The reciprocal interactions between the motor and cognitive systems are critical during development. The thesis investigates this relationship by exploring Executive Functions (EFs) in children with typical and atypical motor coordination, and the effect of this association on academic and language outcomes. Study 1: EFs are higher-order cognitive processes needed for goal-directed behaviour. They involve flexibility of thinking, inhibition of unhelpful responses, strategy development and manipulation of diverse information simultaneously. Children with poor motor skills or Developmental Coordination Disorder (DCD) have demonstrated problems with EFs. However, no studies have explored the development of EFs in DCD longitudinally. Study 1 investigated changes in EFs in children with poor motor skills over two years. Children aged 7-11 years were assessed twice, two years apart, on verbal and nonverbal measures of EFs: executive-loaded working memory; fluency; response inhibition; planning; and cognitive flexibility. Typically developing children (TD: n=17) were compared to those with a clinical diagnosis of DCD (n=17) and those with identified motor difficulties (MD: n=17), but no formal diagnosis. Developmental gains in EFs were similar between groups, although a gap between children with poor motor skills and TD children on nonverbal EFs persisted. Specifically, children with DCD performed significantly more poorly than TD children on all nonverbal EF tasks and verbal fluency tasks at both time points; and children with MD but no diagnosis showed persistent EF difficulties in nonverbal tasks of working memory and fluency. Both groups demonstrated EF difficulties over two years, which may impact on activities of daily living and academic achievement, in addition to their motor deficit. Study 2: Academic underachievement has been identified in children with DCD. However, it is unclear whether it extends to all academic domains and whether it is explained by EF abilities, which play an important role in educational attainment and are poorer in DCD. Study 2 examined academic achievement performance in children with and without motor coordination impairments, taking into account the contribution of EF skills. Children with DCD (n=17) and children with MD (n=32) were compared to TD children (n=41) in measures of reading, spelling and mathematics. Two composite scores of verbal and nonverbal EF respectively were included in the analyses. There was no evidence of academic difficulties in children with MD. Children with DCD demonstrated poorer mathematical ability compared to their TD peers, but performed as accurately on all other academic tasks. These differences in mathematics in the DCD group were still evident after EF was controlled for in the analyses. Nonverbal EF did not predict performance in any of the academic achievement tasks, whereas verbal EF was a significant predictor of mathematical ability. Study 3: Motor coordination is fundamentally interrelated with both EF and language, which in turn are related to each other. Recent investigations on the relationship between EF and language have failed to understand the direction and nature of this association, suggesting a third factor may be involved. Study 3 explored the role of motor coordination in the relationship between EF and language. Measures of verbal EF, nonverbal EF, expressive and receptive language were administered to children with DCD (n=23), MD (n=57) and TD (n=71). A moderation model was tested using Group as the moderating variable, and, next, using motor coordination as a continuous moderating variable (i.e., across groups). Both directions of the association between EF and language were investigated. The relationship between EF and language was not different between groups in any domains, hence Group was not a significant moderator. When using continuous motor skills data, motor coordination was a significant moderator when EF was the predictor of language outcomes, but not when language was the predictor of EF outcomes. Specifically, the interaction between motor coordination and EF had significant effects on language, as the association between EF and language was positive and significant at low and moderate levels of motor skills, but not at high levels of motor skills. In conclusion, in this thesis interactions between EF and motor coordination produced complex effects on academic and language outcomes.

