Identification of hepatocyte nuclear factor 1β-associated disease

Heterozygous mutations and deletions of the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) are the commonest known monogenic cause of developmental kidney disease. However, diagnosis remains challenging due to phenotypic variability and frequent absence of a family history. There is also no consensus as to when HNF1B genetic testing should be performed. This thesis includes work looking at the identification of HNF1B-associated disease. An HNF1B score was developed in 2014 to help select appropriate patients for genetic testing. The aim in chapter 2 was to test the clinical utility of this score in a large number of referrals for HNF1B genetic testing to the UK diagnostic testing service for the HNF1B gene. An HNF1B score was assigned for 686 referrals using clinical information available at the time of testing; performance of the score was evaluated by receiver-operating characteristic curve analysis. Although the HNF1B score discriminated between patients with and without a mutation/deletion reasonably well, the negative predictive value of 85% reduces its clinical utility. HNF1B-associated disease is due to an approximate 1.3 Mb deletion of chromosome 17q12 in about 50% of individuals. This deletion includes HNF1B plus 14 additional genes and has been linked to an increased risk of neurodevelopmental disorders, such as autism. The aim in chapter 3 was to compare the neurodevelopmental phenotype of patients with either an HNF1B intragenic mutation or 17q12 deletion to determine whether haploinsufficiency of the HNF1B gene is responsible for this aspect of the phenotype. Brief behavioural screening showed high levels of psychopathology and impact in children with a deletion. 8/20 (40%) patients with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to 0/18 with a mutation, P=0.004. 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. These results demonstrate that the 17q12 deletion but not HNF1B intragenic mutations are associated with neurodevelopmental disorders; we conclude that the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Extra-renal phenotypes frequently occur in HNF1B-associated disease, including diabetes mellitus and pancreatic hypoplasia. Faecal elastase-1 levels have only been reported in a small number of individuals, the majority of which have diabetes. In chapter 4 we measured faecal elastase-1 in patients with an HNF1B mutation or deletion regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. We found that faecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with a known HNF1B molecular abnormality complaining of chronic abdominal pain, loose stools or unintentional weight loss. Hypomagnesaemia is a common feature of HNF1B-associated disease and is due to renal magnesium wasting. The aim in chapter 5 was to measure both serum and urine magnesium and calcium levels in individuals with an HNF1B molecular defect and compare to a cohort of patients followed up in a general nephrology clinic in order to assess their potential as biomarkers for HNF1B-associated disease. The results of this pilot study show that using a cut-off for serum magnesium of ≤0.75 mmol/L was 100% sensitive and 87.5% specific for the presence of an HNF1B mutation/deletion. All individuals in the HNF1B cohort had hypermagnesuria with fractional excretion of magnesium >4%; a cut-off of ≥4.1% was 100% sensitive and 71% specific. This suggests serum magnesium levels and fractional excretion of magnesium are highly sensitive biomarkers for HNF1B-associated renal disease; if these results are confirmed in a larger study of patients with congenital anomalies of the kidneys or urinary tract they could be implemented as cheap screening tests for HNF1B genetic testing in routine clinical care.Medical Research Counci

A child-centred early years curriculum? How do we increase children's voices to realise this?

The research study considers insights and challenges to listening to young children’s voices in a pre-school in England. The study was motivated by the political and social agendas which assert the fundamental involvement of young children as active decision-makers in all aspects of their lives (for example, the United Nations Convention on the Rights of the Child of 1989 and the Children Act 2004).The researcher aimed for participatory research with the children and staff to explore effective ways in which young children’s communications might be supported through the co-creation of their early years curriculum. The intention was to focus on ‘tools’ and techniques that might support children’s voices which were gaining attention in the academic literature (for example, the Mosaic Approach introduced by Alison Clark and Peter Moss).As a recent early years practitioner at the pre-school, the researcher offers a frank view of the potential complexities of implementing such participatory research. The researcher took an innovative, flexible and highly reflective stance to adapting the research approach in response to the challenges to establishing participation that emerged, using a postmodern framework to assist meaning-making.A substantive finding was that although the ‘tools’ and techniques opened a significant space for beginning to listen to children’s voices, it was the constructions of the underpinning relationships that offered the most potential (and the greatest challenge) for genuinely participating with and hearing children. The study concluded a focus on the latter is paramount for children to be accorded their rights as active decision-makers

An Australian Test of Economic and Political Models of Welfare State Expenditures: 1945 - 1979

This paper tests \u27political\u27 and \u27economic\u27 models of welfare expenditure with post-World War II Australian data. The major antecedents of welfare spending for the overall time period (1945-1979) appeared to be economic growth as mediated by the age of the population and program incrementalism. It was shown, however, that this view misleads rather than clarifies the influence of different factors during specific periods within the overall time series. A periodization of welfare spending was found to be more useful. The periodization analysis showed that the influence of politics on welfare spending is important. Right political strength was found to have a negative impact on spending levels and the equality of aged pensioner incomes. It was also shown that program incrementalism does not reduce inequality

A qualitative exploration of pupil, parent and staff discourses of extended school non-attendance

