Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Understanding file access mechanisms for embedded ubicomp collaboration interfaces

This paper explores the nature of interfaces to support people in accessing their files at tabletop displays embedded in the environment. To do this, we designed a study comparing people's interaction with two very different classes of file system access interface: Focus, explicitly designed for tabletops, and the familiar hierarchical Windows Explorer. In our within-subjects double-crossover study, participants collaborated on 4 planning tasks. Based on video, logs, questionnaires and interviews, we conclude that both classes of interface have a place. Notably, Focus contributed to improved collaboration and more efficient use of the workspace than with Explorer. Our results inform a set of recommendations for future interfaces enabling this important class of interaction -- supporting access to files for collaboration at tabletop devices embedded in an ubicomp environment.

Comparison of Radiation Doses for Catheter Ablation Procedures for Atrial Fibrillation with Percutaneous Coronary Intervention Cases

Background: Catheter ablation procedures for atrial fibrillation (AF) may frequently require long fluoroscopic times. We sought to undertake a review of radiation safety practice in our Cardiac Electrophysiology Laboratory and implement changes to minimize fluoroscopic doses. We also sought to compare the results with radiation doses for percutaneous coronary intervention (PCI) cases performed in our hospital. Methods: Fluoroscopic times and doses for AF ablation procedures performed by a single operator on a Philips Integris H3000 image-intensifier were analysed for 11-month period. Results were compared with all PCI procedures performed over a similar period by multiple operators on a Philips Integris Allura FD system. Comprehensive review of radiation practice in the Electrophysiology laboratory identified the potential to reduce pulse frame rates and doses, and to narrow the field of interest without impacting the performance of the procedure. These changes were implemented and results analysed after a further 11 months. Results: In the pre-intervention period 50 AF catheter ablations had a mean fluoroscopic time of 86.4 min and mean fluoroscopic dose 68.4 Gy/cm2. Post-intervention 75 procedures had a mean fluorosocopic time of 68.9 min (p < 0.0001) and mean dose of 14.3 Gy/cm2 (p < 0.0001) 128 PCI procedures had a mean combined fluoroscopic and image acquisition time of 10.0 min and mean total dose 38.8 Gy/cm2. Conclusions: Catheter ablation procedures for AF may require lengthy use of fluoroscopy but simple modifications to radiation practice can result in marked reductions in radiation dose that compare favourably with PCI case doses

Analysis of an inter-centre, web-based radiation oncology peer-review case conference

Purpose Peer-review programmes in radiation oncology are used to facilitate the process and evaluation of clinical decision-making. However, web-based peer-review methods are still uncommon. This study analysed an inter-centre, web-based peer-review case conference as a method of facilitating the decision-making process in radiation oncology. Methodology A benchmark form was designed based on the American Society for Radiation Oncology targets for radiation oncology peer review. This was used for evaluating the contents of the peer-review case presentations on 40 cases, selected from three participating radiation oncology centres. A scoring system was used for comparison of data, and a survey was conducted to analyse the experiences of radiation oncology professionals who attended the web-based peer-review meetings in order to identify priorities for improvement. Results The mean scores for the evaluations were 82·7, 84·5, 86·3 and 87·3% for cervical, prostate, breast and head and neck presentations, respectively. The survey showed that radiation oncology professionals were confident about the role of web-based peer-reviews in facilitating sharing of good practice, stimulating professionalism and promoting professional growth. The participants were satisfied with the quality of the audio and visual aspects of the web-based meeting. Conclusion The results of this study suggest that simple inter-centre web-based peer-review case conferences are a feasible technique for peer review in radiation oncology. Limitations such as data security and confidentiality can be overcome by the use of appropriate structure and technology. To drive the issues of quality and safety a step further, small radiotherapy departments may need to consider web-based peer-review case conference as part of their routine quality assurance practices.

Stress and Resilience in Combat-Related PTSD: Integration of Psychological Theory and Biological Mechanisms

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder that has a major impact on the ability to function effectively in daily life. PTSD may develop as a response to exposure to an event or events perceived as potentially harmful or life-threatening. It has high prevalence rates in the community, especially among vulnerable groups such as military personnel or those in emergency services. Despite extensive research in this field, the underlying mechanisms of the disorder remain largely unknown. The identification of risk factors for PTSD has posed a particular challenge as there can be delays in onset of the disorder, and most people who are exposed to traumatic events will not meet diagnostic criteria for PTSD. With the advent of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V), the classification for PTSD has changed from an anxiety disorder into the category of stress- and trauma-related disorders. This has the potential to refocus PTSD research on the nature of stress and the stress response relationship. This review focuses on some of the important findings from psychological and biological research based on early models of stress and resilience. Improving our understanding of PTSD by investigating both genetic and psychological risk and coping factors that influence stress response, as well as their interaction, may provide a basis for more effective and earlier intervention.

