Comparison of Glasgow Admission Prediction Score and Amb Score in predicting need for inpatient care.

AIM: We compared the abilities of two established clinical scores to predict emergency department (ED) disposition: the Glasgow Admission Prediction Score (GAPS) and the Ambulatory Score (Ambs). METHODS: The scores were compared in a prospective, multicentre cohort study. We recruited consecutive patients attending ED triage at two UK sites: Northern General Hospital in Sheffield and Glasgow Royal Infirmary, between February and May 2016. Each had a GAPS and Ambs calculated at the time of triage, with the triage nurses and treating clinicians blinded to the scores. Patients were followed up to hospital discharge. The ability of the scores to discriminate discharge from ED and from hospital at 12 and 48 hours after arrival was compared using the area under the curve (AUC) of their receiving-operator characteristics (ROC). RESULTS: 1424 triage attendances were suitable for analysis during the study period, of which 567 (39.8%) were admitted. The AUC for predicting admission was significantly higher for GAPS at 0.807 (95% CI 0.785 to 0.830), compared with 0.743 (95% CI 0.717 to 0.769) for Ambs, P12 hour and >48 hour. GAPS was also more accurate as a binary test, correctly predicting 1057 outcomes compared with 1004 for Ambs (74.2vs70.5%, P=0.012). CONCLUSION: The GAPS is a significantly better predictor of need for hospital admission than Ambs in an unselected ED population

Roche tomography of cataclysmic variables: I. artefacts and techniques

Roche tomography is a technique used for imaging the Roche-lobe filling secondary stars in cataclysmic variables (CVs). In order to interpret Roche tomograms correctly, one must determine whether features in the reconstruction are real, or due to statistical or systematic errors. We explore the effects of systematic errors using reconstructions of simulated datasets and show that systematic errors result in characteristic distortions of the final reconstructions that can be identified and corrected. In addition, we present a new method of estimating statistical errors on tomographic reconstructions using a Monte-Carlo bootstrapping algorithm and show this method to be much more reliable than Monte-Carlo methods which `jiggle' the data points in accordance with the size of their error bars.Comment: 11 pages, 8 figures. Accepted for publication in MNRA

Axions and their Relatives

A review of the status of axions and axion-like particles is given. Special attention is devoted to the recent results of the PVLAS collaboration, which are in conflict with the CAST data and with the astrophysical constraints. Solutions to the puzzle and the implications for new physics are discussed. The question of axion-like particles being dark matter is also addressed.Comment: Updated version of an invited talk at the Axion Training (CERN, December 2005). To appear as a Lecture Notes in Physics (Springer-Verlag), edited by B. Beltran, M. Kuster and G. Raffel

Multicentre, prospective observational study of the correlation between the Glasgow Admission Prediction Score and adverse outcomes

Objectives: To assess whether the Glasgow Admission Prediction Score (GAPS) is correlated with hospital length of stay, 6-month hospital readmission and 6-month all-cause mortality. This study represents a 6-month follow-up of patients who were included in an external validation of the GAPS’ ability to predict admission at the point of triage. Setting: Sampling was conducted between February and May 2016 at two separate emergency departments (EDs) in Sheffield and Glasgow. Participants: Data were collected prospectively at triage for consecutive adult patients who presented to the ED within sampling times. Any patients who avoided formal triage were excluded from the study. In total, 1420 patients were recruited. Primary outcomes: GAPS was calculated following triage and did not influence patient management. Length of hospital stay, hospital readmission and mortality against GAPS were modelled using survival analysis at 6 months. Results: Of the 1420 patients recruited, 39.6% of these patients were initially admitted to hospital. At 6 months, 30.6% of patients had been readmitted and 5.6% of patients had died. For those admitted at first presentation, the chance of being discharged fell by 4.3% (95% CI 3.2% to 5.3%) per GAPS point increase. Cox regression indicated a 9.2% (95% CI 7.3% to 11.1%) increase in the chance of 6-month hospital readmission per point increase in GAPS. An association between GAPS and 6-month mortality was demonstrated, with a hazard increase of 9.0% (95% CI 6.9% to 11.2%) for every point increase in GAPS. Conclusion: A higher GAPS is associated with increased hospital length of stay, 6-month hospital readmission and 6-month all-cause mortality. While GAPS’s primary application may be to predict admission and support clinical decision making, GAPS may provide valuable insight into inpatient resource allocation and bed planning

Nucleobase but not sugar fidelity is maintained in the Sabin I RNA-dependent RNA polymerase

The Sabin I poliovirus live, attenuated vaccine strain encodes for four amino acid changes (i.e., D53N, Y73H, K250E, and T362I) in the RNA-dependent RNA polymerase (RdRp). We have previously shown that the T362I substitution leads to a lower fidelity RdRp, and viruses encoding this variant are attenuated in a mouse model of poliovirus. Given these results, it was surprising that the nucleotide incorporation rate and nucleobase fidelity of the Sabin I RdRp is similar to that of wild-type enzyme, although the Sabin I RdRp is less selective against nucleotides with modified sugar groups. We suggest that the other Sabin amino acid changes (i.e., D53N, Y73H, K250E) help to re-establish nucleotide incorporation rates and nucleotide discrimination near wild-type levels, which may be a requirement for the propagation of the virus and its efficacy as a vaccine strain. These results also suggest that the nucleobase fidelity of the Sabin I RdRp likely does not contribute to viral attenuation