Coronary artery bypass grafting (CABG) is a mainstay in the treatment of coronary heart disease (CHD), a leading cause of premature death in the UK. However, fewer than 60 % of saphenous vein grafts remain patent in the long-term due to the formation of a hyperplastic, occlusive neointima within the grafted vessel. Excessive vascular smooth muscle cell (VSMC) proliferation, migration and extracellular matrix (ECM) synthesis are key events in the pathogenesis of vein graft intimal hyperplasia (IH), and subsequent necrotic core formation and intraplaque haemorrhage further accelerate the process of vein graft failure by forming unstable atherosclerotic lesions. Early IH therefore represents an important target for therapeutic interventions aimed at improving clinical outcomes after CABG. The pleiotropic cytokine transforming growth factor-beta (TGFβ) is highly expressed in restenotic vessels from CHD patients and is acutely upregulated following vein graft implantation in large and small animal models of vein graft disease. To date, most studies investigating the role of TGFβ in IH have used global approaches to target TGFβ, or have focused on the canonical activin receptor-like kinase 5 (ALK5), Smad2/3-mediated pathway. However, TGFβ elicits a diverse range of cellular responses by activating several distinct signalling pathways, and in certain cell types can also signal via ALK1, activating a separate set of receptor-regulated Smad proteins (R-Smads; Smad1/5) that can antagonise ALK5 signalling. Importantly, the role of ALK1 in the pathogenesis of vein graft IH remains unclear and studies have yet to conclusively show whether TGFβ is able to signal via ALK1 in VSMCs. Moreover, in vivo studies indicate that the three mammalian TGFβ isoforms have discrete biological functions, especially during wound healing, a process similar to IH involving cell migration, proliferation and ECM formation. Therefore, the principal aim of this thesis was to dissect the roles of ALK5- and ALK1-mediated signalling in VSMCs during vein graft IH. In addition, this thesis aimed to evaluate whether TGFβ1, TGFβ2 and TGFβ3 differentially regulate VSMC behaviour in the context of vein graft IH. Initially, the expression of the TGFβ isoforms, ALK receptors and R-Smads in VSMCs during the development of IH was evaluated in both small and large animal models of arterial injury and vein graft disease. IHC analysis of wire-injured mouse carotid arteries 14 days post-injury revealed that TGFβ1, TGFβ3, ALK5 and ALK1 were expressed in αSMA+ intimal and medial VSMCs. Interestingly, while nuclear localisation of phosphorylated Smad2/3 (pSmad2/3) within αSMA+ VSMCs was observed in both non-injured and injured vessels, nuclear pSmad1/5 was only detected within VSMCs following vascular injury. IHC analysis of TGFβ signalling components in diseased pre-implantation human saphenous vein (HSV) with pre-existing IH showed that TGFβ1, TGFβ3, TβRII (TGFβ type II receptor), ALK5 and ALK1 were expressed in αSMA+ VSMCs within both the intima and media. Importantly, dual staining for TβRII and ALK5 or ALK1 showed strong co-localisation between ALK5/ALK1 and TβRII. Both pSmad2/3 and pSmad1/5 were localised to the nuclei of intimal αSMA+ VSMCs, suggesting that both ALK5 and ALK1 signalling pathways may be active in these cells. Confocal microscopy analysis of three failed vein graft specimens obtained from patients undergoing cardiac transplantation revealed abundant nuclear-localised pSmad2/3 and pSmad1/5 in αSMA+ intimal VSMCs. These data suggest that both the ALK5 and ALK1 pathways may be activated in VSMCs during the development of IH. Having localised TGFβ1, TGFβ3, TβRII, ALK5, ALK1, pSmad2/3 and pSmad1/5 to intimal vein graft SMCs, subsequent mechanistic characterisation of TGFβ signalling via ALK5/ALK1 was performed in SMC outgrowth cultures from pre-implantation HSV segments from CABG patients (HSVSMC). Affinity labelling and crosslinking studies using 125I-TGFβ1 revealed binding of TGFβ1 to