Emotion processing and social participation following stroke : study protocol

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The importance of glucocorticoid delivery in the development of atherosclerosis

Elevated circulating glucocorticoids are causally linked to increased cardiovascular disease. Atherosclerosis is a key cardiovascular pathology, yet the contribution of glucocorticoids to underlying atherogenesis is unclear. Corticosteroid binding globulin (CBG) regulates glucocorticoid action by controlling systemic bioavailability, with only unbound ‘free’ glucocorticoids able to enter tissue and exert biological effects. Cleavage of CBG by neutrophil elastase (NE) is proposed to enhance bioavailability by reducing its affinity for glucocorticoids, elevating local ‘free’ glucocorticoid levels. Strikingly, Apoe-/- mice lacking NE display reduced atherosclerosis. This thesis addresses the hypothesis that CBG mediates atherogenesis by facilitating glucocorticoid action at sites of plaque development. First, the role of glucocorticoids and their regulation by CBG in atherogenesis was established in an adenovirus-induced murine model of atherosclerosis. Male C57Bl6/J mice were injected with recombinant adeno-associated viral vector serotype 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and fed a Western diet (21% fat; 0.21% cholesterol) for up to 18 weeks. Control mice were fed the same Western diet in the absence of AAV8-PCSK9. Brachiocephalic lesion development in AAV8-PCSK9- treated mice was accompanied by reduced hepatic Serpina6 (CBG) mRNA levels, in parallel with reduced circulating CBG binding capacity. Moreover, AAV8-PCSK9 treatment increased circulating NE protein levels, suggesting the ability of CBG to bind glucocorticoids may also be reduced in this model because of increased cleavage. Surprisingly, AAV8-PCSK9 treatment did not alter circulating total glucocorticoid levels. These data provide the first evidence of CBG dysregulation in this model of atherosclerosis. The increase in circulating NE levels in the AAV8-PCSK9 overexpression model of atherosclerosis resembles that seen in Apoe⁻/⁻ mice, which are resistant to atherosclerotic plaque development in the absence of NE. This suggests that NE may also play a role in atherogenesis in the PCSK9 overexpression model. To test this, male NE deficient mice (Ela⁻/⁻) and WT littermates were administered AAV8-PCSK9 and fed Western diet for 18 weeks. In contrast to published data from Apoe⁻/⁻/Ela-⁻/⁻ double-knockout mice, NE deficiency did not alter brachiocephalic lesion incidence, size, or composition (collagen, smooth muscle cell, and macrophage content), suggesting that NE does not play an important role in the development of lesions in this model of atherosclerosis. Additionally, deletion of NE did not alter total or free glucocorticoid levels in the circulation, indicating that NE-mediated CBG cleavage does not occur in the systemic circulation. The importance of CBG itself in regulating atherogenesis was explored next. To test the hypothesis that deletion of CBG will reduce lesion size through reduced glucocorticoid action, AAV8-PCSK9 was administered to mice lacking CBG (Cbg⁻/⁻) mice and wild type littermates which then received Western diet for 18 weeks. Total and free glucocorticoid levels were decreased in Cbg-/- mice. There was an apparent decrease in incidence of lesion development in the brachiocephalic artery of Cbg⁻/⁻ mice compared with WT controls; however, this did not achieve statistical significance (p=0.1312). This suggests that although CBG regulates the bioavailability of glucocorticoids this does not play an important role in the development of brachiocephalic lesions in the AAV8-PCSK9 model. Furthermore, method development of mass-spectrometry imaging (MSI) was able to detect and quantify local corticosterone in an aortic root lesion (n=1). In conclusion, this thesis presents data demonstrating the first glucocorticoid profiling of mice who develop inducible-atherosclerosis via AAV8-induced over-expression of PCSK9. Despite the reported role of NE in lesion development in the Apoe⁻/⁻ model, this thesis provides evidence that manipulation of CBG, either genetically or indirectly via NE, does not alter the development of lesions in this model. This suggests that the choice of model when investigating factors that influence atherogenesis should be given careful consideration. Future work may involve investigating the effect of NE and CBG deletion on alternative sites of lesion development, e.g., aortic root. Additionally, while this work does not support a role for changes in systemic glucocorticoid bioavailability in mediating plaque developing, advancement in steroid quantification by MSI may allow assessment of local glucocorticoid levels within various regions of atherosclerotic plaques to determine local glucocorticoid action

Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?

Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing’s syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease

A cross-sectional comparison of quality of life between physically active and underactive older men with prostate cancer

Men with prostate cancer experience many side effects and symptoms that may be improved by a physically active lifestyle. It was hypothesized that older men with prostate cancer who were physically active would report significantly higher levels of quality of life (QOL) as assessed by the WHOQOL-BREF and the WHOQOL-OLD. Of the 348 prostate cancer survivors who were invited to participate in the present postal survey, 137 men returned the questionnaires. Those who were physically active had significantly lower prostate specific antigen (PSA) scores and higher social participation than those insufficiently active. These findings offer some support for the benefits of physical activity (PA) within the prostate cancer population in managing the adverse side effects of their treatments on aspects of their QOL. Future research should more closely examine what types of PA best promote improvements in varying aspects of QOL and psychological well-being for prostate cancer survivors

Generation ZX(X)

This document discusses the design and development of Generation ZX(X), a hybrid multi-media event which explored how video games and performance can enhance and complement one another and enliven different types of historical data: oral herstories, lived experience, collective memory and audio-video archives.Generation ZX(X) was a hybrid of live and virtual components: an audiowalk, a social play session (3 video games were developed and played in a pop-up arcade), a film projection and a musical performance. For Generation ZX(X), I worked with third year Games and Art students and staff from Abertay University. The event took place on the 4th May 2018, in Camperdown Park, and at the JTC Furniture Group – the former Timex Camperdown factory. The event was developed as part of Mona Bozdog’s SGSAH ARCS (Applied Research Collaborative Studentship) PhD - Playing with Performance/ Performing Play. Creating hybrid experiences at the fringes of video games and performance.The project engaged with the living memory and heritage of the Timex factory in Dundee, and its aim was to reclaim and rewrite the history of the charged site on Harrison Road and to challenge the ‘official’ history of the local games industry. The project explored the hidden figures of the video games industry: the women who assembled the ZX Spectrum computers in the Timex factory in Dundee, and the ramifications that this labour had for the city’s development as one of UK’s leading games development and education centres. <br/

“We’re happy as we are”: the experience of living with possible undiagnosed dementia.

This is the author accepted manuscript. The final version is available from Cambridge University Press via the DOI in this record. It is estimated that a third of people in the United Kingdom with signs of dementia are living without a formal diagnosis. In Wales, the proportion is nearly half. Some explanations for the gap between prevalence of dementia and number of diagnoses include living with a long-term partner/spouse and systemic barriers to diagnosis. This study recruited participants from the Cognitive Function and Ageing Studies-Wales (CFAS-Wales) cohort, randomly selected from people aged over 65 living in two areas of Wales, who met study criteria for a diagnosis of dementia and did not have a record of a formal diagnosis in general practice records. We aimed to understand more about the contexts and circumstances of people who live with and cope with cognitive difficulties without having a formal diagnosis of dementia. We conducted qualitative interviews with six participants and their spouses, and additionally with four family members of three invited people who were unable to take part. Themes were generated using thematic analysis. We present the argument that there is an adaptive response to low service levels and a complex interaction between the expectations of levels of service, perceptions of the legitimacy of cognitive problems and the right to make demands on services. This paper concludes that more could be done to address barriers to diagnosis and treatment services for those living with symptoms of dementia, but that the value placed on diagnosis by some individuals might be lower than anticipated by government policy.Alzheimer's SocietyEconomic and Social Research Council (ESRC

