The aim of this thesis was to explore perceptual processing in individuals with autism and Asperger's syndrome, and to assess the extent to which the theory of weak central coherence could account for any abnormalities in this area. In Experiment 3:1 we presented individuals with autism with four illusions on a computer and asked them to adjust certain parts to appear the same. The results showed just as susceptible to illusions as those without autism on a computer task contrary to previous literature (Happe, 1996). In Experiment 3:2 we presented the same illusions on card and asked participants to judge whether parts of the stimuli were the same or different as in Happe's procedure. Our results showed that autistic populations succumbed to illusions regardless of whether they verbally judged or manually made adjustments to the stimuli. This ruled out the possibility that procedural differences could account for our failure to replicate Happe's findings. These results show that coherence is intact at low levels of perceptual processing in autism. Our second study (Experiment 4:1) explored whether individual differences in coherence may be able to explain why the results of Experiments 3:1 and 3:2 were not consistent with Happe's findings. We presented a battery of visuo-spatial tasks (block design, embedded figures, Rey complex figure test) and the visual illusion computer task to participants. Performance on these tasks was unable to predict susceptibility to visual illusions, suggesting that perception of illusions may not be related to weak central coherence. Our final investigation explored whether autistic populations were more inclined to rely on visual rather than semantic properties when asked to pair atypically coloured pictures (e. g. blue banana) with colour patches (e. g. yellow or blue). Those with autism relied on background knowledge like control participants choosing the semantically related colour. We then considered whether requiring the participants to name the object before selecting a colour may have influenced them to choose the semantic alternative in Experiment 5:2. Those with autism performed similarly to comparison groups choosing the semantic rather than the visual option. This demonstrated that background knowledge was just as salient to those with autism and Asperger's syndrome as those without autism.

Allergic responses are mainly mediated by immunoglobulin E (IgE) and mast cells or basophils expressing the high-affinity IgE receptor FcεRI. Cross-linking of FcεRI and IgE complexes with allergen induces basophil degranulation and release of inflammatory chemical mediators, leading to clinical symptoms. Common allergy diagnostic tests such as ImmunoCAP, focused on the measurement of specific IgE in patients, commonly lead to misdiagnosis. The allergen-specific IgE in patients’ sera might not always lead to FcεRI cross-linking on mast cells or basophils, resulting in no related clinical symptoms, as observed in some food allergies. In order to mimic the allergic response and generate an in vitro diagnostic device to address these issues, a basophil-microarray platform that couples the diversity of a protein array with the biological output of basophilic cells is being developed. This platform allows testing of up to five thousand allergens using a drop of patient’s blood. In this study, the optimisation steps and preliminary results are presented. The platform in development relies upon the use of a humanised rat basophilic leukaemia (RBL) cell line RBL-703/21 and different methods to measure the levels of basophil activation. ß-hexosaminidase assay showed that the human FcεRI expressing RBL-703/21 cell line was able to bind human IgE in the presence of anti-IgE/allergens and led to degranulation. Fibronectin has shown to greatly avoid cell losses during experiments, calcium ionophore A23187 is an unsuitable positive control due to a fast down regulation of VLA-4 and subsequent detachment of cells. The commercial Ca2+ probe (fluo-4, AM) was shown to efficiently measure the intracellular calcium flux upon activation in the micro-well plate, but due to the lack of a detection system, it can not to be used in the microarray. Two reporter plasmids encoding GFP or DsRed with an NFAT promoter region were transfected into RBL-703/21s and optimised. Both reporter systems were able to detect the presence of functional allergen-specific IgE in the sera of patients, and showed the expected bell–shaped dose response curves. Results correlated with those measured by clinical diagnostic methods. The fluorescence system developed using reporter genes does not need further processing, making it an ideal system for the future development of basophil microarray platforms.

