Background: There is a large body of evidence showing that children experience high levels of Post Traumatic Stress Disorder (PTSD) in the aftermath of a trauma. It is often assumed that the child’s response to the trauma is influenced by: i) the parents’ own symptomatology; ii) the family’s avoidance of trauma reminders and discussion; iii) the general parenting style (e.g. the degree of warmth, criticism and emotional over-involvement); and iv) the general family environment. Given that few attempts have been made to test these hypotheses and research findings have been mixed, determining additional factors affecting children exposed to trauma was important. Aims and Objectives: The purpose of the present study was to add to the existing literature by looking at family factors and their relation to post-traumatic responding in the child. To address this aim we explored the relationship between the child’s self-reported PTSD and: 1) parental expressed emotion; 2) the degree of cohesion, emotional expressiveness and conflict in the family environment; 3) the parent’s self-reported symptoms of PTSD, depression and anxiety; and 4) family post-trauma communication. Method: Twenty-two children (aged 7 – 17 years) exposed to trauma, and their main care-giver, were recruited from child and adolescent mental health services across South-East London. All parents completed self-report measures of PTSD, anxiety and depression, as well as scales rating their child’s anxiety and depression. Parental expressed emotion was rated using a five-minute, audio-taped interview where the parent was asked to talk about their child and their relationship. The parents completed the Family Environment Scale (FES) which measures family cohesion, emotional expressiveness, and conflict. The children completed self-report measures of PTSD, anxiety and depression. Finally, children and parents completed a newly-developed questionnaire that assesses their view of the consequences of talking about the trauma in the family. Results: Contrary to expectations, parental expressed emotion, parental own symptomatology, and the parent’s ratings of the degree of family cohesion, conflict, emotional expressiveness encouraged in the family (measured by the FES) were unrelated to the child’s self-reported PTSD symptomatology. However, poor family communication was associated with PTSD symptoms in the child. Overall, the factors found to most strongly relate to the child’s PTSD severity were the strength of their own negative trauma-related beliefs and comorbid anxiety and depression. Conclusions: Little support was found for the widely held view that parental expressed emotion and parenting/family style directly influence the child post-traumatic responding. The best predictor of the child’s response was their own trauma-related beliefs. On the other hand, family post-trauma communication directly influenced the child’s post-traumatic symptoms levels. Future studies should aim to confirm the findings from the present study and attempt to examine family post-trauma coomunication using multi-method and multi-informant measures in longitudinal and experimental designs.

Background: Infants born prematurely or at term may unfortunately suffer morbidity from ventilator related complications. New ventilation techniques have been developed aimed at reducing that morbidity, but have yet to be fully evaluated. Aim: To optimise the delivery of new techniques using physiological outcome measures. Methods: A series of studies were undertaken. The objectives were: • In prematurely born infants with acute respiratory distress, to determine the optimal level of volume targeted ventilation. • In term and prematurely born infants, to assess the effect on work of breathing of the addition of pressure support (PSV) to synchronised intermittent mandatory ventilation (SIMV) during weaning and then compare the efficacy of PSV to assist control (ACV) in a randomised trial. • To perform in vitro and in vivo assessments of proportional assist ventilation (PAV). • The physiological outcome measures were the transdiaphragmatic pressure time product (PTPdi), respiratory muscle strength, thoracoabdominal asynchrony, tension time index of the diaphragm and assessment of asynchronous events. Results: A volume target of 4ml/kg in comparison to 6ml/kg or no volume targeting resulted in a higher PTPdi (p <0.001). In infants weaning from the ventilator, the PTPdi was 20% lower (p <0.001) during SIMV with PSV in comparison to SIMV alone. No significant difference in the duration of weaning was demonstrated between PSV and ACV. The in vitro PAV study highlighted abnormalities of airway pressure waveform and higher than excepted airway pressures during both elastic and resistive unloading. Conclusions: Low levels of volume targeting even within the ‘physiological’ range significantly increased the work of breathing. A triggered mode supporting all the infant breaths was superior to when a limited number of breaths were supported. When similar inflation times were used, triggered modes supporting all breaths were equally efficacious. Unloading levels affect the efficacy of PAV; these may be determined by using the ventilator calculated respiratory mechanics.

