Background: Sedation withdrawal is one of the terms used to describe the behavioural response to stopping or reducing sedative drugs in physically dependent patients. Withdrawal behaviours differ according to the drug involved and may be unpleasant and interfere with recovery. Recognition of sedation withdrawal is challenging due to differences in patient presentation and may be further complicated by the patient’s condition and concomitant drug therapy. Overall Aim of the full thesis: To improve the accuracy of sedation withdrawal assessment in critically ill children. Objectives and Methods: A mixed methods interactive approach comprising six studies. Study 1 evaluates the psychometric properties of the Sedation Withdrawal Score, Studies 2 and 3 examine the complexities/challenges of withdrawal assessment by critiquing existing tool validation studies, A further three studies examine the nurse and parent perspectives of sedation withdrawal assessment in critically ill children. Study 4 investigates how nurses use a sedation withdrawal tool, Studies 5 and 6 investigate what behavioural signs parents recognise and ascertain parents’ willingness to participate in withdrawal assessments. Key findings: Nurses found withdrawal behaviours difficult to interpret in critically ill children and there were differences in how these behaviours were construed. Parents identified a broader range of behaviours than included in existing tools. Most parents were eager to participate in the assessment. The elusive theoretical basis for the existing approach to withdrawal assessment may account for the lack of a standardisation and poor accuracy of the current tools. A model of the causal relationship between dependence and withdrawal is proposed. Recommendations: The model identifies the diagnostic criteria upon which a definition for Pediatric Withdrawal Syndrome may be based. These criteria also provide a novel framework for withdrawal assessment. Focussing on the shared diagnostic criteria and including the parent perspective of the child’s behaviours may aid the assessment and support decision-making.

The Children Act 1989 imposes a duty on Local Authorities in England to ‘safeguard and promote the welfare of children’ and to ‘promote the upbringing of children by their families’ wherever possible. If, during pregnancy, concerns are identified that suggest the child may be at risk of harm a referral may be made to the Local Authority for a pre-birth assessment. When completing a pre-birth assessment social workers and other professionals are often involved in the process of collecting and analysing information, which will ultimately be used as a basis for planning and decision-making and can have life long consequences for the family. Removing a baby at birth brings with it an inevitable impact on the process of attachment and bonding, as well as the impact of subjecting a family to court proceedings and all of the emotions that entails. However, allowing a baby to be discharged from hospital to a family who are unable to provide appropriate care and protection or do not have the necessary support in place to assist them may result in irreparable harm to, or even the death of the baby. Sitting within the context of general child and family social work assessment, pre-birth assessment has received a very limited amount of specific research attention. This thesis comprises a report on the outcomes of my own research, which was exploratory in nature, and details the findings from a mixed methods study of relevant legal and procedural frameworks in England, Local Safeguarding Children Board procedures and a case study of pre-birth social work assessment practice in one Local Authority. The findings were that pre-birth assessment is a complex process guided by a national and local procedural framework which does not recognise the unique status of the unborn child. Having evolved from a historical perspective based on protecting live children, the procedural guidance is contradictory as it does not acknowledge that an unborn child has no legal status and a pregnant woman maintains rights over her own body. The case study also revealed that social workers in the host LA were practising in an environment of managerial systems which aimed to improve accountability and yet the very systems designed to ensure children did not fall through the ‘safety net’ of professional support were, ironically, prompting systems which made practice in (and research into) pre-birth social work assessment a challenge. A narrow forensic approach to pre-birth assessment was found to have developed, with the documentary process of completing pre-birth Initial and Core Assessments (as defined by the Department of Health (2003) documentation) becoming split from the process of actually ‘doing’ a social work pre-birth assessment.

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.

