Background: The effectiveness of World Health Organization (WHO) guidelines for pneumonia case management in sub-Saharan Africa has been contested. This thesis aims to determine the clinical effectiveness of these guidelines among children admitted to Kenyan hospitals in a period after the introduction of the pneumococcal and Haemophilus influenzae type B (Hib) conjugate vaccines. The studies focus on the treatment of children with chest indrawing pneumonia, who were previously regarded to be at high-risk requiring inpatient treatment but were reclassified as lowrisk (non-severe) in the WHO guidelines updated in 2013. Methods: This thesis consists of: (i) A systematic review linked to a national guidelinedevelopment exercise appraising the evidence for the WHO pneumonia guidelines, (ii) a prospective observational study evaluating adherence to, and effectiveness of the pneumonia guidelines in the national referral hospital in Kenya, (iii) a multi-centre pragmatic randomised controlled trial (RCT) comparing amoxicillin versus benzyl penicillin for chest indrawing pneumonia (iv) a cohort study comparing treatment effects among children enrolled in the antibiotic RCT with a similar group who received routine care, and (v) a multi-centre retrospective cohort study of children hospitalised with pneumonia describing factors associated with mortality, focusing on characteristics that increase risk of death among children who would, under current guidance, be assigned a non-severe classification. Results: Although evidence from clinical trials supported the adoption of oral amoxicillin for severe pneumonia over benzyl penicillin (the standard treatment) for chest indrawing pneumonia, a Kenyan guideline development panel raised concerns of generalizability citing the limited data from sub-Saharan African populations in whom mortality was argued to be high. This concern was explored using prospectively collected observational data from 385 children. Treatment failure and mortality were infrequent (< 2%) for chest indrawing pneumonia where strict definitions requiring documented evidence of clinical deterioration were applied. In comparison, high rates of treatment failure (21.4%) and mortality (10.5%) were observed for severe pneumonia (formerly very severe pneumonia). Using propensity scores to model treatment effects comparing guideline recommended regimens with more costly, broad-spectrum alternatives, similar risks of treatment failure were observed in both groups. Amoxicillin was compared with benzyl penicillin in a pragmatic clinical trial of 527 children that also revealed low and comparable risks of treatment failure (8%) and mortality (< 1%) for the two treatments. Consistent results were observed in an observational cohort of children hospitalised at the same health facilities over the period the trial was conducted. However, analyses of data from > 16000 children suggested that the presence of commonly-occurring clinical signs may be associated with increased risk among children with non-severe pneumonia. Specifically, very low weight-for-age Z score (WAZ) or pallor in children with non-severe pneumonia were shown to be associated with absolute risks of mortality as high as those for severe pneumonia. Conclusions: Findings from locally-conducted observational studies and a clinical trial indicate low risks of treatment failure and mortality among children with chest indrawing pneumonia following treatment with benzyl penicillin monotherapy or amoxicillin. In contrast, mortality for severe pneumonia was greater than 10 percent. These results are consistent with the updated WHO recommendations and have more recently informed the revision of the national policy for pneumonia case management in Kenya. However, these guidelines may apply to sub-populations of children with non-severe pneumonia and either very low WAZ or pallor. This evidence is expected to contribute to ongoing debates on the adoption of WHO guidance for pneumonia case management in similar settings across sub-Saharan Africa where coverage of the Hib and pneumococcal conjugate vaccines is high.

