Computational case-based redesign for people with ability impairment: Rethinking, reuse and redesign learning for home modification practice

Home modification practice for people with impairments of ability involves redesigning existing residential environments as distinct from the creation of a new dwelling. A redesigner alters existing structures, fittings and fixtures to better meet the occupant's ability requirements. While research on case-based design reasoning and healthcare informatics are well documented, the reasoning and process of redesign and its integration with individual human functional abilities remains poorly understood. Developing a means of capturing redesign knowledge in the form of case documentation online provides a means for integrating and learning from individual case-based redesign episodes where assessment and interventions are naturally linked. A key aim of the research outlined in this thesis was to gain a better understanding of the redesign of spaces for individual human ability with the view to computational modelling. Consequently, the foundational knowledge underpinning the model development includes design, redesign, case-based building design and human functional ability. Case-based redesign as proposed within the thesis, is a method for capturing the redesign context, the residential environment, the modification and the transformational knowledge involved in the redesign. Computational simulation methods are traditionally field dependent. Consequently, part of the research undertaken within this thesis involved the development of a framework for analysing cases within an online case-studies library to validate redesign for individuals and a method of acquiring reuse information so as to be able to estimate the redesign needs of a given population based on either their environment or ability profile. As home modification for people with functional impairments was a novel application field, an explorative action-based methodological approach using computational modelling was needed to underpin a case-based reasoning method. The action-based method involved a process of articulating and examining existing knowledge, suggesting new case-based computational practices, and evaluating the results. This cyclic process led to an improvement cycle that included theory, computational tool development and practical application. The rapid explosion of protocols and online redesign communities that utilise Web technologies meant that a web-based prototype capable of acquiring cases directly from home modification practitioners online and in context was both desirable and achievable. The first online version in 1998-99, encoded home modification redesigns using static WebPages and hyperlinks. This motivated the full-scale more dynamic and robust HMMinfo casestudies prototype whose action-based development is detailed within this thesis. The home modification casestudies library results from the development and integration of a novel case-based redesign model in combination with a Human- Activity-Space computational ontology. These two models are then integrated into a relational database design to enable online case acquisition, browsing, case reuse and redesign learning. The application of the redesign ontology illustrates case reuse and learning, and presents some of the implementation issues and their resolution. Original contributions resulting from this work include: extending case-based design theory to encompass redesign and redesign models, distinguishing the importance of human ability in redesign and the development of the Human-Activity-Space ontology. Additionally all data models were combined and their associated inter-relationships evaluated within a prototype made available to redesign practitioners. v Reflective and practitioner based evaluation contributed enhanced understanding of redesign case contribution dynamics in an online environment. Feedback from redesign practitioners indicated that gaining informed consent to share cases from consumers of home modification and maintenance services, in combination with the additional time required to document a case online, and reticence to go public for fear of critical feedback, all contributed to a less than expected case library growth. This is despite considerable interest in the HMMinfo casestudies website as evidenced by web usage statistics. Additionally the redesign model described in this thesis has practical implications for all design practitioners and educators who seek to create new work by reinterpreting, reconstructing and redesigning spaces

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids:focus on the treatment of rheumatoid arthritis

Glucocorticoids (GCs) have powerful and potent anti-inflammatory and immunomodulatory effects in rheumatoid arthritis ( RA) and many other diseases. These effects are mediated by up to four different mechanisms of action: cytosolic glucocorticoid receptor (cGCR)-mediated classical genomic and rapid nongenomic effects, membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects and nonspecific non-genomic effects. On the basis of this detailed knowledge of mechanisms there are currently interesting approaches being considered that may lead to the development of GC drugs and GCR ligands with an improved benefit to side-effect ratio. Another interesting field of GC research is the phenomenon of GCR resistance. Several different mechanisms may mediate this phenomenon; among them are alterations in number, binding affinity, or phosphorylation status of the GCR. Other mechanisms of GC resistance being investigated are polymorphic changes and/or overexpression of (co-) chaperones, the increased expression of inflammatory transcription factors, overexpression of the GCR beta isoform, the multidrug resistance pump, and an altered mGCR expression

Morphological analysis of pits formed on Al 2024-T3 in chloride aqueous solution

It has been used a new image analysis method, based on segmentation by shape parameters, for pits morphology examination from Al 2024 aluminum-copper alloy in chloride aqueous solution. Corrosion behavior of this alloys in naturally aerated 3.5% NaCl solution has been investigated through open circuit potential measurements. Afterwards, pits have been characterized by image analysis taking density and size measurements right from corroded surfaces. Morphological investigation has been conducted for profiles, cut orthogonally from mean surface planes, and observed through light microscopy. Image analysis data could demonstrate that pits are wider than deep, evoluting for conical, quasi-conical or irregular shapes. Most pits have presented a quasi-conical morphology, but the wider ones have evoluted to an irregular shape influenced by sub-surface microstructure. Image analysis based on shape segmentation could enhance the differences on morphological behavior. (C) 2004 Elsevier B.V. All rights reserved

EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis

The objective was to develop evidence -based recommendations and a research and educational agenda for the non-pharmacological management of hip and knee osteoarthritis (OA). The multidisciplinary task force comprised 21 experts: nurses, occupational therapists, physiotherapists, rheumatologists, orthopaedic surgeons, general practitioner, psychologist, dietician, clinical epidemiologist and patient representatives. After a preliminary literature review, a first task force meeting and five Delphi rounds, provisional recommendations were formulated in order to perform a systematic review. A literature search of Medline and eight other databases was performed up to February 2012. Evidence was graded in categories I–IV and agreement with the recommendations was determined through scores from 0 (total disagreement) to 10 (total agreement). Eleven evidence-based recommendations for the nonpharmacological core management of hip and knee OA were developed, concerning the following nine topics: assessment, general approach, patient information and education, lifestyle changes, exercise, weight loss, assistive technology and adaptations, footwear and work. The average level of agreement ranged between 8.0 and 9.1. The proposed research agenda included an overall need for more research into non-pharmacological interventions for hip OA, moderators to optimise individualised treatment, healthy lifestyle with economic evaluation and long-term follow-up, and the prevention and reduction of work disability. Proposed educational activities included the required skills to teach, initiate and establish lifestyle changes. The 11 recommendations provide guidance on the delivery of non-pharmacological interventions to people with hip or knee OA. More research and educational activities are needed, particularly in the area of lifestyle changes