The onset of labour represents the starting point of a perilous challenge in life, as a new born must adapt to an unknown environment. During this adaptation there are several risks: hypoxia, asphyxia, trauma, intervention and, in worst case scenario, death. These risks can be reduced trough electronic fetal monitoring. During this delicate period the study and analysis of the variability in beat-to-beat intervals of fetal heart rate plays a fundamental role in the pursuit of fetal wellbeing, reduction of fetal morbidity and mortality. Given that the use of an animal model allows direct experimental manipulation of the subjects and their environment and considering the ethical issues and difficulties to acquire data related to asphyxia during labour and delivery, linear techniques (time domain and frequency domain) and non-linear techniques (detrended fluctuation analysis, complexity analysis and Poincarè indices and plots) have been initially implemented for the study of heart rate variability (HRV) using data from the animal model. Data was acquired from experiments in which rats were submitted to controlled episodes of asphyxia (0, 1, 3, 5 and 7 min). Linear and non-linear methods highlighted significant differences in HRV before, during and after the insult. We show how, through a multiparametric analysis, it is possible to detect the onset of asphyxia. Furthermore, tracking the changes in heart rate variability along time, we suggest a novel non-invasive way to assess the amount of injury suffered. With this background we applied HRV analysis to data collected during labour and delivery. We have obtained fetal beat-to-beat heart intervals from non-invasive Doppler ultrasound using Wavelet transform, Hilbert-Huang transform and Autocorrelation function, and these were compared with beat to beat heart intervals extracted from invasive scalp fetal ECG used as a gold standard. For the autocorrelation approach the results of HRV obtained from Doppler ultrasound, using both linear and non-linear analysis, correlate very well with those obtained using fetal scalp ECG. We also modelled and measured the recovery time (from nadir to baseline) following a deceleration of fetal heart rate to study the recovery behaviour and its relation with the development of hypoxic scenarios. The results presented here provide a framework to detect and assess asphyxia by means of linear and non-linear techniques. These techniques have been tested first in an animal model and later in data collected during labour and delivery, showing that Doppler ultrasound provides a reliable alternative for assessing fetal heart rate variations non-invasively during pregnancy and delivery, when fetal scalp ECG is not available. Nevertheless more data needs to be collected and studied using the multiparametric HRV analysis described here to fully validate this approach.

In recent years, there has been a rise in the incidence of neonatal infections due to Enterobacteriaceae including Escherichia coli, Enterobacter, Klebsiella and Serratia spp. These are major causative agents in neonatal intensive care unit (NICU) infections. Neonates, especially those born with low birth weight (< 2000g), are fed via a nasogastric tube. Despite recent concerns over the microbiological safety of infant feeds, there has been no consideration that the nasogastric enteral feeding tube may act as a site for bacterial colonisation and act as a locus for infection. Therefore bacterial analysis of used feeding tubes is of importance with regard to identifying risk factors during neonatal enteral feeding. The aims of this study were to determine whether neonatal nasogastric enteral feeding tubes are colonised by opportunistic pathogens in the Enterobacteriaceae, and whether their presence was influenced by the feeding regime. In this research a collection 224 Enterobacteriaceae strains previously isolated from the enteral feeding tubes of neonates on intensive care units have been analysed. This study describes the use of DNA finger printing, via pulsed-field gel electrophoresis (PFGE), to determine if the same strains were isolated on different occasions from the NICUs. Therefore indicating whether certain strains have colonised the NICUs leading to increased exposure and risk to the neonates. The second project aim compared the virulence potential of Enterobacteriaceae, many of which were associated with feeding tubes. Twenty strains were chosen that represented species from the major genera isolated; E. coli, Serratia, Klebsiella and Enterobacter spp. Virulence to mammalian cells has been assessed using attachment and invasion studies of human colonic carcinoma epithelial cells (Caco-2), rat blood brain barrier cells (rBECE4) and human brain microvascular endothelial cells (HBMEC) tissue culture cells. Macrophage survival was studied using the (U937) cell line of human monocyte cells. The analysis has covered attachment and invasion of human intestinal cells, survival in macrophages, and invasion of rat and human brain cells. The results show that certain strains of E. coli k1 isolated from neonatal feeding tubes are able to persist in macrophages and hence be dispersed and potentially cause systemic infections.

