Alzheimer's disease is the most common form (~60-80%) of dementia, currently affecting approximately half a million people in the UK and ~30 million people worldwide. The autosomal dominant form of AD represents a small proportion (~1-2%) of AD cases and is genetically well characterised. The vast majority of AD cases that show symptoms later in life (>65 years of age) are genetically complex. This type of AD, also known as late onset Alzheimer's disease (LOAD) disease, is still highly heritable with an estimated heritability of up to 76% (Gatz et al., 2006). Unfortunately, there is no cure for this devastating disease. Investigating genetic factors influencing the risk of LOAD is imperative for development of effective therapeutic treatments and more accurate diagnosis. A cross-platform comparison of four Genome-wide association studies (GWAS) was performed in an effort to identify novel genetic associations with LOAD (Chapter 3). A TRIM15 SNP rs929156 demonstrated significant evidence of association with LOAD with a p-value approaching genome-wide significance (p = 8.77 x 10-8) and an odds ratio that showed consistent effect on risk (OR = 1.1, p = 0.03). Within this chapter, a bio-informatic program to automate the process of GWAS meta-analysis taking into account linkage disequilibrium (LD) is also presented. Subsequently two fragments of the TRIM15 gene (including both 5’ and 3’ end flanking regions) were sequenced using the ABI SOLiDTM next generation sequencing technology. This was a pilot study using a DNA pooling strategy to determine whether this region harbours multiple rare variants which are associated with the disease (Chapter 4). Lastly, a candidate gene study combined with whole genome analysis was performed in an effort to search for genetic variants influencing human ageing using LOAD GWAS data (Chapter 5).

This thesis explores the role of a large-scale brain network comprising of the insula and anterior cingulate cortex in the pathophysiology of psychosis using structural and functional neuroimaging. Primarily, anatomical changes affecting the grey matter structure and patterns of dysconnectivity involving the insula are investigated. Various meta-analytic studies have reported consistent reduction in insular grey matter across various psychotic disorders. Despite these robust observations, the role played by this brain region in the generation of psychotic symptoms remains unexplored. In this thesis, using a meta-analytic approach, the relevance of insula for the clinical expression of psychosis is highlighted. Further, significant reduction in the cortical folding of the insula was noted in patients with schizophrenia. Reduced gyrification is accompanied by reduced functional connectivity between the insula and the rest of the brain. Using an effective connectivity approach (Granger Causal Analysis), the primacy of insula in driving the dorsolateral prefrontal cortex is demonstrated in healthy controls; this relationship is significantly affected in schizophrenia amounting to aberrant connectivity within a putative salience-execution loop. Reduced primacy of the salience-execution loop relates to illness severity. It is argued that the insula, as a key region of the salience network, plays a crucial role in the generation of symptoms of psychosis. The evidence in support of this theory is discussed, together with its implications for clinical practice aimed at reducing the burden of psychosis.

The aim of this research was to investigate the incorporation of a 'structured approach' to teaching children with autism, with precision teaching assessment methods. The rationale for the research focused on the limited evidence base regarding educational approaches for children with autism (Jones, 2002), and the growing need to provide appropriate educational provision for this group (Ali & Frederickson, 2006). One of the more widely used approaches in the UK is 'Treatment and Education of Autistic and related Communication handicapped Children' (TEACCH) (Tutt, Powell, & Thornton, 2006), with a derivative of this, called a 'structured approach', in place in the local context of the research. The use of fluency building approaches in education, such as precision teaching, has been proposed as potentially beneficial for children with autism due to their dysfluencies and difficulties generalising skills (Weiss, 2001), however there is limited research for this population. The 'structured approach' within the local context did not incorporate fluency building procedures, and therefore the research sought to investigate whether a precision teaching framework could augment a 'structured approach' for children with autism. A pragmatic, mixed methods approach was utilised in this research. It employed a series of three case studies, each incorporating multiple A-B single case experimental designs (SCED), in order to explore the impact of the precision teaching intervention on the pupils' learning, affect, and behaviour. A focus group provided additional information regarding the implementation of the precision teaching intervention. The SCED measures were analysed through graphical visual inspection and the focus group data was thematically analysed. The research found that precision teaching positively augmented a structured approach for the focus children, which was particularly apparent when it was implemented consistently. Improvements were identified in the pupils' learning, affect, and behaviour. The implications of this research are discussed and opportunities for further research highlighted.

