Randomised Controlled Trials (RCTs) are regarded as a ‘gold standard’ technique to evaluate and compare clinical interventions. Strict ethical criteria dictate the participation of humans in clinical research, based on informed consent, voluntary decision making and putting patients’ interests first. Demand for RCTs in Trauma and Orthopaedics is high, but patient recruitment continues to pose a significant challenge, especially when the treatments being compared are obviously different. Lack of blinding, treatment preference and negative perception of random allocation to interventions are among the obstacles which need to be considered. Based on review and analysis of current knowledge, an attempt is made to develop a new recruitment process that incorporates high ethical standards and provision of the best possible clinical care for an individual patient. By integrating the principle of clinical equipoise, modern technology and statistical concepts, such as subjective probability, the Patient Eligibility Assessment through Clinical Equipoise (PEACE) framework has been introduced. This provides an alternative that could be used in trials where the fixed eligibility criteria approach is likely to fail. It was tested involving 77 real clinical cases from a national multi-centre trauma RCT, which compared contrasting treatments. A new trial recruitment approach aiming to avoid direct contact between a patient and a treating clinician was rolled out in the same trial. The feedback was collected from both the clinicians and the patients involved. Thematic analysis of 23 semi-structured interviews improved understanding of the various factors influencing patients’ decision about trial participation. Further typological analysis provided a valuable insight into the different attitudes that patients adopted when faced with the dilemma. In particular, that many are positive towards research involvement, but not comfortable with randomisation based on fixed eligibility criteria. According to these results, a new model for patient recruitment is suggested, which could be researched and tested in future trials.

This thesis aims to explore how individuals and family members have experienced and coped with a life changing diagnosis. Diagnoses are an integral part of medical, physical health and psychological settings. A diagnosis can significantly affect individuals and their families. This thesis explores how individuals and their family members can be supported to cope with a life changing diagnosis. Chapter one is a literature review investigating how religiosity is used by individuals newly diagnosed with breast cancer. After databases and manual searches, fourteen papers that met the inclusion criteria were critically evaluated. Despite the methodological constraints and the conceptual confusion surrounding religiosity, the predominant finding was the double pronged effect of religiosity. Some individuals found religious coping provided them with comfort and meaning making, whereas others found religious coping was associated with negative adjustment to the breast cancer diagnosis. The clinical implications of these findings are discussed in relation to how individuals can be supported using religiosity when diagnosed with breast cancer. Chapter two is a qualitative exploration of parents’ experiences of caring for their child diagnosed with Asperger Syndrome (AS) in adulthood. Eight participants were interviewed using a semi-structured interview and these were analysed using Interpretative Phenomenological Analysis (IPA). Three themes emerged: ‘Parenting the unknown’, ‘Services fumbling in the dark’ and ‘Fear of the future’. All themes were heavily influenced by the lack of understanding of AS amongst professionals and parents. These themes are considered in relation to service provisions for adults with AS and their parents. Chapter three is a reflective account of the researcher’s experience of the interview process of IPA and the dilemmas of shifting from a clinician to a researcher. The researcher further reflects on diagnostic labels, specifically the removal of AS from the Diagnostic Statistical Manual of Mental Disorders-fifth edition.

