Effect of the Synthetic Bile Salt Analog CamSA on the Hamster Model of Clostridium difficile Infection

Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and has gained worldwide notoriety due to emerging hypervirulent strains and the high incidence of recurrence. We previously reported protection of mice from CDI using the antigerminant bile salt analog CamSA. Here we describe the effects of CamSA in the hamster model of CDI. CamSA treatment of hamsters showed no toxicity and did not affect the richness or diversity of gut microbiota; however, minor changes in community composition were observed. Treatment of C. difficile-challenged hamsters with CamSA doubled the mean time to death, compared to control hamsters. However, CamSA alone was insufficient to prevent CDI in hamsters. CamSA in conjunction with suboptimal concentrations of vancomycin led to complete protection from CDI in 70% of animals. Protected animals remained disease-free at least 30 days postchallenge and showed no signs of colonic tissue damage. In a delayed-treatment model of hamster CDI, CamSA was unable to prevent infection signs and death. These data support a putative model in which CamSA reduces the number of germinating C. difficile spores but does not keep all of the spores from germinating. Vancomycin halts division of any vegetative cells that are able to grow from spores that escape CamSA

Nonlinearization and waves in bounded media: old wine in a new bottle

We consider problems such as a standing wave in a closed straight tube, a self-sustained oscillation, damped resonance, evolution of resonance and resonance between concentric spheres. These nonlinear problems, and other similar ones, have been solved by a variety of techniques when it is seen that linear theory fails. The unifying approach given here is to initially set up the appropriate linear difference equation, where the difference is the linear travel time. When the linear travel time is replaced by a corrected nonlinear travel time, the nonlinear difference equation yields the required solution

Chronic Rhinosinusitis: Potential Role of Microbial Dysbiosis and Recommendations for Sampling Sites.

Chronic rhinosinusitis (CRS) is an inflammatory condition that affects up to 12% of the human population in developed countries. Previous studies examining the potential role of the sinus bacterial microbiota within CRS infections have found inconsistent results, possibly because of inconsistencies in sampling strategies. The aim of this study was to determine whether the sinus microbiome is altered in CRS and additionally if the middle meatus is a suitable representative site for sampling the sinus microbiome. Swab samples were collected from 12 healthy controls and 21 CRS patients, including all eight sinuses for CRS patients and between one and five sinuses for control subjects. The left and right middle meatus and nostril swabs were also collected. Significant differences in the sinus microbiomes between CRS and control samples were revealed using high-throughput 16S rRNA gene sequencing. The genus Escherichia was over-represented in CRS sinuses, and associations between control patients and Corynebacterium and Dolosigranulum were also identified. Comparisons of the middle meatuses between groups did not reflect these differences, and the abundance of the genus Escherichia was significantly lower at this location. Additionally, intra-patient variation was lower between sinuses than between sinus and middle meatus, which together with the above results suggests that the middle meatus is not an effective representative sampling site

The High Angular Resolution Multiplicity of Massive Stars

We present the results of a speckle interferometric survey of Galactic massive stars that complements and expands upon a similar survey made over a decade ago. The speckle observations were made with the KPNO and CTIO 4 m telescopes and USNO speckle camera, and they are sensitive to the detection of binaries in the angular separation regime between 0.03" and 5" with relatively bright companions (Delta V < 3). We report on the discovery of companions to 14 OB stars. In total we resolved companions of 41 of 385 O-stars (11%), 4 of 37 Wolf-Rayet stars (11%), and 89 of 139 B-stars (64%; an enriched visual binary sample that we selected for future orbital determinations). We made a statistical analysis of the binary frequency among the subsample that are listed in the Galactic O Star Catalog by compiling published data on other visual companions detected through adaptive optics studies and/or noted in the Washington Double Star Catalog and by collecting published information on radial velocities and spectroscopic binaries. We find that the binary frequency is much higher among O-stars in clusters and associations compared to the numbers for field and runaway O-stars, consistent with predictions for the ejection processes for runaway stars. We present a first orbit for the O-star Delta Orionis, a linear solution of the close, apparently optical, companion of the O-star Iota Orionis, and an improved orbit of the Be star Delta Scorpii. Finally, we list astrometric data for another 249 resolved and 221 unresolved targets that are lower mass stars that we observed for various other science programs.Comment: 76 pages, 6 figures, 11 table

Self-diffusion in dense granular shear flows

Diffusivity is a key quantity in describing velocity fluctuations in granular materials. These fluctuations are the basis of many thermodynamic and hydrodynamic models which aim to provide a statistical description of granular systems. We present experimental results on diffusivity in dense, granular shear in a 2D Couette geometry. We find that self-diffusivities are proportional to the local shear rate with diffusivities along the mean flow approximately twice as large as those in the perpendicular direction. The magnitude of the diffusivity is D \approx \dot\gamma a^2 where a is the particle radius. However, the gradient in shear rate, coupling to the mean flow, and drag at the moving boundary lead to particle displacements that can appear sub- or super-diffusive. In particular, diffusion appears superdiffusive along the mean flow direction due to Taylor dispersion effects and subdiffusive along the perpendicular direction due to the gradient in shear rate. The anisotropic force network leads to an additional anisotropy in the diffusivity that is a property of dense systems with no obvious analog in rapid flows. Specifically, the diffusivity is supressed along the direction of the strong force network. A simple random walk simulation reproduces the key features of the data, such as the apparent superdiffusive and subdiffusive behavior arising from the mean flow, confirming the underlying diffusive motion. The additional anisotropy is not observed in the simulation since the strong force network is not included. Examples of correlated motion, such as transient vortices, and Levy flights are also observed. Although correlated motion creates velocity fields qualitatively different from Brownian motion and can introduce non-diffusive effects, on average the system appears simply diffusive.Comment: 13 pages, 20 figures (accepted to Phys. Rev. E