Children with the congenital heart defect TOF require surgical repair. Their myocardium is exposed to chronic hypoxia due to insufficiently oxygenated blood shunted from the right to the left side of the heart through the VSD, resulting in cyanosis. Such corrective surgery often requires the use of CPB. During these procedures the aortic clamp is applied to allow access to the heart for the surgical correction creating an ischemic environment. When the clamp is removed and blood flow returned, the heart is reperfused. This exposes the myocardium to IR injury. Super-high oxygen (O2) levels are often used in the bypass circuit after the cross-clamp is released. This means during reperfusion the myocardium is exposed to high levels of O2. This is thought to be harmful, especially to children with cyanosis pre-operatively. A growing body of evidence suggests that these high levels of O2 may be damaging to the infant myocardium but the mechanisms are not that well understood. The first aim of this project was to investigate the molecular changes that occur within the infant myocardium in the context of congenital heart disease by comparing myocardium from the cyanotic patient group (TOF patients) and acyanotic patient group (patients with sub-aortic stenosis or truncus arteriosus i.e. disorders requiring myocardial resection but where the myocardium is acyanotic) during the ischemic phase. This was performed to reflect as near to pre-operative gene expression levels as possible. This thesis focused on the expression of inflammatory mediators (TLRs) and stress proteins (HSPs). It was found that TLR4 (p=0.0303), TLR2 (p=0.0177) and HSP27 (0.0303) mRNA expression were significantly higher in the myocardium from the cyanotic patient group compared to the acyanotic patient group. This could indicate a consequence of the hypoxic environment within such myocardium. HSPs are stress proteins, which are induced upon cellular stress. The Aplein receptor (APJ) is upregulated in the heart during ischemia and IR injury and thought to be cardio- protective. Additional work was performed that investigated the protein expression of HSP27 and APJ during the ischemic phase in cyanotic and non-cyanotic TOF myocardium. This expression was compared with various measurements of cardiac function. HSP27 protein expression was significantly elevated in cyanotic myocardium pre-operatively. It was also associated with improved right ventricle function and systemic perfusion. This supports a cardio-protective effect of HSP27 in cyanotic TOF. APJ was found to be associated with 2 improved systemic perfusion when both cyanotic and non-cyanotic patient data were combined. In order to determine if stress genes (HSPs) were inducible in the infant myocardium, they were exposed to classic heavy metal inducers sodium arsenite and cadmium chloride. Of the six HSPs investigated, all were shown to be present within the ischemic myocardium. Myocardial HSP32 (p=0.0156), HSP72 (p=0.0156) and HSP90 (p=0.0156) mRNA expression were significantly increased by exposure to heavy metals. Therefore, HSPs were shown to be inducible in infant myocardium. This was a good experimental control for the re-oxygenation experiment. The expressions of the same genes were also examined in vitro during an attempt to mimic re-oxygenation of the ischemic myocardium when the aortic-clamp is removed. Tissue was removed during the ischemic phase from both cyanotic and acyanotic patients and exposed to differential O2 levels. It was found exposure to 20% and 60% O2 for 4 hours induced mRNA expression of HSP32 (p=0.0391 and p=0.0078 respectively) and HSP72 (p=0.0078 and p=0.0078 respectively). This could indicate cellular stress during re- oxygenation of infant myocardium during surgical correction. No difference was indicated between the cyanotic and acyanotic patient group. The work of this thesis was focused on myocardial mRNA/ protein expression. Whether there is an alteration in circulating inflammatory mediators was not the focus of the present study but the results within this thesis highlighted the need for future studies to look at the effect of circulating factors on myocardial inflammation. This project is novel because it allowed a better understanding of the molecular mechanisms at work within infant myocardium and how they are influenced by re- oxygenation injury. It also examined how they are affected by cyanosis. It has highlighted the best ways in which such investigations could be extended. It has contributed important molecular data to the area of research and could potentially help lead to an improvement in myocardial protection during cardiac surgery with CPB.

It is recognised that research in paediatric palliative and complex care is in the early stages. Chapter One examines the available literature of fathering a child with a chronic, life threatening or life limiting illness. The research reviewed supports the notion that fathers are under-represented in paediatric palliative and complex care. The findings highlight that men express their vulnerability in gender specific ways, which has implications for support and service provision. Particular gaps in the research on fathers are highlighted, in relation to the long term impact of fathering a child with life limiting, life threatening, or chronic condition, fathers’ needs in the marital dyad, and studies on the efficacy of father focused interventions. Chapter Two explores health professionals’ experiences of managing boundaries, in the context of paediatric complex and palliative care in the community. The findings indicate that there are a number of issues relating to boundaries that require balancing and which have an impact on service provision and professional wellbeing. Chapter Three is a reflection on the research journey, particularly developing the boundary discussion with regard to ethics. This includes reflections on research in paediatric palliative care, the boundaries of this research, overlaps with clinical practice, and personal and professional learning.