The United Kingdom (UK) has one of the highest transplant waiting lists in Europe, with currently 7,000 people in the UK waiting for a transplant with many people dying before an organ becomes available (NHSBT 2013). An organ or tissue transplant has been proven to be an effective life enhancing treatment for end-stage organ or tissue failure (Collins 2005). The Department of Health (DH) in 2008 recommended that all health care professionals who had potential involvement in donor patients should receive regular education and training. This study provides an original contribution to knowledge as no research has been undertaken since to evaluate whether these recommendations have been implemented and whether any relationship exists between education and its influence towards health care professionals perceived attitude, confidence, knowledge and decision making within three different health professions working within critical care areas within the NHS. This post-positive mixed methods methodology study utilised a self-completion questionnaire distributed to doctors, nurses and operating department practitioners (ODPs) n=3000 working in Intensive Care, Emergency Departments and Operating Theatres within 18 hospitals and focus group interviews involving 8 nurses from 3 hospitals within England. The questionnaire response rate was 1180; quantitative data was analysed using the Statistical Package for Social Sciences (SPSS). The results revealed that only 23.7% of the sample were given pre-registration donation education and only 56.2% stated they received education as part of post-registration continuing professional development (CPD). Data established knowledge deficits relating to contraindications for solid organ and tissue donation, ability to discuss brain stem death to relatives and differences in clinical management between circulatory and non-circulatory donation approaches. Results found a direct relationship that CPD education improves attitude and participation in donation care amongst health professionals. Data established that there was no bias towards attitude or education provision if the participant worked within a transplant centre versus a non-transplant centre. The study found that there was a direct relationship between the more experienced and senior the practitioner was the more knowledge and confidence they had towards donation. Doctors consistently demonstrated more knowledge and perceived confidence relating to donation issues compared to nurses or ODPs. ODPs consistently demonstrated less knowledge and confidence when compared to doctors and nurses and were less likely to be provided with donation education. Practitioners working within intensive care were significantly more likely to have received donation CPD. The majority of education delivered to health care professionals (HCP) is informally by Specialist Nurses for Organ Donation. The study was underpinned by the theoretical perspectives of Eraut and Dreyfus relating to professional learning and development. This study provides a contemporary assessment of HCPs’ attitude, knowledge and education provision relating to donation establishing that mandatory training as advocated by the DH (2008) and NICE (2011) has not been implemented into frontline practice. The study concluded that HCPs have knowledge deficits relating to organ and tissue donation with education opportunities being limited. The results found a recurring theme that the more experience the HCP has the more knowledge and confidence they have relating to donation. The results will be used to inform and recommend future pre-registration and post registration education and learning strategies relating to donation care.

Cholesterol-rich membrane microdomains have a significant role in cancer progression, particularly in metastasis, and there is evidence that cholesterol inhibitors, most notably statins, can change the behaviour of cancer cells in vitro and in vivo. Cholesterol-rich rafts act as loci for signal receptor-ligand binding, providing a stable scaffold for protein interaction. The purpose of this research was to test the hypothesis that the abundance of these inclusions can be controlled with cholesterol inhibitors and to investigate the effects of these treatments on cancer cells using simple in vitro assays. Flask shaped cholesterol-rich scaffolds in the membrane called caveolae, characterised by the presence of the protein Caveolin-1, are generally associated with proliferation suppression during oncogenesis but with tumour promotion during metastasis. This dual role may be coordinated by the cholesterol content of the raft environment and so be vulnerable to cholesterol inhibitors such as the statins.

This ESRC funded CASE studentship PhD project provides a comprehensive investigation into the referral allocation process within an NHS Trust’s adult mental health facilities, known as Single Point of Access (SPA) meetings. These meetings provide a multidisciplinary environment in which mental health practitioners consider client referrals in the form of letters from, primarily, General Practitioners (GPs) and direct them to appropriate services and interventions. Participants in these meetings can be seen as gatekeepers authorising access to other mental health services. The study was formally identified by NHS Research Ethics procedures as a service evaluation. From an academic perspective it is sociological research heavily informed by Glaserian Grounded Theory (GT) methodology. This approach has uncovered an internal Basic Social Process (BSP) underpinning SPA meetings. It has been named “Handling Role Boundaries”, and it describes how SPA meeting attendees endeavour to work together as they make crucial decisions about clients. Initial research plans included the collection and evaluation of quantitative data which would assess the relative validity of SPA meeting decisions. Unfortunately the quality of available data proved insufficient for this purpose. This provided brief insight into tensions between administrative systems and the real life mechanisms of SPA meetings. Overall, the unfulfilled evaluative purposes of the study provided an opportunity to focus more on clarifying the BSP underpinning SPA meetings. Also explored is how this BSP has wider implications for an understanding of how “mental health difficulties” are framed and provided for. The thesis concludes that Handling Role Boundaries is a highly innovative theory offering major contributions to understanding one social space of mental health professionals. Furthermore, it offers plentiful scope for further research and will be appropriate for many avenues of dissemination.

