Hydralazine is a vasodilator that has been in clinical use for nearly six decades. Despite this, the mechanism of its action in human blood vessels is uncertain. Understanding how hydralazine works may have importance for the better treatment of heart failure and other cardiovascular diseases. In the first Vasodilator Heart Failure trial, hydralazine was shown, in combination with oral nitrates, to reduce mortality in patients with heart failure, treated at a time when the benefits of ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists were not known. As the combination of hydralazine and isosorbide dinitrate was subsequently shown to be less effective than an ACE inhibitor in the second Vasodilator Heart Failure trial, it was little used. Recently, however, the same combination was shown to reduce mortality and morbidity in the African-American Heart Failure Trial. Crucially, in this trial, the patients were already treated with the best currently available drug therapy. Though the patients studied were self-designated African-Americans, it is widely believed that the incremental benefits of the combination of hydralazine and isosorbide dinitrate are as likely to be obtained in other patients. While the vasodilator action of nitrates is well understood, a better understanding of the action of hydralazine (and its interaction with nitrates) could lead to the development of more effective and/or better-tolerated drugs. Nitrate therapy is limited by the development of pharmacological tolerance, possibly secondary to the increased production of reactive oxygen species. Hydralazine co-treatment has been shown to prolong the vasodilator effect of nitrates in animal models and clinical studies, although the mechanism of this protection in humans is uncertain. There are many postulated mechanisms of the vasodilator action of hydralazine, based upon studies carried out - mostly in animals - or animal tissues. Hydralazine reduces contractile responses to a number of vasoconstrictors, and this effect appears greater in arteries than in veins. The most (though not entirely) consistent findings are those suggesting that hydralazine leads to the activation of guanylate cyclase. This action to increase intracellular cGMP, could explain the favourable clinical benefits of its combination with oral nitrates. Hydralazine may affect a number of other vascular enzymes. These include key regulators of vascular superoxide production such as NAD(P)H oxidases. These systems are regulated in vivo and ex vivo by angiotensin-II and aldosterone, and are believed to be pivotal in the development of endothelial dysfunction, a key pathophysiological abnormality in heart failure. Renin-angiotensin system activation and oxidative stress are important (and inter-related) pathophysiological processes in heart failure and other cardiovascular problems. There is experimental evidence that hydralazine may inhibit these vascular and mitochondrial oxidases, and may also act as a radical scavenger, thus helping restore the balance between NO and superoxide in endothelial dysfunction. Inhibition of superoxide production may also help prevent nitrate tolerance: this may be critical in permitting therapeutic synergy between hydralazine and nitrates. However, the evidence emanating from different animal species is contradictory. Surprisingly, the antioxidant effect of hydralazine has never been directly characterised in human blood vessels. In this thesis I investigated the action of hydralazine in human blood vessels. To make this project clinically relevant, I characterised the actions of hydralazine in arteries and veins of various calibre (saphenous vein and internal mammary artery taken at the time of coronary artery bypass surgery and subcutaneous resistance arteries dissected from gluteal biopsies), from patients with low ejection fraction heart failure secondary to coronary artery disease. I also investigated the purported ability of hydralazine to reduce vascular superoxide production. 40 patients undergoing elective coronary artery bypass surgery were recruited for large vessel studies and 20 patients underwent gluteal biopsy, which yielded subcutaneous resistance arteries. Vascular reactivity was assessed using organ bath techniques and wire myography with the construction of cumulative concentration response curves. Production of vascular superoxide was measured using lucigenin chemiluminescence. Summary of results: 1. There was no direct vasodilator effect of hydralazine at therapeutic concentrations (<1 µmol/L). This suggests that the favourable benefits of hydralazine are not simply dependent on direct vasodilatation. 2. There was a modest – but not statistically significant – interaction between hydralazine and endothelium-dependent vasodilatation using carbachol. This is consistent with a trend of potential biological relevance. There was a similarly modest interaction with organic nitrates. These data are consistent with theories that the therapeutic benefits of hydralazine may be partly explained by improved endothelium-dependent vasodilatation and that the interaction with organic nitrates in vivo is not simply dependent on augmented vasodilatation. 3. Hydralazine reduced basal superoxide production in both internal mammary artery [1.09 ± 0.14 nmol/mg/min vs. 0.77 ± 0.16 nmol/mg/min (P=0.026) controls and pre-treated vessels respectively] and saphenous veins [0.77 ± 0.08 nmol/mg/min vs. 0.68 ± 0.08 nmol/mg/min (P=0.018) controls and pre-treated vessels respectively]. A dose-response in superoxide production in saphenous vein (which were more readily available for experimentation) was also evident. 