Focus on quality in healthcare in Ireland.

PURPOSE: The purpose of this paper is to summarise the recent debates and issues on the healthcare system in Ireland, which have come to the fore through media exposure. The implications for these debates on quality are suggested and questions are raised to stimulate further debate. DESIGN/METHODOLOGY/APPROACH: Recent reports and media opinion articles are reviewed in the light of the health reform programme and the increased prosperity due to the Celtic Tiger era in Ireland. FINDINGS: The Health Service in Ireland is not what it should be. Progress has been made but resistance at all levels is significant due to the mistrust and miscommunication between the managerial and clinical personnel which have built up during the past number of years. The trust of the public is at an all-time low. However, once patients are within the system they are satisfied with their care. ORIGINALITY/VALUE: This is a discussion paper which raises more questions than answers and is timely with the focus on quality in healthcare, particularly now as Ireland prepares for a general election for a new government with healthcare a priority issue

The Properties of Brightest Cluster Galaxies in X-Ray Selected Clusters

We present the K-band Hubble diagram for 162 brightest cluster galaxies (BCGs) in X-ray selected clusters, 0.01<z<0.83. The sample incorporates that of Burke, Collins, & Mann (2000) and includes additional infrared data from the 2MASS extended source catalogue. We show that below z=0.1 the BCGs show no correlation with their environment, however, above z=0.1 BCGs in more X-ray luminous clusters are more uniform in their photometric properties. This suggests that there may be two populations of BCGs which have different evolutionary histories.Comment: 2 pages, to appear in the proceedings of the Sesto 2001 conference on tracing cosmic evolution with galaxy cluster

Risk factors associated with Rift Valley fever epidemics in South Africa in 2008-11.

Rift Valley fever (RVF) is a zoonotic and vector-borne disease, mainly present in Africa, which represents a threat to human health, animal health and production. South Africa has experienced three major RVF epidemics (1950-51, 1973-75 and 2008-11). Due to data scarcity, no previous study has quantified risk factors associated with RVF epidemics in animals in South Africa. Using the 2008-11 epidemic datasets, a retrospective longitudinal study was conducted to identify and quantify spatial and temporal environmental factors associated with RVF incidence. Cox regressions with a Besag model to account for the spatial effects were fitted to the data. Coefficients were estimated by Bayesian inference using integrated nested Laplace approximation. An increase in vegetation density was the most important risk factor until 2010. In 2010, increased temperature was the major risk factor. In 2011, after the large 2010 epidemic wave, these associations were reversed, potentially confounded by immunity in animals, probably resulting from earlier infection and vaccination. Both vegetation density and temperature should be considered together in the development of risk management strategies. However, the crucial need for improved access to data on population at risk, animal movements and vaccine use is highlighted to improve model predictions

The XMM Cluster Survey: The Dynamical State of XMMXCS J2215.9-1738 at z=1.457

We present new spectroscopic observations of the most distant X-ray selected galaxy cluster currently known, XMMXCS J2215.9-1738 at z=1.457, obtained with the DEIMOS instrument at the W. M. Keck Observatory, and the FORS2 instrument on the ESO Very Large Telescope. Within the cluster virial radius, as estimated from the cluster X-ray properties, we increase the number of known spectroscopic cluster members to 17 objects, and calculate the line of sight velocity dispersion of the cluster to be 580+/-140 km/s. We find mild evidence that the velocity distribution of galaxies within the virial radius deviates from a single Gaussian. We show that the properties of J2215.9-1738 are inconsistent with self-similar evolution of local X-ray scaling relations, finding that the cluster is underluminous given its X-ray temperature, and that the intracluster medium contains ~2-3 times the kinetic energy per unit mass of the cluster galaxies. These results can perhaps be explained if the cluster is observed in the aftermath of an off-axis merger. Alternatively, heating of the intracluster medium through supernovae and/or Active Galactic Nuclei activity, as is required to explain the observed slope of the local X-ray luminosity-temperature relation, may be responsible.Comment: 13 pages, 6 figures, accepted for publication in Ap

Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping.

Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 1040 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as 'warm spots' for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources. This article is part of the theme issue 'Fifty years of synchrotron science: achievements and opportunities'.The Botnar Foundation (grant number: 6063), the Cystic Fibrosis Trust (Strategic Research Centre Awards 002, 010 & 201) and the Bill and Melinda Gates Foundation, Shorten-TB Award

Variable expression and silencing of CRISPR-Cas9 targeted transgenes identifies the AAVS1 locus as not an entirely safe harbour

Background: Diseases such as hypertrophic cardiomyopathy (HCM) can lead to severe outcomes including sudden death. The generation of human induced pluripotent stem cell (hiPSC) reporter lines can be useful for disease modelling and drug screening by providing physiologically relevant in vitro models of disease. The AAVS1 locus is cited as a safe harbour that is permissive for stable transgene expression, and hence is favoured for creating gene targeted reporter lines. Methods: We generated hiPSC reporters using a plasmid-based CRISPR/Cas9 nickase strategy. The first intron of PPP1R12C, the AAVS1 locus, was targeted with constructs expressing a genetically encoded calcium indicator (R-GECO1.0) or HOXA9-T2A-mScarlet reporter under the control of a pCAG or inducible pTRE promoter, respectively. Transgene expression was compared between clones before, during and/or after directed differentiation to mesodermal lineages. Results: Successful targeting to AAVS1 was confirmed by PCR and sequencing. Of 24 hiPSC clones targeted with pCAG-R-GECO1.0, only 20 expressed the transgene and in these, the percentage of positive cells ranged from 0% to 99.5%. Differentiation of a subset of clones produced cardiomyocytes, wherein the percentage of cells positive for R-GECO1.0 ranged from 2.1% to 93.1%. In the highest expressing R-GECO1.0 clones, transgene silencing occurred during cardiomyocyte differentiation causing a decrease in expression from 98.93% to 1.3%. In HOXA9-T2A-mScarlet hiPSC reporter lines directed towards mesoderm lineages, doxycycline induced a peak in transgene expression after two days but this reduced by up to ten-thousand-fold over the next 8-10 days. Nevertheless, for R-GECO1.0 lines differentiated into cardiomyocytes, transgene expression was rescued by continuous puromycin drug selection, which allowed the Ca 2+ responses associated with HCM to be investigated in vitro using single cell analysis. Conclusions: Targeted knock-ins to AAVS1 can be used to create reporter lines but variability between clones and transgene silencing requires careful attention by researchers seeking robust reporter gene expression

The XMM Cluster Survey: Evidence for energy injection at high redshift from evolution of the X-ray luminosity-temperature relation

We measure the evolution of the X-ray luminosity-temperature (L_X-T) relation since z~1.5 using a sample of 211 serendipitously detected galaxy clusters with spectroscopic redshifts drawn from the XMM Cluster Survey first data release (XCS-DR1). This is the first study spanning this redshift range using a single, large, homogeneous cluster sample. Using an orthogonal regression technique, we find no evidence for evolution in the slope or intrinsic scatter of the relation since z~1.5, finding both to be consistent with previous measurements at z~0.1. However, the normalisation is seen to evolve negatively with respect to the self-similar expectation: we find E(z)^{-1} L_X = 10^{44.67 +/- 0.09} (T/5)^{3.04 +/- 0.16} (1+z)^{-1.5 +/- 0.5}, which is within 2 sigma of the zero evolution case. We see milder, but still negative, evolution with respect to self-similar when using a bisector regression technique. We compare our results to numerical simulations, where we fit simulated cluster samples using the same methods used on the XCS data. Our data favour models in which the majority of the excess entropy required to explain the slope of the L_X-T relation is injected at high redshift. Simulations in which AGN feedback is implemented using prescriptions from current semi-analytic galaxy formation models predict positive evolution of the normalisation, and differ from our data at more than 5 sigma. This suggests that more efficient feedback at high redshift may be needed in these models.Comment: Accepted for publication in MNRAS; 12 pages, 6 figures; added references to match published versio