Functional genetics of type 1 diabetes: between genes and disease

Identification of the cellular mechanisms involved in the occurrence and persistence of autoreactive lymphocytes is key for understanding T1D etiology. Comparing autoreactive T lymphocytes from healthy individuals and T1D patients can provide clues as to what the driving force is for the destruction of β-cells and might designate potential targets for (immune) intervention. Elucidating in what way T1D associated gene variants actually contribute to disease development, i.e. understanding the functional aspects of genetic risk, and how genetic control of autoantigens influences autoimmunity may provide crucial clues to the clarification of the enigma of T1D. This thesis aims to answer several of these issues by investigating the role of transcriptional and post-transcriptional gene control in T1D. Alrijne Zorggroep Novo Nordisk B.V.LUMC / Geneeskund

Challenging the 'new accountability'? Service users' perspectives on performance measurement in family support

After two decades of public management reform, the ‘new accountability’ of performance measurement is a routine feature in the relationships between Australian government agencies and the non-profit organisations they fund to provide child and family services. While performance measurement offers to resolve tensions about how governments manage the quality and productivity of contracted services, the indicators they commonly adopt raise well-documented practical, political and epistemological challenges in social services. Left unresolved, these challenges risk biasing representations of service performance, by emphasising the most tangible dimensions of service activities (such as measures of client throughput) over relationship building and care. Capturing only part of service activity compromises the usefulness of performance data for managing quality and outcomes, and denies policy makers critical information about the value and meaning of care in users’ lives. This thesis identifies and critically explores one set of challenges for performance measurement: the role of service users. Uniquely, I explore how user involvement in social service evaluation can make visible how these services enhance the quality of family and personal life. Using a case study of family support services in New South Wales, the research makes a series of empirical and theoretical contributions to problems of user involvement in social service evaluation. Firstly, the research examines the performance indicators currently used by government to monitor the efficiency and effectiveness of family support services in NSW. This shows that performance indicators in family support capture output more thoroughly than outcome, and confirms the minimal role that service users play in assessing service quality and outcomes. But while service users are largely excluded from participation in performance measurement, theoretical perspectives as diverse as managerialism and feminism treat service users as well placed to capture and report otherwise elusive information about care quality and outcomes. Further, participation in evaluation facilitates the exercise of users’ rights to self-expression and self-determination in the social service delivery and policy process. After identifying the widespread exclusion of service users’ perspectives from performance measurement in NSW family support, the thesis makes its more substantial contribution, in documenting findings from a detailed study involving adult family support service users (parents) and their workers (the ‘Burnside Study’). This qualitative study was conducted in four socio-economically disadvantaged service delivery sites located around New South Wales. Using focus group, interview and observational methods and a modified grounded theory approach, the study contributes exploratory evidence of what these service users think of, and how they think about service quality, outcomes, and evaluation in family support. The parents’ accounts of using family support capture their unfulfilled social ideals and the broader visions of the justice they hoped these social services would help them achieve. Their criteria for measuring service outcomes and service quality, and their views on evaluation methods embody core themes that social theorists have struggled to analyse, about the purpose of social services and the nature of ‘a good life’. The theoretical framework I develop highlights the role of family support in the context of service users’ struggles for social justice, and in particular, their struggles for self-realisation, recognition and respect (Honneth, 1995). The research extends theories of recognition beyond publicly articulated social movements to those struggles in social life and social politics that exist in what Axel Honneth terms the ‘shadows’ of the political-public sphere (2003a: 122). After establishing a conceptual framework that facilitates deeper interpretation of users’ perspectives, I present the findings in three categories: users’ perspectives on service outcomes; users’ perspectives on service quality; and users’ perspectives on evaluation methods. The findings show how service users define ‘service outcomes’ in the context of their struggles for recognition and respect, highlighting the contribution welfare services and welfare professionals make beyond the managerial ‘Three E’s’ of economy, efficiency, and effectiveness. Further, the findings confirm the importance of ‘helping relationships’ to the quality of service delivery in family support, despite the invisibility of service relationships in existing performance indicators. The complexity of worker-client bonds highlights the difficulty of evaluating social services using simple numerical counts of client or service episodes, and plays into broader debates about strategies for revaluing care work, and the role of care recipients. Finally, the findings show the role performance measurement processes and methods might play in facilitating users’ struggles for recognition. Users identified a role for evaluation in making visible the contribution of family support in pursuing their social justice goals, and saw evaluation as an opportunity in itself to facilitate recognition and respect. Overall, the thesis offers concrete evidence about how family support service users experience and define service quality and outcomes, and how they see their own role in evaluating the services they use. The research shows how users’ perspectives both contest and confirm the ‘new accountability’ of performance measurement, pointing to new directions, and further challenges, for conceptualising – and evaluating – social services