4. Hydralazine significantly inhibited angiotensin-II mediated superoxide production in internal mammary arteries [1.68 ± 0.434 nmol/mg/min vs. 0.843 ± 0.144 nmol/mg/min (P=0.032) controls and pre-treated vessels respectively]. Angiotensin II plays a key role in the pathophysiology of heart failure, with pleotropic effects including increased vascular superoxide production through stimulation of NAD(P)H oxidase. Attenuation of angiotensin-II stimulated superoxide production by hydralazine could mechanistically be through interaction with the NAD(P)H oxidase enzyme group; supporting the best available animal data suggesting that hydralazine prevents nitrate tolerance through modulation of this enzyme group. Appropriate recognition must be had to the limitations innate in this work and recognise that all protocols were ex vivo and, as such, none could accurately reflect the complex phenotype recognised in chronic heart failure. The relatively small sample sizes in the study protocols must also be given recognition; however, my group - and others - have published, scientifically meaningful results utilising similar sample sizes. Future developments ought to include larger scale bench and in vivo studies of hydralazine and organic nitrate interaction with particular emphasis on assessing endothelium-dependent vasodilatation. In my studies hydralazine functionally reduced vascular superoxide production; future studies will evaluate this mechanistically with particular emphasis on the NAD(P)H oxidase system.

The aim of this project was to develop a lab-on-chip platform upon which activities in engineering and parasitology can be brought together to create new low cost diagnostic technologies for Human African Trypanosomiasis, a disease also known as sleeping sickness, for use in resource-poor environments like Sub-Saharan Africa. Filtration and separation of particles is essential for many biochemical and analytical assays. This work describes the development of novel techniques to enhance the separation/enrichment of parasites from whole blood. Techniques like chemotaxis, inertial microfluidics and density based separation were used to achieve the separation/enrichment. This thesis describes (i) development of an assay to confirm the chemotaxis of Trypanosoma brucei towards higher concentrations of glucose, (ii) designing, fabrication and use of inertial microfluidic device for continuous sorting of trypanosomes from blood cells, (iii) density based separation of trypanosomes from whole blood using a two phase Dextran-Ficoll system, and (iv) density based enrichment of trypanosomes using surface acoustic waves. This work represents an important step towards improving the detection of trypanosomes in blood for which microscopy is still considered to be the gold standard.

Prevalent patients were over-represented in many pulmonary hypertension registries and clinical trials. These patients have better survival compared with incident patients. As pulmonary hypertension (PH) is diagnosed and managed in designated pulmonary hypertension centres only in the United Kingdom (UK) and Ireland, this provides a unique opportunity to define the demographics, epidemiology and outcomes of a large cohort of purely incident, treatment-naive idiopathic, heritable and anorexigen-associated pulmonary arterial hypertension (PAH) patients. We included all newly diagnosed, treatment naive patients diagnosed in all eight PH centres in the UK and Ireland between January 2001 and December 2009 in our study. We used the same inclusion criteria used in the French and Scottish registries to define our idiopathic, heritable and anorexigen-associated PAH patients. We further refined our criteria for idiopathic, heritable and anorexigen-associated PAH by excluding patients with evidence of parenchymal lung disease on thoracic CT. These excluded patients (refer as Pre-capillary pulmonary hypertension co-existing lung disease in this thesis) were managed as idiopathic PAH by their PH physicians and otherwise satisfied the usual haemodynamic and pulmonary function criteria used to define idiopathic PAH in many PH registries and clinical trials. We divided our idiopathic, heritable and anorexigen-associated PAH patients into two age subgroups according to their median age to study the effect of age on their phenotypes and survival. We also divided our idiopathic, heritable and anorexigen-associated PAH patients into three subgroups according to their year of diagnosis to study the changing epidemiology of the disease over the past decade. We also compared the baseline characteristics and outcomes of our idiopathic, heritable and anorexigen-associated PAH patients with PAH with ‘co-existing lung disease’ patients. Firstly, we confirmed that the demographics, epidemiology and survival of incident idiopathic, heritable and anorexigen-associated PAH has changed compared with patients from the pre-disease targeted therapy era of the 1980s, and continued to evolve in the UK and Ireland over the past decade. The incidence of idiopathic PAH continued to increase over the past decade in the UK and Ireland, most likely reflecting increased referral to the pulmonary hypertension centres. Patients were still referred late with severe functional and haemodynamic impairment. Greater education is needed to raise awareness amongst the non-pulmonary hypertension community of the