The origins of redistributive policy preferences: political socialisation with and without a welfare state

Research on the impact of the macroeconomy on individual-level preferences for redistribution has produced varying results. This paper presents a new theory on the presence of an expansive welfare state during one’s formative years as a source of heterogeneity in the effect that macroeconomic conditions have on individuals’ preferences for redistributive policy. This theory is tested using cohort analysis via the British Social Attitudes surveys (1983–2010), with generations coming of age between the end of World War I and today. Findings confirm that cohorts that were socialised before and after the introduction of the welfare state react differently to economic crises: the former become less supportive of redistribution, while the latter become more supportive. The research sheds light on the long-term shifts of support for the welfare state due to generational replacement

External beam radiation therapy and enadenotucirev: inhibition of the DDR and mechanisms of radiation-mediated virus increase

Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production. We show that EnAd, an Ad3/Ad11p chimeric oncolytic adenovirus currently being trialled in colorectal and other cancers, targets the DDR pathway at a number of junctures. Infection is associated with a decrease in irradiation-induced 53BP1 and Rad51 foci formation, and in total DNA ligase IV levels. We also demonstrate a radiation-associated increase in EnAd production in vitro and in a pilot in vivo experiment. Given the current limitations of in vitro techniques in assessing for synergy between these treatments, we adapted the plaque assay to allow monitoring of viral plaque size and growth and utilised the xCELLigence cell adhesion assay to measure cytotoxicity. Our study provides further evidence on the interaction between adenovirus and radiation in vitro and in vivo and suggests these have at least an additive, and possibly a synergistic, impact on cytotoxicity

Efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute pain after orthopedic trauma: a practice management guideline from the Eastern Association for the Surgery of Trauma and the Orthopedic Trauma Association

OBJECTIVES: Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established. METHODS: Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The working group reached consensus on the final evidence-based recommendations. RESULTS: A total of 19 studies were identified for analysis. Not all outcomes identified as critically important were reported in all studies, and the outcome of pain control was too heterogenous to perform a meta-analysis. Nine studies reported on non-union (three randomized control trials), six of which reported no association with NSAIDs. The overall incidence of non-union in patients receiving NSAIDs compared with patients not receiving NSAIDs was 2.99% and 2.19% (p=0.04), respectively. Of studies reporting on pain control and reduction of opioids, the use of NSAIDs reduced pain and the need for opioids after traumatic fracture. One study reported on the outcome of acute kidney injury and found no association with NSAID use. CONCLUSIONS: In patients with traumatic fractures, NSAIDs appear to reduce post-trauma pain, reduce the need for opioids and have a small effect on non-union. We conditionally recommend the use of NSAIDs in patients suffering from traumatic fractures as the benefit appears to outweigh the small potential risks

Reptilian Heart Development And The Molecular Basis Of Cardiac Chamber Evolution

The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy(1-3). However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles(4-7)? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors(8,9). In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution

Support vector machines improve the accuracy of evaluation for the performance of laparoscopic training tasks

Despite technological advances in the tracking of surgical motions, automatic evaluation of laparoscopic skills remains remote. A new method is proposed that combines multiple discrete motion analysis metrics. This new method is compared with previously proposed metric combination methods and shown to provide greater ability for classifying novice and expert surgeons. For this study, 30 participants (four experts and 26 novices) performed 696 trials of three training tasks: peg transfer, pass rope, and cap needle. Instrument motions were recorded and reduced to four metrics. Three methods of combining metrics into a prediction of surgical competency (summed-ratios, z-score normalization, and support vector machine [SVM]) were compared. The comparison was based on the area under the receiver operating characteristic curve (AUC) and the predictive accuracy with a previously unseen validation data set. For all three tasks, the SVM method was superior in terms of both AUC and predictive accuracy with the validation set. The SVM method resulted in AUCs of 0.968, 0.952, and 0.970 for the three tasks compared respectively with 0.958, 0.899, and 0.884 for the next best method (weighted z-normalization). The SVM method correctly predicted 93.7, 91.3, and 90.0% of the subjects’ competencies, whereas the weighted z-normalization respectively predicted 86.6, 79.3, and 75.7% accurately (p &lt; 0.002). The findings show that an SVM-based analysis provides more accurate predictions of competency at laparoscopic training tasks than previous analysis techniques. An SVM approach to competency evaluation should be considered for computerized laparoscopic performance evaluation systems