Aftercare Following Syndesmotic Screw Placement: A Systematic Review

For ankle fractures, in general, several studies have been published on immobilization (e.g., cast or boot) versus early motion after surgical treatment. However, no studies have been performed to determine the best aftercare strategy for surgically treated patients with ankle fractures with concomitant acute distal tibiofibular syndesmotic injuries. The aim of the present review was to compare the functional outcomes of ankle fractures with syndesmotic injury treated with a cast or boot versus early motion. We performed a systematic review using the electronic databases from January 1, 2000 to September 1, 2012 of the Cochrane Library, PubMed MEDLINE®, EMbase, and Google Scholar. The included studies were those in which ankle fractures with acute distal tibiofibular syndesmotic injuries had been treated with 1 or more syndesmotic screws, with a mean follow-up period of at least 12 months and at least 25 patients included. The functional outcomes, measured using the American Orthopaedic Foot Ankle Society Hindfoot scale, Olerud-Molander Ankle Scale, and Short Musculoskeletal Function Assessment, were compared. A total of 9 studies were identified with a total of 531 patients. The number of included patients ranged from 28 to 93. The mean follow-up period was 12 to 101 months. Of the 9 studies, 3 used an early motion protocol (195 patients) and 6 (336 patients) a protocol of immobilization for at least 6 weeks. For the American Orthopaedic Foot Ankle Society Hindfoot scale, the mean scores for immobilization were 86 to 91 points and for early motion, 84 to 89. For the Olerud-Molander Ankle Scale, the scores for immobilization were 47 to 90 and for early motion, 46 to 82 points. The Short Musculoskeletal Function Assessment score for immobilization was 11 and for early motion ranged from 12 to 27 points. No apparent differences could be detected in the published data considering the functional outcomes between immobilization versus an early motion protocol in ankle fractures with acute distal tibiofibular syndesmotic injuries treated with a syndesmotic screw. However, level 1 and 2 studies on this subject are lacking

Aerosol delivery from spacers in wheezy infants: a daily life study

The aims of this study were to assess and compare dose delivery and dose variability of pressurized metered dose inhalers (pMDI)/spacers in wheezy infants in daily life and to investigate factors influencing aerosol delivery. In an open randomized crossover study in 25 wheezy infants aged 5-26 months, a metal spacer (Nebuchamber), a detergent coated (DC) and a non-detergent coated (nonDC) plastic spacer (Babyhaler) were tested at home for 7 days each. Budesonide (200 microg b.i.d) was administered via a Nebuchamber or fluticasone (125 microg b.i.d) via a Babyhaler. Aerosol was trapped in filters, positioned between the spacer and face mask. Cooperation was scored on diary cards. Electrostatic charge (ESC) of the spacers was measured. Evaluations of the administration technique were made from video recordings. Median (range) dose delivery of the filters expressed as per cent (%) of nominal dose, was 34% (3-59), 23% (1-49), and 41% (12-55) for the Nebuchamber, nonDC-Babyhaler, and DC-Babyhaler respectively. Considerable dose variability was found, median (range) within-subject dose variability, expressed as coefficient of variation, for the Nebuchamber (49% (15-249)) was significantly higher when compared with both nonDC- (36% (12-325)) and DC-Babyhalers (27% (10-122)), for which dose variabilities were similar. Detergent coating was effective to reduce electrostatic

FDG-PET/CT for differentiating between aseptic and septic delayed union in the lower extremity

Background: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) has proven to have a high diagnostic accuracy for the detection of bone infections. In patients with delayed union it may be clinically important to differentiate between aseptic and septic delayed union. The aim of this study was to evaluate the efficacy and to assess the optimal diagnostic accuracy of FDG-PET/CT in differentiating between aseptic and septic delayed union in the lower extremity. Methods: This is a retrospective study of consecutive patients who underwent FDG-PET/CT scanning for suspicion of septic delayed union of the lower extremity. Diagnosis of aseptic delayed union or septic delayed union was made based on surgical deep cultures following PET/CT scanning and information on clinical follow-up. FDG-uptake values were measured at the fractured site by use of the maximum standardized uptake value (SUVmax). Sensitivity, specificity and diagnostic accuracy of FDG-PET/CT were calculated at various SUVmax cut-off points. Results: A total of 30 patients were included; 13 patients with aseptic delayed unions and 17 patients with septic delayed unions. Mean SUVmax in aseptic delayed union patients was 3.23 (SD ± 1.21). Mean SUVmax in septic delayed union patients was 4.77 (SD ± 1.87). A cut-off SUVmax set at 4.0 showed sensitivity, specificity and diagnostic accuracy of FDG-PET/CT were 65, 77 and 70% to differentiate between aseptic and septic delayed union, respectively. Conclusion: Using a semi-quantitative measure (SUVmax) for interpretation of FDG-PET/CT imaging seems to be a promising tool for the discrimination between aseptic and septic delayed union

Technological shocks mechanism on Macroeconomic Variables: A Dynamic Stochastic General Equilibrium (DSGE) approach.

As Ghana assumes a position of oil producer and middle-income country, it must learn to effectively deal with the related pressures from shocks. We analyze the effects of productivity shocks on Ghana’s total output using the multi-sector dynamic stochastic general equilibrium (DSGE) model. It was actualized that a productivity shock results in a temporary shrinkage in the final goods sectors due to the reallocation of labour from the final and intermediate goods sectors. We demonstrated that technological shock induces an initial fall in marginal cost of production but later rises to reach equilibrium