changing epidemiology of the disease. We have used our incident study cohort of idiopathic, heritable and anorexigen-associated PAH to validate currently available survival prediction models in PAH. Our results suggested that some survival prediction models performed better than others. We observed different phenotypic characteristics and survival between younger and older idiopathic, heritable and anorexigen-associated PAH patients. Baseline variables with prognostic significance were also different between younger and older idiopathic, heritable and anorexigen-associated PAH patients. Interestingly, obesity was associated with better survival in older patients but the contrary in younger patients. We also explored the prognostic significance of short term improvement in six minute walk distance and functional class in response to treatment in incident idiopathic, heritable and anorexigen-associated PAH. Change in six minute walk distance after three months of pulmonary hypertension treatment was associated with improved survival in patients with low baseline six minute walk distance. Change in functional class at six months was also predictive of survival in our idiopathic, heritable and anorexigen-associated PAH patients. Finally, we observed that pre-capillary pulmonary hypertension with co-existing lung disease patients who otherwise satisfied the usual haemodynamic and pulmonary function criteria for idiopathic PAH had significantly different demographics and worse survival compared with idiopathic PAH patients. Better characterisation of this subgroup of PH patients will avoid bias from inclusion of these patients as idiopathic PAH in future clinical trials.

The use of cardiovascular magnetic resonance (CMR), particularly in the cardiovascular research setting, has grown exponentially in the past 20 years. While CMR is increasingly used in clinically, it has yet to be incorporated into routine clinical practice and guidelines in the majority of conditions. One of the main reasons for this is the relative paucity of evidence for its diagnostic and prognostic utility and cost-effectiveness compared to more established non-invasive imaging techniques such as echocardiography and nuclear imaging. For CMR to become part of routine clinical care, more evidence of its utility is required. The aim of this thesis was to demonstrate the clinical utility of CMR by using it to examine 5 clinical questions that pose a relevant dilemma to physicians in a cohort of patients referred for clinically indicated CMR studies. CMR has two major advantages over echocardiography, the most commonly used technique in our centre (and most worldwide). Firstly, it is the gold standard for assessment of left ventricular volumes and function, and secondly, it has the ability to characterise the myocardium using specific imaging sequences and intravenous gadolinium contrast (known as late gadolinium enhancement – LGE). The first study in this thesis explored the potential benefit of a CMR protocol using these benefits to predict prognosis in an unselected cohort of patients. In this study I found that the assessment of myocardial function using ejection fraction and deformation imaging (strain) and assessment of the presence of fibrosis using LGE had incremental prognostic significance in addition to clinical predictors of outcome in all patients, including in those with ejection fractions greater than 35% (commonly thought to predict higher risk patients). During scanning of this cohort of patients, it became apparent that CMR imaging of myocardial scar in patients with a history of prior myocardial infarction (MI) had the ability to identify fat within the infarcted territory, known as lipomatous metaplasia, which had been recognised pathologically but is not identified by echocardiography. The tissue characterisation ability of CMR has for the first time allowed this to be identified non-invasively ante-mortem. Pathological studies had suggested that lipomatous metaplasia was associated with adverse remodeling, while recent animal studies had suggested that the presence of myocardial fat within infarcts was pro-arrhythmogenic. In this study I showed that the presence of lipomatous metaplasia was indeed independently associated with mortality and ventricular arrhythmias, suggesting that it perhaps provides an arrhythmogenic substrate. The next study explored the use of LGE in addition to established clinical markers in patients undergoing implantable cardioverter-defibrillator (ICD) implantation for ischaemic or dilated cardiomyopathy. These patients met the current clinical criteria for ICD implantation and also had testing of NT-proBNP, a marker of cardiac strain that is associated with adverse prognosis. The patients all underwent pre-implantation CMR. I found that the presence of LGE and a high NT-proBNP was associated with a higher risk of death and ICD activation, perhaps hinting at a role for CMR in providing further risk stratification in this group of patients. Following on from this, I looked at the diagnostic capabilities of CMR. Characterisation of patients with mildly impaired left ventricular systolic function is important as early identification of cardiomyopathy can potentially allow early institution of life-saving therapies. Mild left ventricular impairment can however also be associated with the normal myocardial adaptations to exercise, known as athlete’s heart. This poses a diagnostic dilemma, which may not be easily solved using current imaging techniques. I