Emotional intelligence development in student radiation therapists: A longitudinal pilot study

Emotional intelligence (EI) is defined as “the ability to recognise, understand and manage emotions in ourselves and others” [1]. Initially identified as a concept applied to leadership and management, EI is now recognised as an important skill in a number of areas, including healthcare [2]. Empathy (the ability to see the world through someone else’s eyes) is known to play an important role in the therapeutic relationship with patients [3]. As EI has been shown to improve empathy [4], it is clear that developing the EI of student health professionals should benefit patients in the long term. It is not surprising, then, that a number of studies have investigated the role of EI in medical, dental and nursing students, however there is little reported evidence relating to EI development in pre-registration radiation therapy (RT) students.

Emotional intelligence development in radiation therapy students: A longitudinal study

Purpose: Emotional intelligence (EI) is an increasingly important aspect of a health professional’s skill set. It is strongly associated with empathy, reflection and resilience; all key aspects of radiotherapy practice. Previous work in other disciplines has formed contradictory conclusions concerning development of EI over time. This study aimed to determine the extent to which EI can develop during a radiotherapy undergraduate course and identify factors affecting this. Methods and materials: This study used anonymous coded Likert-style surveys to gather longitudinal data from radiotherapy students relating to a range of self-perceived EI traits during their 3-year degree. Data were gathered at various points throughout the course from the whole cohort. Results: A total of 26 students provided data with 14 completing the full series of datasets. There was a 17·2% increase in self-reported EI score with a p-value<0·0001. Social awareness and relationship skills exhibited the greatest increase in scores compared with self-awareness. Variance of scores decreased over time; there was a reduced change in EI for mature students who tended to have higher initial scores. EI increase was most evident immediately after clinical placements. Conclusions: Radiotherapy students increase their EI scores during a 3-year course. Students reported higher levels of EI immediately after their clinical placement; radiotherapy curricula should seek to maximise on these learning opportunities.

Quality of life changes during conformal radiation therapy for prostate carcinoma

BACKGROUND: The objective of this study was to describe prospectively quality of life (QOL) before and after radiotherapy for patients with prostate carcinoma. METHODS: Forty-three patients with T1-T3 prostate carcinoma who underwent conformal external beam radiation therapy were randomized either to the complete European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire (EORTC QLQ-C30) or the Medical Outcomes Study Group Short Form Health Survey (SF-36) at baseline, at 3 weeks and 6 weeks after initial treatment, and at 6 weeks and 5 months after the completion of radiotherapy. The measures were self-reported patient QOL, and values are given as the mean +/- standard error of the mean. Changes in QOL are described from baseline to the end of treatment in both questionnaire groups. RESULTS: Emotional role functioning, as measured with the SF-36 questionnaire, significantly improved from 68.2 +/- 9.9 at baseline to 93.3 +/- 5.2 at the end of therapy (P = 0.02). The EORTC QLQ-C30 questionnaire revealed consistent values of emotional functioning during treatment (72.7 +/- 5.9 at baseline) but showed a significant improvement 6 weeks after therapy (89.0 +/- 4.4; P = 0.01). Role functioning deteriorated from 80.1 +/- 6.5 at baseline to 62.5 +/- 8.8 at the end of radiotherapy (P = 0.02). Symptoms of fatigue were shown to increase significantly from 26.9 +/- 6.0 at baseline to 37.7 +/- 7.6 at the end of therapy (P = 0.02). No significant changes in the other dimensions were observed in either questionnaire. CONCLUSIONS: After radiotherapy for prostate carcinoma, patients experience a temporary deterioration of fatigue and role functioning, as measured with the EORTC QLQ-C-30. Despite physical deterioration, the authors observed an improvement in emotional functioning scores with both questionnaires. This may have been due to psychological adaptation and coping.

