The impact of vancomycin susceptibility on treatment outcomes among patients with methicillin resistant Staphylococcus aureus bacteremia

<p>Abstract</p> <p>Background</p> <p>Management of methicillin-resistant <it>Staphylococcus aureus </it>(MRSA) bacteremia remains a challenge. The emergence of MRSA strains with reduced vancomycin susceptibility complicates treatment.</p> <p>Methods</p> <p>A prospective cohort study (2005-2007) of patients with MRSA bacteremia treated with vancomycin was performed at an academic hospital. Vancomycin minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for stored MRSA isolates. Cox regression analysis was performed to predict 28-day all-cause mortality.</p> <p>Results</p> <p>One hundred sixty-three patients with MRSA bacteremia were evaluated. One hundred twelve patients (68.7%) had bacteremia due to MRSA with a vancomycin MIC ≥ 2 <it>ug</it>/mL. Among strains with a vancomycin MIC ≥ 2 <it>ug</it>/mL, 10 isolates (8.9%) were vancomycin-intermediate <it>S. aureus </it>(VISA). Thirty-five patients (21.5%) died within 28 days after the diagnosis of MRSA bacteremia. Higher vancomycin MIC was not associated with mortality in this cohort [adjusted hazard ratio (aHR), 1.57; 95% confidence interval (CI), 0.73-3.37]. Vancomycin tolerance was observed in 4.3% (7/162) of isolates and was not associated with mortality (crude HR, 0.62; 95% CI, 0.08-4.50). Factors independently associated with mortality included higher age (aHR, 1.03; 95% CI 1.00-1.05), cirrhosis (aHR, 3.01; 95% CI, 1.24-7.30), and intensive care unit admission within 48 hours after the diagnosis of bacteremia (aHR, 5.99; 95% CI, 2.86-12.58).</p> <p>Conclusions</p> <p>Among patients with MRSA bacteremia treated with vancomycin, reduced vancomycin susceptibility and vancomycin tolerance were not associated with mortality after adjusting for patient factors. Patient factors including severity of illness and underlying co-morbidities were associated with the mortality.</p

Sonic hedgehog signalling mediates astrocyte crosstalk with neurons to confer neuroprotection

Sonic hedgehog (SHH) is a glycoprotein associated with development that is also expressed in the adult CNS and released after brain injury. Since the SHH receptors patched homolog-1 and Smoothened are highly expressed on astrocytes, we hypothesized that SHH regulates astrocyte function. Primary mouse cortical astrocytes derived from embryonic Swiss mouse cortices, were treated with two chemically distinct agonists of the SHH pathway, which caused astrocytes to elongate and proliferate. These changes are accompanied by decreases in the major astrocyte glutamate transporter-1 and the astrocyte intermediate filament protein glial fibrillary acidic protein. Multisite electrophysiological recordings revealed that the SHH agonist, smoothened agonist suppressed neuronal firing in astrocyte-neuron co-cultures and this was abolished by the astrocyte metabolic inhibitor ethylfluoroacetate, revealing that SHH stimulation of metabolically active astrocytes influences neuronal firing. Using three-dimensional co-culture, MAP2 western blotting and immunohistochemistry, we show that SHH-stimulated astrocytes protect neurons from kainate-induced cell death. Altogether the results show that SHH regulation of astrocyte function represents an endogenous neuroprotective mechanism

Detection of lensing substructure using ALMA observations of the dusty galaxy SDP.81

We study the abundance of substructure in the matter density near galaxies using ALMA Science Verification observations of the strong lensing system SDP.81. We present a method to measure the abundance of subhalos around galaxies using interferometric observations of gravitational lenses. Using simulated ALMA observations, we explore the effects of various systematics, including antenna phase errors and source priors, and show how such errors may be measured or marginalized. We apply our formalism to ALMA observations of SDP.81. We find evidence for the presence of a $M=10^{8.96\pm 0.12} M_{\odot}$ subhalo near one of the images, with a significance of $6.9\sigma$ in a joint fit to data from bands 6 and 7; the effect of the subhalo is also detected in both bands individually. We also derive constraints on the abundance of dark matter subhalos down to $M\sim 2\times 10^7 M_{\odot}$, pushing down to the mass regime of the smallest detected satellites in the Local Group, where there are significant discrepancies between the observed population of luminous galaxies and predicted dark matter subhalos. We find hints of additional substructure, warranting further study using the full SDP.81 dataset (including, for example, the spectroscopic imaging of the lensed carbon monoxide emission). We compare the results of this search to the predictions of $\Lambda$CDM halos, and find that given current uncertainties in the host halo properties of SDP.81, our measurements of substructure are consistent with theoretical expectations. Observations of larger samples of gravitational lenses with ALMA should be able to improve the constraints on the abundance of galactic substructure.Comment: 18 pages, 13 figures, Comments are welcom

Effect of genotype × alcoholism interaction on linkage analysis of an alcoholism-related quantitative phenotype