found that the use of a further CMR parameter to characterise tissue, T1 mapping, was able to discriminate between patients with early DCM and exercisers with normal physiological myocardial adaptation, perhaps providing a solution to this diagnostic challenge. The final study explored the utility of dobutamine stress CMR (DSCMR) to diagnose significant coronary artery disease (CAD) in patients with left bundle branch block (LBBB) and clinically suspected CAD. CAD is the most common cause of LBBB, yet LBBB causes myocardial abnormalities that can make it difficult diagnose CAD non-invasively, leading many patients to be referred for invasive coronary angiography (ICA) to confirm the diagnosis. Despite this, a substantial proportion of the patients with LBBB will not have significant CAD, meaning that ICA would be unnecessary. This study compared DSCMR with dobutamine stress echocardiography, with ICA as the gold standard. I found that DSCMR was significantly more accurate in diagnosis than dobutamine stress echocardiography, perhaps providing a technique that could be used as a gatekeeper to ICA. This thesis shows that CMR can provide important diagnostic and prognostic information in a variety of cardiac conditions and can potentially help guide clinical decision-making. Larger studies should be performed to confirm these findings, allowing for determination of cost-effectiveness and incorporation of CMR into routine clinical management.

Introduction: Erectile Dysfunction (ED) is known to impact on the lives of men but few studies have sought to assess the impact of ED on women and there are no qualitative studies that have compared accounts from women and their partners on the impact of ED on the relationship. Current trends in prescribing of ED treatment focus on men and consider ED to be a male medical problem. Aim: The aim of this study was to obtain knowledge on how ED affected the lives of women and their partners and to gain insight into the impact of ED from a couple’s perspective. Methods: Qualitative accounts from women on the impact of ED were obtained from one to one semi structured interviews and from clinical interviews with their partners. Interviews were audio taped and tape recordings transcribed. The study sample consisted of heterosexual couples and compared feedback on the impact of ED from interviews with men seeking erectogenic treatment and their partners. Men attended routine appointments at a secondary care specialist clinic following referral to the clinic by their GP and were interviewed. Feedback from interviews with men was recorded in hospital case-notes. Men with severe ED that met the inclusion criteria were invited to participate in the study and if they agreed were asked to deliver information about the study to their partners. Interview appointments were arranged for women that agreed to participate in the study and informed consent was obtained from both partners. Transcriptions of interviews with women were analysed using grounded theory. The size of the population sample was dictated by the theoretical relevance of the data in relation to the research enquiry. New concepts and new avenues of enquiry ceased to emerge from analysis of transcriptions after fifteen interviews. Results: Women expressed that ED consumed their partners and reported that their partner’s perception of “solving the problem” focussed on restoration of erectile function. These data were verified by men. Women expressed that they attempted to confront “the problem” by encouraging their partners to seek help but men delayed seeking help due to embarrassment. Women felt isolated and upset at the lack of reciprocity and struggled to make sense of their partner’s perspective, as men communicated to women that the sexual act was of optimum importance in terms of defining the relationship. Men expressed concern that their partners might seek sexual activity “elsewhere” which reinforced perception among women that men defined the relationship in terms of sex. Women were concerned that ED was a symptom of an underlying condition yet men ignored their advice to seek help. Erectile dysfunction affected men’s confidence and caused lack of self esteem. Men reported that ED impacted on their masculinity. Women expressed that ED caused significant disruption to their lives and agreed to their partners using treatment if it was likely to improve their quality of life by having a positive effect on their partner’s mood. Conclusions: Women were aggrieved and disappointed that ED had such a devastating influence on their relationship. The emotional trauma that women experienced and expressed suggested that feelings of hurt might prevail regardless of treatment outcomes. Women were disappointed that the bond in their relationship was weakened by ED and their partner’s reluctance to communicate. Men expressed fear of “losing everything” and felt that restoration of erectile function would solve all of theirs and their partner's problems. Lack of communication resulted in men and women relying on perception of how ED affected their partners. Although this study did not provide solutions to the problems that couples experienced it produced data that was unique in terms of insight into the impact of ED on women and their partners and identified the importance of considering the couple’s perspective on the problem when assessing ED. Further research is required into the impact of ED on couples as understanding of how ED impacts on a couple’s relationship is poor.

