X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency characterised by severe immune dysregulation and is caused by mutations in the SH2D1A gene. Clinical manifestations vary and include haemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinaemia, often triggered by Epstein-Barr virus (EBV) infection. SLAM-associated protein (SAP) is a key regulator of immune function in T, NK, and NKT cells and defects in this protein lead to the cellular and humoral immune defects described in patients. Treatment options for XLP are limited and currently haematopoietic stem cell transplant (HSCT) is the only curative option. Results are variable and dependent on a good donor match and absence of active infection at transplant. Somatic gene therapy is now successfully used to correct certain severe immunodeficiencies and offers a potential cure in XLP. The use of self-inactivating (SIN) lentiviral vectors with transgene expression driven by non-viral promoters has improved the biosafety profile of haematopoietic stem cell gene therapy procedures. In this study we have successfully corrected both cellular and humoral defects in a SAP deficient murine model using a SIN lentiviral vector with a codon optimised SAP transgene under the transcriptional control of the elongation factor 1α short form (EFS) promoter. Initial attempts with a non-codon optimised version of SAP led to insufficient protein expression levels to restore immune function. We also assessed the CD2 locus control region (LCR) to evaluate any lymphoid specificity to permit more regulated SAP expression but were unable to demonstrate any benefit with this regulatory element. The results presented here provide proof of concept for the development of gene therapy for XLP and further work is warranted to improve the efficiency of gene transfer, secure engraftment of long term repopulating haematopoietic stem cell progenitors and additional characterisation of immune reconstitution after gene therapy.

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Approximately 3.3 million (41 %) of global child deaths occur among children in the first 28 days of life (the neonatal period). Neonatal death reduction is imperative to achieving the 4th millennium development goal (MDG-4) which seeks to reduce global child deaths by two-thirds its levels in 1990 come 2015. Three direct causes: infections, asphyxia, and prematurity or low birthweight and its complications account for approximately 80% of these deaths, majority of which are preventable. Infection is the single most important cause in about a third (and up to half in high mortality settings) of all neonatal deaths. However, care seeking for sick newborns is generally poor and besieged by myriads of barriers with many newborn deaths occurring at home with no contact with health providers. Trials in south Asia have shown that prompt detection and treatment of newborn infections coupled with effective preventive measures can significantly reduce newborn deaths. The Ghana Newhints home visits cluster randomised controlled trial (CRT) is the first trial in sub-Saharan Africa to evaluate the impact of a community-based strategy on newborn care practices and neonatal mortality.

Children in areas of highly seasonal malaria transmission in the Sahel should receive SMC with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). These drugs retain their efficacy in the areas where SMC is recommended, but alternative regimens are needed if SMC is used in other areas or if these drugs start to lose efficacy. The aim of this study was to investigate the suitability of dihydroartemisin-piperaquine (DHAPQ) for SMC, using a non-inferiority trial design. 1500 children randomized to receive SPAQ or DHAPQ monthly from August to October, and a cohort of untreated children outside the trial, were followed-up for malaria. SPAQ was more efficacious than DHAPQ, but the difference was within the margin set for non-inferiority. Both regimens gave a very high level of protection lasting 4 weeks. Protection was related to dosage. Both regimens were well tolerated, incidence of mild adverse events decreased in successive months, consistent with toleration to study drugs. In malaria cases, the frequency of the CVIET haplotype of pfcrt, the 86Y polymorphism of pfmdr1, and pfdhfr59 and dhps437 mutations, was greater among children who received SPAQ than in untreated children. However the number of cases, and the prevalence of parasitaemia, was much lower in treated children, reducing the scope for SMC to select for resistance. The frequency of the CVIET haplotype of PfCRT, thought to be associated with resistance to PQ, was not increased in children treated with DHAPQ. There was an enormous burden of malaria in the untreated children. SMC with SPAQ should be introduced for children in Burkina Faso without delay. DHAPQ is a potential alternative regimen in areas where SPAQ cannot be used but there are some drawbacks associated with its use. There is a need to develop alternative long-acting drugs with simple regimens that can be used for chemoprevention of malaria.

