Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Characterization of heparin-binding site of tissue transglutaminase:its importance in cell surface targeting, matrix deposition, and cell signaling

Tissue transglutaminase (TG2) is a multifunctional Ca2+ activated protein crosslinking enzyme secreted into the extracellular matrix (ECM), where it is involved in wound healing and scarring, tissue fibrosis, celiac disease and metastatic cancer. Extracellular TG2 can also facilitate cell adhesion important in wound healing through a non-transamidating mechanism via its association with fibronectin (FN), heparan sulphates (HS) and integrins. Regulating the mechanism how TG2 is translocated into the ECM therefore provides a strategy for modulating these physiological and pathological functions of the enzyme. Here, through molecular modelling and mutagenesis we have identified the HS binding site of TG2 202KFLKNAGRDCSRRSSPVYVGR222. We demonstrate the requirement of this binding site for translocation of TG2 into the ECM through a mechanism involving cell surface shedding of HS. By synthesizing a peptide NPKFLKNAGRDCSRRSS corresponding to the HS binding site within TG2, we also demonstrate how this mimicking peptide can in isolation compensate the RGD-induced loss of cell adhesion on FN via binding to syndecan-4, leading to activation of PKCa, pFAK-397 and ERK1/2 and the subsequent formation of focal adhesions and actin cytoskeleton organization. A novel regulatory mechanism for TG2 translocation into the extracellular compartment that depends upon TG2 conformation and the binding of HS is proposed.

Risk, seasonality and the asymmetric behaviour of stock returns

For some time there has been a puzzle surrounding the seasonal behaviour of stock returns. This paper demonstrates that there is an asymmetric relationship between systematic risk and return across the different months of the year for both large and small firms. In the case of both large and small firms systematic risk appears to be priced in only two months of the year, January and April. During the other months no persistent relationship between systematic risk and return appears to exist. The paper also shows that when systematic risk is priced, the size of the systematic risk premium is higher for large firms than for small firms and varies significantly across the months of the year.

Risk homeostasis theory in simulated environments

This thesis has two aims. First, it sets out to develop an alternative methodology for the investigation of risk homeostasis theory (RHT). It is argued that the current methodologies of the pseudo-experimental design and post hoc analysis of road-traffic accident data both have their limitations, and that the newer 'game' type simulation exercises are also, but for different reasons, incapable of testing RHT predictions. The alternative methodology described here is based on the simulation of physical risk with intrinsic reward rather than a 'points pay-off'. The second aim of the thesis is to examine a number of predictions made by RHT through the use of this alternative methodology. Since the pseudo-experimental design and post hoc analysis of road-traffic data are both ill-suited to the investigation of that part of RHT which deals with the role of utility in determining risk-taking behaviour in response to a change in environmental risk, and since the concept of utility is critical to RHT, the methodology reported here is applied to the specific investigation of utility. Attention too is given to the question of which behavioural pathways carry the homeostasis effect, and whether those pathways are 'local' to the nature of the change in environmental risk. It is suggested that investigating RHT through this new methodology holds a number of advantages and should be developed further in an attempt to answer the RHT question. It is suggested too that the methodology allows RHT to be seen in a psychological context, rather than the statistical context that has so far characterised its investigation. The experimental findings reported here are in support of hypotheses derived from RHT and would therefore seem to argue for the importance of the individual and collective target level of risk, as opposed to the level of environmental risk, as the major determinant of accident loss.

Real options and multinational investments : an empirical study of risk, performance and organisational awareness

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT This thesis is a cross-disciplinary study of the empirical impact of real options theory in the fields of decision sciences and performance management. Borrowing from the economics, strategy and operations research literature, the research examines the risk and performance implications of real options in firms’ strategic investments and multinational operations. An emphasis is placed on the flexibility potential and competitive advantage of multinational corporations to explore the extent to which real options analysis can be classified as best practice in management research. Using a combination of qualitative and quantitative techniques the evidence suggests that, if real options are explored and exploited appropriately, real options management can result in superior performance for multinational companies. The qualitative findings give an overview of the practical advantages and disadvantages of real options and the statistical results reveal that firms which have developed a high awareness of their real options are, as predicted by the theory, able to reduce their downside risk and increase profits through flexibility, organisational slack and multinationality. Although real options awareness does not systematically guarantee higher returns from operations, supplementary findings indicate that firms with evidence of significant investments in the acquisition of real options knowledge tend to outperform competitors which are unaware of their real options. There are three contributions of this research. First, it extends the real options and capacity planning literature to path-dependent contingent-claims analysis to underline the benefits of average type options in capacity allocation. Second, it is thought to be the first to explicitly examine the performance effects of real options on a sample of firms which have developed partial capabilities in real options analysis suggesting that real options diffusion can be key to value creation. Third, it builds a new decision-aiding framework to facilitate the use of real options in projects appraisal and strategic planning.