ALK5, ALK1 and TβRII, as well as the accessory receptors endoglin and betaglycan in HSVSMC. qRT-PCR confirmed the expression of these receptors at the RNA level, while immunoblotting revealed that treatment with all three TGFβ isoforms could induce a rapid increase in pSmad2 as well as pSmad1/5. Immunocytochemistry demonstrated the nuclear localisation of both pSmad2/3 and pSmad1/5 signalling complexes following stimulation of HSVSMC with TGFβ1, while qRT-PCR evaluation of ALK5 and ALK1 target genes (SERPINE1 and ID1, respectively) confirmed the transcriptional activation of both ALK signalling pathways by all three TGFβ isoforms. Importantly, pharmacological inhibition of ALK5 or ALK1 (using SB525334 or K02288, respectively) or siRNA-mediated knockdown of ALK5 or ALK1 in TGFβ-stimulated HSVSMC, reduced the expression of pSmad2 and pSmad1/5, respectively, confirming that TGFβ can bind to and signal through both ALK5 and ALK1 in HSVSMC. Functional assays performed in HSVSMCs indicated that TGFβ1, TGFβ2 and TGFβ3 regulate VSMC proliferation and migration in a similar manner in vitro. To gain insight into how the ALK5 and ALK1 TGFβ signalling pathways regulate VSMC proliferation, migration and apoptosis, functional assays were performed in HSVSMC treated with TGFβ1 ± SB525334 or K02288. Pharmacological inhibition of ALK5 or ALK1 did not significantly alter HSVSMC proliferation in response to TGFβ1. Interestingly, TGFβ1-mediated HSVSMC migration was significantly attenuated in the presence of ALK1 small molecule inhibitor, K02288, whereas inhibition of ALK5 signalling by SB525334 had no significant effect on HSVSMC migration. TGFβ1 protected from hydrogen peroxide-induced HSVSMC apoptosis and inhibition of ALK5 or ALK1 signalling reversed this effect. These studies indicate that TGFβ signalling via ALK5 and ALK1 differentially regulates HSVSMC migration, but not proliferation or apoptosis. Data output from the Human TGFβ/BMP RT2 Profiler PCR Arrays suggested that several TGFβ signalling pathway genes were differentially expressed following rTGFβ treatment in HSVSMCs, whereby some TGFβ isoform-specific effects on gene expression were observed. However, following validation, no TGFβ isoform-specific effects on gene expression were detected. Whole genome expression profiling of migrating HSVSMCs treated with TGFβ1 ± SB525334 or K02288 was performed in order to compare the gene expression profiles directly regulated by ALK5 and ALK1. In total, the expression of 3,235 genes was modulated by TGFβ1 treatment compared with non-stimulated HSVSMCs, approximately half of which appeared to be co-ordinately dysregulated following ALK5 and ALK1 inhibition. Two groups of putative ALK5- and ALK1-specific transcriptional targets were chosen for more detailed evaluation and validation. qRT-PCR validation in HSVSMC confirmed fibroblast growth factor 2 (FGF2) and Mal, T-cell differentiation protein like (MALL) as ALK5-specific target genes, and fatty acid desaturase 1 (FADS1), H1 histone family member 0 (H1F0) and scavenger receptor class A member 3 (SCARA3) as ALK1-specific target genes. Together, this data indicates that TGFβ regulates HSVSMC behaviour during the pathogenesis of vein graft IH by activating distinct, ALK receptor-specific transcriptional networks. Overall, the findings from this thesis indicate that the ALK1/Smad1/5 TGFβ signalling pathway is activated following vascular injury and induces specific transcriptional changes to promote VSMC migration. Moreover, these studies indicate that TGFβ1, TGFβ2 and TGFβ3 regulate VSMC behaviour in a similar manner in vitro and all isoforms appear to have equivalent effects on the induction of established ALK5 and ALK1 target genes. Together, these findings highlight the potential of targeting non-canonical TGFβ signalling pathways in the setting of vein graft failure.

Thesis awarded by published work, incorporating papers arising from research carried out in the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford.