Aims: Caring for a child with emotional and/or behavioural problems can cause considerable stress for parents, which can in turn impact adversely on parent-child relationships. A difficult family environment increases the risk of negative outcomes for both children and their parents, and plays a key role in the evolution and recurrence of psychotic symptoms. This study will examine the applicability of a cognitive model of caregiving to a group of parents of clinically referred children, and associations between the family environment and severity of Psychotic-Like Experiences (PLEs). Method: Parents (or those in loco parentis; n=44) of clinically referred children were interviewed using standardised measures, to examine their coping strategies, threat appraisals, mood, social support, child difficulties and levels of expressed emotion (EE). Children were also asked to self-report their difficulties (PLEQ and SDQ). Results: Parents reported high levels of depression and anxiety, which were predicted by their threat appraisals about their children’s problems, and were associated with less adaptive coping, less social support, and more threatening appraisals. Parent mood predicted EE in the parent-child relationship, and was significantly correlated with higher reports of child emotional and behavioural difficulties. Child-reported difficulties were not associated with parent factors. Conclusion: Findings support the application of the cognitive model of caregiving to parents of clinically referred children, and suggest novel parent-focused interventions to reduce caregiver distress. Such interventions would also have the potential to reduce the future risk of mental health problems for both children and their parents.

This thesis investigates cognitive mechanisms underlying youths’ vulnerability for involvement in bullying and developing adjustment problems. The aim of this thesis was threefold: (1) investigate whether early cognitive functioning acts as a developmental marker for children’s later involvement in bullying; (2) investigate the cognitive processing of bullied children and whether these skills were associated with adjustment problems; (3) investigate whether early cognitive functioning acts as a differential marker for bullies and non-bullies who have other antisocial behaviour problems. Participants were members of the Environmental-Risk (E-Risk) Longitudinal Twin Study, a nationally representative sample of 2,232 children and their families, and the Dunedin Multidisciplinary Health and Development Study, a longitudinal birth cohort of 1037 children born in Dunedin, New Zealand. Using multiple informant reports, measures of bullying, antisocial behaviours, cognitive functioning, child-specific and family factors were collected during childhood, adolescents and adulthood. Poor theory of mind (ToM) in early childhood predicted becoming a victim or bully-victim in adolescence over and above child-specific and family factors. For bullies, the risk of having poor ToM was overridden by socioeconomic deprivation and child maltreatment. Bullied children reported biased interpretation of their environments when compared to their non-bullied co-twin. Children who used biased attribution styles when interpreting the cause of negative events had higher levels of adjustment problems. Bullies did not differ in their early cognitive processing, temperament and family environment from children with high antisocial behaviours, but did from children with moderate antisocial behaviours. Being a bully or having antisocial behaviours predicted adjustment problems in adolescence and adulthood. Being a bully had an independent effect on substance use in adolescence and emotional problems in adulthood over and above the risk posed by having antisocial behaviours. Findings from this thesis identify cognitive functioning as an early developmental marker for children’s involvement in bullying and a mechanism that may be negatively affected by children’s bullying experiences. Supporting positive cognitive development throughout childhood may help to reduce children’s risk of being involved in bullying and maintain healthy cognitive processing techniques that promote mental wellbeing.

Looked After Children (LAC) were previously thought to be too damaged to use psychotherapy, however practice has moved on and LAC are increasingly making up a larger proportion of psychotherapist’s case loads. The literature in this field consists predominantly of individual case studies focusing on the internal worlds of LAC. Although the experiences of psychotherapists working with this cohort have started to be thought about, this research uses Grounded Theory to explore the collective experiences and technical considerations of seven psychotherapists who were interviewed about their work with LAC. This approach enables a systematic exploration of this type of work and provides a more comprehensive understanding of current practice. The research reveals that it is possible to find specificity in the psychotherapeutic work being done with LAC and it both confirms previous ideas in this field as well as producing new insights. The categories produced by Grounded Theory enabled a theory to be developed about the work psychotherapists do externally with the network of adults surrounding the child and internally with the individual child in therapy. The external work is divided into problems in the network, the value of work with networks and the impact of this work on the individual relationship with the child. Internal work with the child is divided into a) making and pacing interpretations, b) whether to work with the transference and maternal transference, c) countertransference responses to deprivation and stretching boundaries, d) challenges to analytic neutrality and e) positivity. Overall the material has important implications for practice as psychotherapists feel they are often more flexible, warm and active with LAC. This research helps us to re-think what psychotherapy is for this cohort and encourages psychotherapists to feel that it is their psychoanalytic understanding, rather than strict analytic traditional approaches which can help reach these children.