Reports of inter-ethnic differences in metabolism for phenytoin and carbamazepineh have raised questions concerning the importance of monitoring serum levels to the standardised population therapeutic concentrations. Although the pharmacokinetics of phenytoin, carbamazepine, valproic acid and phenobarbitone displayed both intra and inter-individual variations, the influence of ethnicity is still unclear. This thesis has thus set its objectives of investigating the impact of ethnicity on the efficacy of these therapeutic ranges and pharmacokinetics of these drugs. A total 1554 serum concentrations were randomly selected by a set of criteria from 470 Malays, 423 Chinese and 322 Indian of adult and paediatric patients. The Mantel-Haenzel method was used to estimate for inter-ethnic differences in response to the defined therapeutic ranges. The influence of ethnicity on pharmacokinetics was examined by the test of heterogeneity of the slopes estimates in the linear relationship of either serum concentration or clearance to dose. Coefficient of variation on the ratios of the above relationships was used to measure for inter individual variation. The results showed a highly variable response to treatment within the defined therapeutic ranges. Therapeutic response is not dependent on ethnicity and age although the latter was determined on carbamazepine and valproic acid treated patients only. The pharmacokinetics of carbamazepine, valproic acid and phenobarbitone showed high inter-individual variations and were unaffected by weight, age or ethnicity. Similar high inter-individual variation for phenytoin pharmacokinetic parameters (Km and Vmax) were observed. However, Km and Vmax(mg/day) of adult Chinese patients were significantly lower than Malay or Indian patients. The relationship between Km and Vmax and age or weight were insignificant. These findings demonstrate that Malaysian patients only differed in handling phenytoin therapy and support the use of ethnic specific phenytoin pharmacokinetic parameters during therapy.

The aim of this thesis was to identify both patient and carer factors relating to caregiver strain in spouses of stroke patients. The secondary aim was also to assess the effectiveness of an intervention in reducing levels of strain, involving the provision of cognitive assessment information to both patients and spouses. Previous research has not investigated specific cognitive impairment after stroke in relation to strain and reports of the relationship between patient disability and strain are not consistent. Assessment of physical function and detailed neuropsychological examination was carried out with stroke patients in Nottingham, Derby and Mansfield as part of a prospective, multicentre, single-blind randomised controlled trial. The assessment battery included measures of general mental state, language, perception, memory, executive function and praxis. Individualised information about cognitive function was provided in verbal and written form to each patient and carer. Carer strain was assessed in 57 spouses three and six months later. Around a third of spouses experienced significant strain. Results confirmed the importance of patient physical function with disability becoming an important factor with time. Basic self-care skills (Barthel Index) measured at three and six months, were significantly associated with carer strain at six months. Impairment of the patient's general mental state on the Mini-Mental State Examination (MMSE) and communication difficulties on the Sheffield Screening Test for Aphasia (SST) were related to carer strain and were also associated with emotional rather than physical strains. Carer strain was not significantly associated with other cognitive deficits, including impairments of perception, memory, executive function and praxis. Previous research has not assessed specific carer characteristics in relation to strain. In order to identify these, 222 spouses of stroke patients were sent questionnaire measures of strain, stress, mood, handicap, adjustment, social support, life satisfaction and personality and their perceptions of the patient's mood and independence in activities of daily living. Univariate analysis suggested that strain was associated with increased carer handicap, high stress, poor mood, 'chance' health locus of control, expression of depressed mood, low optimism, low positive affectivity, high negative affectivity and low self-esteem. Strain was also related to poor adjustment, low satisfaction with life, less emotional and practical support and a greater discrepancy between actual and ideal levels of support and increased help from professional services. Strained carers also perceived poor mood and increased disability in the stroke patient. Multivariate analysis indicated that the most important factors were low carer mood on the General Health Questionnaire-12 (GHQ-12), poor perceived patient independence in activities of daily living on the Extended Activities of Daily Living Scale (EADL) and high negative affectivity on the Positive and Negative Affect Schedule (PANAS). The relationship between these factors and strain needed to be tested prospectively. In a multicentre study of 116 spouses in Nottingham and Leicester, carers were sent the CSI, GHQ-12, EADL and PANAS at three and six months after the stroke. Again, over a third of carers experienced significant strain. Results confirmed those of the previous study and mood, perceived disability and negative affectivity at three months were found to predict high levels of carer strain six months after stroke. The most important caregiver factors were therefore the spouse's appraisal of their partner's disability, together with two emotional components of subjective well-being, one transient and one stable. The results also highlighted the role of other factors, including incontinence, disturbed sleep, communication difficulties and the amount of time spent caregiving in carer strain. Early identification of carers who may be at risk of strain later on will enable services to be targeted at prevention rather than cure. There was a non-significant trend towards reduced strain in carers who had received information about cognitive deficits after stroke. Spouses may benefit from individualised information about their partner's stroke. Strain is emotionally laden and services might focus on teaching effective coping strategies to reduce depression and provide emotional support. More research is needed to identify services that are effective in alleviating or indeed preventing strain. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.