The aim of this study was to investigate the cellular mechanism(s) that underpins contractile dysfunction in the streptozotocin (STZ)-induced diabetic rat heart compared to age-matched control heart. In some experiments, a clinically relevant concentration of the volatile anaesthetic halothane (0.6 mM) was used examine its effect on contractile properties of STZ-induced diabetic heart. Diabetes was induced in male Wistar rats by a single i.p. injection of STZ (60 mg Kg-1, body weight) which, resulted in an experimental model of type 1 diabetes that was characterised by hypoinsulinaemia, hyperglycaemia, increases in osmolarity and decreases in body and heart weights. Total cation contents (Ca2+ Cu2+ Zn2+ Fe2+) were significantly (P<0.05) increased in the STZ-induced diabetic heart compared to age-matched controls. The majority of experiments were carried out on ventricular myocytes following 8-12 weeks of STZ treatment. L-type calcium (Ca2+) current (ICa,L) was measured in patch clamped ventricular myocytes in whole cell mode, using a cesium-based pipette solution and a holding potential of -40 mV and test potentials between —30 and 50 mV. The amplitude of ICal. was significantly (P<0.05) decreased in the STZ-induced diabetic myocytes compared to age-matched control. Furthermore, halothane further reduced the peak ICal, to levels in both age-matched control STZ-induced diabetic myocytes. Contraction was measured in electrically stimulated myocytes via a video-edge detector and results showed that the amplitude of contraction as a percentage of resting cell length (% RCL) was significantly (P<0.01) greater in STZ-induced diabetic myocytes (6.8 ± 0.5 %, n32) compared to that of age matched control (4.1 ± 1.04 %, n=27). Moreover, the 1pk of contraction was found to be significantly (P<0.01) longer in diabetic myocytes (164.1 ± 7.4 ms, n=30 Vs. 132.3 ± 5.9 ms, n=27) compared to control, respectively. Halothane evoked significant (P<0.05) reductions in the amplitude of contraction in control myocytes. The amplitude of contraction was significantly (P<0.01) reduced further in STZ-induced myocytes compared to the response in the absence of halothane. In voltage clamped myocytes however, contraction was peak amplitude of contraction was greater in control compared to STZ induced myocytes. Since contraction is ultimately dependent on cytosolic Ca 2+, it was relevant to measured free intracellular Ca 2+ concentrations ([Ca 2+]) using the fluorescent dye fura-2. Basal resting Ca2+ (measure by fluorescence ratio units) was significantly (P<0.01) increased in STZ-induced diabetic myocytes following 8 weeks of treatment compared to age-matched control (0.599 ± 0.009 ratio units, n=23 Vs. 0.521 ± 0.012 ratio units, n=23) , respectively. Electrically stimulated cardiac myocytes (1 Hz) induced Ca 2+ transients that had a longer time from the peak (tpk) of Ca2+ transient to half decay ( 1 decrn). Moreover, in the presence of halothane, the amplitude of electrically stimulated Ca 2+ transient release was significantly (P<0.05) decreased in control and STZ-induced myocytes but was not significantly altered between control and STZ-induced myocytes. Following a caffeine-induced Ca 2+ release, 1 1/2 of Ca decay was significantly (P<0.01) longer (43%) in myocytesobtained from STZ-induced compared to age-matched controls. However, in the presence of 10 mM nickel chloride (NiCl 2), the rate of Ca 2+ efflux out of the cell was similar in both control and diabetic myocyte. Myofilament sensitivity was studied by plotting the relationship between contraction and Ca 2+ in controland STZ-induced diabetic myocytes. The results show that myofilament sensitivity for Ca2+ is increased in the STZ-induced myocytes but is significantly (P<0.05) reduced following the application of halothane. In conclusion, the results have shown that in electrically stimulated STZ-induced diabetic myocytes, the increase in contraction is primarily caused by an increase in myofilament Ca2+ sensitivity, and not through an increase in Ca 2+ release from the SR. Moreover, in the STZ-induced diabetic myocytes an alteration in Na+/Ca2+ -exchanger may contribute to a prolonged Ca2+ transient. It is suggested that prolonged Ap duration in the diabetic heart leads to increased Ca 2+ influx albeit a reduced lCa.t. which may overcompensate for a decrease in SERCA function (that has been reported in the diabetic heart. Misra el at 1999) and may lead to similar SR Ca 2 load and release in both diabetic and control myocytes. Following. SR Ca 2+ release it is suggested that the increased myofilament Ca 2+ sensitivity in STZ-induced myocytes leads to an increase in contraction that has been reported in this study. In voltage clamped STZ-induced diabetic myocytes, a decrease in lCa.l. was mirrored by a decrease in the peak amplitude of contraction. It is suggested that in voltage clamped myocytes from STZ-induced hearts, that are not influenced by the Ap, decreased lCa.L, may lead to a reduced Ca 2+ influx and subsequent SR Ca2+ release. Reduced Ca 2+ release from the SR, may not be compensated for by the increase in myofilament Ca 2+ sensitivity in the diabetic heart, and may ultimately lead to a reduction in the amplitude of contraction that has been reported in this study. It has also been shown that, following the application of halothane. the lCa.L, Ca2+ transient and amplitude of contraction were significantly more decreased in STZ-induced myocytes compared to that of control. It is suggested that reduced myofilament Ca2+ sensitivity in the presence of halothane contributes to the changes in contraction. However, it is also likely that another mechanism such as fractional Ca 2+ release and/or SR Ca2+ load may also be affected by the actions of halothane in the diabetic heart.

