This thesis examines and describes children's and adolescent's responses to burn injuries, with a specific focus on traumatic responses. Fifty five children, adolescents and their parents took part in this longitudinal study, a recruitment rate of 35% of the total population. All of the children had sustained accidental burn injuries of varying severity at least one month before their first assessment. Children were aged between three and eighteen years, and the mean age was seven years. Children under 6 years were not personally assessed. Parents reported on these children using the Child Behaviour Checklist (CBCL), and the Posttraumatic Stress Reaction Index- parent version (PTS-RI). Children over six years took part in the Diagnostic Interview for Children and Adolescents (DICA), and completed the Impact of Events Scale (IES), the Children's Posttraumatic Stress Reaction Index (C-PTS-RI), the Fear Survey Schedule (FSS) and the Depression Self-Rating Scale (DSRS). Parents of these children also completed DICA, the PTS-RI and the CBCL. At six months, all procedures were repeated. Generally, children and adolescents adjusted well following their burn injuries. Traumatic symptoms had been experienced by over half the children, with intrusive symptoms most common. 14% had a PTSD diagnosis at some time since their burn injury. A quarter of the children were reported to have general borderline or clinical behavioural problems using the CBCL. Over half the children reported symptoms of depression. The results are described with reference to the existing literature on children's traumatic responses and children's responses to burn injuries. It is suggested that there may be a "normal" acute trauma response following burn injury. Theory surrounding children's response to burn injury is examined and directions for a new theory encompassing trauma and injury in the context of development are proposed. The methodological limitations to the study are discussed and recommendations are made.

Exogenous surfactant therapy has dramatically improved survival in extremely preterm infants, however the turnover of exogenous and synthesis of endogenous surfactant components are still poorly understood in this group. Additionally there is evidence for this patient group that improving nutrition improves long-term outcomes in respiratory function, growth and neurodevelopment. Phosphatidylcholine (PC) is the dominant phospholipid in both surfactant and in plasma and can be synthesised from choline by one of two pathways: the CDPcholine pathway, which is present in all nucleated cells, or by three sequential methylations of phosphatidylethanolamine in the PEMT pathway, which is localised to hepatocytes and is the primary source of polyunsaturated PC species and de novo synthesis of choline. This study quantified choline phospholipid metabolism and pulmonary surfactant kinetics in preterm infants in vivo. Children aged between 23 and 28 weeks gestation and in receipt of exogenous surfactant were intravenously infused with [methyl-D9]choline chloride within 48 hours of birth. Lipid extracts from sequential plasma and endotracheal aspirate samples were then analysed by electrospray ionisation tandem mass spectrometry (ESIMS/ MS). Fractional incorporation into newly synthesised PC species is demonstrated rapidly in plasma samples at a higher rate than previously reported in adults, indicating a high level of hepatic activity for CDP-choline. Analysis of the PC species derived from the PEMT pathway shows significantly lower flux in this pathway than reported in adults. Finally incorporation into surfactant PC species is very low initially before rising slowly over several days and with the rapid changes in other acidic phospholipids suggests a rapid recycling of components of the exogenous surfactant not equilibrating with the CDP-choline pathway thereby providing evidence for the first time of differing rates of exogenous surfactant recycling versus de novo synthesis in the human preterm infant. This study proves that the technique works in the clinical environment, is sensitive and rapid enough to provide data in a clinically relevant timeframe, opening the possibility for translational use to identify biomarkers for disease progression.

This thesis represents an attempt to further our knowledge of the ophthalmic complications of spina bifida and hydrocephalus by means of literature review and a long term clinical study, and to determine whether regular ophthalmic supervision can assist in the general management of affected children. The ophthalmic complications of spina bifida have often been reported in the literature and thought to merit regular supervision of affected children, yet few centres currently offer this service. In this study 322 children attending one regional centre were examined repeatedly over a six year period by one ophthalmologist. Ophthalmic complications were found to be very common. They frequently provided evidence of raised intracranial pressure due to shunt dysfunction even when other objective evidence was lacking. Every spina bifida and hydrocephalus clinic should have an ophthalmalogist in its medical team. Preservation of visual function and early diagnosis of raised intracranial pressure in these children should result from this arrangement.