Background: Shoulder pain is a common, costly condition with variable prognosis. Commonly used treatments for shoulder pain in primary care include: (i) advice & analgesia, (ii) exercise and/or manual therapy, and (iii) corticosteroid injection. Current guidelines do not assist clinicians in optimal treatment selection for this condition. Prognostic factors help identify subgroups likely to have poor prognosis, however their potential to help clinicians decide between different treatments is unclear. Methods: A systematic review identified which patient attributes modify effects of these three treatments. Clinical consensus workshops were conducted with 21 UK-based clinicians who manage shoulder pain to identify patient attributes relevant to treatment decision making. The impact of these attributes on treatment choice was studied in a conjoint analysis study of decision-making for shoulder pain. Results: The review identified 20 potential treatment effect moderators, with low quality evidence. Clinical consensus workshops identified 12 salient patient attributes. The conjoint study received responses from 387 clinicians (31 countries, 64% UK). Results showed that 11 of the 12 attributes discriminated between treatment choices, following adjustment for responders’ country, profession, and experience. Recommending injection was most strongly associated with lack of improvement (OR 2.81, 95%CI 2.16; 3.65), previous positive response to injection (2.79, 2.07; 3.76), and patient preference (2.41, 1.82; 3.19). Recommending physiotherapy was most strongly influenced by patient preference (2.77,2.16; 3.55), presence of weakness/instability (2.05, 0.79; 1.23) and previous positive response to physiotherapy (2.22, 1.76; 2.80). Not recommending corticosteroid injection was associated with traumatic onset and unstable diabetes or cardiac issues, whereas not recommending physiotherapy was associated with sleep disturbance and high pain. Discussion: The relative importance of patient attributes that influence shoulder treatment selection was quantified. Logical clinical patterns emerged suggesting that specific patient attributes guide clinicians treatment selection. Future research is indicated to assess if identified attributes indeed modify treatment effects.

This is an edition of the Middle English Lylye of Medicynes, a fifteenth-century translation of Bernard of Gordon’s Latin Lilium Medicinae (completed in 1305). The Lylye is contained in Oxford Bodleian Library MS. Ashmole 1505 as a sole text. Although there are multiple witnesses in Latin, there are no other known Middle English witnesses of this text. The Lylye is arranged in a ‘head to toe’ format (beginning with diseases of the head and proceeding downward) with accompanying guidelines for diagnosis and prognosis. Although the text does contain some medical theory and aetiology (based on thought from Arabic medicine, specifically Ibn Sīnā, and Antiquity, predominantly Galen and Hippocrates), it is mainly comprised of a large volume of medicinal recipes and treatments.

The aim of this thesis was to establish the extent, impact and stability of cognitive functioning in Adult Congenital Heart Disease (ACHD) patients. A cross-sectional and a follow-up study were conducted to address these objectives. The aims of the cross-sectional study were to i) identify the extent of cognitive impairments ii) compare cognitive performance across structural complexity groups, iii) identify factors associated with cognition in ACHD. The follow-up study aimed to evaluate the stability of cognitive functioning over time and identify predictors of change. Three hundred and ten ACHD patients from the Heart Hospital, London were recruited. Participants were divided into four structural complexity groups: Tetralogy of Fallot (ToF), Transposition of the Great Arteries (TGA), Single Ventricle (SV) and Simple. Each participant completed a neuropsychological (NP) test battery and psychosocial self-report questionnaires. The results showed ACHD patients with IQ below the normative mean score. Impairment in executive function, attention and motor function were noted. The TGA group had the worst overall cognitive functioning. The Simple group performed significantly better than the TGA and SV groups on attention. Demographic, clinical and mood factors were associated with cognitive function. No association between cognitive functioning and Quality of Life was found. In the follow-up study 153 participants were followed-up (over 4 years). The NP test battery was re-administered to assess change over time. Mood, demographic and clinical factors were assessed to identify predictors of change in cognitive functioning. The results indicated both a decline and an improvement in performance on tests assessing attention, memory, executive functioning and motor functioning. Education and oxygen saturation levels predicted change in memory. The results of this study address a gap in the literature and highlight the extent of cognitive impairments in ACHD. It also indicates a range of intrinsic and modifiable factors that are associated with and predict change in cognitive outcomes. The clinical implications of the findings are discussed. Recommendations for clinical practice include regular, ongoing assessment of cognition in ACHD patients.

