and analysed using modern day research into the same policies. Results: The analysis has resulted in a revisionist argument that policies affecting public health in a positive way did exist in a sophisticated manner in the Islamic Caliphate albeit in an inconsistent manner. The study complements the works of medical historians who identified a “Golden Age” in the later era of the Caliphate with advancements in medical science with a potential “Golden Age” in the early era related to the social determinants of health. Conclusion: This thesis provides for the first time a chronological study of policies affecting public health in an era of public health history that has not been studied before. In addition it provides for the first time a modern analysis of these policies.

The aim of this thesis is to conduct an empirically informed and philosophically robust ethical analysis of health-related human research undertaken during armed conflicts using the case study of Darfur, west Sudan (2004-2012). It adopts an empirical bioethics approach that combines the collection and analysis of empirical data with traditional philosophical analysis. The empirical data were collected using a systematic review of the studies that were conducted in Darfur during the chosen study period, followed by a qualitative project in Sudan. The qualitative findings were used to inform the philosophical discussion where the lines of arguments suggested by the project participants1 and the literature were scrutinized. This empirically-informed approach was chosen to overcome some of the shortcomings of the use of an abstract philosophical theorization when applied alone to an applied ethics field like humanitarian (research) ethics. Four main themes emerged and are discussed in the light of the relevant literature. The overall thesis is that the mainstream research ethical governance models are inadequate to ethically guide humanitarian activities as they lack the needed moral representativeness and operational feasibility. To overcome these problems, I argue that ethical oversight should shift from individualistic autonomy-based bioethics to relational autonomy and trust-based bioethics and from committee-based to community- situated governance models.

Successful synaptic transmission at the neuromuscular junction depends on the precise alignment of the nerve terminals with the postsynaptic specialization of the muscle fiber. It is increasingly apparent that this precision is achieved during development and maintained in the adult through signals exchanged between motoneurons and their target muscle fibers that serve to coordinate their spatial and temporal differentiation. There is increasing evidence that retinoic acid (RA), a derivative of Vitamin A, plays important roles in the development of nervous system. Here we specifically test this notion by examining the effect of RA on synaptic activity at developing neuromuscular synapse in Xenopus cell culture using whole-cell patch clamp recording. Bath application of RA rapidly (with a 10~15 min latency) and specifically enhances the spontaneous ACh secretion and the action of ¡@RA is reversible. The synaptic potentiation induced by RA was not occluded in the presence of protein synthesis inhibitor, Anisomycin and Cycloheximide,¡@suggesting this is transcription-independent. Selective RAR