This study describes developments and in vitro characterisation of lipid microparticles prepared using spray-drying for drug delivery to the lung via dry powder inhalers. Bioadhesive formulations such as prochitosome or chitosome powders have been introduced to overcome the drawbacks of liposome instability and potentially provide significant increase in the residence time of drug in the lung. Mannitol or lactose monohydrate (LMH) aqueous solutions were spray dried at inlet temperatures of 90, 130, 170 or 210ºC. Soy phosphatidylcholine and cholestrol (1:1 mole ratio) were used in all formulations. Cholesterol was added to increase vesicle membrane rigidity. Proliposomes containing salbutamol sulphate (SS) were prepared by incorporating various lipid:carrier (mannitol or LMH; 1:2, 1:4, 1:6, 1:8 and 1:10 w/w). Prochitosomes including SS or beclomethason dipropionate (BDP) were prepared by adding various chitosan glutamate:lipid ratios of 1:10, 2:10, 3:10 and 5:10 w/w. Chitosomes, including various cryoprotectants (mannitol, LMH, trehalose or sucrose), were prepared by including chitosan glutamate to liposomes generated from ethanol-based proliposomes in the ratio of 3:10 w/w chitosan to lipid. The spray-drying parameters for generation of dry powders were optimised by using an inlet temperature of 120ºC, outlet temperature of 73 ± 3°C, aspirator rate of 100%, suspension feed rate of 11%, and spray flow rate of 600 L/h using B-290 Buchi mini spray-dryer. The production yields were 48.1±2.84%, 69.73±2.05%, 61.33±2.51% and 58.0±3.0% for mannitol and 50.66±3.51%, 68.0±2.0%, 73.66±1.52%, 59.0±2.64% for LMH at 90, 130, 170 or 210ºC, respectively. The size of the particles were smaller than 5 µm for both carriers at of 90 and 130 ºC, whilst larger than 5 µm at inlet temperatures of 170 and 210 ºC. Particles had smooth, spherical and smaller size at 90 and 130 ºC than inlet temperatures of 170 and 210 ºC. Mannitol kept its crystalline properties after spray-drying, whilst LMH changed to amorphous at all drying temperatures. Mannitol-based proliposome particles were uniform, small and spherically shaped. In contrast, LMH-based proliposome particles were irregular and large. Entrapment efficiency of SS was higher for LMH-based proliposomes, however, fine particle fraction (FPF) was higher for proliposomes containing mannitol. Higher FPF was obtained for proliposome containing lipid to mannitol ratio of 1:6 (FF= 52.6%). Vesicles size decreased with increasing carrier ratio and the zeta potential was slightly negative for all formulations studied. Prochitosomes were small, porous and spherically shaped particles. Higher FPF was achieved for prochitosome powders containing chitosan to lipid ratio of 3:10 and 5:10 for both SS (FPF = 58.12±2.86% and 70.25±2.61% respectively) and BDP (FPF = 61.89±9.04% and 61.56±3.13% respectively). Zeta potential and the fraction of mucin adsorbed on the vesicles increased upon increasing chitosan concentration. Vesicle size decreased with increasing chitosan concentration. Entrapment efficiency (EE) of the formulations containing BDP was higher than that for SS. Moreover, the drug EE was higher using chitosomes compared to liposomes. LMH and trehalose-based liposome or chitosome particles were spherical with less tendency of agglomeration compared to mannitol and sucrose-based particles. Powders containing LMH, trehalose or sucrose were amorphous, whilst mannitol-based powder was crystalline. The FPF values were 14.39±1.81%, 32.29±0.15, 48.99±2.22% and 50.79±3.19% for mannitol, sucrose, LMH and trehalose-based liposome formulations, respectively. However, FPF% values were higher for chitosomes, being 23.48±3.38%, 33.89±0.66%, 54.88±1.85% and 55.9±2.74% for mannitol, sucrose, LMH and trehalose-based chitosomes, respectively. The EE of SS was increased upon coating liposome surface with chitosan regardless of cryoprotectant type. In conclusion, the findings of this study have demonstrated the potential of lipid microparticles in pulmonary drug delivery and that prochitosomes or chitosomes may offer great potential for enhancing drug resident time in the lung.

No description available.

