Rationale and design of "Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)" study : A randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.Peer reviewedFinal Published versio

The monitoring of an existing cast iron tunnel with distributed fibre optic sensing (DFOS)

Instrumentation is vital to tunnelling projects for validation of design assumptions, monitoring of trigger levels during construction and also serving as a feedback loop to understand the deformation mechanisms of the particular problem which could be used to improve future designs. It can also be used for long term monitoring of the tunnel for maintenance purposes. Distributed fibre optic sensing (DFOS) systems based on brillouin optical time domain reflectometry are able to provide continuous and distributed strain measurements to be taken along the entire length of, for example, an existing cast iron tunnel where the fibre optic cable length is fully attached. This enables engineers to understand the stresses and strains that develop within the lining caused by external influences; which in this case, the construction of a new tunnel directly underneath it, rather than relying on discrete point measurements of displacement from conventional methods of monitoring. Nonetheless, proper installation of DFOS is of paramount importance to obtain high quality data. This paper aims to provide some practical guidance on the planning and installation of DFOS and presents a brief case study on the monitoring of London’s Royal Mail tunnel during the construction of the large Crossrail platform tunnel, located directly below it at Liverpool Street Station. It demonstrates the potential benefits of using such systems in complex tunnelling scenarios.The authors would like to gratefully note the contributions in the form of logistical and technical support from Crossrail (particularly Mike Black, Stephen Roberts, Alison Norrish and Chris Dulake), Royal Mail (particularly Mitch Harris), ARUP (particularly Mike Devriendt), CH2 M Hill (particularly Peter Wright). This project would not have been possible without the financial support from Laing O’Rourke for the first author’s PhD studentship as well as the continuous support from the UK Engineering and Physical Sciences Research Council (EPSRC) and Innovate UK through their funding of the Centre for Smart Infrastructure and Construction (CSIC) at Cambridge.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s13349-015-0109-

Monitoring the effects of tunnelling under an existing tunnel-fibre optics

Underground tunnel networks are at the heart of United Kingdom's infrastructure, carrying more than 1,100 million passengers each year along its 249 miles long network via 11 underground lines, serving 270 stations.With a complex existing underground rail network already in place; it is inevitable that new tunnels will be constructed within close proximity to existing tunnels. At London Liverpool Street Station, the new eastbound Crossrail platformtunnel was constructed underneath the existing Royal MailTunnel at a parallel alignment over a length of over 100m with a clear distance of less than 2m separating the two. Fibre optic strain sensing system based on Brillouin Optical Time Domain Reflectometry (BOTDR) was installed to measure continuous strain profiles of the cast iron linings of Royal Mail Tunnel. This has provided valuable insights to the deformation mechanisms both during the pilot and final tunnel enlargement. © 2014 Korean Geotechnical Society

BOTDR Distributed Fibre Optic Strain Sensing for the Monitoring of an Existing Cast Iron Tunnel

Constructing tunnels in highly congested urban cities is a challenge, as the construction will inevitably take place in close proximity to existing structures both above and below ground. As more tunnels are being constructed, it is inevitable that some tunnels will be constructed in close proximity to existing tunnels and monitoring of the existing tunnels in this case is paramount for the design and construction works. The discrete nature of conventional monitoring instrumentation requires significant interpolation and judgement in order to understand the overall behaviour of the tunnel itself. Subsequently, conservative design approaches will have to be adopted to cater for the gaps in knowledge, which could lead to unnecessary delays and high costs. Distributed fibre optic strain sensing systems based on Brillouin Optical Time Domain Reflectometry (BOTDR) could offer an alternative; in this paper a case study is presented where fibre optic cables were deployed to monitor the response of the cast iron Royal Mail tunnel in the vicinity of London Liverpool Street Station during the construction of Crossrail’s new platform tunnel directly below it. Single mode single core tight-buffered cables were attached directly to the intrados of the cast iron tunnel lining of the Royal Mail tunnel to understand its response during the construction works. This paper focuses on the challenges and considerations in deploying the fibre optic system in the tunnel and presents some of the data, which demonstrates the potential benefit of using such a system in real, complex tunnelling scenarios

BOTDR Distributed Fibre Optic Strain Sensing for the Monitoring of an Existing Cast Iron Tunnel

Constructing tunnels in highly congested urban cities is a challenge, as the construction will inevitably take place in close proximity to existing structures both above and below ground. As more tunnels are being constructed, it is inevitable that some tunnels will be constructed in close proximity to existing tunnels and monitoring of the existing tunnels in this case is paramount for the design and construction works. The discrete nature of conventional monitoring instrumentation requires significant interpolation and judgement in order to understand the overall behaviour of the tunnel itself. Subsequently, conservative design approaches will have to be adopted to cater for the gaps in knowledge, which could lead to unnecessary delays and high costs. Distributed fibre optic strain sensing systems based on Brillouin Optical Time Domain Reflectometry (BOTDR) could offer an alternative; in this paper a case study is presented where fibre optic cables were deployed to monitor the response of the cast iron Royal Mail tunnel in the vicinity of London Liverpool Street Station during the construction of Crossrail’s new platform tunnel directly below it. Single mode single core tight-buffered cables were attached directly to the intrados of the cast iron tunnel lining of the Royal Mail tunnel to understand its response during the construction works. This paper focuses on the challenges and considerations in deploying the fibre optic system in the tunnel and presents some of the data, which demonstrates the potential benefit of using such a system in real, complex tunnelling scenarios

Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype

Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis

Semiotricidad, representaciones cognitivas y enseñanza reflexiva

Este proyecto se propuso: Analizar y describir las representaciones cognitivas que los sujetos construyen durante su proceso de crecimiento, acerca de su propia habilidad motriz. Identificar y describir las relaciones entre las representaciones acerca de la propia habilidad motriz y la actuación semiotriz de los sujetos. Describir las relaciones entre las representaciones acerca de la propia habilidad, la actuación semiotriz y los procesos de socialización de los sujetos que participan del estudio. Analizar la incidencia del método de enseñanza reflexiva en los procesos de socialización, actuación semiotriz y constitución de representaciones sobre la propia habilidad motora.Panel: "Discursos y Prácticas Corporales"Departamento de Educación Físic

3D-Image analysis platform monitoring relocation of pluripotency genes during reprogramming

Nuclear organization of chromatin is an important level of genome regulation with positional changes of genes occurring during reprogramming. Inherent variability of biological specimens, wide variety of sample preparation and imaging conditions, though pose significant challenges to data analysis and comparison. Here, we describe the development of a computational image analysis toolbox overcoming biological variability hurdles by a novel single cell randomizing normalization. We performed a comparative analysis of the relationship between spatial positioning of pluripotency genes with their genomic activity and determined the degree of similarity between fibroblasts, induced pluripotent stem cells and embryonic stem cells. Our analysis revealed a preferred positioning of actively transcribed Sox2, Oct4 and Nanog away from the nuclear periphery, but not from pericentric heterochromatin. Moreover, in the silent state, we found no common nuclear localization for any of the genes. Our results suggest that the surrounding gene density hinders relocation from an internal nuclear position. Altogether, our data do not support the hypothesis that the nuclear periphery acts as a general transcriptional silencer, rather suggesting that internal nuclear localization is compatible with expression in pluripotent cells but not sufficient for expression in mouse embryonic fibroblasts. Thus, our computational approach enables comparative analysis of topological relationships in spite of stark morphological variability typical of biological data sets