Summary 1) Background Drug-eluting stents (DES) reduce in-stent restenosis, hitherto a frequent complication of percutaneous coronary intervention (PCI). Despite the reduction in recurrent symptoms and the need for repeat procedures, only highly selected patient groups with simple coronary lesions were studied in the initial trials, and long-term outcome or safety data were initially limited. The lack of long term data was compounded by reports of late stent thrombosis, potentially threatening the safety of the device. DES are more expensive than bare metal stents (BMS), so there is a significant increase the procedural cost of PCI. The uptake of DES in clinical practice created pressure on healthcare budgets leading to explicit rationing in some countries. This thesis comprises a programme of original work addressing three related aspects of DES use: DES use in clinical practice (Scotland and internationally), “off-label” use of DES and appropriate use of DES (a modified Delphi consensus study). 2) Drug-eluting stent use in clinical practice Relatively little was known about the actual application of DES in clinical practice. Anecdotal accounts suggested there were geographical practice variations within Scotland and internationally. Scottish practice was analysed with the aim of determining whether DES use varied between hospitals and operators within the Scottish NHS beyond the influence of clinical factors. In examining international practice the aim was to show whether the adoption and use of DES varied between countries and to determine whether practice changed after the stent thrombosis controversy. a. Clinical practice variation within Scotland - methods and results Using data from the Scottish Coronary Revascularisation Registry, multi-level logistic regression analysis was performed, analysing for variations in DES use at hospital, operator and patient level. Overall, DES were used in 47.6% of lesions, but varied between hospitals (range 30.6%-61.8%, χ2=341.6, p<0.0001). There was significant between-operator variation in the null model. This was attenuated by the addition of hospital as a fixed effect. Nonetheless, the final model demonstrated significant between-operator variability and between-hospital variation, after case-mix adjustment. b. Drug-eluting stent use internationally - methods and results This study involved collaboration between centres from four countries with established PCI registries: APPROACH Registry (Alberta, Canada), BWGIC (Belgium), Mayo Clinic PCI Registry (USA) and the Scottish Coronary Revascularisation Registry. Customised graphics software was employed to perform trend analysis examining variations in DES use over time, and by clinical sub-group. 178,504 lesions treated between January 2003 and September 2007 were included. In the Mayo Clinic Registry rapid adoption to a peak of 91% DES use for all lesions by late 2004 was observed. Alberta and Scotland showed delayed adoption with lower peak DES use, respectively 56 and 58% of lesions by early 2006. Adoption of DES in Belgium was more gradual and peak use of 35% lower than other registries. Reductions in DES use were seen in all datasets during 2006, though this varied in absolute and relative terms and by clinical sub-group. c. Conclusions Practice variations were found at operator and hospital level within Scotland and between countries internationally. Influences on stent choice in the “real world” are likely to be multi-factorial; on an international level, macro-economic forces exerting their influence through healthcare system regulation, payment systems, level of funding and central control are particularly important. It was also clear from the multilevel study of Scottish practice, however, that a clinical consensus does not exist. 3) “Off-label” use of drug-eluting stents DES are often used for “off-label” indications, untested in RCTs, where observational studies demonstrate complications are higher when compared to “on-label” use. The aim was to determine whether clinical outcomes differ following DES and BMS implantation in a patient cohort defined by DES “off-label” indications. a. Methods and results Patients who underwent coronary stenting for an “off-label” indication between January 2003 and September 2005 in Scotland were included. Clinical outcomes were determined using linkage to national admission and death databases. Propensity scores were calculated using important baseline variables and DES were matched to BMS on a one-to-one basis to provide a fair comparison. The final study population comprised 1,642 well matched patients. Event-free survival was calculated over 24 months using the Kaplan-Meier method. All-cause death was more common following BMS during follow-up. No difference in the rates of MI was noted. Target vessel revascularisation was reduced in patients treated with DES. b. Conclusions The largely reassuring findings of this study should be seen in the context of a subsequent growing body of literature also suggesting similar risks for DES and BMS when compared for both on-label and off-label use. Although the benefits of DES were evident, the absolute reduction in TVR was lower than previously demonstrated in RCTs. 4) Appropriate use of drug-eluting stents - a modified Delphi consensus study Best practice with respect to stent selection during PCI was poorly defined, as evidenced by the lack of detailed clinical guidance on the use of DES and wide practice variation demonstrated. It was not clear whether in any given setting there had been either underuse - potentially forfeiting the benefits of DES, or overuse - where benefits may be outweighed by risks. The aim was to use an expert panel to develop criteria for the appropriate use of DES using the modified Delphi method, to determine the extent to which current practice in Scotland met the appropriateness criteria and to validate the criteria by analysing clinical outcomes a. Methods, results, conclusions Consensus criteria for appropriate DES use were defined using a modified Delphi questionnaire. Expert panelists were used to define levels of appropriate use and were compared to clinical practice. The results suggested that current overall rates of DES use are acceptable. Better targeting of DES to the most appropriate lesions may be possible with the aims of reducing the known geographical inequities and maximising clinical benefit. Finally, using similar methods to chapter 4, it was shown that underuse of DES in appropriate patients was associated with higher levels of target vessel revascularisation without any difference in MI or death.