This thesis examines the effectiveness of social problem solving programmes and the efficacy of an assessment tool designed for mentally disordered offenders (MDOs) and intellectually disabled (ID) offenders in secure hospital settings. Firstly, a systematic review concluded that all studies reported benefits of the social problem solving programmes with MDOs. Several studies also identified that shorter revised programmes had lower drop-out rates, and were more cost-effective. Methodological limitations were identified and suggested further research is needed. Secondly, Interpretative Phenomenological Analysis (IPA) was utilised to explore the meanings ID offenders in a secure hospital attribute to their experience of the Thinking Skills Offender Programme (TSOP). Five themes emerged and participants’ conveyed a sense of hope in relation to their treatment, discussed challenges they faced, identified the impact the TSOP had on factors contributing to their offending behaviour, and wanted to share their experiences with a wider audience. Further research to develop effective programmes for ID offenders is discussed. Thirdly, an assessment and treatment of an adult male violent offender with ID and Autistic Spectrum Disorder (ASD) who undertook the TSOP in a medium secure unit is examined. The findings highlighted the difficulties in assessing and treating such patients using conventional methods and the need for standardised assessments and interventions for this population is discussed. Finally, the reliability and validity of the Novaco Anger Scale and Provocation Inventory (NAS-PI) is examined with MDOs and ID offenders. Its clinical utility in inpatients settings and limitations are also discussed. This thesis has highlighted the benefits of social problem solving programmes with MDOs and ID offenders, difficulties of conducting research with this population, and the need for further rigorous research into assessments and interventions.