Calendar effects and the pricing of risk:the UK evidence

For some time there has been a puzzle surrounding the seasonal behaviour of stock returns. This paper demonstrates that there is an asymmetric relationship between risk and return across the different months of the year. The paper finds that systematic risk is only priced during the months of January, April and July. Variance risk and firm size are priced during several months of the year including January. An analysis of the relative behaviour of size based securities reveals that firm capitalization makes a valuable contribution to the magnitude of risk premiums.

Knowledge engineering for mental-health risk assessment and decision support

Mental-health risk assessment practice in the UK is mainly paper-based, with little standardisation in the tools that are used across the Services. The tools that are available tend to rely on minimal sets of items and unsophisticated scoring methods to identify at-risk individuals. This means the reasoning by which an outcome has been determined remains uncertain. Consequently, there is little provision for: including the patient as an active party in the assessment process, identifying underlying causes of risk, and eecting shared decision-making. This thesis develops a tool-chain for the formulation and deployment of a computerised clinical decision support system for mental-health risk assessment. The resultant tool, GRiST, will be based on consensual domain expert knowledge that will be validated as part of the research, and will incorporate a proven psychological model of classication for risk computation. GRiST will have an ambitious remit of being a platform that can be used over the Internet, by both the clinician and the layperson, in multiple settings, and in the assessment of patients with varying demographics. Flexibility will therefore be a guiding principle in the development of the platform, to the extent that GRiST will present an assessment environment that is tailored to the circumstances in which it nds itself. XML and XSLT will be the key technologies that help deliver this exibility.

Premature cardiovascular events and mortality in south Asians with type 2 diabetes in the United Kingdom Asian Diabetes Study - effect of ethnicity on risk

Background/Aim - People of south Asian origin have an excessive risk of morbidity and mortality from cardiovascular disease. We examined the effect of ethnicity on known risk factors and analysed the risk of cardiovascular events and mortality in UK south Asian and white Europeans patients with type 2 diabetes over a 2 year period. Methods - A total of 1486 south Asian (SA) and 492 white European (WE) subjects with type 2 diabetes were recruited from 25 general practices in Coventry and Birmingham, UK. Baseline data included clinical history, anthropometry and measurements of traditional risk factors – blood pressure, total cholesterol, HbA1c. Multiple linear regression models were used to examine ethnicity differences in individual risk factors. Ten-year cardiovascular risk was estimated using the Framingham and UKPDS equations. All subjects were followed up for 2 years. Cardiovascular events (CVD) and mortality between the two groups were compared. Findings - Significant differences were noted in risk profiles between both groups. After adjustment for clustering and confounding a significant ethnicity effect remained only for higher HbA1c (0.50 [0.22 to 0.77]; P?=?0.0004) and lower HDL (-0.09 [-0.17 to -0.01]; P?=?0.0266). Baseline CVD history was predictive of CVD events during follow-up for SA (P?and short period of follow-up are key limitations. Longer follow-up is required to see if the observed differences between the ethnic groups persist. Conclusion - South Asian patients with type 2 diabetes in the UK have a higher cardiovascular risk and present with cardiovascular events at a significantly younger age than white Europeans. Enhanced and ethnicity specific targets and effective treatments are needed if these inequalities are to be reduced.

Understanding the IT-related attitudes and needs of persons with age-related macular degeneration : a case study

In the UK, 20 per cent of people aged 75 years and over are living with sight loss; this percentage is expected to increase as the population ages (RNIB, 2011). Age-Related Macular Degeneration (AMD) is the UK’s leading cause of severe visual impairment amongst the elderly. It accounts for 16,000 blind/partial sight registrations per year and is the leading cause of blindness among people aged 55 years and older in western countries (Bressler, 2004). Our ultimate goal is to develop an assistive mobile application to support accurate and convenient diet data collection on which basis to then provide customised dietary advice and recommendations in order to help support individuals with AMD to mitigate their ongoing risk and retard the progression of the disease. In this paper, we focus on our knowledge elicitation activities conducted to help us achieve a deep and relevant understanding of our target user group. We report on qualitative findings from focus groups and observational studies with persons with AMD and interviews with domain experts which enable us to fully appreciate the impact that technology may have on our intended users as well as to inform the design and structure of our proposed mobile assistive application.

