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This thesis reports a series of laboratory and clinical studies designed to investigate the acute effect of surgical palliation on ventricular function in children with functionally single ventricle anatomy. Ventricular volume and pressure were measured using a combined pressure-conductance catheter. Initial laboratory-based experiments were performed using a physical model of the left ventricle, which allowed examination of the measurement techniques used in the clinical studies but under controlled conditions. These experiments identified a non-linear conductance-absolute volume relationship and demonstrated for the first time that the calibration coefficient, \(\alpha_{SV}\) produced a significant, volume-dependent measurement error. These experiments also demonstrated that conductance volume measurements were adversely influenced by other electrical signals. The ventricular electrogram produced clinically important measurement error that has not previously been described. Two clinical studies were then undertaken to investigate the separate effects of the bidirectional cavo-pulmonary anastomosis (BCPA) and the completion total cavo-pulmonary connection (TCPC). These studies represent the core of the thesis. Both procedures were associated with significant changes in the pressure and volume conditions of the dominant ventricle. In addition, the BCPA was associated with a substantial and immediate improvement in ventricular systolic function but this was accompanied by an increase in diastolic chamber stiffness. By contrast, the TCPC was not associated with a significant change ventricular systolic or diastolic function in spite of the changes in ventricular load. Comparable changes were observed in patients with a dominant ventricle of either left or right ventricular morphology. These studies provide a more detailed understanding about the acute events that accompany surgical palliation in children with functionally single ventricle anatomy. These findings confirm the validity of staged surgical palliation in the management of these children.

CHAPTER ONE: The literature review critically evaluates research that has explored the psychological impact of parental acquired brain injury (ABI) on children. The review identifies a number of factors that affect the psychological well-being of children, including both adverse and protective factors. Evidence from the studies reviewed indicates that children are vulnerable to experiencing a range of emotional and behavioural difficulties following parental ABI. Clinical implications of the review findings are discussed, and directions for future research considered. CHAPTER TWO: The empirical paper aimed to explore the role of mutual support in Traumatic Brain Injury (TBI) survivors’ reformation of their identity among individuals attending a mutual support group. Using a Grounded Theory approach, a model of the participants experience was developed. The core category reflected how participants regained a sense of self through getting to know the “new” me. Five conceptual categories were identified in relation to identity formation: pre-injury self, comparison with others; accessing the social world of brain injury; purpose and self-efficacy; and acceptance of the post-injury self. The findings highlight a potentially important role for mutual support in identity reformation following TBI and implications for brain injury rehabilitation programmes are discussed. CHAPTER THREE: The third paper presents my personal and professional reflections of the research process and how my views have changed over the course of training. To illustrate these changes, elements of the grounded theory model proposed in the empirical paper (Chapter 2) have been applied to my own experiences. It is hoped that this approach will evidence my experience and exploration of getting to know the scientist-practitioner.

Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

This thesis explores the appropriateness of suitably trained children's nurses undertaking the pre-operative assessment of children prior to day case and minor surgery. The central focus of the study is a 60 subject hypothesis refining randomised controlled trial (RCT), comparing the pre-operative assessment of children carried out by suitably trained nurses with the assessment carried out by senior house officers (SHO's). Findings demonstrate significantly greater accuracy by nurses in the detection of abnormalities in children's history, when compared with the SHO's. No significant difference is demonstrated between the performance of nurses and SHO's in detecting abnormalities within the physical examination, or in the correct identification of children who have no detectable abnormalities. However, these findings of 'no significant difference' must be substantiated within a larger equivalence trial before assurances can be given that paediatric pre-operative assessment might safely be transferred from SHO's to nurses. Supplementary data explores the perspectives of parents and practitioners with regard to children's nurses undertaking a pre-operative assessment role. The views of parents, gathered via questionnaires, are supportive of the initiative. The views of nurses and SHO's involved in the RCT are similarly supportive, although the conduct of in-depth interviews with the nurses also reveals insights into their perceived vulnerability when carrying out such expanded roles. The views of anaesthetists are less positive, and convey a reluctance to accept nurses carrying out the pre-operative assessment of children. Finally, a national survey explores the views of nurses and SHO's involved in paediatric pre-operative assessment, revealing that nurses attribute significantly greater importance and enjoyment to the pre-operative assessment role when compared with SHO's. This factor may in part explain the greater accuracy demonstrated by nurses in the RCT, but such speculation must be substantiated by further enquiry. This study contributes to the nursing literature in offering what is thought to be the first systematic UK exploration of the role of the paediatric nurse within pre-operative assessment. It is also the first study, as far as the author is aware, to demonstrate significantly greater accuracy in history taking by nurses when compared with doctors, in a paediatric specific UK study. It therefore makes a meaningful contribution to both the paediatric and expanded role evidence bases. It also offers systematically informed hypothesis generation to underpin the ongoing exploration of an expanded nursing role within paediatric pre-operative assessment.

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.