Children with disruptive behaviour disorders include a complex pattern of causation and comorbidity. As such, it is important to identify problems at early stages of development so that intervention can target relevant areas. Computerised assessments and interventions for children with disruptive behaviour disorders offer several advantages over traditional approaches. These include speed, accuracy, engagement, agreeability, and cost. The first chapter of this thesis discusses the utility of five computerised packages that could be used to screen populations for the disorders. It examines issues relating to test administration, reliability, agreeability, cost, and validity and makes appropriate recommendations. The second chapter describes an empirical study, which examined the effectiveness of a computerised token economy system to encourage learning in children with emotional and behavioural difficulties. This study also investigated the role of self-esteem in relation to learning problems and the disruptive behaviour disorders. The final chapter involves a discussion of new frontiers of mental health technology based on personal practice and reflection.

Type I diabetes effects over 16,500 children in the UK. For these young people, care is needed to maintain 'near normal' blood glucose levels in order to relieve the unpleasant symptoms of high and low blood glucose. Although good metabolic control may decrease the risk of severe long term complications, adolescents often have difficulty juggling all the aspects of a complex and demanding treatment regimen, and poor adherence is commonplace. The literature review proposes a theoretical framework for understanding the role of responsibility in the management of type 1 diabetes during adolescence. The pattern of responsibility is explored in relation to the individual and their interpersonal context. In terms of health outcome, the effects of individual and shared responsibility are considered, necessitating a balance between the adolescent's assumption of responsibility and their level of parental involvement. Suggestions for clinical practice are discussed, methodological limitations raised, and future research opportunities identified. The role of dietary self efficacy in predicting self care during adolescence is established. Using data for two distinct phases of adolescence, paper 1 examines whether social support from family and friends makes any additional contribution to the prediction of dietary self care, over and above that of self efficacy. For the younger group (aged 12-13), the prediction of self care is improved by better perceived support from friends. An interactive effect of shared family responsibility is also reported, confirming the importance of shared responsibility, between parent and child, to facilitate good self management as highlighted in the literature review. None of the variables are significant predictors of self care in the older group (14-18 year olds).

Anxiety in young people with Asperger's syndrome (AS) is of serious concern. With a greater prevalence of girls with AS than previously considered, there is a paucity of research into experiences of anxiety in this population. Girls with AS and their parents may seek help through professional Western Herbal Medicine (WHM), the practice of which has little research evidence. The aim of this study is to explore experiences of girls in Scotland with AS and anxiety during a course of WHM treatment, described by the girls, their mothers and the herbalists. A Hermeneutical or Interpretive Phenomenological longitudinal case-study approach included a purposive sample of 3 girls, their mothers and 3 Western Medical Herbalists (WMH) (n=9). Innovative methods developed to address specific needs of the girls comprised of licensed computer interview software ‘In My Shoes' and an online diary facility. Individual interviews took place with all participants, second interviews held with girls and mothers, were transcribed verbatim and thematic analysis carried out. The study was endorsed by Edinburgh Napier University Faculty of Health, Life and Social Sciences Research Ethic and Governance Committee and the National Autistic Society. Informed consent was given by all participants. Where can we be what we are? was identified as a theme within a narrative of marginalisation in which individuals whose needs are marginalised turn to a treatment marginalised within the prevailing biomedical health care model. Anxiety manifests in girls with AS in a number of ways including chronic insomnia, emotional outbursts and school refusal. The WHM treatment had beneficial effects. However, access to, and compliance with, the treatment, may be inequitable. There is an urgent need for greater support for girls with AS and families, with an evidence base underpinning appropriate intervention. Diagnosis needs to be accompanied by acceptance in society and the availability of future opportunities. Further qualitative research in this area would increase insight and understanding and provide support for the development of larger scale studies. The creation of ‘best practice' guidelines in WHM for the treatment of girls with AS is recommended as is a pragmatic clinical trial of WHM for girls with AS and anxiety. key terms: Girls, Asperger's, anxiety, Western Herbal Medicine, hermeneutic interpretive phenomenology, methods, In My Shoes