There is increasing evidence to support a role for vascular oxidative stress in the development of endothelial dysfunction and coronary artery disease (CAD). The prevalence of CAD in patients with type 2 diabetes (T2D) is more than ten times greater than in the general population and CAD patients with T2D display poorer clinical outcomes than those without. Previous investigations carried out within this laboratory have demonstrated endothelial dysfunction and elevated superoxide (O2-) production throughout the vessel wall in saphenous veins from patients with advanced CAD. However, the molecular basis for these findings was not investigated, nor was the effect of T2D. Consequently, the aim of this study was to investigate a number of molecular determinants of oxidative stress in primary human saphenous vein endothelial cells (HSVECs) from CAD patients both with and without T2D, the hypothesis being that oxidative stress leads to endothelial dysfunction in CAD and is exacerbated in those patients with T2D. Initial experiments confirmed the findings of previous studies, revealing significantly elevated O2- levels and impaired endothelium-dependent relaxation in portions of saphenous vein from patients with CAD related to those from healthy control subjects. In addition, results demonstrated more severe endothelial dysfunction in vessels from CAD patients with T2D relative to those CAD patients without this additional cardiovascular risk factor. Attempts to characterise cellular sources of elevated O2- production in the endothelium of patients with CAD revealed that while HSVEC endothelial nitric oxide synthase (eNOS) is not a major source of O2- generation in CAD, nicotinamide adenine (phosphate) dinucleotide (NAD(P)H) oxidase contributes to excess O2- production in the endothelium of patients with this cardiovascular disease. Further cellular investigation revealed a significant increase in expression of mitochondrial superoxide dismutase (SOD2) in HSVECs from CAD patients, in particular those with T2D. Mitochondrially-derived reactive oxygen species (mtROS) are reported to contribute to oxidative stress and endothelial dysfunction in CAD and T2D and, as such, this increase in SOD2 expression is likely to represent an adaptive response to elevated mitochondrial O2- production. In addition, analysis of gene expression microarray data revealed differential expression of a number of genes potentially linked to mitochondrial function, serving to support a key role for mitochondrial dysfunction in the pathogenesis of CAD and T2D. Additional molecular studies focused on AMP-activated protein kinase (AMPK). Proposed as a candidate target for therapeutic intervention in endothelial dysfunction, AMPK stimulates eNOS, leading to nitric oxide (NO) production in cultured endothelial cells. Furthermore, it has recently been reported that endothelial AMPK is activated in a mtROS-mediated manner. With SOD2 expression data indicating an increase in mtROS production in the endothelium of patients with CAD, AMPK activity was investigated and compared in HSVECs isolated from these patients and control subjects. AMPK activity was significantly greater in cells from patients with CAD, despite no change in activity of upstream kinases, LKB1 and Ca2+/calmodulin-dependent kinase kinase (CaMKK). On stratifying CAD patients according to the presence of T2D, AMPK activity was found to be significantly increased in the endothelium of those patients with CAD and T2D as compared to those with CAD alone. Given the potentially elevated levels of mtROS production in the endothelium of patients with CAD, it seemed likely that endothelial AMPK activation in CAD patients was occurring in an mtROS-mediated manner and that this activation was enhanced in those CAD patients with T2D who display more severe endothelial dysfunction and increased SOD2 expression, consistent with increased mtROS production. In order to test this hypothesis, HSVECs isolated from vessels of CAD patients were treated with the mitochondria-targeted antioxidant, MitoQ10. Results demonstrated a significant decrease in AMPK activation in cells from those CAD patients with T2D on treatment with MitoQ10. The same effect was not seen in cells from CAD patients without T2D. These findings indicate that AMPK is activated in a mtROS-mediated manner in endothelial cells isolated from CAD patients with T2D and suggest a role for the kinase in defence against oxidative stress and endothelial dysfunction in these individuals. In summary, a wide range of molecular techniques have been employed to investigate cellular mechanisms underlying the oxidative stress and endothelial dysfunction associated with CAD. Results suggest mitochondria contribute to the increased O2- production and endothelial dysfunction observed in vessels from CAD patients. In addition, findings indicate a novel, mtROS-mediated activation of AMPK in the endothelium of patients with CAD and T2D. Therefore, mitochondria-targeted antioxidants, used in combination with pharmacological activators of AMPK, may have enhanced potential in prevention and treatment of coronary artery disease in patients with type 2 diabetes.