The effect of visual support strategies on the quality of life of children with cerebral palsy and cerebral visual impairment/perceptual visual dysfunction in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: Cerebral visual impairment (CVI), including perceptual visual dysfunction (PVD), is common in children with cerebral palsy (CP). Inventories of questions relating to practical aspects of visual perception in everyday life, in particular the closed-ended Insight Questions Inventory (IQI), can be used to assess CVI/PVD. Studies linking responses to the inventory with specific visual support strategies, aimed at modifying the child's environment and/or behaviour to minimize the impact of the CVI/PVD, have been piloted. The IQI and tailored strategies have not been used in an African population, nor have they been tested in a controlled trial. This trial will compare the effectiveness of the IQI and linked visual support strategies versus general supportive treatments on the quality of life of children with CVI/PVD and CP through a randomized controlled trial. METHODS/DESIGN: This is a prospective, double-blind, parallel-arm, randomized controlled trial. The primary outcome is change in quality of life scores between the two arms of the trial at 6 weeks, assessed using the Paediatric Quality of Life Inventory (PedsQL) generic 4.0 and CP 3.0 module. All children will undergo baseline assessment including the Open Questions Inventory, IQI, PedsQL 3.0, PedsQL 4.0 generic, and the Strengths and Difficulties Questionnaire (SDQ). Eligible children with CP aged 4 years to < 16 years will be stratified and blocked by the age groups 4-9 and 10 to < 16 years and by Gross Motor Function Classification System (GMFCS) levels 1-3 and 4-5. Families in the intervention arm will receive tailored insight visual support strategies and telephone calls during the 6-week trial period. The control arm will receive standard treatment and the intervention after the 6-week trial period. Follow-up interviews will be performed in both arms at 6 weeks with a repeat administration of the PedsQL CP 4.0 and 3.0, the IQI and the SDQ. Secondary outcomes include a change in functional vision. DISCUSSION: This randomized controlled trial will provide evidence of the effectiveness of this intervention for children with CP in a resource-poor setting. TRIAL REGISTRATION: Pan African Clinical Trials Registration, PACTR201612001886396 . Registered on 3 December 2016

Increasing uptake of hepatitis C virus infection case- finding, testing, and treatment in primary care: evaluation of the HepCATT (Hepatitis C Assessment Through to Treatment) trial

Background Hepatitis C virus (HCV) infection is a key cause of liver disease but can be cured in more than 95% of patients. Around 70 000 people in England may have undiagnosed HCV infection and many more will not have been treated. Interventions to increase case-finding in primary care are likely to be cost-effective; however, evidence of effective interventions is lacking. The Hepatitis C Assessment Through to Treatment (HepCATT) trial assessed whether a complex intervention in primary care could increase case-finding, testing, and treatment of HCV.Aim To investigate the feasibility and acceptability of the HepCATT intervention.Design and setting A qualitative study with primary care practice staff from practices in the south west of England taking part in the HepCATT trial.Method Semi-structured interviews were carried out with GPs, nurses, and practice staff to ascertain their views of the HepCATT intervention at least 1 month after implementing the intervention in their practice. Normalisation process theory, which outlines the social processes involved in intervention implementation, informed thematic data analysis.Results Participants appreciated the HepCATT intervention for increasing knowledge and awareness of HCV. Although some initial technical difficulties were reported, participants saw the benefits of using the audit tool to systematically identify patients with HCV infection risk factors and found it straightforward to use. Participants valued the opportunity to discuss HCV testing with patients, especially those who may not have been previously aware of HCV risk. Future implementation should consider fully integrating software systems and additional resources to screen patient lists and conduct tests.Conclusion When supported by a complex intervention, primary care can play a crucial role in identifying and caring for patients with HCV infection, to help stem the HCV epidemic, and prevent HCV-related illnes

Increasing uptake of Hepatitis C virus infection case-finding, testing and treatment in primary care:HepCATT (Hepatitis C Assessment Through to Treatment Trial) qualitative evaluation

Hepatitis C virus (HCV) infection is a key cause of liver disease but can be cured in more than 95% of patients. Around 70 000 people in England may have undiagnosed HCV infection and many more will not have been treated. Interventions to increase case-finding in primary care are likely to be cost-effective; however, evidence of effective interventions is lacking. The Hepatitis C Assessment Through to Treatment (HepCATT) trial assessed whether a complex intervention in primary care could increase case-finding, testing, and treatment of HCV