The impact of perceptions and skills of teaching staff on the building of a dyslexia friendly school

This dissertation comprises a study of the perceptions and skills of teaching staff working with children with Specific Learning Difficulties (SpLD) in an inclusive, mainstream setting. The aims of the dissertation are to review recent and relevant literature, to audit the knowledge and skills of staff in this area, to identify strengths and areas for development in teaching and learning for children with SpLD within this setting, to enhance self-confidence of teaching skills of staff in this school and to put in place criteria to enable subsequent application of the Dyslexia Friendly Schools Initiative Quality Mark. The initial approach within a mainstream primary school setting was to gather data from a comprehensive, anonymous questionnaire (qualitative/quantitative data) designed using a combination of open and closed questions. All teaching staff were invited to participate. Data from the questionnaire was triangulated by selecting key participants for classroom observation and interview: a teacher of some years' experience, a newly qualified teacher and a teaching assistant working with children with a range of additional needs. The research and findings demonstrate the paradigm shift in the perception and management of dyslexia in recent educational history and evidence the importance of training staff in building positive perceptions and developing and implementing dyslexia friendly teaching skills and learning strategies. This dissertation suggests that such teaching and learning strategies are also appropriate for all children within this setting

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma

Development of the major trauma case review tool

Background: As many as half of all patients with major traumatic injuries do not receive the recommended care, with variance in preventable mortality reported across the globe. This variance highlights the need for a comprehensive process for monitoring and reviewing patient care, central to which is a consistent peer-review process that includes trauma system safety and human factors. There is no published, evidence-informed standardised tool that considers these factors for use in adult or paediatric trauma case peer-review. The aim of this research was to develop and validate a trauma case review tool to facilitate clinical review of paediatric trauma patient care in extracting information to facilitate monitoring, inform change and enable loop closure. Methods: Development of the trauma case review tool was multi-faceted, beginning with a review of the trauma audit tool literature. Data were extracted from the literature to inform iterative tool development using a consensus approach. Inter-rater agreement was assessed for both the pilot and finalised versions of the tool. Results: The final trauma case review tool contained ten sections, including patient factors (such as pre-existing conditions), presenting problem, a timeline of events, factors contributing to the care delivery problem (including equipment, work environment, staff action, organizational factors), positive aspects of care and the outcome of panel discussion. After refinement, the inter-rater reliability of the human factors and outcome components of the tool improved with an average 86% agreement between raters. Discussion: This research developed an evidence-informed tool for use in paediatric trauma case review that considers both system safety and human factors to facilitate clinical review of trauma patient care. Conclusions: This tool can be used to identify opportunities for improvement

Paediatric trauma systems and their impact on the health outcomes of severely injured children: Protocol for a mixed methods cohort study

Background Injury is a leading cause of death and disability for children. Regionalised trauma systems have improved outcomes for severely injured adults, however the impact of adult orientated trauma systems on the outcomes of severely injured children remains unclear. The objective of this study is to review the processes of care and describe the impacts of a regionalised trauma system on the outcomes of severely injured children. Methods This article describes the design of a mixed methods cohort study evaluating the paediatric trauma system in New South Wales (NSW), the most populous state in Australia. Recommendations and an implementation strategy will be developed for aspects of the paediatric trauma care system that require change. All injured children (aged < 16 years) requiring intensive care, or with an Injury Severity Score (ISS) ≥ 9 treated in NSW, or who died following injury in NSW in the 2015–16 financial year, will be eligible for participation. Injury treatment and processes will be examined via retrospective medical record review. Quality of care will be measured via peer review and staff interviews, utilising a human factors framework. Health service and cost outcomes will be calculated using activity based funding data provided by the Ministry of Health. Health-related quality of life (HRQoL) proxy measures will occur at baseline, 6 and 12 months to measure child HRQoL and functional outcomes. Discussion This will be the first comprehensive analysis undertaken in Australia of the processes and systems of care for severe paediatric injury. The collaborative research method will encourage clinician, consumer and clinical networks to lead the clinical reform process and will ultimately enable policy makers and service providers to ensure that children seriously injured in Australia have the best opportunity for survival, improved functional outcome and long-term quality of life

Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice

Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9–/– mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy