Rheumatoid Arthritis (RA) is a chronic auto-immune disease that causes in ammation in the joints. Left uncontrolled, this prolonged in ammation can lead to pain and structural damage, resulting in erosions to the bones and total breakdown of the surrounding cartilage. Structural joint damage, measured by plain radiographs, is an important outcome measure of RA. It provides an objective marker of disease activity to assess any improvements or failures of treatments in controlling for the disease. Increased long-term joint damage has been linked with increased functional disability and decreased quality of life for RA patients. While a range of studies have looked at radiographic outcomes from observational data, they tend to be restricted to historical cohorts, with little long-term data on how radiographic progression may have changed in line with changes in clinical management. Additionally, these studies have not used the appropriate statistical methods to account for non-normal data distributions and within-patient variation over time. As a result, the main aim of this thesis is to investigate the long-term progression of structural joint damage in patients with early RA. The speci c objectives were to; (1) investigate the current evidence base to identify common methods in measuring and analysing radiographic outcomes, (2) assess what statistical methods are most appropriate in modelling long-term radiographic data, (3) use these models to understand the natural progression of radiographic damage using data from two UK inception cohorts, and nally, (4) expand these models to investigate the long-term relationship of radiographic damage with two important clinical outcomes; disease activity and functional disability. The analysis is based on longitudinal data from two UK prospective, multi-centre, early RA observational cohorts. These cohorts represent two distinct eras in the management and treatment of RA, making them invaluable for investigating how key RA outcomes have progressed in clinical practice over time. Using multi-level count models, precise rates of radiographic progression for both cohorts are presented. The models look at how seropositive RA and increased disease activity are related to increased radiographic progression, and what impact this has on functional disability. The results show that rates of radiological damage have declined dramatically in recent years. Possible attributable factors to these declines include both milder disease and more e ective treatment strategies. Analysis of the earlier cohort (1986-2001) shows how seropositive RA and increased disease activity lead to clinically meaningful increases in radiological damage. Conversely, their impact on patients in the more recent cohort (2002-2011) suggest that their e ect on radiographic progression is reduced, where increases in radiological damage were not larger than clinically meaningful thresholds. This has large implications on the debate around the use of biologic therapies in patients with less severe RA. However more data is sorely needed, particularly long-term radiographic data from those patients on biologics treatments, before any de nitive conclusions can be made. The possible impact of these declines on functional disability appears to be relatively small. The analysis shows that radiographic damage is more strongly associated with functional disability in later disease, but there is little evidence to indicate that declines in radiographic damage has lead to large improvements in long-term functional disability. These ndings are explored within the framework of a dual-pathway model, which suggests that functional disability is caused by two distinct mechanisms, either structural joint damage, or through increased pain. Research so far has predominantly focused on pharmacological treatments in reducing in ammation. More research is needed to explore the role of psychosocial factors and pain perception in order to create a more holistic treatment programme for RA patients.

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Many researchers have highlighted the dire prospects for biodiversity in fragmented agricultural landscapes and stressed the need for increasing the area of, and connectivity between, natural ecosystems. Some have advocated the use of naturally regenerating forest ecosystems for sequestering atmospheric carbon, with opportunities for dual restoration and carbon benefits. However, no studies have explicitly explored the feasibility of obtaining such dual benefits from a regenerating woody ecosystem. This thesis aims to provide a detailed assessment of the restoration and carbon potential of Brigalow regrowth, an extensive naturally regenerating ecosystem throughout the pastoral regions of north eastern Australia. It combines observational, experimental and modelling techniques to describe the agricultural legacy of pastoral development, identify constraints to restoration and explore methods to remove these constraints. A review of existing ecological knowledge of Brigalow ecosystems is provided in chapter 3, along with discussion of policy and socio-economic issues that are likely to influence how and to what extent regrowth is utilised for restoration and carbon purposes in the Brigalow Belt. The review found restoring regrowth is likely to have benefits for a wide range of native flora and fauna, including the endangered bridled nailtail wallaby. Knowledge gaps exist relating to the landscape ecology of Brigalow regrowth and the impacts of management and climate change on carbon and restoration potential. Also, a conflict exists between short-term carbon sequestration and long-term restoration goals. Regional demand for high biomass regrowth as a carbon offset is likely to be