This thesis examines the cognitive-psychological theory of autism, specifically the "theory of mind" account. According to this theory, autistic people lack the ability to attribute mental states to other people and this underlies their social communication difficulties. In the introductory chapters, autism is described, followed by a consideration of different theoretical accounts of the normal child's theory of mind and empirical evidence on the autistic child's theory of mind. Finally, the introduction discusses whether the different theoretical accounts can explain autism. A series of experiments are then described which investigated normal and autistic children's ability to understand knowledge as a mental state. Experiment 1 established a baseline for the subsequent experiments and included three groups of normal children with mean ages of four years nine months, five years nine months and six years nine months. In this experiment the children's ability to differentiate the cognitive mental terms "know" and "guess" with reference to their own and another person's mental states was examined. Results of this experiment indicated that all three groups of children could differentiate "know" and "guess" in reference to their own and another person's mental state. Experiments 2 and 3 compared the ability to differentiate "know" from "guess" with reference to their own and another persons mental state of high language level autistic children, low language level autistic children, children with Down's syndrome, four-year- old and five-year-old normal children. Results of these experiments showed that the high language level autistic children were able to refer to their and another person's mental state of knowledge. In addition the results were related to a number of measures of language ability. Experiment 4 compared the ability to attribute knowledge and ignorance to themselves and another person of high language level autistic children, low language level autistic children, four-year-old and five-year-old normal children. In one task the experimental question involved the mental term "know", in another task, the term "could help" was used. Results of this experiment showed that all four groups of children performed significantly better in the "know" task than in the "help" task. Performances on the tasks was again related to the children's language skills. The thesis reaches two main conclusions. First that autistic children do not totally lack a theory of mind, since high language level autistic children were able to refer to their and another person's knowledge state. Second, autistic children's language level is a strong predictor of their performance on theory of mind tasks. The thesis concludes by discussing a number of issues involved in autism research and indicating future directions for research.