Liaison mental health services provide mental health care, including assessment, interventions and sign posting to further specialist care, for those who present with mental health needs in non-mental health settings. Liaison mental health services in the United Kingdom most frequently exist within, but are not limited to general hospital provision. The commissioning of these services is however inconsistent, having developed in an ad hoc manner, and the evidence base for an appropriate structure remains limited. This thesis reports an extensive literature review which identifies that to date there has been no published detailed exploration of the experiences of service users of liaison mental health care. Only recently has research been published which tentatively identifies the ability of liaison mental health services to reduce costs to general hospitals of mental health presentations and co-morbidity. The empirical element of this programme of research is a study of the experiences of service users of a liaison mental health service, offered within a general hospital setting. The service users have experiences of both inpatient and emergency department care. The study utilises a secondary data analysis methodology to provide an in depth interpretation of these experiences. Data were analysed using a grounded theory constant comparative method. A core category of ‘negotiating and navigating the system’ emerged as service users’ experienced psychological distress as they attempted to manage their own resources and expectations as a personal safety net. It is only when this personal strategy fails to alleviate their symptoms that they attempt to find help from professional services within the general hospital. Gaining access to assessment by the liaison mental health service requires the service user to negotiate a complex system of care. This experience is represented in the study utilising a conceptual map of their journey, using the analogy of a road to explore the enablers and barriers to an effective experience of liaison mental health care. A model of liaison mental health care is required that ensures provision of educational support for non-mental health professionals within the general hospital setting. This education needs to acknowledge that those who are having their first experience of a mental health issue often do not know where else to seek help, other than the emergency department, because it represents the ‘front door’ of health care. The adoption of a comprehensive model of liaison mental health care is a priority for all general hospital settings in order to achieve improved service user experience, cost efficiency and integrated health care provision.

Patients with heart failure (HF) are at risk of sudden cardiac death (SCD). Most SCD is caused by ventricular tachyarrhythmias events (VTE) that can be treated with an implantable cardioverter-defibrillator (ICD). Identifying patients at risk of VTE remains a clinical challenge. The microvolt T-wave alternans (MTWA) test examines beat-to-beat fluctuations in the morphology of the electrocardiographic T-wave. The presence of significant alternans is thought to reflect dynamic instability of repolarisation and be mechanistically linked to VTE. Observational studies in highly selected populations have suggested that MTWA testing may be used as a non-invasive tool for identifying patients at risk of VTE who, by implication, may benefit from primary prevention ICD therapy. However, to date, no study has investigated the use of MTWA testing in a real-life population of patients with HF. The main aims of this study were to evaluate the applicability of MTWA testing in an unselected cohort of patients with HF receiving contemporary pharmacological therapy and determine the prevalence and incremental prognostic value of this test. Between 1st December 2006 and 12th January 2009, 1003 patients hospitalised with decompensated HF were recruited. 648 patients returned for MTWA testing one month following hospital discharge. The mean age of those returning for MTWA testing was 70.8 years (SD 10.6) and 58% were male. 318 patients (49%) were ineligible for MTWA testing due to atrial fibrillation (AF), pacemaker-dependency or physical inability to undertake the treadmill test. Of 330 patients who underwent MTWA treadmill testing, 100 (30%) were positive, 78 (24%) were negative and 152 (46%) were indeterminate. The majority of indeterminate tests (75%) occurred because of failure to achieve the target heart rate due to chronotropic incompetence, secondary to beta-blocker therapy or physical limitations. There were more abnormal clinical characteristics associated with an indeterminate result, than a positive or negative result. There was no significant difference in crude all-cause mortality rates between the three MTWA groups. MTWA was analysed in the accepted way of non-negative (positive and indeterminate) and negative, but this did not alter the results. MTWA had no incremental prognostic value when added to a multivariable model containing the strongest predictors of mortality in this study. The independent predictors of all-cause mortality following stepwise multivariable modelling were; lower body mass index, New York Heart Association class III-IV, previous myocardial infarction, elevated B-type natriuretic peptide concentration and elevated troponin levels. In summary, MTWA treadmill-testing was not widely applicable in typical patients with HF and failed to predict mortality risk. At present MTWA cannot be endorsed as a tool for improving risk stratification in HF.