Background: Recovery is a complex and contested concept. Many studies have explored the meaning of the concept from the perspectives of service users suffering from mental illness. However, too little attention has been paid to the experiences of Black African service users (BASUs) living in England. At the time of writing this work there were no studies that have explored recovery from the perspectives of BASUs in England. Aims of the study: The aim of the present study is to explore experiences of recovery from mental illness of BASUs in England. Methodology and methods: Semi-structured interviews were conducted with twelve BASUs. The interviews were analysed using Interpretative Phenomenological Analysis (IPA). Findings: Five superordinate themes were derived from the analysis: (1) it is different in Africa; (2) it all started in England; (3) shattered; 4) ‘freaked out’; and (5) focus on recovery. An in-depth explanation of these superordinate themes and the related subordinate themes is presented. The findings highlight the multifaceted ways in which BASUs understand their experiences of mental illness and recovery. Discussion: The insight gained from these findings provided rich information about the complexities of the participants’ experiences of recovery from mental illness. Participants’ explanatory models of mental illness included the complexities of migration, African-centred worldviews and negative life experiences. Participants conceptualised recovery in the context of their social and cultural backgrounds, remission or eradication of symptoms, spirituality, resourcefulness, resilience and unique personal identities. An emerging conceptual model of recovery is formed (Figure 3). Findings are discussed considering existing theory and literature. Implications for clinical practice in relation to the provision of care and promoting recovery for BASUs in England are considered.

The perceived value of interprofessional collaboration, in the provision of services, has continued to be prominent in the United Kingdom’s contemporary health and social care policy, however, there has been limited empirical evidence of how the interpersonal elements of this are created and sustained within operational teams. This qualitative research provides important insight into the experiences of National Health Service (NHS) staff working in the specialist area of Intermediate Care. It ascertains their perception of the presence of interprofessional collaboration within their respective services, the impact that this had on the staff within them and the factors that had affected its evolution. Semi-structured interviews were undertaken during 2014 and 2015 to collect and analyse data from clinical staff working in five intermediate care services and a Constructivist Grounded Theory approach was utilised to abstract themes from the data obtained. The findings offer an original contribution to knowledge through determining that the presence of adversity in the workplace was a significant factor in creating and sustaining interprofessional collaboration within the services in this study. A strong, collective identity for their respective social groups was formulated by the participants through situated learning, with a greater emphasis placed on interpersonal relationships, rather than interprofessional competencies. Theorising the findings, the participants interacted in their contextualised settings, communicating with each other to attain and maintain consensus, applying coping strategies to manage the internal and external stressors affecting them. By working dynamically in this way, consistency of meanings, behaviours and culture were negotiated, offering an assurance of stability and order within settings that were frequently affected by change. These four components were labelled the 4Cs of Interprofessional Collaboration. The strength of these components was evident, even though an exercise to explore the constituent elements of the participants’ services discovered that all of the participants perceived the construction of their respective services differently, reinforcing the presence of subjective, multiple realities. The results of this study offer an improved recognition that creating and sustaining interprofessional collaboration is a process in constant flux to manage the internal and external stressors affecting it. It requires proactive action, mutual engagement, “Facilitating Interaction” and negotiation between individuals, to develop shared mental models. Participants worked flexibly within defined parameters of practice maintaining Dynamic Consistency in order to achieve this.