Australian innovation ecosystem: A critical review of the national innovation support mechanisms

Innovation is understood as the combination of existing ideas or the generation of new ideas into new processes, products and services, and widely viewed as the main driver of growth in contemporary economies. In the age of the knowledge economy, successful economic development is intimately linked to a country’s capacity to generate, acquire, absorb, disseminate, and apply innovation towards advanced technology products and services. This development approach is labelled as knowledge-based economic development and highly associated with a capacity embodied in a country’s national innovation ecosystem. The research reported in this paper aims to critically review the Australian innovation ecosystem in order to provide a better understanding on the potential impacts of policy and support mechanisms on the innovation and knowledge generation capacity. The investigation places Australia’s innovation system and national-level innovation support mechanisms under the microscope. The methodology of the study is twofold. Firstly, it undertakes a critical review of the literature and government policy documents to better understand the innovation policy and support mechanisms in the country. It, then, conducts a survey to capture Australian innovation companies’ perceptions on the role and effectiveness of the existing innovation incentive programs. The paper concludes with a discussion on the key insights and findings and potential policy and support directions of the country to achieve a flourishing knowledge economy.

The mechanisms of human renal epithelial cell modulation of autologous dendritic cell phenotype and function

Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down-modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders.

DCAF4, a novel gene associated with leucocyte telomere length

Background Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Results Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24. Conclusions We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

Emotional intelligence development in student radiation therapists: A longitudinal pilot study

Emotional intelligence (EI) is defined as “the ability to recognise, understand and manage emotions in ourselves and others”. Initially identified as a concept applied to leadership and management, EI is now recognised as an important skill in a number of areas, including healthcare [2]. Empathy (the ability to see the world through someone else’s eyes) is known to play an important role in the therapeutic relationship with patients [3]. As EI has been shown to improve empathy [4], it is clear that developing the EI of student health professionals should benefit patients in the long term. It is not surprising, then, that a number of studies have investigated the role of EI in medical, dental and nursing students, however there is little reported evidence relating to EI development in pre-registration radiation therapy (RT) students.

Anti-bacterial surfaces: Natural agents, mechanisms of action, and plasma surface modification

Strategies that confine antibacterial and/or antifouling property to the surface of the implant, by modifying the surface chemistry and morphology or by encapsulating the material in an antibiotic-loaded coating, are most promising as they do not alter bulk integrity of the material. Among them, plasma-assisted modification and catechol chemistry stand out for their ability to modify a wide range of substrates. By controlling processing parameters, plasma environment can be used for surface nano structuring, chemical activation, and deposition of biologically active and passive coatings. Catechol chemistry can be used for material-independent, highly-controlled surface immobilisation of active molecules and fabrication of biodegradable drug-loaded hydrogel coatings. In this article, we comprehensively review the role plasma-assisted processing and catechol chemistry can play in combating bacterial colonisation on medically relevant coatings, and how these strategies can be coupled with the use of natural antimicrobial agents to produce synthetic antibiotic-free antibacterial surfaces.

Tripogon loliiformis elicits a rapid physiological and structural response to dehydration for desiccation tolerance

Resurrection plants can withstand extreme dehydration to an air-dry state and then recover upon receiving water. Tripogon loliiformis (F.Muell.) C.E.Hubb. is a largely uncharacterised native Australian desiccation-tolerant grass that resurrects from the desiccated state within 72 h. Using a combination of structural and physiological techniques the structural and physiological features that enable T. loliiformis to tolerate desiccation were investigated. These features include: - (i) a myriad of structural changes such as leaf folding, cell wall folding and vacuole fragmentation that mitigate desiccation stress; - (ii) potential role of sclerenchymatous tissue within leaf folding and radiation protection; - (iii) retention of ~70% chlorophyll in the desiccated state; - (iv) early response of photosynthesis to dehydration by 50% reduction and ceasing completely at 80 and 70% relative water content, respectively; - (v) a sharp increase in electrolyte leakage during dehydration, and; - (vi) confirmation of membrane integrity throughout desiccation and rehydration. Taken together, these results demonstrate that T. loliiformis implements a range of structural and physiological mechanisms that minimise mechanical, oxidative and irradiation stress. These results provide powerful insights into tolerance mechanisms for potential utilisation in the enhancement of stress-tolerance in crop plants.

Season of birth and location of residence: Defining the role of ultraviolet radiation exposure on childhood temperament and behaviour

This thesis added new insight to research knowledge about the role that season and ultraviolet radiation (UV) exposure during pregnancy has on children's temperament and behaviours, using a nation-wide longitudinal study. It was found that young children born in summer months are likely to have problematic behaviours. The thesis also found that summer-born children are likely to receive lowest levels of UV exposure during the gestational period. Finally, this work showed that low gestational UV exposure is associated with an increased risk of behavioural problems in children.