Introduction The number of prescriptions dispensed for opioid medicines has increased in the U.K. in the last two decades and studies have shown patients are receiving opioids for longer periods than in the past. There is a lack of evidence as to the effectiveness of these drugs when used long-term, as efficacy evidence is taken from short clinical trials in populations who do not have the comorbidities commonly seen in chronic pain patients. Large observational studies of patients prescribed opioid medicines outside of clinical trials, have identified that some patients taking long-term opioids are reporting they are still in high levels of pain. There is also a concern that patients are receiving high dosages of opioid medicines without effective pain relief. However, no studies in the U.K. have looked at the proportion of patients who continue to receive opioids (for all conditions) in the long-term or at high dosages so we do not know how opioid use develops in the U.K. Research from other countries has also identified that long-term and high dose use is linked to patient characteristics such as patient demographics and psychological and physical comorbidities. For example, a prior history of depression has been found to increase the risk of long-term and high dose use. This is of concern as this may indicate that patients may be potentially medicating the depression with the opioid. This may not be the case in the U.K. due to key factors such as the structure of the health system, so the aim of this thesis was to see if this phenomenon could potentially be occurring in the U.K. Methods This thesis was a retrospective observational cohort study of patients receiving opioid medicines for non-cancer conditions using data from a U.K. derived primary care database, the clinical practice research datalink (CPRD). Patients were included in the study if they received a prescription for opioid medication at any point in the year 2009 and followed, where possible to January 2015 (though data was collected for baseline variables prior to 2009). This thesis consists of a series of longitudinal analyses that attempt to define and describe the probability of long-term use and proportion of patients who receive high dosages in the U.K and seeks to understand how baseline characteristics (such as having a comorbid condition occurring before opioid use starts) affect the probability of long-term and high dose use. Competing risks methods were used to calculate the probability of continuation of opioid medicines (using death as a competing risk) and to determine long-term use. Cox regression models were used to determine whether baseline factors (such as prior antidepressant use) were associated with discontinuation of long-term use. Calculation of odds ratios were used to predict whether baseline characteristics predicted high dose use. Cox regression was also used to predict time to discontinuation of high dose use. Results In the U.K., 10.58% of patients received opioid medicines to treat non-cancer pain in the year 2009. Of the non-cancer patients included in the study, 41.41% were patients who received opioids in the six months prior to 2009 and the remaining were new users of opioid medicines. In the new user opioid group, 5.75% continued to be prescribed opioids for at least one year. When including new and existing users of opioid medicines, one in thirty people in the U.K. population who started opioids for non-cancer pain in 2009 were continuously prescribed opioids for a full year. Patients who were female, received an antidepressant before opioid use started and were in the youngest age category were more likely to continue opioid use past 2 years. The probability of continuing to take opioid medicines is higher in patients who have been receiving opioids for longer and are on higher dosages; in patients who had received over 10mg OMEQ for over two years, over half of patients continued to receive prescriptions for opioid medicines for the five year period study after 2009. In the U.K. population, one in a hundred opioid medicine users were prescribed a high dose (estimated dosage received >120mg oral morphine equivalents per day for at least 91 days) for non-cancer pain in their first 91 days of use in the year 2009. Patients receiving high dosages were likely to be receiving multiple opioid drug types and to receive preparations with multiple release profiles. In new users of opioid medication, the odds of high dose use were increased in patients who were younger (aged 18-49 years), had 3 or more comorbidities or were in receipt of an antidepressant or benzodiazepine and/or anti-anxiety drug before or after opioid use started. In new and existing users of opioid medicines, patients who were receiving high dosages were more likely to be diagnosed or be recorded with symptoms of depression or anxiety and to have been prescribed an antidepressant or benzodiazepine and/or other anti-anxiety drug in the youngest age group compared to the older age groups. Of the patients that were prescribed high dosages of opioid medicines for at least 91 days, 37.64% of patients did not have a second consecutive high dose quarter due to death or stopping high dose use. Almost one in five patients who had a high dose quarter continued to have a high dose for the next three years (22.98%). Older patients, patients prescribed weak opioids and/or tramadol discontinued high dose use at a faster rate than younger patients. Conclusion Both high dose and long-term use were found to be associated with a prior prescribing of antidepressants before opioid use started, suggesting that in the U.K. psychological comorbidities are associated with continued and high dose opioid use. Further work is required to measure outcomes within these groups and to understand the care that these patients have already received. Most patients who start opioid medicines in the U.K. stop taking them in their first year of use. However, of those who continue use past two years, a large proportion continue for the full five year period. Similarly, only a small proportion of patients receive high dosages of opioid medicines but once this use is established, many patients have a high probability of continuation. Further work should be undertaken to facilitate effective review of these patients in practice.

Wayne B. Nottingham. / "December 10, 1956." "This report is identical with material published in Handbuch der Physik, Volume XXI, 1956." / Includes bibliographical references. / Army Signal Corps Contract DA35-039-sc-64637 Project 102B Dept. of the Army Projects 3-99-10-022 DA3-99-10-000

by R.M. Freund and J.R. Vera. / "September 1997." / Includes bibliographical references (p. 28-29).