The presented work unites several distinct lines of research, asserting that the broader construct of complexity (with its various connotations) may be uniquely relevant and informative to our understanding and management of psychotic disorders. Part 1 outlines the candidate’s contributions to the development of EEG methodology in clinical populations in an effort to most directly capture neural noise and complexity. The advent of oscillatory analysis facilitated the study of ongoing background activity of the EEG. Further exploration of this background activity demonstrated that increased neural noise (as quantified by Lempel-Ziv complexity) is highly correlated with, and conceptually very relevant to, positive symptoms of psychosis. Part 2 describes how considering the complexity of clinical psychosis states justifies the use of human laboratory studies using psychotomimetic drugs such as tetrahydrocannabinol and ketamine. Part 3 explains how the ideas and inferences from the work in Parts 1 and 2 can inform the environment of psychotic disorders, specifically the candidate’s work in prescribing practices and first episode psychosis service design. The thesis concludes that EEG studies of clinical populations face particular methodological challenges, however the resultant technical advancements have expanded our view of neural function to the particular benefit of our understanding of psychosis. EEG measures of complexity may be amongst the most sensitive biomarkers associated with positive symptoms, however more empirical research is called for to confirm this observation. Human laboratory studies of psychotomimetic drugs in healthy humans may continue to prove useful, in circumventing the phenomenological and patho-etiological complexity of clinically occurring psychosis. As a next step, multi-modal studies (combining biophysical signals, individual phenomenology and even population level outcomes) in combination with data mining techniques might further characterize the complexity within psychosis. Psychotic disorders, as complex problems, warrant framing and intervention informed by complexity.

Background: Recent developments in our understanding of the biology of cancer has provided the opportunity to develop targeted agents with more specific pharmacological activity against cancer cells. Despite this shift toward targeted drug discovery, the much hoped-for paradigm shift in cancer treatment has not been realised. Tumour heterogeneity, plasticity and genomic instability are issues that contribute to this problem. One approach to circumvent these issues is to adopt a phenotypic based approach to drug evaluation where compounds with multiple mechanisms of action leading to a desirable phenotypic effect can be identified. The challenge with such an approach is to retain selectivity toward cancer cells as opposed to non-cancer cells. Aims: The aim of this study is to apply a phenotype based drug evaluation program that incorporates a measure of selectivity to the preclinical evaluation of a series of novel organometallic complexes. Methods: In this study, a series of novel inorganic complexes were evaluated against cancer and non-cancer cell lines. The primary evaluation procedures involved chemosensitivity testing with compounds being selected for further studies based upon (i) potency (ii) an in vitro selectivity index (SI) defined as the IC50 for non-cancer cells divided by the IC50 for cancer cells and (iii) comparable or improved properties than cisplatin, oxaliplatin and carboplatin with respect to potency and selectivity. Those compounds that met the selection criteria were evaluated further with the initial aim of characterising key pharmacological events such as cell cycle effects and induction of apoptosis. Results and Discussion: Initial studies focused on the clinically approved platinum based with cisplatin and oxaliplatin being significantly more potent than carboplatin. Selectivity for cancer over non-cancer cells was observed with selectivity index (SI) values typically in the range of 0.85-9.71, 0.36-3.35 and 2.18-7.44 for cisplatin, oxaliplatin and carboplatin respectively. A total of 210 test compounds were evaluated in this thesis and of these, a total of 91 compounds exhibited potency values equal to or better than the platinates. In contrast however, only 64 compounds had superior SI values compared to platinates. Of these, the most promising compounds were a series of large molecular weight metallohelicates that exhibited potency (in the nM range) and SI values up to a maximum of 93 (nearly 28 times higher than the best performing platinum drug). Analysis of these compounds demonstrated that they do not induce apoptosis, but preliminary data suggests that they induce an autophagic death response. Conclusions: The results of this study have demonstrated that a phenotypic based drug evaluation process based upon potency and selectivity in vitro is capable of identifying novel chemical entities with promising properties. This screen has more discriminatory power than potency alone and the concept of an 'in vitro selectivity index' has proved valuable in identifying a series of novel metallohelicate compounds as potential anti-cancer drugs. Significant further work is required to identify their mechanism(s) of action and pharmacological properties but their potential ability to induce autophagic cell death over apoptosis is of interest.