Childhood obesity has become a major public health challenge. Work has already been done that focuses on schools and possible interventions in this area but there is apparently very little that targets the family environment and specifically looks at the family food culture within different generations. In recognition of the fact that the family environment has an important role to play in tackling the childhood obesity epidemic, this research aimed to redress the balance and examined the affect of the family on children's eating behaviours within an intergenerational context. The research process was governed by a qualitative, grounded theory approach that initially explored eating behaviours within different generations using sixteen focus group discussions. Following this, twenty seven semistructured one-to-one interviews were conducted that investigated eating behaviours of different generations within families, incorporating two types of families, those with an obese child and those with a normal weight child. What emerged was a substantive theory based on ordering of eating that explained differences in eating behaviours between the various families. The theory of ordering of eating enriches our understanding of familial influences on children's eating behaviours. It demonstrates how micro and macro order affects family choices concerning food and eating and the development of children's eating behaviours within this context. In addition, ordering of eating addresses the 'how' of eating and not simply the 'what' of eating. Current strategies for tackling childhood obesity tend to be more aligned with a medical approach where the emphasis is on controlling diet and the type of food intake which is a product of disordered eating behaviours. Focusing on family eating patterns and a return to the enjoyment of eating represents an innovative and promising alternative for those concerned with the development of interventions aimed at children's eating and childhood obesity, as these research findings demonstrate.

The objective of this study is to find out whether a reduction in body weight will reduce health risk factors. To fulfil this objective an intervention study has been conducted among Saudi obese females in the childbearing age (18-45). Interview questionnaires were completed in the intervention and non-intervention group to collect baseline data; the intervention group has undergone a specific diet regimen, physical exercise and nutrition programme. Vital signs including heart rate (PS) and blood pressure (BP) for both groups were recorded at the beginning of the study and after the intervention. Blood biochemical investigations were conducted between both groups at the beginning of the study and after the intervention. Data was analysed using SPSS (version 10). Results showed that baseline data of both intervention and non-intervention group were similar in relation to anthropometrics measurements and BMI. A significant difference was found at day 60 between the intervention and non-intervention group in weight and BMI. Analysis of biochemical variables showed insignificant statistical differences at day -60 in total cholesterol, LDL, and FBS. A statistical difference was found between the intervention and non-intervention group at day-60 in relation to the studied vital signs, systolic and diastolic BP A remarkable change in participants’ knowledge, attitudes, and practices was observed among the intervention group between day-1 and day-60. For example being a yo-yo dieter was reported by 85.2% of the group in day-1 and by 14.81% in day-60 and eating outside was reported by 81.5% in day-1 and by 18.5% in day-60. In conclusions, the use of a combined intervention programme of diet, physical exercise and health education is effective in weight reduction. Regular assessment of vital signs (PS and BP), biochemical laboratory investigations (CHOL, HDL, LDL, TG and FBS) are feasible tools for follow up and early detection of obesity complications. A sustained reduction in body weight is one of the preventive measures to avoid obesity complications. Despite the efforts done during this study, some limitations such as the small sample size and the short duration of intervention can be considered.

This thesis investigates how various signal processing techniques can be applied to diagnose problems in the medical domain. In particular it concentrates on breathing problems often experienced by premature babies who undergo artificial respiration. Medical Decision Support is an area of increasing research interest. The neonatal intensive care unit (NICU) is a prime example. This thesis describes the investigation of techniques to be used as the core of a decision support device in Edinburgh's NICU. At present physiological signals are taken from the patient and archived, little diagnostic use is made of these signals and no investigation has taken place into their diagnostic relevance. Within the scope of the work an investigation has taken place into the application area and some of its current problems have been identified. From these a physiological problem, respiratory disorder, was identified with characteristics which made it worthy of detailed study: it was extremely common, moreover expert knowledge and data about it already existed. With the current techniques the development of respiratory disorder is often missed or diagnosed too late. Signal processing techniques were evaluated with a view to applying them to predict the onset, or classify the development of, respiratory disorder, and a multi-layer perceptron network was chosen to perform as a classifier in the decision support tool. A number of tests were run which included an investigation of the efficiency of the chosen feature extraction techniques and the diagnostic relevance (with respect to the condition under investigation) of the signals being used to assist in diagnosis. Results show that at present the signals of greatest diagnostic relevance are not always used: a decision support device can be developed using a multi-layer perceptron classifier in combination with other signal processing techniques. The thesis also identifies other techniques where there is potential for improving the decision support tool's predictive and classification ability.