Crohn`s Disease (CD) and Ulcerative Colitis (UC), two types of Inflammatory Bowel Disease (IBD), are chronic, relapsing inflammatory conditions of the gastro-intestinal tract. Approximately 25% of cases are diagnosed in childhood and adolescence; affected children suffer from symptoms such as abdominal pain, bloody diarrhoea, fatigue, and poor nutritional state. Poor growth, in terms of both height and weight, precedes diagnosis and further weight may be lost with successive inflammatory exacerbations. Changes in height and weight are used as a marker of both disease severity and response to treatment, but the associated changes in body composition with changes in weight are poorly characterised and understood, and rarely assessed in routine clinical care. Being able to determine the nature and size of any deficits in lean and fat mass may provide a better understanding of the disease process, whilst gains in height and lean tissue, relative to increases in fat mass, could also be used to mark the effectiveness of clinical management and improvement in nutritional state. Exclusive enteral nutrition is now being used in preference to anti-inflammatory therapy in children with IBD, but there are increasing concerns that the focus on weight gain as children move into remission with only modest gains in height reflects an inappropriate mix of tissue deposition with greater gains in fat than lean. The central hypothesis of this thesis is that children with IBD present at diagnosis with a lean deficit, greater that that which can be simply attributed to their lack of height, and that conventional therapy, including exclusive enteral nutrition, may not adequately correct the nutritional state and deficit of lean tissue. In order to test this hypothesis, the work described in this thesis is presented in three parts. Firstly, a cross-sectional study of a convenient sample of children with CD and UC drawn from the regional IBD outpatient clinic to explore the extent and nature of the differences in height, weight and BMI expressed as SD scores, together with simple measures of body composition using anthropometry. This initial study confirmed that whilst as a group, both CD and UC children exhibit only modest deficits in height, weight and BMI there was marked variance across the group with more pronounced deficits in some children. Lower Upper Arm Muscle Area SD scores and higher Triceps skinfold thickness SD scores would support the proposition of a general lean deficit and fat excess, even in children with BMI range within ± 2SD. The second part explored different approaches to assessing body composition by i) determining the concurrent and face validity of different bioelectrical impedance devices using deuterium dilution space as a reference method and ii) the potential of using SIFT-MS to conduct real-time near-patient measures of deuterium abundance on breath vapour was examined in comparison to measures of deuterium abundance in saliva and urine assessed by both SIFT-MS and IRMS. These studies demonstrated important differences in lean mass were evident between devices. Deuterium abundance in saliva and urine by SIFT-MS was directly comparable to that by IRMS although higher levels of D O administration were required for optimal analytical performance; greater imprecision was evident in determining deuterium abundance in breath. The third part described detailed measures of body composition (anthropometry, DXA, deuterium abundance in saliva by IRMS, and BIA) in a prospective inception cohort of eleven children with CD studied at diagnosis, and followed for the first year of treatment from active disease into remission using exclusive enteral nutrition. Lean deficits identified using both DXA and Upper Arm Muscle Area was evident at diagnosis greater than that which could be attributed to shortness. Treatment was associated with gains in height and weight, but in contrast to previous reports where corticosteroids were only used to induce remission, gains in lean mass over the first year of treatment using exclusive enteral nutrition were observed which were greater than that which could be attributed to an increase in height that reflect at least a partial correction of the lean deficit.

No description available.

The origins of respiratory disease, such as asthma in childhood and COPD in later life are unclear. Maternal smoking during pregnancy and low birth weight is associated with increased risk of asthma, poor lung function in adults and COPD in old age. Exposure to oxidative stress and poor nutrition in utero is thought to cause damage to the lung and alter the normal course of lung development. Glutathione S-transferases (GST) are potent antioxidants. In this work, genetic polymorphisms that alter GST enzyme activity were genotyped in a family-based childhood asthma cohort (341 families, n = 1508) and analysed to investigate whether they alter the risk of developing asthma when individuals are exposed to environmental tobacco smoke. Real-time PCR based copy number variation methodology was developed to genotype the common gene deletion polymorphism of GSTT1 and GSTM1 genes, for other GST genes (GSTP1 and GSTO2) SNP haplotypes were constructed. A rare GSTO2 haplotype was negatively associated with asthma susceptibility, atopy severity, and FEV1 values. Asthmatic children with a GSTT1 gene deletion, or a common GSTP1 haplotype, developed more severe asthma compared to individuals with a GSTT1 gene or non-carriers of the GSTP1 haplotype. Total IgE levels were increased in GSTT1*0 individuals when exposed to tobacco smoke in early life, suggesting a gene-environment interaction. GSTO2 may be a shared susceptibility locus for asthma in childhood and COPD in later life. Animal models of maternal protein-restriction during pregnancy can induce hypertension, diabetes and endothelial dysfunction in offspring and in some of these models alterations to lung gene expression and lung architecture have been reported. This work established that a rat model of maternal dietary protein-restriction during pregnancy known to induce hypertension in the offspring, results in persistent alterations to the expression of genes in the lungs of adult offspring (120 days), including genes involved in glucocorticoid action (Hsd11b2), growth (Igf1 & 2 and Pcdh1) and alveolar development (Tp53). Lung microRNA expression profiles were also altered in response to exposure to protein restriction in utero. These findings suggest a role for nutritional programming in respiratory disease susceptibility in later life and a role for microRNAs in the study of the developmental origins of health and disease in general. Further work will include the investigation of epigenetic mechanisms that control nutritional programming in lungs of animals exposed to protein-restriction in utero. This work has demonstrated that GST polymorphism is a risk factor for childhood asthma and certain genotypes can offer some protection against the development of severe asthma. There was little evidence to suggest that GST polymorphism modulates the effects of smoke exposure in early life. In addition, we have demonstrated that maternal diets that are poor in nutrition could predispose her offspring to respiratory disease in later life by altering the course of normal lung development in early life or response to environmental stimuli in later life.