Background: A high rate of sleep disturbances have been reported in individuals with Williams syndrome (WS), but the underlying aetiology has yet to be identified. Melatonin and cortisol levels are known to affect and regulate sleep/wake patterns. We investigated the changing levels of these hormones in order to explore any relationship with sleep disturbances in children with WS. Methods: Twenty seven children with WS and 27 typically developing (TD) children were recruited. Sleep was monitored using actigraphy and pulse oximetry. Parents completed Children’s Sleep Habit Questionnaire (CSHQ). Saliva and first void morning urine samples were collected from the children. Saliva was collected at three time points: 4-6pm, before bedtime and first thing after awakening. Levels of salivary melatonin and cortisol were analysed by enzyme linked immunoassays. For determination of melatonin, cortisol and their metabolites in urine samples, specific Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) method was developed. Results: CSHQ and actigraphy indicated that children with WS were significantly affected by several types of sleep disturbances, including: abnormally high sleep latency and excessive night waking. Children in WS group had shallower falls in salivary cortisol levels and less pronounced rises in salivary melatonin at bedtime compared to TD controls (p < 0.01 and p = 0.04 respectively). Furthermore, it was found that children with WS also had significantly higher levels of bedtime cortisol compared to TD controls (p = 0.03). Using UHPLC-MS/MS analysis it was shown that children with WS secrete less melatonin during the night compared to healthy controls (p < 0.01). Also, levels of cortisone, a metabolite of cortisol were significantly higher in the WS group (p = 0.05). Conclusions: We found that children with WS had significant sleep disturbances which may be associated with their increased bedtime cortisol and lower evening melatonin. Both hormones play a significant role in the circadian rhythm and sleep/wake cycle, therefore it was necessary to look closely at these endocrine markers in individuals suffering from sleep disorders. Sleep problems in children with WS may adversely affect daytime activity and the quality of life, as well as social, emotional, health and economic functioning of the entire family. Hence, finding their cause is of great importance for affected children and their families.

Ventilation inhomogeneity is a well recognised feature in older children and adults with asthma, even during asymptomatic periods. However, little is known about physiological changes in the airways, particularly small airways in preschool wheezers. This thesis investigated whether indices of ventilation inhomogeneity derived from multiple breath washout (MBW) were abnormal in asymptomatic preschool wheezers; whether MBW indices were more sensitive for detecting airways disease than specific airways resistance (sRaw); and whether there were differences in pulmonary function according to wheeze phenotype and atopic status. Preschool children (aged between 4-6 years) with recurrent wheeze, underwent pulmonary function assessments and were compared with age matched healthy controls. Fraction of exhaled nitric oxide (FeNO); MBW indices [lung clearance index (LCI), functional residual capacity (FRC), conductive (Scond) and acinar (Sacin) airways ventilation inhomogeneity] and sRaw were measured. Subgroup analysis was performed according to temporal wheeze phenotype of episodic (viral) and multi-trigger wheeze, and atopic status. FeNO and pulmonary function were compared in 72 healthy controls and 62 wheezers [episodic (n=28), multi-trigger (n=34; atopic (n=39), non-atopic (n=23)]. Group differences between healthy controls and wheezers were seen for FeNO, LCI, Scond and sRaw. FeNO was abnormal in 9/62 (15%), LCI in 16/62 (26%), Scond in 22/60 (37%) and sRaw in 12/62 (19%) wheezers. Multi-trigger wheezers had significantly higher LCI, Scond and sRaw than episodic wheezers. LCI was abnormal in 13/34 (38%), Scond in 21/34 (62%), and sRaw in 10/34 (29%) multi-trigger wheezers. In contrast, LCI was abnormal in 3/28 (11%) and Scond in 1/28 (3.5%), and sRaw in 2/28 (7%) episodic (viral) wheezers. There were no differences between atopic and non-atopic phenotypes. MBW indices in particular Scond detect airways disease in preschool wheezers more frequently than sRaw. Pulmonary function tests in particular Scond discriminate between episodic (viral) and multi-trigger wheezers, irrespective of atopic status providing physiological validation to clinical patterns of wheeze.

This volume is divided into three distinct parts. First, the literature review focuses on the experiences of parents raising children with congenital dermatological conditions (CDDCs). After summarising findings from studies about parents with children with non-dermatological congenital disfigurement and atopic dermatitis, the review focuses in more detail on the limited research into the experiences of parents raising children with CDDCs. Findings highlight that parents raising children with CDDCs am reporting high levels of practical, social and emotional difficulties. Part two presents an empirical paper investigating the functioning of parents raising children with CDDCs, and the relationship between these parents' and their children's functioning. Results showed that whilst on most measures, parents reported significantly better than average functioning, mothers were significantly struggling from poor mental health status. Parent and child functioning were significantly related and there was a potentially emerging trend for child's attachment style to moderate some of the transfer of their parents' negative experiences. The results highlighted professionals need to screen mothers raising children with COOCs for poor psychosocial functioning. This study was completed as part of a group research project investigating the factors underlying the variation in functioning of children with CODCs. Finally, the third part of this volume comprises a critical appraisal. This report reflects on key decisions made about sampling for the research, the choice of measure for measuring child attachment style, and the pros and cons of working as part of a research group.