In order to understand and interact with the world, our brains must integrate information from multiple sensory modalities to create coherent representations of scenes and events. The integration of visual, tactile and proprioceptive inputs underpins the subjective sense of self and body ownership. This, in turn, underlies the development of social processes including self-awareness, imitation and empathising, which are impaired in autism spectrum disorders (ASD). Evidence suggests that the social functioning deficits characterising ASD could contribute to atypical sensory integration underlying body representation. However, the exact mechanisms underlying sensory integration difficulties have not been specified. Moreover, it is not clear when, and how, visual, tactile and proprioceptive integration matures in typical development. This is important to establish, in order to compare how and why this integration may differ in ASD populations. This thesis firstly aimed to investigate the typical development of multisensory integration underlying body representation. Experiment One found that the ability to optimally integrate visual and proprioceptive inputs during hand localisation increases with age from very little integration in 4-year-olds to almost adult-like in typically developing 10- to 11-year-olds. Experiments Two and Three showed that sensitivity to the spatial constraints of visuo-proprioceptive integration, and sensitivity to the temporal constraints of visuo-tactile integration, develops with age in 4 to 11-year-olds. Together these studies suggest that the maturation of adult-like multisensory integration for body representation follows a protracted time course over childhood. The second aim of this thesis was to investigate the evidence for two prominent theories of atypical sensory integration underlying body representation in ASD. These are 1) an over-reliance on proprioception and 2) temporally extended sensory binding. Experiment Four examined whether trypically developing (TD) adults with a high number of autistic traits exhibit an over-reliance on proprioception. No evidence was found for this, which could indicate that atypical sensory integration is only present in individuals with a clinical diagnosis of ASD. Experiments Five and Six found evidence for temporally extended visuo-tactile integration in children with ASD, compared to TD control participants. Though no evidence was found for a fundamental over-reliance on proprioception, extended binding may have led to reduced processing of temporal synchrony over modality-specific information (i.e. proprioception). Experiment Seven and Eight found no evidence of proprioceptive over-reliance or temporally extended sensory binding in adults with ASD, relative to a TD control group. I conclude that children with ASD demonstrate temporally extended visuo-tactile binding. This represents a developmental delay rather than a life-long deficit; however, it could have a life-long impact on sensory sensitivities and social processing.

Infant regulatory problems (crying, sleeping, feeding) are a common concern for parents and practitioners. Although there is now good evidence of the long-term adverse influences of infant regulatory problems on mental health, in particular if they co-occur together (multiple regulatory problems), important gaps remain regarding the precursors of regulatory problems. In particular, it is unclear whether and how sensitive parenting and/or neurodevelopmental vulnerability are involved in the development of multiple regulatory problems. Furthermore, do regulatory problems impair the development of the infants’ relationship to their mothers, i.e. attachment? This thesis explores neurodevelopmental vulnerability and sensitive parenting as precursors of multiple regulatory problems, and whether multiple regulatory problems increase the likelihood of insecure and/or disorganised attachment. The thesis consists of four studies and uses preterm birth as a natural model to assess neurodevelopmental vulnerability due to the interruption caused by preterm birth on the key processes of brain development. Study 1, a meta-analysis, explored the relationship between neurodevelopmental vulnerability and maternal sensitivity by comparing maternal sensitivity in preterm and full-term infants. Findings indicate that having an infant with neurodevelopmental vulnerability does not alter mothers’ sensitive parenting. In Study 2, using the Growth of at risk Infants (GAIN) study, the effect of neurodevelopmental vulnerability on regulatory problems across the first 18 months was investigated. Very preterm/very low birth weight infants experienced more multiple regulatory problems at term and 18 months compared to full-term infants. In Study 3, the longitudinal relationship between neurodevelopmental vulnerability, maternal sensitivity and multiple regulatory problems across infancy was explored allowing for reciprocal associations between maternal sensitivity and multiple regulatory problems across infancy. Both maternal sensitivity and multiple regulatory problems were moderately persistent from term to 18 months. Consistent with our previous findings, it was revealed that neurodevelopmental vulnerability had an enduring impact on multiple regulatory problems. On the other hand, maternal sensitivity at term had only a short-term negative impact on multiple regulatory problems at 3 months. No evidence for a reciprocal influence of maternal sensitivity and multiple regulatory problems was found. Finally, Study 4 examined whether early multiple regulatory problems at 3 and 6 months increase the likelihood of insecure and/or disorganised attachment. Findings revealed that multiple regulatory problems as early as 3 months increased the risk of both insecure and in particular, disorganised attachment at 18 months. In conclusion, neurodevelopmental vulnerability increases the risk of multiple regulatory problems, which are moderately persistent across the first 18 months of life. Furthermore, multiple regulatory problems do not impair maternal sensitivity but have adverse effects on the infants’ relationship with their mothers by increasing the risk of insecure and disorganised attachment. Clinicians should be aware that multiple regulatory problems are a significant potential risk factor for poorer infant-mother relationship.