Trauma experience influences an individual’s emotional wellbeing, self-concept and relationships (e.g., Beck, Grant, Clapp, & Paylo, 2009) as well as increasing their risk of experiencing trauma in the future (Copeland, Keeler, Angold, & Costello, 2007). Accordingly clinical guidance for trauma presentations recommends treatment to alleviate distress and improve emotional wellbeing (van der Hart et al., 2006). Correspondingly, a literature review, using a meta-synthesis design, explored how adults experience talking therapies for complex trauma. From this, two themes were identified which noted that, in contrast to remaining detached from the trauma and associated difficulties as a means of surviving, adults were able to access therapy and instead reconnect with their trauma experience, others, and importantly self. This finding highlighted that exploring the impact of trauma on self is important and underrepresented in literature. Given research exploring self and trauma remains limited to adults, the research paper explored how children and young people self construe following a traumatic event(s). Seven young people completed a Trauma Symptoms Checklist Children – Alternative (TSCC-A) measure. Following this a pictorial self characterisation (Kelly, 1955; Ravenette, 1996), based on personal construct psychology, was used to encourage a creative and developmentally appropriate exploration of how they construed. These included four overarching themes which were developed using thematic analysis (Braun & Clarke, 2006): The Inferior Self, The Misfortunate Self, The Protective Self and The Enhanced Self. The clinical implications of this suggest that working therapeutically with the metaphor “self as community” (Mair, 1977) offers powerful opportunities to explore and understand different selves, reduce vast differences between selves, and to develop healthier core constructs. Future specialist trauma interventions should emphasise the importance of exploring self from the perspective of the individual (e.g., Ronen, 1996). Finally the critical appraisal provides reflections on the limitations and strengths of this research.

This doctoral thesis explores the lived experiences of fathers of children with an autism spectrum disorder (ASD). It includes a literature review, a research paper, a critical review and an ethics section. The literature review aimed to provide a comprehensive understanding of the experiences' of parents of children with ASD by synthesising the available qualitative literature. The meta-synthesis yielded four third-order themes: Adjusting to ASD; Coping with the Challenges of ASD; The Personal Impact of ASD; The relational impact of ASD. The findings suggest that parenting a child with ASD is a complex experience which can ./ have a multi-faceted impact upon parents. Clinical implications, limitations and recommendations for future research are discussed; specifically that future research should differentiate between mothers' and fathers' experiences. Having identified the absence of any studies exploring the experience of fathers of children with ASD, the research paper aimed to address this gap in the evidence-base. Oneto- one semi-structured interviews were conducted with nine participants. Transcripts were analysed using interpretative phenomenological analysis. Four over-arching themes were identified and discussed in relation to previous literature: 'ASD unites and divides'; 'life revolves around the child with ASD'; 'becoming a different person' and 'the highs and lows of the ASD journey'. The findings suggest that fathers are an integral part of the ASD journey and experience both positive and negative consequences. Clinical implications and recommendations for future research are discussed. The critical review explored three pertinent issues associated with the research paper: the experience of conducting research with fathers; the questionable fluidity of the boundaries between research and therapy; and participants' positive reflections and the implications that this has for future research. These issues are discussed in relation to the existing literature.

Introduction: Traumatic dental injuries are considered a dental public health problem due to their high prevalence worldwide. Major complications can be associated with trauma, affecting the quality of life of patients and their parents/carers. Information retention has been reported to decrease following stressful situations. It is important to understand the information seeking behavior (ISB) of these families to help them understand and retain information provided regarding dental trauma. Aims: To investigate the ways in which dental trauma patients and their parents, look for information, the reasons why, and the types of information they would like to receive. Also to draw comparisons between children and their parents regarding ISB. Method: This was a mixed qualitative and quantitative prospective study included two phases. Phase one involved qualitative data collection from in-depth interviews conducted with trauma patients and their parents. These interviews were analysed using framework analysis and commonly occurring concepts identified. Phase II of the study involved distributing patient and parent questionnaires, based on the themes and subthemes identified from the interviews. Results of phase I: One-to-one in-depth interviews were conducted with 10 patients and 11 parents. Patients’ interviews identified 10 main themes while parents’ interviews identified 8 main themes. Each one of these themes incorporated subthemes. The themes were used to develop patient and parent-based questionnaires, which were piloted with 13 patients prior to phase II. Results of phase II: questionnaires were distributed to 68 patients and 70 parents. Initially, the majority of patients wanted to know if their tooth could be saved, possible outcomes and planned procedures to treat their teeth. Concerns during treatment were mainly about function and aesthetics. Patients preferred to receive this information verbally from their dentist. Parents initial concerns were similar to the patients’, and included the possible long-term outcome, severity of the trauma, possibility of maintaining the tooth and available treatment options. During treatment, the majority of parents were also worried about aesthetics and the possibility of the tooth losing vitality. In the long-term, parents were mostly concerned about available treatment options when their V children reached adulthood. Parents’ preferred to receive written information in the form of summary letter or booklet. Conclusion: It is important to understand that the information needs of patients and parents differ and to tailor information provision for each group accordingly.