There is high demand for Speech and Language Therapy but even with initiatives to address the shortage of therapists, Speech and Language Therapy services struggle to satisfy demand – tele-technology could be a solution. A Speech and Language Therapy service for a paediatric caseload using a desktop video-conferencing system (Skype) was established. A pilot study with three participants determined the feasibility of the Skype Speech and Language Therapy service and trialled measures of clinical activity, Therapist-child interaction, technological utility, and costs. Eleven participants aged between 7 and 14 years with varying therapy needs took part in the main study. Each received a mix of face-to-face (F2F) and Skype Speech and Language Therapy over the ten session trial period. Data were collected for every session using a session profile; adults supporting the children were asked for their views using a questionnaire at the beginning and end of the trial; the child participants were interviewed after the trial period was over; one F2F and one Skype session was video recorded for each participant; work activity was recorded along with identifiable costs of the F2F and Skype Speech and Language Therapy sessions. The level of clinical activity was equivalent between F2F and Skype Speech and Language Therapy sessions, with parents reporting positive views concerning Skype intervention, and growing acceptance of Skype interaction. The analysis of the therapist-child interaction showed broadly similar patterns between the Skype and F2F sessions, with the exception on the use of requests, clarifications, acknowledgements and confirmations where differences were observed. Technological utility was acceptable with minimal audio and visual distortions. Costs for Skype Speech and Language Therapy were substantially lower than the F2F sessions. This research showed that, for the families participating in this research, Speech and Language Therapy services delivered using tele-technology can provide an acceptable alternative to F2F intervention.

This thesis investigated psychosocial and neuropsychological outcome following childhood stroke. Part 1, the literature review, critically evaluated 38 outcome studies of childhood stroke. This demonstrated that a significant number of children experience difficulties in a wide range of neuropsychological and psychosocial areas. Health related quality of life (HRQoL) can also be significantly reduced. Methodological issues limited the conclusions that could be drawn regarding the predictors of outcome. Part 2, the empirical paper, investigated HRQoL, neuropsychological and psychosocial outcome in forty-nine children who had experienced stroke. The findings show that children's HRQoL, as rated by the child, parent and teacher, is significantly reduced across several domains of functioning. Predictors of HRQoL include self-esteem, behaviour, executive function and neurological severity. Parental well-being and family functioning were associated with children's HRQoL. Particular neuropsychological vulnerabilities were identified in attention, executive function and expressive language. Difficulties with emotional regulation, inattention and peer relationships were also highlighted. Part 3, the critical appraisal, addresses the strengths and methodological limitations of the study. Cognitive and psychosocial interventions from other areas of paediatric psychology were discussed that could be potentially developed for children who have experienced stroke. This study was conducted with collaboration with another researcher (Bancroft, 2010, unpublished DClinPsy thesis). Victoria Bancroft recruited nine adolescent participants who also took part in this study for a qualitative study (see Appendix E).

Haemodynamic instability is common during critical illness when homeostatic mechanisms are attenuated or already at the limit of their efficacy. Intubation is a crucial life-saving intervention which seeks to stabilize respiratory and cardiovascular function, but itself represents an additional, short-term haemodynamic challenge. This thesis aimed to investigate changes in heart rate during intubation of critically ill children. Heart rate was chosen as a crude measure of haemodynamic stability because it is most readily available even in time-critical pre-hospital settings. Focusing on heart rate also raised the question of the benefits of atropine pre-medication The first study was an international survey of Paediatric Intensivists using the Delphi methodology. There was agreement that there is a risk of death during intubation. There was no agreement about the capacity of atropine to reduce the incidence of bradycardia, hypotension or death. An observational study of 414 intubations in critically ill children was used to provide data for the thesis. Reductions in heart rate were common amongst first intubations in neonates, children between 28 days of age and eight years and further intubations in both groups. The limitations of using the minimum heart rate as a measure of haemodynamic disturbance were considered. An alternative measure of the change in heart rate, or ‘lost-beats’, was proposed and investigated. Atropine use was associated with less of a fall in heart rate and fewer lost heart beats during intubation. There was a strong association between a low heart rate and an increased incidence of arrhythmias and conduction abnormalities during intubation. Arrhythmias and conduction abnormalities were reduced, but not eliminated, by atropine pre-medication. Sinus tachycardia was not observed to convert to ventricular tachycardia or fibrillation when atropine was used. Mortality during critical care intubation was low (<0.5%). Atropine could not be statistically proven to have an effect on mortality during intubation although was associated with reduced intensive care mortality in children over 28 days of age but not in neonates. The association of atropine pre-medication with reduced PICU mortality in children over one month is unexpected and requires further investigation. A rabbit model of endotracheal intubation was used to investigate the consequences of vagal activation on blood pressure in hypovolaemia and endotoxaemia. Hypovolaemic rabbits observed a significantly smaller decrease in blood pressure after vagal stimulation than that in control rabbits. The relative change in blood pressure after vagal stimulation was similar between the endotoxaemic rabbits and controls. This finding suggests that different disease states may influence the haemodynamic function during intubation.