Raising a child is not easy for any parent, however for those whose child also has a disability, the process is even more complex. The papers presented here explore the experiences of parents who have a child with a disability. From understanding parents’ experiences in more details, it is hoped that support can be tailored to serve the needs of parents better and improve the outcomes for children. Chapter one details a meta-synthesis, reviewing qualitative articles which address the experience of parents’ with a child with congenital heart disease. Twelve overarching themes are presented, capturing parents’ responses, the parent-child attachment and parental resilience. Recommendations are made for how to support parents and areas of development for healthcare professionals are identified. Chapter two details a qualitative study examining the experiences of eight fathers of children with autism. Interpretative Phenomenological Analysis is used to provide an in-depth account of their lived experiences and three superordinate themes are presented. The results identify resilience and challenges fathers experience, both within themselves and within their relationships. Clinical implications and future directions are discussed. Chapter three provides a reflective account of the research process. It addresses the issue of reflexivity, considering how the researcher’s position may have influenced the research and how the process of undertaking the research influenced the researcher.

Developing trust and security with a new primary caregiver may be particularly difficult for children who have experienced trauma, separation and loss within their birth families and through the care system. However, the development of a secure attachment can protect against future psychosocial and emotional difficulties, prevalent in fostered and adopted children. It is important to better understand the influences upon, and experiences of, attachment relationships that develop within this context, in order to inform policy and practice in promoting attachment security within new families. Chapter one is a systematic review of the literature exploring the links between maternal sensitivity, mind-mindedness and attachment security in children who are adopted and fostered. Twelve studies were included in the review following database and manual searches. In line with studies in birth families, maternal sensitivity was shown to have a partial influence on attachment security. Stronger relationships were found in foster care and longitudinal adoption studies. The impact of mind-mindedness may be related to the developmental stage of the child. Methodological limitations are suggested to have limited the strength of findings, and are considered in addition to future research, policy and practice implications. Chapter two is an in-depth exploration of the lived experiences of seven mothers who adopted an older child, aged four to seven. The study focuses upon the experience within the first years after placement of developing mother-child relationships, using an Interpretative Phenomenological Analysis approach. Three overarching themes emerged from the data. These pertained to the sense of fragility experienced within relationships as a consequence of children_ïs rejection and challenging behaviours; mothers_ï commitment to their children; and the process of acceptance. Implications for future research, clinical practice and policy are discussed with particular regard to the need for increased support and training. Chapter three is a reflective account of experience during the research process. The reflexive process is explored, and parallels are drawn between the researcher and the participant ïs experience, and issues of reflexivity as a researcher and clinician. Attention is given to the process of developing acceptance across the journey of research.