A polymerase mechanism-based strategy for viral attenuation and vaccine development

Live, attenuated vaccines have prevented morbidity and mortality associated with myriad viral pathogens. Development of live, attenuated vaccines has traditionally relied on empirical methods, such as growth in nonhuman cells. These approaches require substantial time and expense to identify vaccine candidates and to determine their mechanisms of attenuation. With these constraints, at least a decade is required for approval of a live, attenuated vaccine for use in humans. We recently reported the discovery of an active site lysine residue that contributes to the catalytic efficiency of all nucleic acid polymerases (Castro, C., Smidansky, E. D., Arnold, J. J., Maksimchuk, K. R., Moustafa, I., Uchida, A., Götte, M., Konigsberg, W., and Cameron, C. E. (2009) Nat. Struct. Mol. Biol. 16, 212-218). Here we use a model RNA virus and its polymerase to show that mutation of this residue from lysine to arginine produces an attenuated virus that is genetically stable and elicits a protective immune response. Given the conservation of this residue in all viral polymerases, this study suggests that a universal, mechanism-based strategy may exist for viral attenuation and vaccine development. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc

Vaccine-derived mutation in motif D of poliovirus RNA-dependent RNA polymerase lowers nucleotide incorporation fidelity

All viral RNA-dependent RNA polymerases (RdRps) have a conserved structural element termed motif D. Studies of the RdRp from poliovirus (PV) have shown that a conformational change of motifDleads to efficient and faithful nucleotide addition by bringing Lys-359 into the active site where it serves as a general acid. The RdRp of the Sabin I vaccine strain has Thr-362 changed to Ile. Such a drastic change so close to Lys-359 might alter RdRp function and contribute in some way to the attenuated phenotype of Sabin type I. Here we present our characterization of the T362I RdRp.Wefind that the T362I RdRp exhibits a mutator phenotype in biochemical experiments in vitro. Using NMR, we show that this change in nucleotide incorporation fidelity correlates with a change in the structural dynamics of motif D. A recombinant PV expressing the T362I RdRp exhibits normal growth properties in cell culture but expresses a mutator phenotype in cells. For example, the T362I-containing PV is more sensitive to the mutagenic activity of ribavirin than wildtype PV. Interestingly, the T362I change was sufficient to cause a statistically significant reduction in viral virulence. Collectively, these studies suggest that residues of motif D can be targeted when changes in nucleotide incorporation fidelity are desired. Given the observation that fidelity mutants can serve as vaccine candidates, it may be possible to use engineering of motif D for this purpose

DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo.

Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic

RNA virus population diversity, an optimum for maximal fitness and virulence

The ability of an RNA virus to exist as a population of genetically distinct variants permits the virus to overcome events during infections that would otherwise limit virus multiplication or drive the population to extinction. Viral genetic diversity is created by the ribonucleotide misincorporation frequency of the viral RNA-dependent RNA polymerase (RdRp). We have identified a poliovirus (PV) RdRp derivative (H273R) possessing a mutator phenotype. GMP misincorporation efficiency for H273R RdRp in vitro was increased by 2-3-fold that manifested in a 2-3-fold increase in the diversity of the H273R PV population in cells. Circular sequencing analysis indicated that some mutations were RdRp-independent. Consistent with the population genetics theory, H273R PV was driven to extinction more easily than WT in cell culture. Furthermore, we observed a substantial reduction in H273R PV virulence, measured as the ability to cause paralysis in the cPVR mouse model. Reduced virulence correlated with the inability of H273R PV to sustain replication in tissues/organs in which WT persists. Despite the attenuated phenotype, H273R PV was capable of replicating in mice to levels sufficient to induce a protective immune response, even when the infecting dose used was insufficient to elicit any visual signs of infection. We conclude that optimal RdRp fidelity is a virulence determinant that can be targeted for viral attenuation or antiviral therapies, and we suggest that the RdRp may not be the only source of mutations in a RNA virus genome

High-frequency A-type pulsators discovered using SuperWASP

We present the results of a survey using the WASP archive to search for high-frequency pulsations in F-, A- and B-type stars. Over 1.5 million targets have been searched for pulsations with amplitudes greater than 0.5 millimagnitude. We identify over 350 stars which pulsate with periods less than 30 min. Spectroscopic follow-up of selected targets has enabled us to confirm 10 new rapidly oscillating Ap stars, 13 pulsating Am stars and the fastest known δ Scuti star. We also observe stars which show pulsations in both the high-frequency domain and the low-frequency δ Scuti range. This work shows the power of the WASP photometric survey to find variable stars with amplitudes well below the nominal photometric precision per observation