Despite 100 years after the discovery of thyroxine, controversy still exists regarding optimal thyroid hormone replacement therapy. Several anecdotal reports suggest that thyroxine alone therapy does not normalise psychological wellbeing. My cross-sectional study (n=1922) provided the first evidence in support of the hypothesis that a small proportion of patients on thyroxine alone therapy have increased psychological morbidity despite having normal TSH (publication 1). My second study was the largest randomised placebo controlled study to date to compare the effects of thyroxine alone and combined T3/T4 therapy over a 12 months period. This categorically proved that thyroxine alone therapy should be the first choice for hypothyroid patients (publication 2). Further genetic analysis of the deiodinase genes showed that a sub-group of hypothyroid patients with an SNP on D2 gene do have reduced psychological wellbeing on thyroxine alone therapy and improve on combined T3/T4 therapy compared to those without (publication 5). Both these findings were shown only by our study and were possible because of the large size (n=700). Detailed analysis of the various thyroid hormones and their ratio from our study showed that in addition to TSH, free T4 should be taken into account when treating hypothyroid patients (publication 4). My pharmacokinetic study provided the crucial and first evidence of the profiles of thyroid hormones on once a day combined T3/T4 therapy, highlighting the need to use either slow-release T3 or multiple doses of T3 in a day (publication 3). Our invited commentary and review (publications 6-8 & 10) have highlighted the importance of “individualised set points” for thyroid hormones, the complexity of thyroid hormone transport and actions as well as an algorithm for approaching hypothyroid patients. My other work (publication 9) was the first to test the possibility and provided the first evidence of deiodinase gene polymorphisms affecting circulating thyroid hormone levels and their possible role in psychological wellbeing in normal population. Thus, my work in the area, “Psychological wellbeing in patients of thyroid hormone replacement therapy” has provided several landmark findings, resulting in 10 publications including 4 in JCEM, 2 in Lancet and 1 in Clinical Endocrinology.

The aim of this research was to explore the potential of routinely collected primary care data to support the identification of individuals for cardiovascular risk reduction. The work involved a systematic literature review of reminder interventions operating at the point of care; a randomised controlled trial of a novel software tool to facilitate the targeting of individuals at risk of cardiovascular disease; and an exploration of qualitative issues relevant to the challenge of cardiovascular risk reduction in current practice. The Systematic review resulted in a narrative synthesis and a meta-analysis. It concluded that reminder interventions are generally effective at changing practitioner behaviour, but the effect is inconsistent, probably dependent on organisational context, and difficult to predict. The e-Nudge trial involved 19 practices in Coventry and Warwickshire, who used the e-Nudge software tool for two years. This tool was programmed for the project by the clinical software company EMIS. Whilst the primary outcome (cardiovascular event rate) was not significantly reduced in this timescale, a beneficial effect was demonstrated on the adequacy of data to support risk estimation and on the visibility of the at risk population. A new means of addressing the problem of undiagnosed and late-diagnosed diabetes was also discovered. Qualitative aspects of this area of care are presented through a discussion of ethical issues, a limited series of interviews with members of the public included in the appendix, and extensive field notes taken throughout the research. These provide some context in support of the e-Nudge trial. Routinely collected data of UK general practice provide a potentially rich resource to support primary cardiovascular disease prevention, but practical, ethical and conceptual issues must all be addressed to optimise their impact. This conclusion forms the thesis to be explored and justified through this dissertation.