Das Ziel dieser Dissertation ist es, einen umfassenden Blick auf die Qualitätsmerkmale von Unternehmen zu werfen. Dabei werden zwei verschiedene Ansätze verfolgt, verglichen und verbunden, um diese "Unternehmensqualität" zu erfassen. Es handelt sich dabei einerseits um ein in der Praxis weit verbreitetes Unternehmens-entwicklungsmodell, das EFQM Modell 2010 und andererseits um ein auf einer selbst durchgeführten Metaanalyse aufbauendes Modell. Diese Metaanalyse basiert dabei auf der wesentlichen wissenschaftlichen Literatur der letzten 10 Jahre im Bereich des allgemeinen beziehungsweise strategischen Managements. Dabei wurden insgesamt 249 Artikel analysiert und eingebracht. Aufbauend auf den Ergebnissen dieser Studie und dem EFQM Modell 2010 wurde eine quantitative Datenerhebung mit Hilfe eines Fragebogens durchgeführt (n=218). Die Ergebnisse dieser Erhebung zeigen, dass primär interne Faktoren die Performanceunterschiede zwischen Unternehmen erklären. Diese Aussage bezieht sich insbesondere auf komplexe Fähigkeiten wie organisationales Lernen, die Unternehmenskultur, die Flexibilität und die Ambidexterity des Unternehmens. Eine weitere Aussage dieser Arbeit ist, dass zwischen der wissenschaftlichen Literatur (den Ergebnissen der Metaanalyse) und dem EFQM Modell 2010 eine hohe inhaltliche Übereinstimmung besteht. Daraus lässt sich schließen, dass die Wissenschaft und die Praxis sehr ähnliche Ansichten betreffend den erforderlichen Qualitäten zur erfolgreichen Führung von Unternehmen vertreten.

As well as cognitive decline and neuropathological changes, Alzheimer’s disease (AD) is also characterized by non-cognitive behavioural symptoms like restlessness, wandering, agitation, confusion and profound disruptions of circadian rhythms. This group of symptoms is commonly referred to as ‘Sundowning’ and typically occurs in the late afternoon, evening or at night and causes significant problems for Carers. There are no specific drug treatments for these symptoms. One contributory factor is that little is known about the biological basis of these symptoms in Alzheimer’s disease. There is evidence, however, that they may arise as a consequence of abnormal circadian rhythms. Circadian rhythms characterize a number of human physiological and behavioural systems including energy metabolism, sleep-wake cycles, cardiovascular activity, body temperature and locomotor activity. Several studies have demonstrated a role for chromatin modifications in normal circadian function. In mammals, circadian rhythms are generated by a transcriptional-translational feedback loop in which the components of the positive limb (CLOCK and BMAL1), activate the components of the negative limb (the cryptochrome and period proteins). CLOCK possesses intrinsic histone acetyltransferase activity which has been implicated in the circadian control of gene expression. Disrupted rhythmic expression of the core clock genes has also been demonstrated in patients and AD mouse models. With a view to establishing a potential animal model to study the biological basis of Sundowning symptoms, we investigated whether a transgenic mouse model of AD, APPswe/PS1dE9 exhibits circadian alterations in locomotor activity, chromatin modifications and expression of clock genes. The effect of age on altering rhythms in locomotor activity was also investigated. Results show that the APPswe/PS1dE9 mutation alters levels and patterns in locomotor activity at all ages tested, most notably in the activity travelled in the last 2 hours of the dark phase, which is potentially relevant to the disturbance previously reported in AD patients. C57BL/6J and CD1 mice also showed evidence of altered circadian profile with age for locomotor activity. Biomolecular studies revealed altered rhythmic expression of the core clock genes as well as day/night rhythmic chromatin modifications. In summary, these studies reveal altered circadian regulation of locomotor activity, chromatin modification and clock gene expression in APPswe/PS1dE9 mice. They also provide strong evidence that disruption of circadian rhythms of locomotor activity has biomolecular analogies in a widely available model of AD. The APPswe/PS1dE9 model of AD demonstrates the potential to serve as a tool in understanding the neuropathology of circadian abnormalities in Alzheimer’s disease and a model system to test novel therapeutic agents.