Understanding the ways in which practitioners can identify and manage undernutrition is important within developing world countries. There is still much uncertainty when it comes to understanding which measures of undernutrition are the most effective predictors of adverse outcomes. This thesis explores how children grow and applies statistical methodology to three longitudinal growth datasets with frequent measurements in the first two years, seeking new insights into how measures of undernutrition can be used to predict future adverse outcomes. The three datasets are diverse - from Malawi, South Africa and Pakistan, the latter of which contains 4 subsets of different socioeconomic groups. The large number of children within the sets made it possible to test several different hypotheses. Growth charts (or reference charts) are charts which allow practitioners to compare a given infant’s anthropometric measurements with a reference population. We developed growth charts from the available datasets using Generalised Additive Models for Location Scale and Shape (GAMLSS), a method which allows users to flexibly model distributions of measurements over time. The reference charts we developed describe the growth of samples of children, many of whom will not have grown at a healthy rate. It is preferable to compare children with healthy infants from a composite external standard. The World Health Organization (WHO) growth standard was developed from a variety of populations from across the globe which describes the growth of a ‘healthy’ population. This suggests an aspirational model, as opposed to a reference, which describes how a sample of children actually grow. In this thesis GAMLSS was used to determine whether real populations of pre-school children from the developing world fit this international standard. We found that relatively affluent populations fit the standard well, or even outperform it, while more deprived populations fall away to varying degrees, then mainly track parallel to the WHO mean beyond 6 months. This suggests that after the first 6 months children from the developing world have rates of weight gain roughly on par with the standard, although the children are much lighter. Plotting measurements on growth charts identifies those whose weight Z score or centile is falling relative to the reference. However, children initially at the extremes tend to regress toward the mean. Conditional weight gain (CWG) takes this expected movement into account, but can only be used within the population in which the child originates, due to certain statistical assumptions. We developed a generalised measure of CWG for use with the WHO external standard. This measure requires the correlation between pairs of groups of measurements at different time points, as the amount of regression to the mean is synonymous with this correlation. If data are not available at these time points, they can be interpolated by firstly computing correlations between all available data, then modelling the resulting matrix. We found that these correlation matrices are heterogeneous within the developing world. Therefore, constructing a generalised correlation model was not possible. This makes the use of the new generalised measure of CWG impractical without access to correlation models computed from local data. However, the measure may be useful within the developed world, where correlation matrices may be less variable. The analysis then explored the ways that children move between different nutritional states, defined as healthy, thin (wasted) and/or short (stunted), over 3-6 month (m), 6-9m and 9-12m timeframes, and the probability these states will lead to death. We used stochastic models to explore the probability of moving state conditional on previous state, exploring the pathways children take through different states over time. Within all timeframes, children who were wasted as well as stunted were more likely to die than wasted children, who were in turn more likely to die than stunted children. Furthermore, as children age, the conditional risk of death in the next time period decreases. However, relative to healthy children, all children were less vulnerable within the middle period (6-9m) regardless of state. Children who were wasted were at significantly higher risk than healthy children of later wasting, or becoming stunted as well as wasted, over all timeframes. However, wasting alone significantly increased the risk of later stunting only in the 3-6m timeframe. Across the 3-6-9m timeframes children were much more likely to move from either healthy to healthy to stunted, or healthy to stunted to stunted, than from healthy to wasted to stunted. This indicates children are more likely to move directly into a stunted state than from healthy to stunted via wasted. Change in weight (growth) has been shown to be a predictor of mortality in populations of children, but it is not clear if this measure is more predictive than the latest weight (size). Using weighted Cox proportional hazards models, we determined which of these measures is the most valuable predictor of mortality for the majority of children within each individual dataset, conducting analyses using variable levels of weightings for children at the extremes. We included weight-for-age and height-for-age as predictors within our models to determine what combination of predictors best predict mortality. In all unweighted analyses, size was the best predictor of time until death. However, as the weighting increased, growth entered as the best predictor in populations with low rates of undernutrition. In contrast, size always remained the strongest predictor within populations with high rates of undernutrition, since in these populations, such a high proportion of children fall away from within the centre of the normal range, making growth pattern non-discriminating. This programme of work applied statistical techniques to three diverse longitudinal datasets, gaining insights into how children grow between different socio-economic backgrounds. We investigated measures of size and measures of growth, utilising methods that control for the inevitable fact that healthy children at the centre of the population distribution tend to dominate analyses. Furthermore, these methods were both multidimensional and time dependant, providing us with a useful framework to assess child growth while controlling for influential factors. The results should improve understanding of both the aetiology of undernutrition and its clinical management.

No description available.

This research project sets out to explore the lived experience of Being and caring for a child with a Life Limiting Condition. This research uses van Manen’s (1990) conceptualisation of hermeneutic phenomenology that is both a research methodology and a method. The first empirical work is a preliminary study using focus groups with professionals. The findings of this work acts as a backdrop to the further two studies that involve interviewing, in-depth, twenty eight parents and five children. The second study details the parents’ lived experiences and the final study looks at five parent-child dyads and their combined lifeworlds. In keeping with the phenomenological methodology, data was analysed using Template Analysis (King, 2004). It is a rare opportunity to observe and speak with children with Life Limiting Conditions and so gain insight into their lives. Their vulnerability is often characterised by rare and difficult-to-diagnose conditions, significantly shortened life spans with compromised quality of life. For the participants, the experience of Life Limiting illness was not only personal, but was also transactional, communicative and profoundly social. The challenge is one of Being thrown into an abnormal unready world which compels one to consider the paradoxical temporality of the here and now. This brings recognition of being the same as others in a lived space, but also being different in a fundamental way that has a significant impact. The challenge is met by adapting to the environment to find new ways of Being. This research encourages readers to thoughtfully reflect on what is it like for these families and those involved in their care, and to consider practice improvements that address the triadic experience (of child, parent and professional). The full significance of such reflection will ideally promote further questioning and inquiry, in keeping with the always provisional nature of phenomenological inquiry.

No description available.

