Translational Research of Audiovisual Biofeedback: An investigation of respiratory-guidance in lung and liver cancer patient radiation therapy

Through the act of breathing, thoracic and abdominal anatomy is in constant motion and is typically irregular. This irregular motion can exacerbate errors in radiation therapy, breathing guidance interventions operate to minimise these errors. However, much of the breathing guidance investigations have not directly quantified the impact of regular breathing on radiation therapy accuracy. The first aim of this thesis was to critically appraise the literature in terms of the use of breathing guidance interventions via systematic review. This review found that 21 of the 27 identified studies yielded significant improvements from the use of breathing guidance. None of the studies were randomised and no studies quantified the impact on 4DCT image quality. The second aim of this thesis was to quantify the impact of audiovisual biofeedback breathing guidance on 4DCT. This study utilised data from an MRI study to program the motion of a digital phantom prior to then simulating 4DCT imaging. Audiovisual biofeedback demonstrated to significantly improved 4DCT image quality over free breathing. The third aim of this thesis was to assess the impact of audiovisual biofeedback on liver cancer patient breathing over a course of stereotactic body radiation therapy (SBRT). The findings of this study demonstrated the effectiveness of audiovisual biofeedback in producing consistent interfraction respiratory motion over a course of SBRT. The fourth aim of this thesis was to design and implement a phase II clinical trial investigating the use and impact of audiovisual biofeedback in lung cancer radiation therapy. The findings of a retrospective analysis were utilised to design and determine the statistics of the most comprehensive breathing guidance study to date: a randomised, stratified, multi-site, phase II clinical trial.. The fifth aim of this thesis was to explore the next stages of audiovisual biofeedback in terms of translating evidence into broader clinical use through commercialisation. This aim was achieved by investigating the the product-market fit of the audiovisual biofeedback technology. The culmination of these findings demonstrates the clinical benefit of the audiovisual biofeedback respiratory guidance system and the possibility to make breathing guidance systems more widely available to patients

Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation

Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. METHODS: This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. DISCUSSION: We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health

The effects of grain size, dendritic structure and crystallographic orientation on fatigue crack propagation in IN713C nickel-based superalloy

The polycrystalline IN713C produced via investment casting is one of the widely-used nickel-based superalloy in automotive and aerospace industries. This alloy, however, has an apparent inhomogeneous microstructure generated during casting and contains dendritic structure that gives rise to strain localisation during loading. Yet, the effect of dendritic structure, grain size and shape as well as crystallographic orientation, which directly influence fatigue property and deformation micromechanism in the components, is rarely studied. In the present study, IN713C cast bars are tailored with three different grain structures, i.e., transition, equiaxed and columnar, with substantial grain size variations. The produced bars were tested under strain controlled LCF (Low Cycle Fatigue) and stress controlled HCF (High Cycle Fatigue) conditions at 650 °C. The results showed that most of fatigue cracks initiated from casting pores and fatigue life extended in the microstructure with a small grain size during both HCF and LCF loadings. It is also demonstrated that fatigue striations were mainly observed within dendritic areas during crack propagation, whereas the higher GND (Geometrically Necessary Dislocation) density were predominantly observed in the interdendritic areas. Here, we propose a concept of ‘Crack Propagation Unit (CPU)’ for better description of deformation mechanism at local scale during fatigue loading by combining fracture surface characteristic methodology and dislocation distribution analyses within the dendritic structural unit. Furthermore, this model to understand the deformation micromechanism can provide a new perspective on the interpretation of Hall-Petch relationship in casting materials that contain dendritic structure. This is further demonstrated via direct correlation of the high crack propagation resistance with the crack path divergence instead of the dislocation pile-up at the grain boundary or in-between the γ/γ′ channels. Moreover, by utilising serial sectioning method followed by layered EBSD scanning, quasi-3-D grain orientation mappings were obtained, and crystallographic texture information were directly correlated with the fracture surface observations. This allowed an investigation of the influence of orientation of individual grains and micro/macro texture on crack propagation rate. The critical stage of crack propagation in fatigue life and its correlations with microstructural features is established, offering potential practical applications by controlling the investment casting process parameters

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Plate fixation or intramedullary fixation of humeral shaft fractures: An updated meta-analysis

Background The optimal approach to operative treatment of humeral shaft fractures remains debatable. Previously published trials have been limited in size and have been inconclusive regarding important patient outcome variables following treatment with either intramedullary nails or plates. We conducted a meta-analysis of available trials comparing treatment of humeral shaft fractures

Structural Brain Magnetic Resonance Imaging to Rule out Comorbid Pathology in the Assessment of Alzheimer\u27s Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials over the Past 10 Years

Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer\u27s disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity

Can the dark energy equation-of-state parameter w be less than -1?

Models of dark energy are conveniently characterized by the equation-of-state parameter w=p/\rho, where \rho is the energy density and p is the pressure. Imposing the Dominant Energy Condition, which guarantees stability of the theory, implies that w \geq -1. Nevertheless, it is conceivable that a well-defined model could (perhaps temporarily) have w<-1, and indeed such models have been proposed. We study the stability of dynamical models exhibiting w<-1 by virtue of a negative kinetic term. Although naively unstable, we explore the possibility that these models might be phenomenologically viable if thought of as effective field theories valid only up to a certain momentum cutoff. Under our most optimistic assumptions, we argue that the instability timescale can be greater than the age of the universe, but only if the cutoff is at or below 100 MeV. We conclude that it is difficult, although not necessarily impossible, to construct viable models of dark energy with w<-1; observers should keep an open mind, but the burden is on theorists to demonstrate that any proposed new models are not ruled out by rapid vacuum decay.Comment: 29 pages, 8 figures, minor corrections, reference adde