high but ambiguities in carbon policy threaten to diminish the use of natural regrowth for reforestation projects. A large cross-sectional study of regrowth is presented in chapter 4. Data were analysed using multi-level / hierarchical Bayesian models (HBMs). Firstly, we found that repeated attempts at clearing Brigalow regrowth increases stem densities and densities remain high over the long term, particularly in high rainfall areas and on clay soils with deep gilgais. Secondly, higher density stands have slower biomass accumulation and structural development in the long term. Spatial extrapolations of the HBMs indicated that the central and eastern parts of the study region are most environmentally suitability for biomass accumulation, however these may not correspond to the areas that historically supported the highest biomass Brigalow forests. We conclude that carbon and restoration goals are largely congruent within regions of similar climate. At the regional scale however, spatial prioritisation of restoration and carbon projects may only be aligned in areas with higher carbon potential. Given the importance of stem density in determining restoration and carbon potential, an experimental thinning trial was established in dense Brigalow regrowth in southern Queensland (chapter 5). Four treatments were applied in a randomised block design and growth and mortality of a subset of stems was monitored for two years. Data were analysed using mixed-effects models and HBMs and the latter were subsequently used to parameterise an individual-based simulation model of stand structural development and biomass accumulation over 50 years. The main findings of this study were that growth and mortality of stems is influenced by the amount of space available to each stem (a neighbourhood effect) and that thinning accelerates structural development and increases woody species diversity. The examination of neighbourhood effects is taken further by considering drought-related mortality in a Eucalyptus savanna ecosystem (chapter 6). For this work a multi-faceted approach was employed including spatial pattern analyses and statistical models of stem survival to test three competing hypotheses relating to neighbourhood effects on drought related tree mortality. The main finding of this study was that neighbour density and microsite effects both influence drought-related mortality and the observed patterns can readily be explained by an interaction between these two factors. As a whole, this thesis contributes the following scientific insights: (1) restoration and carbon goals may be aligned for naturally regenerating woody ecosystems, but the degree of goal congruence will vary across the landscape in question, (2) while some woody ecosystems retain an excellent capacity to regenerate naturally, the agricultural legacy may still have long term effects on restoration and carbon potential, (3) neighbourhood effects that operate at the stem scale strongly influence dynamics at the ecosystem scale.

La conception des machines électriques a une longue tradition et l’approche « business as usual » est un processus itératif d’essais et d’erreur, certes convergent mais nécessairement stoppé prématurément, car trop couteux. Un perfectionnement récent a consisté à remplacer les prototypes et les maquettes par des prototypes virtuels, entièrement numériques, comme ceux fournis par la méthode des éléments finis. Néanmoins, le procédé s’arrête toujours sur une frustration car le concepteur n’est jamais sûr d’avoir exploré complètement l’espace de conception qui s’offre à lui. La démarche de conception optimale se propose d’améliorer ce processus en le guidant, c'est-à-dire en proposant une méthodologie, et en l’automatisant, c'est-à-dire en proposant des outils logiciels. Mais dans cette démarche apparaissent de nombreuses difficultés. Ainsi, les objectifs généraux de cette thèse sont multiples. Il s’agit de définir des problèmes d'optimisation spécifiques représentatifs des choix structurels et d’élaborer des benchmarks de référence : discret, multiphysique, multidisciplinaire, multi-objectif et multi-niveaux. Ensuite, il faut rechercher, adapter et qualifier les méthodes d'optimisation les mieux à même de résoudre ces problèmes. Enfin, les différentes méthodes d'optimisation proposées sont implantées et testées de façon à prouver leur efficacité et leur adaptation. Un objectif secondaire mais important est de les capitaliser et diffuser les connaissances élaborées / The design of electrical machinery has a long tradition and the business as usual approach is a tries and errors iterative process, certainly converging but necessarily stopped prematurely as too expensive. A recent upgrade has been to replace the prototypes and models by virtual prototypes, fully numerical, such as those provided by the finite element method. Nevertheless, the process stops always on a frustration, because the designer is never sure to have completely explored the design space that offers to him. The optimal design approach proposes to improve this process by guiding it, i.e. by proposing a methodology and by equiping it, i.e. by providing software tools. But in this approach many difficulties appear. Thus, the general objectives of this thesis are multiple. It is to define specific representative optimization problems of the structural choices and develop reference benchmarks of optimization: discrete, multi-physics, multidisciplinary, multi-objective and multi-level. Then, it must seek, adapt and describe the best optimization methods able to solve these problems. These methods are implemented and tested in order to prove their efficiency and adaptation. A secondary but important objective is to capitalize and disseminate the developed knowledge