Introduction: Promoting the mental health of young people is identified as a key priority in the United Kingdom (Department of Health & Department for Education, 2017). Particular groups in the population are at an increased risk of poorer mental health outcomes, for example, it is known that there is a high comorbidity between autism and mental health conditions, with an increase in prevalence around adolescence (de Bruin, Ferdinand, Meester, de Nijs & Verheij, 2006). Consequently, there has been a call for research that explores approaches to support the management of emotional issues for people with autism (Pellicano, Dinsmore & Charman, 2014). In response, this study presents the first evaluation of the Autism, Emotional Well-being and Adolescence (AEWA) psychoeducation programme for families of children with autism. The programme aims to develop parents' understanding of emotional wellbeing and how to promote it, with a particular focus on adolescence. Method: A mixed methods approach was used in the study. The quantitative aspect of the study utilised a quasi-experimental pre- and post-design to explore the relationship between the AEWA programme and parents' perceived knowledge and confidence. Data was collected from nine participants in the experimental group and ten participants in the wait-list control group using a specifically constructed measure. The qualitative design involved exploring patterns in the experiences of six participants who attended the AEWA programme, using thematic analysis on the data gathered in semi-structured interviews. Results: The quantitative results suggested that attending the AEWA programme leads to an increase in parents' perceived knowledge and confidence in their ability to meet the emotional well-being needs of their child with autism, through the potential challenges of adolescence. These results were supported by the qualitative findings. The thematic analysis results suggest that participants valued the content of the programme, the structure and approach to delivery and the opportunity to come together offered by the programme. It was also suggested that following the AEWA programme, participants experienced some changes and challenges. Conclusion: The evidence suggests a psychoeducation programme aimed at parents of children with autism, focusing on emotional well-being and challenges in adolescence, can have a positive impact on parents. This has the potential to support the developmental context of individuals with autism, as they grow older and the challenges change. Given these finding and considering the methodological limitations identified in this study, it appears research would benefit from further investigation in this area.

This thesis is an investigation that combines historical research into military records and genealogy in the examination of the brief military career and death in courageous circumstances of George P. Cole. It also considers the policies of the U.S. military as regards battlefield treatment of deaths, immediate burial and subsequent repatriation of the remains. The author draws upon family records, official government reports and the recollections of the friends and superiors of the deceased.

The aim of this thesis is to examine the competition patterns that exist between originators and generics by focusing on the articulations between regulation and incentives to innovate. Once the characteristics of regulation in pharmaceutical markets is reviewed in the first chapter and an analysis of some current challenges related to cost-containment measures and innovation issues is performed, then in the second chapter, an empirical study is performed to investigate substitution patterns. Based on the EC´s merger decisions in the pharmaceutical sector from 1989 to 2011, this study stresses the key criteria to define the scope of the relevant product market based on substitution patterns and shows the trend towards a narrower market in time. Chapters three and four aim to analyse in depth two widespread measures, the internal reference pricing system in off-patent markets, and risk-sharing schemes in patent-protected markets. By taking into account informational advantages of originators over generics, the third chapter shows the extent to which the implementation of a reference price for off-patent markets can contribute in promoting innovation. Finally, in the fourth chapter, the modeling of risk-sharing schemes explains how such schemes can help in solving moral hazard and adverse selection issues by continuously giving pharmaceutical companies incentives to innovate and supplying medicinal products of a higher quality. / In dieser Arbeit werden erstmals die Merkmale der Regulierung auf Pharmamärkten beschrieben und die aktuellen Fragen bezüglich der verschiedenen Marktteilnehmer (Patienten, Ärzte, Krankenkassen) vorgestellt, die im Verlauf dieser Dissertation beantwortet werden: Was sind die Substitutionsmuster auf den Pharmamärkten? Wie kann Preiswettbewerb gefördert werden ohne die Innovationsanreize zu gefährden? Wie können Patienten mit innovativen Arzneimitteln versorgt werden ohne das Haushaltsbudget zu gefährden? Um die erste Frage zu beantworten wird in dem zweiten Teil dieser Dissertation die Definition der relevanten Marktabgrenzung auf Pharmamärkten untersucht. Hierbei wird die Praxis der Europäischen Kommission zur Marktabgrenzung im Bereich Fusionen durch eine ökonometrische Analyse untersucht, um die Substitutionskriterien ausführlich zu analysieren. Der dritte Teil dieser Arbeit untersucht die Funktion sowie die Auswirkungen eines internen Referenzpreissystems auf die Innovationsanreize von Pharmaunternehmen. Zu diesem Zweck werden zunächst die existierenden Verzerrungen im Wettbewerb zwischen Originalpräparaten und Generika betrachtet. Daraufhin sollen die Auswirkungen der Implementierung eines Referenzpreissystems erläutert werden. Die abschließenden Schlussfolgerungen unterstreichen die Relevanz eines solchen Systems, um Anreize für Innovationen zu setzen. Nach der Analyse des Referenzpreissystems für Produkte, die nicht mehr unter Patentschutz stehen, um den Preiswettbewerb zu stärken, bezieht sich der vierte und letzte Teil auf die Vereinbarungen zur Risikoteilung, die eine Alternative sind, um kosteneffiziente innovative Arzneimittel verfügbar zu machen. Zu diesem Zweck werden Vereinbarungen zur Risikoteilung theoretisch in Bezug auf Fragestellungen zu moralischem Risiko und adverser Selektion untersucht. Im weiteren Verlauf der Arbeit wird gezeigt, dass Vereinbarungen zur Risikoteilung wünschenswert sind, weil sie Firmen Anreize geben, im Laufe des Lebenszyklus eines Arzneimittels zu investieren. Dazu kann bewiesen werden, dass nur eine Firma mit einem effizienten Produkt eine Vereinbarung zur Risikoteilung anbieten würde. Als Schlussbemerkungen werden weitere Forschungsaspekte, vor allem biologische Präparate, angesprochen.