This thesis has investigated the role of patient held beliefs about injury and recovery in the development of late whiplash syndrome (LWS) following an acute whiplash injury. Beliefs about injury and recovery have the potential to influence outcome. These beliefs are potentially modifiable through physiotherapy management and gaining greater understanding into how they influence outcome can potentially improve physiotherapy management of acute whiplash injuries. Mixed methods were used to investigate the role of these beliefs in the development of LWS. Following a systematic literature review, a prospective cohort study was carried out to identify risk factors for LWS as well as Neck Disability Index Scores and participant perceived improvement at follow up. This was complemented by a qualitative study designed to gain greater insight into the patient’s experience of recovering from a whiplash injury. Patients’ expectations of outcome were found to influence the development of LWS, in particular, their expectations of time to recovery. Patients’ expectations of treatment benefit were found to influence outcome to a lesser degree. The patients’ belief about their ability to cope with their neck problem (self-efficacy) was shown to influence outcome in the short term but not long term follow up. The use of passive coping strategies may moderate the influence of these types of beliefs. The qualitative study highlighted the importance of realistic expectations, the value of reassurance from health professionals and how the patient’s understanding of pain are important in identifying potential barriers to recovery. This thesis has also presented detailed information about the clinical presentation of individuals who have sustained a whiplash injury and explored patterns of recovery amongst individuals. This will help clinicians to understand the nature of whiplash injuries and how they impact on patients which has the potential to improve patient management.

This thesis consists of three papers, a literature review, an empirical paper and a reflective paper. The main focus of the literature review is on ‘understanding of minds’ and the development of this ability in siblings of children with a diagnosis on the autism spectrum (DAS). Evidence from clinical and non-clinical populations suggests that this group may be particularly vulnerable with regard to developing difficulties associated with an understanding of minds. Methodological issues are discussed and the findings are summarised with particular reference to clinical and ethical implications. The empirical paper reports on a study of factors associated with the wellbeing of parents of children with DAS. Measures of parental competence, child difficulties, family cohesion, relationship satisfaction and the impact of the child with DAS on the parental relationship and siblings, were all obtained from parents of school age children with DAS. Parental competence, depression in the other partner, and family and relationship variables were found to be associated with parental wellbeing. Parental stress was predicted by child pro-social behaviour. Differences were found between mothers and fathers on a number of variables. In addition to pro-social behaviour, maternal stress was further predicted by child behaviour problems. Maternal depression was predicted by age, the impact of the child on the parental relationship and the impact of the child on siblings. Results were considered within the context of a number of methodological issues. Implications for clinical interventions for families of children with DAS were discussed. The thesis concludes with reflective material drawn from observations made whilst recruiting participants, collecting data and by contact with research participants. The paper summarizes with an account of the areas of learning arising from these reflections.

The role of the Clinical Psychologist has developed to incorporate that of the reflective practitioner. This thesis aims to consider how reflective practice is incorporated into personal and professional development by clinical psychologists and trainees, and what impact it may have upon clinical practice. The first chapter of the thesis reviews the relevant literature from the past 10 years relating to the use of personal therapy among therapists and the links to reflective practice. The findings suggest that a number of studies demonstrate some benefits of personal therapy for therapists. However, the literature lacks a unified theoretical explanation of the processes that occur during personal therapy and of their influence on the development of reflective practice. This chapter offers a critique of the literature and proposes a potential model for understanding the development of reflexivity through personal therapy. Chapter Two is an exploratory study of clinical psychologists’ experiences of personal development groups whilst in training. The study adopts an interpretive phenomenological approach to the analysis and results are presented through four super-ordinate themes. The results suggest that personal development groups are seen as an effective method of developing reflective practice by participants. The processes which encourage and hinder this are also explored. The research suggests that engaging in reflective practice may become a luxury after training in some cases and this may result in an increased strain on the therapist. The clinical and research implications of the study are discussed. Chapter Three provides a reflective account of the author’s experience of the research process including; choosing the research topic, developing the research question, relationship to the research and personal experiences of personal development groups. The paper comments on the presence of bias within the research, the impact of conducting the study on the researcher and reflections on themes arising from the empirical paper.

No description available.

