COMPUTATIONAL MECHANICS OF THE SCLERA AND OPTIC NERVE HEAD (ONH): EFFECTS OF ONH SIZE AND PRESSURE RANGE

ABSTRACT Computational modeling was performed to study how loss of compliance of the eye and abnormally high pressures result in changes in stresses and strains that may impact the optic nerve in diseases such as glaucoma. Hemispherical finite element models of the eye were created in which scleral thickness varied from the equatorial region to the optic nerve head (ONH). Nonhomogeneous material properties were used to model the ONH as a continuous region softer than the adjacent sclera. The ONH and an adjacent buffer zone in the sclera were modeled with enough detail that the size of the ONH could be changed to account for variations observed in humans. The model was provided with appropriate dimensions typical of patients and nonlinear material properties with decreased compliance. Models with different ONH sizes were inflated in small steps to 55 mmHg (7.33 kPa), providing deformed configurations at intermediate pressures of 15, 30 and 45 mmHg, respectively. Color-coded maps of stress and strain components were rendered directly on deformed configurations of the eye model; and animations were produced that show both spatial and temporal variations of stresses and strains as internal pressure increases. Three-dimensional stresses and accompanying finite strains were similar for ONH sizes ranging form 1.5 to 2.5 mm in diameter. Stress and strain differences were estimated as pressure was increased from 15 to 25 mmHg, 30 to 40 mmHg, and 45 to 55 mmHg. Substantial changes occurred in stress and strain differences as the pressure range was varied with large changes occurring in the lowest pressure range for strain components and moderate increases in stress differences as pressures increase. INTRODUCTION High internal eye pressures associated with diseases such as glaucoma may contribute to elevated stresses in the sclera and increased deformation of the ONH. These mechanical factors may result in optic nerve damage emphasizing the need for detailed experimental studies correlated with realistic computational analysis under pathophysiologic conditions [1]

The wave and tidal resource of Scotland

As the marine renewable energy industry evolves, in parallel with an increase in the quantity of available data and improvements in validated numerical simulations, it is occasionally appropriate to re-assess the wave and tidal resource of a region. This is particularly true for Scotland - a leading nation that the international community monitors for developments in the marine renewable energy industry, and which has witnessed much progress in the sector over the last decade. With 7 leased wave and 17 leased tidal sites, Scotland is well poised to generate significant levels of electricity from its abundant natural marine resources. In this state-of-the-art review of Scotland's wave and tidal resource, we examine the theoretical and technical resource, and provide an overview of commercial progress. We also discuss issues that affect future development of the marine energy seascape in Scotland, applicable to other regions of the world, including the potential for developing lower energy sites, and grid connectivity

Adapting realist synthesis methodology: The case of workplace harassment interventions

Realist synthesis techniques can be used to assess complex interventions by extracting and synthesizing configurations of contexts, mechanisms, and outcomes found in the literature. Our novel and multi‐pronged approach to the realist synthesis of workplace harassment interventions describes our pursuit of theory to link macro and program level theories. After discovering the limitations of a dogmatic approach to realist synthesis, we adapted our search strategy and focused our analysis on a subset of data. We tailored our realist synthesis to understand how, why, and under what circumstances workplace harassment interventions are effective. The result was a conceptual framework to test our theory‐based interventions and provide the basis for subsequent realist evaluation. Our experience documented in this article contributes to an understanding of how, under what circumstances, and with what consequences realist synthesis principles can be customized

Towards a peri-urban political ecology of water quality decline

Recent years have witnessed an expanding body of peri-urban and urban scholarship. However, recent scholarship has yet to adequately address the central role of politics and power shaping water quality decline. The article focuses on the trans-Hindon region which is part of Ghaziabad city, close to India’s capital, Delhi. We draw upon urban political ecology and peri-urban scholarship to explain the role of politics and power shaping water quality decline. We argue in favour of creating stronger synergy between peri-urban and UPE debates as part of conceptualising water quality decline. The article shows that as a complex socio-political challenge, water quality decline is centrally shaped by the intensifying linkages between urban and peri-urban forms of development and as a result deserves central attention as part of both these debates