Advancing age and bleeding risk are the strongest barriers to anticoagulant prescription in atrial fibrillation

In clinical practice many patients with atrial fibrillation (AF) at high thromboembolic risk fail to receive adequate oral anticoagulation (OAC) [1]. The complex management of anticoagulant therapy [frequent international normalised ratio (INR) monitoring because of narrow therapeutic window, interaction with food and alcohol, concomitant medications and comorbities], the overestimation of bleeding risk and the underestimation of stroke risk, may partially explain physicians' reluctance to prescribe anticoagulation. In the current issue of Age and Ageing, Pugh and Mead [2] report a systematic review on physicians' attitudes concerning anticoagulant treatment among AF patients. Through surveys (questionnaire, clinical vignette and interview) on hypothetical case scenarios, they have identified the barriers to effective anticoagulant prescription, as follows: increasing age, bleeding risk or previous bleeding, fall risk, co-morbidities (e.g. chronic alcoholism or cognitive impairment) and lack of compliance. In particular, advanced age has been reported as the most striking reason for with-holding anticoagulation, while risk of falls and previous bleeding are also disproportionate barriers to warfarin prescription.

Describing and communicating uncertainty within the semantic web

The Semantic Web relies on carefully structured, well defined, data to allow machines to communicate and understand one another. In many domains (e.g. geospatial) the data being described contains some uncertainty, often due to incomplete knowledge; meaningful processing of this data requires these uncertainties to be carefully analysed and integrated into the process chain. Currently, within the SemanticWeb there is no standard mechanism for interoperable description and exchange of uncertain information, which renders the automated processing of such information implausible, particularly where error must be considered and captured as it propagates through a processing sequence. In particular we adopt a Bayesian perspective and focus on the case where the inputs / outputs are naturally treated as random variables. This paper discusses a solution to the problem in the form of the Uncertainty Markup Language (UncertML). UncertML is a conceptual model, realised as an XML schema, that allows uncertainty to be quantified in a variety of ways i.e. realisations, statistics and probability distributions. UncertML is based upon a soft-typed XML schema design that provides a generic framework from which any statistic or distribution may be created. Making extensive use of Geography Markup Language (GML) dictionaries, UncertML provides a collection of definitions for common uncertainty types. Containing both written descriptions and mathematical functions, encoded as MathML, the definitions within these dictionaries provide a robust mechanism for defining any statistic or distribution and can be easily extended. Universal Resource Identifiers (URIs) are used to introduce semantics to the soft-typed elements by linking to these dictionary definitions. The INTAMAP (INTeroperability and Automated MAPping) project provides a use case for UncertML. This paper demonstrates how observation errors can be quantified using UncertML and wrapped within an Observations & Measurements (O&M) Observation. The interpolation service uses the information within these observations to influence the prediction outcome. The output uncertainties may be encoded in a variety of UncertML types, e.g. a series of marginal Gaussian distributions, a set of statistics, such as the first three marginal moments, or a set of realisations from a Monte Carlo treatment. Quantifying and propagating uncertainty in this way allows such interpolation results to be consumed by other services. This could form part of a risk management chain or a decision support system, and ultimately paves the way for complex data processing chains in the Semantic Web.

Effectiveness and uptake of screening programmes for coronary heart disease and diabetes:a realist review of design components used in interventions

