Maximal Graphs and Spacelike Mean Curvature Flows in Semi-Euclidean Spaces

Two main results are proved. The first is for the maximal graph system in semi-Euclidean spaces. Existence of smooth solutions to the Dirichlet problem is proved, under certain assumptions on the boundary data. These assumptions allow the application of standard elliptic PDE methods by providing sufficiently strong a priori gradient estimates. The second result is a version of Brian White’s local regularity theorem, but now for the spacelike mean curvature flow system in semi-Euclidean spaces. This is proved using a version of Huisken’s monotonicity formula. Under the assumption of a suitable gradient bound, this theorem will give a priori estimates that allow such flows to be smoothly extended locally

Human sound localisation cues and their relation to morphology

Binaural soundfield reproduction has the potential to create realistic threedimensional sound scenes using only a pair of normal headphones. Possible applications for binaural audio abound in, for example, the music, mobile communications and games industries. A problem exists, however, in that the head-related transfer functions (HRTFs) which inform our spatial perception of sound are affected by variations in human morphology, particularly in the shape of the external ear. It has been observed that HRTFs simply based on some kind of average head shape generally result in poor elevation perception, weak externalisation and spectrally distorted sound images. Hence, HRTFs are needed which accommodate these individual differences. Direct acoustic measurement and acoustic simulations based on morphological measurements are obvious means of obtaining individualised HRTFs, but both methods suffer from high cost and practical difficulties. The lack of a viable measurement method is currently hindering the widespread adoption of binaural technologies. There have been many attempts to estimate individualised HTRFs effectively and cheaply using easily obtainable morphological descriptors, but due to an inadequate understanding of the complex acoustic effects created in particular by the external ear, success has been limited. The work presented in this thesis strengthens current understanding in several ways and provides a promising route towards improved HRTF estimation. The way HRTFs vary as a function of direction is compared with localisation acuity to help pinpoint spectral features which contribute to spatial perception. 50 subjects have been scanned using magnetic resonance imaging to capture their head and pinna morphologies, and HRTFs for the same group have been measured acoustically. To make analysis of this extensive data tractable, and so reveal the mapping between the morphological and acoustic domains, a parametric method for efficiently describing head morphology has been developed. Finally, a novel technique, referred to as morphoacoustic perturbation analysis (MPA), is described. We demonstrate how MPA allows the morphological origin of a variety of HRTF spectral features to be identified

The time and space of Richard Coudenhove-Kalergi’s Pan-Europe, 1923-1939

This thesis investigates the historical geographies of the Pan-European Union, and its founder and leader Count Richard Coudenhove-Kalergi, focusing in the main on the period from 1923 to 1939. A mixed-race Austrian aristocrat, philosopher and writer who made it his life’s mission to see Europe politically united, Coudenhove-Kalergi’s was a singular life, which he used to his advantage by weaving his life story into his political campaigning. The thesis opens by investigating the relationship between a life lived and a life told, and about the consequences for researchers attempting to recover his biography. The bulk of the thesis looks at the ways in which Pan-Europeanism both responded and itself contributed to shaping three broad sets of spatial and temporal ideas, each revolving around the notion of a supranational European polity. First, it confronts the way history was invoked both to bring into being a ‘literature’ that would add prestige to its arguments, and to craft a narrative arc that would add the force of apparent inevitability to its arguments. Second, it looks at the way in which Pan-Europeanism employed a form of spatial reasoning that shared many points of reference with the German school of geopolitik, despite a fundamentally incompatible view of international politics. And third, it analyses the Pan-European invention of ‘Eurafrica’ as a neo-colonial system that would offer a ‘third path’ internationalism that fell between the imperialism of the British Empire, and the Mandate-based theory of international governance advocated by the League. Each of these sets of ideas, I argue, persisted both outside the bounds of the Pan-European Union, and after its eventual marginalisation

Elastin is Localised to the Interfascicular Matrix of Energy Storing Tendons and Becomes Increasingly Disorganised With Ageing

Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons; behaviour provided by specialisation of the IFM to enable repeated interfascicular sliding and recoil. With ageing, the IFM becomes stiffer and less fatigue resistant, potentially explaining why older tendons become more injury-prone. Recent data indicates enrichment of elastin within the IFM, but this has yet to be quantified. We hypothesised that elastin is more prevalent in energy storing than positional tendons, and is mainly localised to the IFM. Further, we hypothesised that elastin becomes disorganised and fragmented, and decreases in amount with ageing, especially in energy storing tendons. Biochemical analyses and immunohistochemical techniques were used to determine elastin content and organisation, in young and old equine energy storing and positional tendons. Supporting the hypothesis, elastin localises to the IFM of energy storing tendons, reducing in quantity and becoming more disorganised with ageing. These changes may contribute to the increased injury risk in aged energy storing tendons. Full understanding of the processes leading to loss of elastin and its disorganisation with ageing may aid in the development of treatments to prevent age related tendinopathy