Studies have shown that genetic and environmental factors and their interactions affect several alcoholism phenotypes. Genotype × alcoholism (G×A) interaction refers to the environmental (alcoholic and non-alcoholic) influences on the autosomal genes contributing to variation in an alcoholism-related quantitative phenotype. The purpose of this study was to examine the effects of G×A interaction on the detection of linkage for alcoholism-related phenotypes. We used phenotypic and genotypic data from the Collaborative Study on the Genetics of Alcoholism relating to 1,388 subjects as part of Genetic Analysis Workshop 14 problem 1. We analyzed the MXDRNK phenotype to detect G×A interaction using SOLAR. Upon detecting significant interaction, we conducted variance-component linkage analyses using microsatellite marker data. For maximum number of drinks per a 24 hour period, the highest LODs were observed on chromosomes 1, 4, and 13 without G×A interaction. Interaction analysis yielded four regions on chromosomes 1, 4, 13, and 15. On chromosome 4, a maximum LOD of 1.5 at the same location as the initial analysis was obtained after incorporating G×A interaction effects. However, after correcting for extra parameters, the LOD score was reduced to a corrected LOD of 1.1, which is similar to the LOD observed in the non-interaction analysis. Thus, we see little differences in LOD scores, while some linkage regions showed large differences in the magnitudes of estimated quantitative trait loci heritabilities between the alcoholic and non-alcoholic groups. These potential hints of differences in genetic effect may influence future analyses of variants under these linkage peaks

Cosmic Ray Acceleration at the Forward Shock in Tycho's Supernova Remnant: Evidence from Chandra X-ray Observations

We present evidence for cosmic ray acceleration at the forward shock in Tycho's supernova remnant (SNR) from three X-ray observables: (1) the proximity of the contact discontinuity to the forward shock, or blast wave, (2) the morphology of the emission from the rim of Tycho, and (3) the spectral nature of the rim emission. We determine the locations of the blast wave (BW), contact discontinuity (CD), and reverse shock (RS) around the rim of Tycho's supernova remnant using a principal component analysis and other methods applied to new Chandra data. The azimuthal-angle-averaged radius of the BW is 251". For the CD and RS we find average radii of 241" and 183", respectively. Taking account of projection effects, we find ratios of 1:0.93:0.70 (BW:CD:RS). We show these values to be inconsistent with adiabatic hydrodynamical models of SNR evolution. The CD:BW ratio can be explained if cosmic ray acceleration of ions is occurring at the forward shock. The RS:BW ratio, as well as the strong Fe Ka emission from the Tycho ejecta, imply that the RS is not accelerating cosmic rays. We also extract radial profiles from ~34% of the rim of Tycho and compare them to models of surface brightness profiles behind the BW for a purely thermal plasma with an adiabatic shock. The observed morphology of the rim is much more strongly peaked than predicted by the model, indicating that such thermal emission is implausible here. Spectral analysis also implies that the rim emission is non-thermal in nature, lending further support to the idea that Tycho's forward shock is accelerating cosmic rays.Comment: 39 pages, 10 figures, accepted by Ap

Induced mannosidosis-excretion of oligosaccharides by locoweed-intoxicated sheep

AbstractDaily urine samples were collected from a locoweed-fed sheep, and the oligosaccharide content examined by thin-layer and liquid chromatography. An unusual pattern of urine oligosaccharides was observed, which appears to be characteristic of loco intoxication. Changes in the pattern could be correlated with the onset of visible disease, which occurred approximately 5 weeks after the typical urine sugars were first detected. HPLC showed that these sugars consisted of two homologous series of oligosaccharides containing one and two residues of 2-acetamido-2-deoxy-D-glucose, respectively

An integrated biochemical prediction model of all-cause mortality in patients undergoing lower extremity bypass surgery for advanced peripheral artery disease

BackgroundPatients with advanced peripheral artery disease (PAD) have a high prevalence of cardiovascular (CV) risk factors and shortened life expectancy. However, CV risk factors poorly predict midterm (<5 years) mortality in this population. This study tested the hypothesis that baseline biochemical parameters would add clinically meaningful predictive information in patients undergoing lower extremity bypass operations.MethodsThis was a prospective cohort study of patients with clinically advanced PAD undergoing lower extremity bypass surgery. The Cox proportional hazard model was used to assess the main outcome of all-cause mortality. A clinical model was constructed with known CV risk factors, and the incremental value of the addition of clinical chemistry, lipid assessment, and a panel of 11 inflammatory parameters was investigated using the C statistic, the integrated discrimination improvement index, and Akaike information criterion.ResultsThe study monitored 225 patients for a median of 893 days (interquartile range, 539-1315 days). In this study, 50 patients (22.22%) died during the follow-up period. By life-table analysis (expressed as percent surviving ± standard error), survival at 1, 2, 3, 4, and 5 years, respectively, was 90.5% ± 1.9%, 83.4% ± 2.5%, 77.5% ± 3.1%, 71.0% ± 3.8%, and 65.3% ± 6.5%. Compared with survivors, decedents were older, diabetic, had extant coronary artery disease, and were more likely to present with critical limb ischemia as their indication for bypass surgery (P < .05). After adjustment for the above, clinical chemistry and inflammatory parameters significant (hazard ratio [95% confidence interval]) for all-cause mortality were albumin (0.43 [0.26-0.71]; P = .001), estimated glomerular filtration rate (0.98 [0.97-0.99]; P = .023), high-sensitivity C-reactive protein (hsCRP; 3.21 [1.21-8.55]; P = .019), and soluble vascular cell adhesion molecule (1.74 [1.04-2.91]; P = .034). Of the inflammatory molecules investigated, hsCRP proved most robust and representative of the integrated inflammatory response. Albumin, eGFR, and hsCRP improved the C statistic and integrated discrimination improvement index beyond that of the clinical model and produced a final C statistic of 0.82.ConclusionsA risk prediction model including traditional risk factors and parameters of inflammation, renal function, and nutrition had excellent discriminatory ability in predicting all-cause mortality in patients with clinically advanced PAD undergoing bypass surgery