Objective - To evaluate behavioural components and strategies associated with increased uptake and effectiveness of screening for coronary heart disease and diabetes with an implementation science focus. Design - Realist review. Data sources - PubMed, Web of Knowledge, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register and reference chaining. Searches limited to English language studies published since 1990. Eligibility criteria - Eligible studies evaluated interventions designed to increase the uptake of cardiovascular disease (CVD) and diabetes screening and examined behavioural and/or strategic designs. Studies were excluded if they evaluated changes in risk factors or cost-effectiveness only. Results - In 12 eligible studies, several different intervention designs and evidence-based strategies were evaluated. Salient themes were effects of feedback on behaviour change or benefits of health dialogues over simple feedback. Studies provide mixed evidence about the benefits of these intervention constituents, which are suggested to be situation and design specific, broadly supporting their use, but highlighting concerns about the fidelity of intervention delivery, raising implementation science issues. Three studies examined the effects of informed choice or loss versus gain frame invitations, finding no effect on screening uptake but highlighting opportunistic screening as being more successful for recruiting higher CVD and diabetes risk patients than an invitation letter, with no differences in outcomes once recruited. Two studies examined differences between attenders and non-attenders, finding higher risk factors among non-attenders and higher diagnosed CVD and diabetes among those who later dropped out of longitudinal studies. Conclusions - If the risk and prevalence of these diseases are to be reduced, interventions must take into account what we know about effective health behaviour change mechanisms, monitor delivery by trained professionals and examine the possibility of tailoring programmes according to contexts such as risk level to reach those most in need. Further research is needed to determine the best strategies for lifelong approaches to screening.

Before and after modelling:risk knowledge management is required

Risk and knowledge are two concepts and components of business management which have so far been studied almost independently. This is especially true where risk management is conceived mainly in financial terms, as, for example, in the banking sector. The banking sector has sophisticated methodologies for managing risk, such as mathematical risk modeling. However. the methodologies for analyzing risk do not explicitly include knowledge management for risk knowledge creation and risk knowledge transfer. Banks are affected by internal and external changes with the consequent accommodation to new business models new regulations and the competition of big players around the world. Thus, banks have different levels of risk appetite and policies in risk management. This paper takes into consideration that business models are changing and that management is looking across the organization to identify the influence of strategic planning, information systems theory, risk management and knowledge management. These disciplines can handle the risks affecting banking that arise from different areas, but only if they work together. This creates a need to view them in an integrated way. This article sees enterprise risk management as a specific application of knowledge in order to control deviation from strategic objectives, shareholders' values and stakeholders' relationships. Before and after a modeling process it necessary to find insights into how the application of knowledge management processes can improve the understanding of risk and the implementation of enterprise risk management. The article presents a propose methodology to contribute to providing a guide for developing risk modeling knowledge and a reduction of knowledge silos, in order to improve the quality and quantity of solutions related to risk inquiries across the organization.

Milk feeding, solid feeding, and obesity risk:a review of the relationships between early life feeding practices and later adiposity

Childhood obesity is a major health issue with associated ill-health consequences during childhood and into later adolescence and adulthood. Given that eating behaviors are formed during early childhood, it is important to evaluate the relationships between early life feeding practices and later child adiposity. This review describes and evaluates recent literature exploring associations between child weight and the mode of milk feeding, the age of introducing solid foods and caregivers’ solid feeding practices. There are many inconsistencies in the literature linking early life feeding to later obesity risk and discrepancies may be related to inconsistent definitions, or a lack of control for confounding variables. This review summarizes the literature in this area and identifies the need for large scale longitudinal studies to effectively explore how early life feeding experiences may interact with each other and with nutritional provision during later childhood to predict obesity risk.

Resilience and adaptation of small and medium-sized enterprises to flood risk

Purpose – The UK has experienced a number of flood events in recent years, and the intensity and frequency of such events are forecast to further increase in future due to changing climatic conditions. Accordingly, enhancing the resilience of small and medium-sized enterprises (SMEs) – which form an important segment in a society – to flood risk, has emerged as an important issue. However, SMEs often tend to underestimate the risk of flooding which tends to have a low priority in their business agenda. The purpose of this paper is to undertake an investigation of adaptation to the risk of flooding considering community-level measures, individual-level property protection, and business continuity and resilience measures. Design/methodology/approach – A total of four short case studies were conducted among SMEs to identify their response to flood risk, and what measures have been undertaken to manage the risk of flooding. Findings – It was observed that SMEs have implemented different property-level protection measures and generic business continuity/risk management measures, based on their requirements, to achieve a desired level of protection. Practical implications – SMEs are likely to positively respond to property-level adaptation following a post-flood situation. It is important that information such as costs/benefits of such measures and different options available are made accessible to SMEs affected by a flood event. Social implications – Implementation of property-level adaptation measures will contribute towards the long term adaptation of the existing building stock to changing climatic conditions. Originality/value – The paper contributes towards policy making on flood risk adaptation and SME decision making, and informs policy makers and practitioners.