The time and space of Richard Coudenhove-Kalergi’s Pan-Europe, 1923-1939

This thesis investigates the historical geographies of the Pan-European Union, and its founder and leader Count Richard Coudenhove-Kalergi, focusing in the main on the period from 1923 to 1939. A mixed-race Austrian aristocrat, philosopher and writer who made it his life’s mission to see Europe politically united, Coudenhove-Kalergi’s was a singular life, which he used to his advantage by weaving his life story into his political campaigning. The thesis opens by investigating the relationship between a life lived and a life told, and about the consequences for researchers attempting to recover his biography. The bulk of the thesis looks at the ways in which Pan-Europeanism both responded and itself contributed to shaping three broad sets of spatial and temporal ideas, each revolving around the notion of a supranational European polity. First, it confronts the way history was invoked both to bring into being a ‘literature’ that would add prestige to its arguments, and to craft a narrative arc that would add the force of apparent inevitability to its arguments. Second, it looks at the way in which Pan-Europeanism employed a form of spatial reasoning that shared many points of reference with the German school of geopolitik, despite a fundamentally incompatible view of international politics. And third, it analyses the Pan-European invention of ‘Eurafrica’ as a neo-colonial system that would offer a ‘third path’ internationalism that fell between the imperialism of the British Empire, and the Mandate-based theory of international governance advocated by the League. Each of these sets of ideas, I argue, persisted both outside the bounds of the Pan-European Union, and after its eventual marginalisation

Comparing alternating pressure mattresses and high-specification foam mattresses to prevent pressure ulcers in high-risk patients: the PRESSURE 2 RCT

Background: Pressure ulcers (PUs) are a burden to patients, carers and health-care providers. Specialist mattresses minimise the intensity and duration of pressure on vulnerable skin sites in at-risk patients. Primary objective: Time to developing a new PU of category ≥ 2 in patients using an alternating pressure mattress (APM) compared with a high-specification foam mattress (HSFM). Design: A multicentre, Phase III, open, prospective, planned as an adaptive double-triangular group sequential, parallel-group, randomised controlled trial with an a priori sample size of 2954 participants. Randomisation used minimisation (incorporating a random element). Setting: The trial was set in 42 secondary and community inpatient facilities in the UK. Participants: Adult inpatients with evidence of acute illness and at a high risk of PU development. Interventions and follow-up: APM or HSFM – the treatment phase lasted a maximum of 60 days; the final 30 days were post-treatment follow-up. Main outcome measures: Time to event. Results: From August 2013 to November 2016, 2029 participants were randomised to receive either APM (n = 1016) or HSFM (n = 1013). Primary end point – 30-day final follow-up: of the 2029 participants in the intention-to-treat population, 160 (7.9%) developed a new PU of category ≥ 2. There was insufficient evidence of a difference between groups for time to new PU of category ≥ 2 [Fine and Gray model HR 0.76, 95% confidence interval (CI) 0.56 to 1.04; exact p-value of 0.0890 and 2% absolute difference]. Treatment phase sensitivity analysis: 132 (6.5%) participants developed a new PU of category ≥ 2 between randomisation and end of treatment phase. There was a statistically significant difference in the treatment phase time-to-event sensitivity analysis (Fine and Gray model HR 0.66, 95% CI 0.46 to 0.93; p = 0.0176 and 2.6% absolute difference). Secondary end points – 30-day final follow-up: new PUs of category ≥ 1 developed in 350 (17.2%) participants, with no evidence of a difference between mattress groups in time to PU development, (Fine and Gray model HR 0.83, 95% CI 0.67 to 1.02; p-value = 0.0733 and absolute difference 3.1%). New PUs of category ≥ 3 developed in 32 (1.6%) participants with insufficient evidence of a difference between mattress groups in time to PU development (Fine and Gray model HR 0.81, 95% CI 0.40 to 1.62; p = 0.5530 and absolute difference 0.4%). Of the 145 pre-existing PUs of category 2, 89 (61.4%) healed – there was insufficient evidence of a difference in time to healing (Fine and Gray model HR 1.12, 95% CI 0.74 to 1.68; p = 0.6122 and absolute difference 2.9%). Health economics – the within-trial and long-term analysis showed APM to be cost-effective compared with HSFM; however, the difference in costs models are small and the quality-adjusted life-year gains are very small. There were no safety concerns. Blinded photography substudy – the reliability of central blinded review compared with clinical assessment for PUs of category ≥ 2 was ‘very good’ (kappa statistic 0.82, prevalence- and bias-adjusted kappa 0.82). Quality-of-life substudy – the Pressure Ulcer Quality of Life – Prevention (PU-QoL-P) instrument meets the established criteria for reliability, construct validity and responsiveness. Limitations: A lower than anticipated event rate. Conclusions: In acutely ill inpatients who are bedfast/chairfast and/or have a category 1 PU and/or localised skin pain, APMs confer a small treatment phase benefit that is diminished over time. Overall, the APM patient compliance, very low PU incidence rate observed and small differences between mattresses indicate the need for improved indicators for targeting of APMs and individualised decision-making. Decisions should take into account skin status, patient preferences (movement ability and rehabilitation needs) and the presence of factors that may be potentially modifiable through APM allocation, including being completely immobile, having nutritional deficits, lacking capacity and/or having altered skin/category 1 PU. Future work: Explore the relationship between mental capacity, levels of independent movement, repositioning and PU development. Explore ‘what works for whom and in what circumstances’. Trial registration: Current Controlled Trials ISRCTN01151335. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 52. See the NIHR Journals Library website for further project information

Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe

Mineralization can be an incidental ultrasonographic finding in equine tendons and ligaments

Tendon/ligament mineralization is recognized in horses but information regarding its clinical significance is limited. The aims of this observational study were to report the structures most commonly affected by ultrasonographically detectable mineralization and, for these, determine frequency of diagnosis and key clinical features. Cases presented at our hospital in April 1999–April 2013 and September 2014–November 2015 were included: a total of 27 horses (22 retrospective, five prospective). Mineralizations were most common in deep digital flexor tendons (10) and suspensory ligament branches (eight), representing 10% and 7% (estimated), respectively, of horses diagnosed with injuries to these structures during the study. Two deep digital flexor tendon and three suspensory ligament branch cases showed bilateral mineralization. Deep digital flexor tendon mineralization was restricted to the digital flexor tendon sheath, most commonly in the proximal sheath (±sesamoidean canal), and seven of 10 cases involved hindlimbs. Suspensory ligament branch mineralization was visible in the same ultrasound window as the proximal sesamoid bones in 10/11 limbs and six of eight cases involved forelimbs. Previous corticosteroid medication was a feature of one deep digital flexor tendon and one suspensory ligament branch case. Mineralization was associated with lameness in some but not all limbs. Mineralized foci within the deep digital flexor tendon preceded hypoechoic lesion formation in two limbs. Of the cases with deep digital flexor tendon or suspensory ligament branch injury only, one of three and two of three cases, respectively, became sound. Findings indicated that tendon/ligament mineralization can be associated with lameness in some horses, but can also be an incidental finding

Site-Specific Analysis of Inflammatory Markers in Discoid Lupus Erythematosus Skin

Prior studies identified T cells, B cells, and macrophages in the inflammatory infiltrate and up-regulation of their protein products in discoid lupus erythematosus (DLE) skin; however, they lacked rigorous analyses to define their specific locations in skin. Thus, we compared expressions of selected T cell, B cell, and macrophage markers in five areas of DLE, psoriasis, and normal skin. Immunostainings for CD3, CD4, CD8, CD20, CD68, CXCR3, CXCL10, and TIA-1 were performed in biopsies of 23 DLE lesional skin, 11 psoriasis lesional skin, and 5 normal skin. Three independent observers used a graded scale to rate each marker’s presence in the epidermis, dermatoepidermal junction (DEJ), perivascular area, periadnexal area, and deep dermis. DLE lesional skin contained an increased abundance of CD3+, CD8+, and CD68+ cells at the DEJ, and CD20+ and CD68+ cells in the periadnexal area versus psoriasis and normal skin. CXCR3, CXCL10, and TIA-1 were elevated in periadnexal sites of DLE lesional skin versus psoriasis lesional skin. The aggregation of T cells, B cells, macrophages, and their protein products (CXCR3, CXCL10, and TIA-1) in the DEJ and periadnexal area of DLE lesional skin may contribute to the pathology of DLE through a coordinated, sophisticated process