Depression is twice as prevalent among people with long-term physical conditions (LTPCs), and it confers an increased risk of additional morbidity and early mortality. Psychological interventions such as those based on cognitive behavioural therapy (CBT), can improve outcomes but widespread provision is problematic. Written emotional disclosure (WED) is a brief, inexpensive intervention that may offer a pragmatic solution. Its effects, however, are unclear, since reviews have drawn different conclusions and used inadequate methodology. A methodologically robust systematic review of RCTs, evaluating WEDs effects on psychological health and quality of life (QoL) in adults with LTPCs, concluded that WED may be effective for reducing negative affect including depression, and some associated outcomes. However, future endeavours must improve methodological rigor and explore WED for LTPCs impacted by negative affect. Type 2 diabetes is consistent with this specification yet understudied in WED. An exploratory RCT investigating WED for improving depressive symptom severity, and some secondary outcomes, in adults with Type 2 diabetes was undertaken. A test of WEDs anticipated effect, further exploration of this and an investigation of feasibility was initially intended. However, ethical and recruitment issues necessitated that the objectives be narrowed down to a focus on feasibility and a very much exploratory analysis of the effectiveness of WED. Recruitment was via primary care supplemented with online support groups, albeit secondary care was also attempted. The study identified that WED may be acceptably and feasibly implemented as part of general practice in the UK and for use with LTPCs in this context, specifically Type 2 diabetes. However, ethical and recruitment also issues necessitated delivery of WED to patients with none or very low-level depressive symptoms, for whom it may cause iatrogenic harm. However, a number of methodological issues substantially undermined these findings. Further research addressing the pitfalls associated with previous endeavours is required before consideration of WED in primary care for LTPCs including Type 2 diabetes.

Syringomyelia is a disease in which fluid-filled cavities, called syrinxes, form in the spinal cord causing progressive loss of sensory and motor functions. Invasive monitoring of pressure waves in the spinal subarachnoid space implicates a hydrodynamic origin. Poor treatment outcomes have led to myriad hypotheses for its pathogenesis, which unfortunately are often based on small numbers of patients due to the relative rarity of the disease. However, only recently have models begun to appear based on the principles of mechanics. One such model is the mathematically rigorous work of Carpenter and colleagues. They suggest that a pressure wave due to a cough or sneeze could form a shock-like elastic jump, which when incident at a stenosis, such as a hindbrain tonsil, would generate a transient region of high pressure within the spinal cord and lead to fluid accumulation. The salient physiological parameters of this model are reviewed from the literature and the assumptions and predictions re-evaluated from a mechanical standpoint. It is found that, while the spinal geometry does allow for elastic jumps to occur, their effects are likely to be weak and subsumed by the small amounts of damping that have been measured in the subarachnoid space. The analysis presented here does not support the elastic-jump hypothesis for syrinx formation. Furthermore, the site of maximum transpial pressure dierential due to a cough-induced pulse is most likely to be at the site of pulse origin|not, as supposed, at a distant reflection site. This suggests that there must be some other localising factor more critical to providing the necessary conditions for syrinx formation. Two coaxial tube models are developed that incorporate Darcy's law separately in the pial membrane and the spinal cord tissue. It is shown that permeability plays opposing roles in the spinal cord and pia for wave attenuation; the propagation of a pressure wave is aided by a less-permeable pia but a more-permeable spinal cord. This may have implications in a syringomyelic cord. To understand the dynamic interaction of the fluid and solid components of the spinal cord tissue Biot's theory of poroelasticity is employed. It is concluded that physiological frequencies are probably too low for poroelastic dissipation to be of signicance in such a soft and weak material as the spinal cord. Accumulating evidence in the last decade from animal studies implicates arterial pulsations in syrinx formation. In particular, Bilston and colleagues suggested that a phase difference between the pressure pulse in the spinal subarachnoid space and the perivascular spaces, due to a pathologically disturbed blood supply, could result in a net in flux of cerebrospinal fluid into the spinal cord. A lumped-parameter model is developed of the cerebrospinal system to investigate this conjecture. It is found that although this phase-lag mechanism may operate, it requires the spinal cord to have an intrinsic storage capacity due to the collapsibility of the contained venous reservoir. If this storage requirement is met then the results presented here suggest that, on mechanical grounds, a syringo-subarachnoid shunt may be a better surgical treatment option than a subarachnoid bypass for post-traumatic syringomyelia.