There is growing evidence that children's subjective interpretations of events may differ significantly from those of adults; yet children's voices and children's knowledge regarding hospital care remain largely unexplored. This study was undertaken to determine what counted as voice in work with hospitalised children, and explore children's subjective interpretations and knowledge as in-patients. Influenced by critical ethnographic methods, the study was undertaken in two phases with children who had been in-patients in one English tertiary referral children's ward. Phase one involved reconnaissance with 6 children to explore what mattered most to them regarding their in-patient experience. Phase two involved field work undertaken over six months, on a nephro-urology ward, and included in-depth work with nine children. Voice became manifest in what the children said but also through the non-verbal mechanisms of resisting and being silent. In this study, the children chose which voice to present when they participated in the study and that voice was accepted without question. Inductive analysis revealed that the children shared the experience of being in trouble. While they were in-patients, recognition of their competence was fluid=and contingent on structural and material factors. When their competence was denied, some of the children fought hard to re-establish their claim as authentic and knowledgeable individuals. However, while all of the children who participated in this study, regardless of ability, were capable commentators on their experiences, their capacity to work in their own best interests was sometimes challenged. During these episodes, they relied heavily on supportive adults. In the absence of supportive adults they often became marooned and subject to routinised care.

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency, characterised by serious infections and inflammation. It can be managed conservatively, with prophylactic antimicrobials, or curatively with haematopoietic stem cell transplant (HSCT). In the UK and Ireland there are cohorts of children managed both conservatively and curatively. Previous research has shown patients with CGD have low intelligence and increased emotional difficulties. Chronic diseases are known to result in poor quality of life. This study aimed to evaluate: clinical outcome; quality of life; emotional well being and cognitive function in children managed conservatively and curatively. Children were identified from specialists centres and advertising through special interest groups. Clinical data were collected from medical records. Children and parents completed questionnaires measuring quality of life, emotional and behavioural difficulties and self-esteem. Children underwent brief IQ tests. Results were compared to published norms for healthy children. Non-HSCT and post-HSCT groups were compared. 78 children were identified. 59 (80%) living children were recruited. Clinical information was available for 62 children (four deceased). 30 (48%) children had undergone HSCT. Children with CGD had 0.71 episodes of infection/admission/surgery per CGD life year (95%CI 0.69-0.75 events per year). Post-HSCT children had 0.15 events per transplant year (95%CI 0.09- 0.21 events per year). Post-HSCT survival was 90%. Parents and children reported quality of life significantly below normal for in the non-HSCT group. Post-HSCT scores were not significantly different from healthy norms. Parents of non-HSCT children reported increased emotional difficulties compared to healthy children. IQ was normal in both groups. Children with CGD have more serious infections, episodes of surgery and admissions compared to post-HSCT children. They also have poorer quality of life and are at risk of emotional difficulties. Post-HSCT children have normal quality of life. Cognitive function is normal in both non-HSCT and post-HSCT children.

Discrete data, often known as frequency or count data, comprises of observations which can only take certain separate values, resulting in a more restricted numerical measurement than those provided by continuous data and are common in the clinical sciences and epidemiology. The Poisson distribution is the simplest and most common probability model for discrete data with observations assumed to have a constant rate of occurrence amongst individual units with the property of equal mean and variance. However, in many applications the variance is greater than the mean and overdispersion is said to be present. The application of the Poisson distribution to data exhibiting overdispersion can lead to incorrect inferences and/or inefficient analyses. The most commonly used extension of the Poisson distribution is the negative binomial distribution which allows for unequal mean and variance, but may still be inadequate to model datasets with long tails and/or value-inflation. Further extensions such as Delaporte, Sichel, Gegenbauer and Hermite distributions, give greater flexibility than the negative binomial distribution. These models have received less interest than the Poisson and negative binomial distributions within the statistical literature and many have not been implemented in current statistical software. Also, diagnostics and goodness-of-fit statistics are seldom considered when analysing such datasets. The aim of this thesis is to develop software for analysing discrete data which do not follow the Poisson or negative binomial distributions including component-mix and parameter-mix distributions, value-inflated models, as well as modifications for truncated distributions. The project’s main goals are to create three libraries within the framework of the R project for statistical computing. They are: 1. altmann: to fit and compare a wide range of univariate discrete models 2. discrete.diag: to provide goodness-of-fit and outlier detection diagnostics for these models 3. discrete.reg: to fit regression models to discrete response variables within the gamlss framework These libraries will be freely available to the clinical and scientific community to facilitate discrete data interpretation.