Background: Prostate cancer affects over 40,000 men in the United Kingdom each year. The UK Government’s pledge to reduce inequalities within cancer care, relating to prostate cancer, has predominantly focused on the experiences of heterosexual men and overlooked the experiences of gay men. Hence, current recommendations relating to prostate cancer care may not reflect the unique needs of this marginalised group. Aims: This study aimed to explore the impact of prostate cancer on gay men to understand how the disease affected their life and, identify any specific psychosocial or support needs. Methods: This interpretive phenomenological study was guided by van Manen’s methodological and analytical approach. Twelve gay men were recruited from across the UK. Semi-structured interviews were conducted to explore participants’ experiences of prostate cancer. Analysis: Interpretative data analysis incorporating hermeneutic principles identified themes and sub-themes which were reflected through the lens of Merleau-Ponty’s four lifeworld existentials. Findings: The context in which prostate cancer is experienced is unique to gay men. Themes which convey the bodily impact of the disease (Corporeality) include ‘violation of identity’, ‘assault of the physical body’ and ‘the power of potency’. The changing sense of time (temporality) is revealed within themes of ‘threat to eternal youth’, ‘living in a state of flux’, ‘disrupted lives’ and ‘past, present and future horizons’. Relationships with others (relationality) are illuminated through the themes ‘the quest for mutual respect and equality’, ‘locating information’, ‘to tell or not to tell’, ‘changes and challenges’ ‘friendship’ and ‘in pursuit of peers’. Finally, the intimacy of space (spatiality) is uncovered within the themes ‘yearning for community’, ‘the power of proximity’ and ‘isolation’. Conclusions: This is the first UK study to explore the experiences of gay men with prostate cancer, and identified unmet needs unique to gay men diagnosed with prostate cancer which have implications for clinical practice, health policy and groups which provide support to men with prostate cancer.

Background: Patellofemoral pain (PFP) is a condition that has been described as 'the Loch Ness monster of the knee' and the 'black hole of orthopaedics' due to its indefinable and expansive nature when addressing the aetiology, management and treatment. Although significant and clinically important changes have been observed with the joint biomechanics, psychosocial factors, brain activity and neuromuscular activity a lack of understanding of PFP still remains. The overall aim of the study was to provide a unique and multifaceted investigation into the motor unit control, biomechanical, neuromuscular and psychosocial factors in understanding the movement control of PFP subjects and the response to a common clinical intervention. Method: Non-symptomatic (n=13) and symptomatic subjects (n=13) performed a single limb isometric squat in two conditions, no tape and with a medial glide tape application. Motor unit data from the Vastus Medialis (VM) and Vastus Lateralis (VL) was recorded using sEMG Decomposition. Muscle activity of the Gastrocnemius (GAS), Rectus Femoris (RF), Biceps Femoris (BF) and Gluteus Medius (GMed) were collected using sEMG. Kinematic and kinetic data from the lower limb were recorded. All systems were synchronised for simultaneous data collection. Measures of conscious motor processing were made using the Movement Specific Reinvestment Scale and pain levels recorded using the Numerical Rating Scale. Results: Grouped Tape Response: The mean motor unit firing exhibited an increase in the VM firing rate and a decrease in the VL firing rate within the tape condition, across both subject groups, suggesting a modification in the load bias across the Vasti muscles. The common drive, a physiological phenomenon describing common fluctuations in the motor unit firings and consequently a measure of the nervous systems signals to control pools of motor units, increased in the VM and decreased for the VL in response to the tape condition in symptomatic subjects showing that the tape may be providing enhanced feedback to the nervous system that responded by modifying the 'control' to the motor units. There were no changes however in the non-symptomatic subject group, perhaps suggesting their motor units were already controlled efficiently. Motor unit recruitment analyses, through regression analysis of the motor unit firing rate and knee joint moment, showed the VM motor units in the nonsymptomatic subjects were recruitment at a higher firing rate in the tape condition but interestingly no change in the VL and no change in the symptomatic subjects. Both non-symptomatic and symptomatic subjects demonstrated significant reductions in transverse plane knee joint range of moment, illustrating a more controlled rotational knee joint after the application of tape. There were no significant changes found in the coronal or sagittal joint mechanics. Symptomatic subjects demonstrated a propensity to consciously control their movements, suggestively disrupting automatic motor control tasks. Symptomatic subjects presented with pain scores of 4.2/10 on the numerical rating scale. Individual Tape Response: Exploration of individuals' response to tape, opposed to pooling data and treating as homogenous groups, exhibited a non-uniform response with variable increases, decreases and no changes across the different measurements taken. The exploration