Rett Syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene, are the primary cause of the disorder. Despite the dominant neurological phenotypes that characterise RTT, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as growth retardation (reduced height and weight), skeletal deformities (scoliosis/kyphosis), reduced bone mass and low energy fractures are also common yet under-reported clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any such defects, I have conducted series of histological, imaging and biomechanical tests of bone using an accurate genetic (functional knockout) mouse model of RTT. Initial experiments using a GFP reporter mouse line demonstrated the presence of MeCP2 in bone cells and the effective silencing on the gene in functional knockout mice. Different aspects of the study were conducted in different types of bone tissues that were especially suited for individual assays. For instance, biomechanical three point bending tests were conducted in long bone (femur) whilst trabecular geometry measures were measured in spinal vertebrae. Both hemizygous Mecp2stop/y male mice in which Mecp2 is silenced in all cells and female Mecp2stop/+ mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation (XCI), revealed, lighter and smaller long bones and significant reductions in cortical bone mechanical properties (~ 39.5% reduction in stiffness, 31% reduction in ultimate load and 37% reduction in Young’s modulus respectively in Mecp2stop/y male mice; %) and material properties (microhardess reduced 12.3% in Mecp2stop/y male mice and 14% inMecp2stop/+ female mice) as compared to age wild type control mice. Micro structural analysis conducted using µCT also revealed a significant reduction in cortical (54% reduction in cortical thickness, 30% in bone volume, 20% in total area, and 38% in marrow area) and trabecular (~30% in trabecular thickness) bone parameters as compared to age matched wild-type controls MeCP2-deficent mice. Histological analysis using Sirius red staining as a marker of collagen revealed a ~25% reduction in collagen content in MeCP2 deficient mice as compared to age matched wild type controls. In experiments designed to establish the potential for reversal of MeCP2-related deficits, unsilencing of Mecp2 in adult mice by tamoxifen-induced and cre-mediated excision of a stop cassette located at the endogenous Mecp2 locus (male; Mecp2stop/y, CreER and female; Mecp2+/stop, CreER), resulted in a restoration of biomechanical properties towards the wild-type levels. Specifically, Male Mecp2stop/y, CreER mice displayed improvement in mechanical properties (stiffness 40%, ultimate load 10%, young’s modulus 61% and micro hardness 12%) and structural bone parameter (trabecular thickness 80%) as compared to Mecp2stop/y male mice. Female Mecp2+/stop, CreER, displayed a significant improvement (19%) in microhardess measures as compared to Mecp2 deficient mice. Overall, the results of my studies show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies for Rett Syndrome.

Attachment theory describes the importance of the child’s early relationship with the caregiver and insecure attachment has been identified as a risk factor for adolescent self-harm. Research presented in this thesis aims to further our understanding of this relationship by firstly exploring whether attachment impacts on self-harm via its effect on coping, secondly examining how peer attachment styles relate to self-harm and finally establishing what role attachment has in the repetition of self-harm and other related outcomes. Study 1, an online survey of 314 undergraduate students,revealed that attachment has an indirect effect onself-harm through coping. Higher quality of attachment was association with greater reliance on problem-focused (adaptive) coping, which in turn was associated with a decreased risk of having self-harmed. Furthermore, poorer paternal attachmentwas associated withlower appraisal of problem-solving skills, which in turn was associated with an increased risk of having self-harmed. Study 2 prospectively examined self-reported peer attachment as a risk factor for self-harm over 6-months amongst adolescents (n= 4508) in school years 8-11. Findings indicated that insecure attachment at baseline significantly predicted self-harm at follow-up, even after adjusting for baseline covariates (school year, gender, previous self-harm and levels of anxiety and depression). Lastly, study 3 hypothesised that insecure attachment would be associated with poorer outcomes over 6-months amongst adolescents aged 12-17 years who had self-harmed and been referred to Specialist CAMHS. Attachment styles were classified using the Child Attachment Interview: a validated assessment for young people. Compared to secure adolescents, those with insecure maternal attachment were more likely to repeat self-harm and showed less improvement in problem-solving. There were no differences between the groups in concordance with therapy. These findings provide novel insights into the relationship between attachment and self-harm and highlight the importance of considering attachment when planning treatment and assessing the risk of future self-harm.