Unexplained Sudden Unexpected Death in Infancy (SUDI) is a diagnosis where a definitive cause of death cannot be ascertained. It remains the most common diagnosis in infant death at autopsy, despite the performance of a range of investigations including histology, microbiology and chemical pathology. Of all infant deaths with a demonstrable cause, infection is the most common finding. Recent research has shown that in some cases of unexplained SUDI, there is supportive evidence of an infectious process. Recent advances in diagnostic pathology include immunohistochemistry on formalin-fixed, paraffin-embedded (FFPE) tissue, proteomics and metabolomics. However, there are few techniques, which have transitioned from clinical practice into use during autopsy. Current techniques used at autopsy in cases of sudden infant death were assessed to see whether there was support for an infectious process. This included a retrospective analysis of all infant autopsies performed at a single centre over a fourteen-year period. Also, current consensus opinion was evaluated to determine areas of diagnostic difficulty. Cohort groups of infant deaths were selected for the application of novel immunohistochemical staining and proteomic analysis from FFPE tissues. The findings indicate that infection remains the commonest identifiable cause of death in SUDI, even over a 100 year time period, supported by recent demographic data. Unexplained SUDI cases were confirmed as having an increased incidence of positive blood cultures for infections of uncertain significance, including Staphylococcus aureus and Escherichia Coli. Evaluation of organ weights at autopsy demonstrated no significant associations, although the thymus was smaller in cases of infectious deaths. Blood/bile acylcarnitine levels showed differential expression in 3 different cohorts. Immunohistochemical staining revealed infectious deaths had a characteristic profile of expression including upregulated C Reactive Protein and ICAM-1. Protein expression was investigated with development of an applicable technique for usage in autopsy FFPE tissue. Subsequently, a pilot study of the utilisation of proteomics in the diagnosis of SUDI was performed with effective extraction of peptides and the identification of bacterial proteins in different cohorts. This thesis has demonstrated new techniques for the investigation of SUDI with establishment of supportive evidence for infectious deaths which are applicable for future use in autopsy cases.

Medulloblastoma is a malignant embryonal tumour of the cerebellum which most commonly affects children. A subset of tumours is thought to arise from cerebellar granule cell precursors (GCPs) that fail to undergo normal neuronal development, following the hyper-activation of the Sonic hedgehog (Shh) signalling pathway. To identify candidate genes that might be important for medulloblastoma pathogenesis, I investigated patterns of gene expression and alternative splicing in 14 paediatric medulloblastoma and five normal cerebellar samples using Affymetrix Human Exon arrays. Statistical analysis of the gene expression data identified a group of medulloblastomas with a molecular signature of Shh pathway activation. These tumours showed higher expression levels of genes involved in spindle formation, cytokines, and cell cycle regulation. Further studies using an in vitro mouse GCP cell culture model, in which Shh is necessary for the maintenance of the progenitor state, showed that a selection of candidate genes was also over-expressed when GCPs were cultured in the presence of Shh, as compared to control cells, as well as in human medulloblastoma cell lines. Ongoing and future in vitro experiments will investigate the potential role of candidate genes in sustaining the growth of precursor and tumour cells. Exon-level analysis of gene expression showed that abnormal expression of different transcript variants is likely to occur in medulloblastoma. I selected several examples of differential exon usage and validated these using an independent set of normal and tumour specimens. Tumour-associated splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases of different medulloblastoma molecular subgroups. Interestingly, Shh-treated GCPs recapitulated the splicing patterns observed in the tumour samples for six out of the eight genes analysed, suggesting that the preferential expression of specific transcript forms is regulated during normal cerebellar development. The possible relationship between inappropriate splicing and medulloblastoma pathogenesis will be the subject of future investigation.