A variety of individual and population based approaches to prevention and management of obesity are required and there is an increasing interest in functional foods and natriceuticals. Conjugated linoleic acid (CLA) has generated enormous interest in this context due to their ability to modulate PPAR’s and the associated metabolic processes. Aims & methods: This study aimed to investigate the effects of CLA supplementation in a randomised, double blind crossover trial on inflammation, vascular function and metabolic profiles in subjects with the metabolic syndrome. Results: This study utilised a cross-over design to investigate any differences in outcomes using 9,11 CLA isomer in comparison to the CLA mixture. The results revealed no significant differences at baseline between the two groups and a relatively small number of significant outcomes (peripheral SBP, aPWV, HDL-cholesterol, adiponectin, platelet aggregation and HOMA B). As there was a lack of substantial differences in the two treatments and an inconsistency in specifying these differences to a specific isomer, further analysis was undertaken combining the data from both groups and comparing the outcomes at baseline and at the end of the treatment using a paired‘t’ test. Results from this sub analysis showed a significant increase in circulating sRAGE levels (‘p’=0.002) along with reductions in aortic PWV (‘p’=0.003) and markers of endothelial and platelet function. There were no changes in body composition or insulin sensitivity although adiponectin levels were elevated (‘p’=0.003) and resistin levels decreased markedly (‘p’<0.005) following the treatment. Conclusions: Dietary supplementation with CLA seems to produce a number of vascular benefits which are noted to be independent of its metabolic effects and mediated possibly by attenuating inflammation through changes in circulatory sRAGE. This is of considerable clinical relevance and may open new perspectives and offer effective strategies to reduce the CVD burden in the metabolic syndrome.

Adverse drug events (ADEs) are a significant cause of patient morbidity and hospital admissions. There are many studies in this area in Western countries. However, little is known about the prevalence and patterns of such events in Malaysia. Health care professionals are in the best position to reduce and prevent adverse drug events. In order to devise preventive strategies based on the prevalence studies, it is important to understand the current practices of health care professionals in this area. This study aimed to determine the different occurrences of ADEs in a Malaysian public hospital as well as the experiences of some Malaysian pharmacists’ of ADEs. A study of an observational chart review determined the prevalence of adverse drug event-related admissions in a tertiary public hospital and drugs implicated in such. This was achieved through a prospective review of the patients’ medical notes and charts in two medical wards. All cases were assessed using a classification tool which was developed after a pilot study. Following this, a postal survey of some Malaysian pharmacists explored their experiences about ADEs: the types of ADEs they have observed, actions taken in response to these incidents and their awareness of and involvement in adverse drug reaction reporting, and their attitudes towards this task. Both studies revealed that the occurrence of adverse drug events was high in Malaysia – the chart review study found that 39% of admissions to two medical wards were related to ADEs whilst more than half of the sample pharmacists revealed having observed them in their daily work activities. Moreover, cardiovascular drugs, anti-diabetics, anti-asthmatics, and analgesics were responsible for more than 80% of the admissions related to an ADE. Similar drug classes were also associated with ADEs as recounted by the pharmacists. Moreover they claimed to have communicated with patients about ADEs: on the ADE experienced by a patient, proper use of medicine, importance of adherence, alternate medicines and other appropriate measurements. Although more than 80% hospital and clinic pharmacists claimed to have reported adverse drug reactions, less than 20% of community pharmacists have claimed sending a report. This may have resulted from their lack of awareness of the procedures and processes of reporting an adverse drug reaction. Compared to other countries, the prevalence of ADEs is higher in Malaysia. It remains to be an important cause of patient injury and hospital admissions. Some useful strategies such as educational intervention on main causes of adverse drug events, monitoring of patients, and appropriate prescribing should be targeted at all health care professionals to prevent its likely future occurrences. Pharmacists play an important role in preventing ADEs by providing education and counselling to patients. Furthermore, as they were able to identify ADEs in their daily work activities, they should be included in any prevention programs. Documenting ADEs and interventions taken in relation to those ADEs should be encouraged, as this will be useful in monitoring the occurrence of ADEs and sharing the documented information with others could improve awareness and therefore improve prevention.