No description available.

This descriptive study explored the congruency between the Prepared Childbirth couple's planned antenatal coaching support style and the observed coaching support style and the couple's postpartal perceptions of the coaching support style. Also explored were the relationship of coach's support style and the degree of the couple's postpartal satisfaction with the childbirth experience. A rrodified version of Campbell's Antenatal Questionnaire and Postpartal Questionnaire (1980) and Standley and Anderson's Naturalistic Observation Fonn were utilized for this study and administered to 10 Prepared Childbirth couples for labor observation and detennination of coaches' support styles. The researcher was not able to observe two of the couples in the sample during labor to determine the coach's style. Data collected from these two couples could only be used to answer twu of the four hypotheses, resulting in 16 subjects in the sample for these instead of 20. Only five of 16 subjects accurately predicted the coaching style that was observed. Six of the 16 subjects' postpartal perceptions of the coaching style agreed with the observer's classification. TWelve out of 20 subjects had congruent antepartal expectations and postpartal perceptions even though the coach may have demonstrated a different support style than planned. Based on the findings of the study, the majority of the subjects were not able to predict the support style that the individual coach would derronstrate during his wife's labor. This had little effect on postpartal satisfaction. The wives of coaches who utilized the "interactive through instrumentation" support style had the lowest rating of satisfaction with the childbirth a-perience. These wives also reported more complications occurring in labor during their postpartal interview.

Thesis (M.S.)--Boston University

Down's syndrome (DS) is a congenital disorder caused by trisomy of chromosome 21, giving rise to symptoms including intellectual disability, poor muscle tone and characteristic facial features. Located on chromosome 21 is a gene encoding ubiquitin specific protease 25 (USP25), a member of the deubiquitinating family of enzymes. Studies of partial trisomies have revealed that although the USP25 gene is situated outside the critical region of chromosome 21 required to be triplicated to induce full DS symptoms, it is in a region linked to mild mental retardation and muscle hypotonia. Previous data has shown that, when overexpressed, USP25 forms novel rod shaped structures approximately 3-5 μm in length and 0.3-0.6 μm wide, and with a copy number, on average, of no more than 1-2 per cell. These structures do not associate with any known cellular organelle or with any component of the cytoskeleton. In this work, endogenous USP25 rods were detected in cultures of primary human foetal astrocytes, and a comparison of healthy and DS human primary foetal astrocytes revealed that in the DS culture a higher percentage of astrocytes contain rods. The domains of USP25 required for rod formation were identified using a series of GFP-tagged deletion constructs. USP25 rods could be purified from HEK293 cells using subcellular fractionation techniques and were assayed for deubiquitinating activity; however, none was detected suggesting that rods may be catalytically inactive. Interacting partners of USP25 were identified using mass spectrometry, but none were found to localise in rods. Additionally, a USP25 null human embryonic stem cell line was generated in order to interrogate the function of USP25 in astrocytes, and was found to be deficient in maintaining the integrity of an epithelial cell layer in an in vitro model of the blood brain barrier.