Approximately 10 in 100,000 children develop inflammatory arthritis every year and a large proportion of those are diagnosed as having Juvenile Idiopathic Arthritis (JIA). A major cause of suffering in the disease is pain, and indeed it contributes significantly to the morbidity of this condition when assessed by various disability scores. Pain from affected joints causes sleep disturbance, limits normal activities, disrupts school attendance and results in considerable psychosocial stress. Very little is understood about arthritic pain processing in the immature nervous system. Both clinical and neurobiological studies in animal models show that CNS nociceptive connections differ in juveniles and adults and that the normal maturation of these connections depends upon early life stress and pain experience. The immaturity of synaptic connections and integrated circuits means that children’s pain experience is different from that of adults and may impact upon pain in later life. It was our aim to develop and characterise a rodent model of joint inflammation to better understand the neurobiological basis of joint pain in early life and to establish whether joint inflammation in childhood influences joint pain sensitivity as an adult. In the first results chapter (Chapter 2), the normal development of joint evoked and cutaneous reflexes were mapped out over the postnatal period. In the second Results chapter (Chapter 3), monoarthritis of the ankle was induced in Sprague-Dawley rats of different postnatal ages using complete Freund’s adjuvant (CFA) and the effect of this inflammation upon spinal circuits was studied using behavioural and electrophysiological measures. Electromyographic (EMG) recordings show that inflammation leads to widespread reflex hypersensitivity to mechanical stimuli in young animals that differs significantly from the effects of adult joint inflammation. In adults, a significant attenuation of reflexes, or ‘protective inhibition’ phase was observed at 24 hours and 4 days post-inflammation, followed by a ‘hypersensitivity phase’ at 10 days when reflexes to pinch were dramatically enhanced. These effects were not detected with simple behavioural observation. In the third results chapter (Chapter 4), the long-term effects of joint inflammation (6 weeks) were investigated and shown to be highly dependent upon the age at which the inflammation occurred. Baseline nociceptive reflexes were enhanced in animals that had experienced joint inflammation when young (postnatal day (P) 8) but slightly reduced if the inflammation had occurred at the same time interval, but in adult life. The effects of a second injury in adulthood also depended on the past history of the animal. Animals first inflamed in early life, displayed a significantly greater ‘protective inhibition’ than adult inflamed controls, while animals first inflamed in adult life displayed enhanced hypersensitivity to joint inflammation. The results here describe previously unknown characteristics and mechanisms of joint pain in early life which will contribute to a better understanding and treatment of pain in JIA.

This thesis explores the relationship between attachment and psychosocial adjustment in children with congenital dermatological disfigurements. It is part of a joint project carried out with two other trainees from DCL (Jenny Gibson and Khibza Hussain) and a trainee from Royal Holloway (Rebecca Mason) (see Appendix A for details). Part 1, the Literature Review, systematically considers the small evidence base of empirical studies that have investigated the nature of the attachment relationship in children with congenital disfigurements. The studies reviewed find little evidence for disruption to the attachment relationship in this clinical group. In Part 2, the Empirical Paper, the study carried out focuses on a clinical population of school-aged children with congenital dermatological disfigurements. The aim of the study was to explore the relationship between attachment and psychological adjustment in this specific group. The study found that the-levels of difficulty children with congenital dermatological disfigurements experienced in specific areas of adjustment could be differentiated on the basis of their attachment style. In Part 3, the Critical Appraisal, reflections are made on some of the issues that arose as a result of carrying out research in this field. Four areas are focused on; defining and understanding central concepts in the research, thinking in terms of resilience rather than difficulties, and the cultural and social implications of research in this field.