Extended school non-attendance (ESNA) is presented in the literature as a difficulty that can result in negative outcomes for the pupil, not only with regard to academic attainment but mental health difficulties, relationship problems and reduced future prospects. In the political context of increased legislation regarding the requirements for pupils be in receipt of suitable educational provision, a legal discourse of ESNA has become entrenched. This sits alongside a dominant clinical discourse which positions school non-attendance as a within child, medicalised construct. Whilst early research aligned extended non-attendance with anxiety, subsequent findings have constructed such attendance difficulties as multi-factorial, interactive and individual. In the existing research, there is little which includes the pupil voice to examine their construction of the attendance difficulty. This qualitative exploration therefore, aimed to examine the construction of the reasons for ESNA by the pupils, parents and school staff, through examining the discourses of participants. The findings of the analysis highlighted the heterogeneity of ESNA and are illustrative of the disparate constructions of the participant groups. The results are discussed in the context of the current literature and the implications of the findings are considered in terms of strategic prevention, identification and intervention of attendance difficulties

How Discourses Stifle the Primary Health Care Strategy's Intent to Reduce Health Inequalities

New Zealand’s Primary Health Care Strategy (PHCS) has a stated commitment to defined populations who suffer disproportionately from ill health. This thesis examines whether some prevailing discourses actually decrease the focus on health inequalities. Words and ideas shared by a group can be considered a discourse when the underpinning values serve a social and political function for that group. To examine whether discourse was constraining health care I considered the nursing and medical media pertaining to both the PHCS and the primary health care nursing framework and sought their dominant discourses. I found that the nursing and medical media focused on predominantly professional and industrial issues. These were expressed very differently with the medical media reacting to the ramifications of the PHCS especially Primary Health Organisations (PHOs), while the nursing media had a visioning quality, imagining how nursing could function in primary health care (PHC). The result was that, in the media studied, the upheaval of the PHCS left professionals mainly wondering about their own professional interests, rather than considering what those who suffer from health inequalities needed. The discourse of the PHCS may also serve political rather then altruistic purposes. I found historical examples of where discourse had underpinned health policy and I suggest that current (Ministry of Health) MOH discourse values decentralised community health decision making. The decentralised community health model of small community PHOs situates the responsibility for health locally. This health responsibility may gloss over factors in community health which are affected by Government policy such as employment policy, and thus should be dealt with centrally by legislation. These factors have been found to be the most pertinent in health inequalities. So while models of community partnerships may seem to place communities as agents in their own health, this downplays the determinants of health which are beyond their control. Moreover the multiple PHOs through the country, while costly in the repetition of bureaucracy, also make analysis of the PHCS difficult, since there is in effect multiple Primary Health Care Strategies being played out in each area, as interventions of various qualities are implemented. Having shown that discourse can decrease the focus on health inequalities due to other professional and political drivers. I then looked at health initiative concepts which are effective, efficient and equitable given the current set up of PHOs and nursing innovations

Understanding Safety Performance Using Safety Climate And Psychological Climate

This paper aims to explore the relationship between psychological climate, safety climate and safety performance. Safety research is increasingly expanding from a central focus on safety specific explanations of safety performance, to encompass more general management principles (e.g. leadership, role stress, and performance management). This research aims to contribute to this body by exploring the way in which psychological climate can be used to explain safety performance. This paper compares the fit of three competing models of safety performance using structural equation modelling. In the first model safety performance is predict by safety climate only, in the second by psychological climate only and the third is a saturated model using both safety and psychological climate. Comparison of the models revealed that the saturated model provides a better and more parsimonious explanation of safety performance than safety climate alone

Coercion versus co-optation: Western relations with the MPLA and FRELIMO from 1956 to 1976.

This thesis analyses the development of Western relations with the Popular Movement for the Liberation of Angola (MPLA) and the Front for the Liberation of Mozambique (FRELIMO) from 1956 to 1976. It concludes that nationalist attitudes were influenced by eleven factors, of which only one--perception of Western policies--was consistently present in every time period. Even when a movement was becoming increasingly hostile to the West due to other factors, perception of a friendly Western attitude was capable of producing a positive nationalist response. Although seven factors shaped Western policies, in general governments reacted in accord with the impact of nationalist policies on interests deemed important. For cold war-focussed countries, a movement's policies were only examined to determine their influence on that international competition. Because both nationalist groups had ties with the socialist world, and because Portugal threatened to deny Western access to the Azores base if the West courted the nationalists, cold war-focussed states such as the United States avoided co-optation initiatives. Those states with wider ties to the area tended to evaluate the impact of the whole spectrum of nationalist policies on regional interests when determining strategies. Countries with broad ties to the region, such as Britain, were capable of overlooking a movement's socialist alliances and adopting co-optation policies if the group was deemed willing and able to further the Western state's interests in the region. The thesis also concludes that co-optation policies would have better protected Western interests than the coercion or neglect strategies so often selected and that such an approach would have produced stronger results in FRELIMO than in the MPLA. However, due to the interplay of other factors, even if subjected to consistently positive Western policies neither movement would have become a close Western ally