Emotional distress is common after stroke and has a negative impact on rehabilitation outcome. The aim of this thesis was to identify factors relating to emotional distress after stroke to inform future interventions. This thesis developed a theoretical framework to guide the study of emotional distress and included stroke and demographic characteristics, background information, disability (personal and extended activities of daily living and aphasia) and psychosocial factors (coping, locus of control and social support). This thesis consisted of three studies. The first study developed and validated the Stroke Cognitions Questionnaire Revised (SCQR), as previous studies used cognitions assessments not appropriate for this population. The SCQR assesses the frequency of positive and negative stroke-related cognitions. The scale was developed from treatment notes of depressed stroke patients. The scale had high internal consistency, inter-rater and test retest reliability, and concurrent validity. Depression (Beck Depression Inventory; BDI) was characterized by a preponderance of negative cognitions and, to a lesser extent, a decrement in positive cognitions. This supports the cognitive model of depression. The second study evaluated factors that predicted the severity of depression in a sample of 112 depressed patients recruited to a randomised controlled trial of cognitive behaviour therapy between one and six months post-stroke. Communication impairment (Sheffield Screening Test for Acquired Language Disorders; SST) at recruitment was predictive of severe depression (BDI) at recruitment. Patients with greater communication impairment (SST) and a more external locus of control (Recovery Locus of Control Scale; RLOC) at recruitment were more likely to remain depressed at six months follow-up. Patients who remained depressed at follow-up were more severely depressed at recruitment. The main study of this thesis evaluated the proposed theoretical framework of emotional distress. In a prospective longitudinal study, 100 patients were recruited from hospital at one month post-stroke and assessed on communication (SST), personal activities of daily living (ADL; Barthel Index), distress (Visual Analogue Mood Scales, Visual Analogue Self-Esteem Scale and Stroke Aphasic Depression Questionnaire). Patients who were not aphasic completed additional assessments of distress (Hospital Anxiety and Depression Scale, Beck Depression Inventory II), recovery locus of control (RLOC), coping (Brief COPE) and cognitions (SCQR). Patients were reassessed on the same measures at six months (n=92), in addition to extended ADL (Extended ADL Index) and social support (Significant Others Scale; SOS). Communication impairment and dependence in personal ADL were predictive of distress at one month. Communication impairment and dependence in extended ADL were predictive of distress at six months. In non aphasic patients, externality of locus of control was also predictive of distress at one months and six months and actual social support was predictive of distress at six months. The relationship between coping and distress was mediated by locus of control. Distress remained persistent at six months post-stroke. The factors found to predict distress (communication impairment, recovery locus of control and activity level) will help identify patients at risk of distress. Also, this demonstrates the need to include aphasic patients. The risk factors are amenable to psychological intervention, such as cognitive behaviour therapy and coping skills training. Future research should evaluate the proposed interventions.

This study provides the result of a doctorate research into the impact of existential psychotherapeutic interventions with people experiencing chronic eating disorders. The results indicate that positive outcomes are correlated to therapeutic interventions which concentrate on the clients own perception of control and choice over their own eating habits. The research aim was to explore both the effects and the effectiveness of existential therapy in altering the individuals subjective interpretation of their Self when they are deeply immersed in the experience of disordered eating. Interventions went beyond the cognitive-behavioural approaches into the implementation of existential psychotherapy which helped individuals to explore the existential concerns of life, choice, hope, social inclusion and love within the context of their own sense of Being. This focus led to an improvement in all study subjects and a reduction in the use of mental health resources. All individuals entered the study following assessment criteria which included chronicity, lengthy use of mental health services and past therapeutic interventions. Three diagnostic criteria were included, Anorexia Nervosa, Bulimia Nervosa and Morbid Obesity. Data presented in the study supported the original premise that all three eating disorders share underlying similarities and justify the inclusion of the diagnostic criteria of morbid obesity within the study. Therapy was either in closed groups or individual and consisted of a fixed number of one-hour sessions. Therapeutic techniques included cognitive-behavioural therapy and person-centred counselling focusing on self-esteem and self-assertion, as well as an existential focus on dualistic perception of the mind/body, the conscious sense of the present and the affective bond with food itself. A series of therapeutic phases were structured to demonstrate the progress from interventions in self-esteem and self-assertion to existential concerns and principles. Taking therapy beyond cognitive-behavioural techniques involved the application of Yaloms' (1980) and Strasser and Strassers' (1997) Existential Therapy and an exploration of Duker and Slades' (1988) concepts of the fragmentation of the sense of Self in individuals experiencing eating disorders. The research demonstrated important differences between the professional perception of appropriate eating and alteration in weight as successful clinical outcomes, and the clients’ dependency on disordered eating as a source of release from interacting with others. Mental health interventions were perceived by clients as attempts to stop such a release without providing a substitute. A clear sense of loss was presented by all study subjects when eating was controlled by others. In most cases disordered eating was habitual and the emotional effects of raised or lowered glucose levels gave a sense of numbness and nothingness which was actively pursued. This was also attained when disordered eating was combined with other self-harm behaviours. Mental health practitioners inadvertently prevented the attainment of a sense of numbness by their focus on eating and body weight. The encouragement of food regimes causes increased anxiety for all clients leading to poor compliance levels. The research results have the potential to impact on mental health education and clinical services as the data indicates that individuals with disordered eating gain more benefit when the therapeutic focus is less on restoring appropriate eating habits and more on the individuals sense of Self; the importance of food intake as a source of escape from others and escape from the internal awareness of Self.