of the data with this method is in line with common clinical presentation of PFP subjects and presents rationale for new ways to view the data as to not mask the true physiological behaviours. Comparison of groups: Motor unit recruitment analyses comparing the subject groups demonstrated that symptomatic subjects had a significantly different motor unit recruitment strategy for the Vasti muscles, where the larger motor units were firing faster compared to the non-symptomatics larger motor units in both VM and VL for the same level of force. Symptomatic subjects demonstrated a lower common drive to the VM and higher common drive in the VL compared to non-symptomatic subjects, which after the application of tape became the same level as the non-symptomatics. Symptomatic subjects also exhibited significantly lower muscle activity in the GAS, BF, RF and GMed, thus suggestively increasing the muscle activity bias to the Vasti muscles. No changes were seen in the joint biomechanics or mean motor unit firing rate between the groups. Discussion These findings suggest that the nervous system offers a portfolio of solutions to control and distribute force, which can be manipulated through a common taping intervention. The results show that the motor unit firing rate in the VM increases and decreases in the VL, coupled with altered motor unit recruitment strategies thus inferring that there may be a re-distribution of force across the Vasti with the application of tape. This is interestingly complimented with an increase of common drive in the VM and decrease in the VL between subject groups. The presence and then change of common drive within the Vasti so that the motor units are firing in unison, more so with tape, and providing a tantalising prospect that the VM muscle is acting more efficiently and controlled with tape. The novel findings of the neuromuscular system and its modification were alongside the increase in torsional joint control. However, it is evident that the motor unit firing rate, common drive and motor unit recruitment present variable responses amongst individuals, offering different solutions to achieve the same goal; increasing the force and its control within the muscle. The underlying mechanism for the observed findings are unable to be expressed definitively, however it can be deduced that the application of tape presents proprioceptive feedback to the muscle that alters the motor unit pool; consequently adjusting the force and its control within and across muscles leading to an increase in knee stability. Conclusion: The key implications from this work is that the application of tape can offer clinically meaningful changes to the sensory-motor control system, through the manipulation and alteration of the motor unit pool, suggestively from an enhanced proprioceptive feedback mechanism. However, researchers and clinicians should consider the individualistic responses and the potential to mask true physiological findings by assuming homogeneity within patient populations with data analyses and clinical decision processes respectively. This work offers unique and novel insights into both the behaviour of patients with Patellofemoral Pain and also the effects of a taping intervention, thus providing additional clinical understanding and also tantalizing opportunities for future work exploring musculoskeletal or neurological disorders and insight into the sensory-motor control strategies.

The term agenda setting has been used variably across the healthcare literature, in particular in writings on doctor-patient communication, medical education, and behaviour change. No attempt has yet been made to integrate these different conceptualisations. This impacts both investigation and teaching of this communication skill. The studies in this thesis aim to clarify a conceptual foundation, and to develop a measure of agenda setting, for use in teaching clinicians. A context of long-term condition management was selected. In these clinical encounters clinician and patient agendas naturally intersect and may disagree, and patient participation is essential to effective management. Phase 1 of this thesis involved a structured literature review, and focus group study with clinicians in primary and secondary care to map components of agenda setting. These were refined through a consensus group study involving patients, clinicians, researchers and educators. An integrated model of agenda setting is proposed that adopts new terminology: agenda mapping involves establishing shared focus, and agenda navigation involves tracking natural shifts in focus throughout an interaction. Agenda mapping includes six core domains: (1) identifying patient talk topics, (2) identifying clinician talk topics, (3) agreeing shared priorities, (4) agreeing focus, (5) collaboration, and (6) engagement. Clarifying these domains established a foundation for measurement. Phase 2 of this thesis addresses measurement of agenda mapping. A review of measures confirmed that no existing measure includes all agenda mapping domains. The Evaluation of AGenda mapping skiL Instrument (EAGL-I) was developed, and tested in a study with third year medical students. EAGL-I scores were shown to represent reliable and valid assessment of agenda mapping. Conditions, under which reliable assessment may occur, are also discussed. Educators and researchers now have a tool for use in teaching agenda mapping to clinicians. Further investigation of agenda mapping in long-term condition management may also now progress.