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

A Phase I Study of Ad5-GUCY2C-PADRE in Stage I and II Colon Cancer Patients

Background Ad5-GUCY2C-PADRE is a replication-deficient human type 5 recombinant adenovirus (Ad5) vaccine encoding guanylyl cyclase C (GUCY2C) fused to the PAn DR Epitope (PADRE). GUCY2C, a paracrine hormone receptor producing the second messenger cyclic GMP (cGMP), is selectively expressed by intestinal epithelial cells and a subset of hypothalamic neurons, but not other tissues. Importantly, GUCY2C is over-expressed in nearly all primary and metastatic human colorectal tumors. Preclinical studies in mice demonstrated selective tolerance of GUCY2C-specific CD4+ T cells, but not CD8+ T or B cells, necessitating inclusion of the exogenous CD4+ T helper cell epitope PADRE to maximize GUCY2C-specific CD8+ T-cell and antibody responses and antitumor efficacy, without autoimmunity. Patients and Methods This is an open-label, single arm “proof-of-concept” study evaluating a single dose level of Ad5-GUCY2C-PADRE as a vaccine for surgically-treated, node-negative colon cancer subjects (NCT01972737). Patients received a single intramuscular administration of 1011 Ad5-GUCY2C-PADRE viral particles. Safety and immunomonitoring were examined at 30, 90 and 180 days following vaccination. Primary objectives were to determine the safety, tolerability, and toxicity of Ad5-GUCY2C-PADRE and to determine whether Ad5- GUCY2C-PADRE induces GUCY2C-specific immune responses. The study employed a joint efficacy-toxicity design and included stopping rules for either efficacy or toxicity.Results here were obtained during the planned interim analysis following accrual of 10 subjects. Results The vaccine was well tolerated, producing only mild adverse events (AEs). Short-lived injection site pain/swelling, body aches, and chills were the most commonly observed AEs and occurred in 30-40% of subjects. GUCY2C-specific antibody and T-cell responses were observed in a subset of subjects. Consistent with preclinical mouse data, T-cell responses were composed of CD8+, but not CD4+, T cells. Importantly, GUCY2C-specific responses occurred only in subjects with low Ad5 neutralizing antibody (NAb) titers at the time of vaccination, suggesting that pre-existing Ad5 immunity limits Ad5-GUCY2C-PADRE immunogenicity. Conclusions Interim analysis of 10 subjects receiving Ad5-GUCY2C-PADRE demonstrates proof-of-concept that GUCY2C is immunogenic in humans and that GUCY2C-directed vaccination is safe. Moreover, the presence of GUCY2C-specific antibody and CD8+ T-cell, but not CD4+ T-cell, responses is consistent with selective CD4+ T-cell tolerance observed in mouse models. These data establish GUCY2C as a safe and immunogenic target for immunotherapy in cancer patients. Poster presented at: Immunotherapy of Cancer (SITC) 30th Annual Meeting in National Harbor Maryland.https://jdc.jefferson.edu/petposters/1001/thumbnail.jp

Creating a model of diseased artery damage and failure from healthy porcine aorta

Large quantities of diseased tissue are required in the research and development of new generations of medical devices, for example for use in physical testing. However, these are difficult to obtain. In contrast, porcine arteries are readily available as they are regarded as waste. Therefore, reliable means of creating from porcine tissue physical models of diseased human tissue that emulate well the associated mechanical changes would be valuable. To this end, we studied the effect on mechanical response of treating porcine thoracic aorta with collagenase, elastase and glutaraldehyde. The alterations in mechanical and failure properties were assessed via uniaxial tension testing. A constitutive model composed of the Gasser-Ogden-Holzapfel model, for elastic response, and a continuum damage model, for the failure, was also employed to provide a further basis for comparison (Calvo and Pena, 2006 and Gasser et al., 2006). For the concentrations used here it was found that: collagenase treated samples showed decreased fracture stress in the axial direction only; elastase treated samples showed increased fracture stress in the circumferential direction only; and glutaraldehyde samples showed no change in either direction. With respect to the proposed constitutive model, both collagenase and elastase had a strong effect on the fibre-related terms. The model more closely captured the tissue response in the circumferential direction, due to the smoother and sharper transition from damage initiation to complete failure in this direction. Finally, comparison of the results with those of tensile tests on diseased tissues suggests that these treatments indeed provide a basis for creation of physical models of diseased arteries