The purpose of this study was to display increase in eccentric hamstring strength after 10-weeks training program. Secondly, if such an increase occurred, would this strength change result in altered landing kinetics and improved jumping performance? 27 recreational female athletes assigned into experimental (n = 14) and control (n = 13) groups. Baseline measures of landing kinetics were collected using a force plate, strength data and proprioceptive measurements were evaluated using an isokinetic dynamometer and vertical jump performance were determined by a jumping mat. Results indicated that NHST group increased their eccentric hamstring strength after eccentric strength training program (week-1 = 233.6&plusmn / 27.5, week-10 = 253.8&plusmn / 28.4 Nm/kgbw / p&lt / .05). The results demonstrated that there were significant differences in landing mechanics for NHST group. PVGRF (week-1 = 6.2&plusmn / 0.9, week-5 = 5.3&plusmn / 0.9 / p&lt / .05), PAPGRF (week-1 = 1.1&plusmn / 0.2 &amp / week-10 = 0.8&plusmn / 0.3 / p&lt / .05) and APImp results demonstrated significant differences in trained group (week-1 = 78.1&plusmn / 13.6 &amp / week-10 = 67.8&plusmn / 9.2 / p&lt / .05). NHST group exhibited significant increase in vertical jumping ability (week-1 = 0.25&plusmn / 0.0 &amp / week-10 = 0.27&plusmn / 0.0 cm / p&lt / .01). This study supported the following points: 1) increases in the eccentric hamstring strength were evident after NHST program, 2) the increases in isokinetic strength were sufficient to cause alterations in landing kinetics to decrease the applied joint forces, so the NHST program would be an influential factor in decreasing the lower extremity injuries, and 3) the increase in the efficiency of force transfer at the final take off phase of jumping contributed to a higher performance in vertical jump.

Kinematic analysis of basketball shooting is evolving, however the effects of fatigue on free throw shooting have not been studied. Therefore the effects of fatigue on the kinematics of free throw shooting among elite male basketball players was assessed. Ten healthy male collegiate basketball players participated in the study. Resting and fatigue heart rates of the participants were measured. After a 15 minute warm-up period, markers were placed on seven locations on the shooting arm&rsquo / s side upper and lower extremities. The free throw shots were recorded with two digital cameras at a speed of 60 frames/s at a stereoscopic position. Data were analyzed with the photogrammetry technique. Each participant performed free throw shots (pre-fatigue condition) until the two successful and two unsuccessful shots were collected. Then participants completed a fatigue protocol, which included sprints and squat jumping, until reaching their volitional exhaustion and free throw shots were repeated (post-fatigue condition). The elbow, trunk, knee and ankle joint angles were measured. Successful and unsuccessful shots were compared for pre- and post-fatigue conditions. The results demonstrated that fatigue did not affect free throw shooting and there was no significant joint angle difference (p&gt / .05) between successful and unsuccessful shots (p&gt / .05). It was concluded that fatigue does not affect the kinematics of free throw shooting of healthy male collegiate basketball players and there were no differences in the kinematics of selected joint angles for successful and unsuccessful free throw shots.