Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment. Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions. Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018

Watching dark solitons decay into vortex rings in a Bose-Einstein condensate

We have created spatial dark solitons in two-component Bose-Einstein condensates in which the soliton exists in one of the condensate components and the soliton nodal plane is filled with the second component. The filled solitons are stable for hundreds of milliseconds. The filling can be selectively removed, making the soliton more susceptible to dynamical instabilities. For a condensate in a spherically symmetric potential, these instabilities cause the dark soliton to decay into stable vortex rings. We have imaged the resulting vortex rings.Comment: 4 pages, 4 figure

Density-Functional Theory of Quantum Freezing: Sensitivity to Liquid-State Structure and Statistics

Density-functional theory is applied to compute the ground-state energies of quantum hard-sphere solids. The modified weighted-density approximation is used to map both the Bose and the Fermi solid onto a corresponding uniform Bose liquid, assuming negligible exchange for the Fermi solid. The required liquid-state input data are obtained from a paired phonon analysis and the Feynman approximation, connecting the static structure factor and the linear response function. The Fermi liquid is treated by the Wu-Feenberg cluster expansion, which approximately accounts for the effects of antisymmetry. Liquid-solid transitions for both systems are obtained with no adjustment of input data. Limited quantitative agreement with simulation indicates a need for further improvement of the liquid-state input through practical alternatives to the Feynman approximation.Comment: IOP-TeX, 21 pages + 7 figures, to appear, J. Phys.: Condens. Matte

Collective oscillations of two colliding Bose-Einstein condensates

Two 87Rb condensates (F=2, m_f=2 and m_f=1) are produced in highly displaced harmonic traps and the collective dynamical behaviour is investigated. The mutual interaction between the two condensates is evidenced in the center-of-mass oscillations as a frequency shift of 6.4(3)%. Calculations based on a mean-field theory well describe the observed effects of periodical collisions both on the center-of-mass motion and on the shape oscillations.Comment: 5 pages, 3 figures, revtex - revised versio

Factors Influencing Appropriate Firing of the Implanted Defibrillator for Ventricular Tachycardia/Fibrillation Findings From the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)

ObjectivesThe purpose of this study was to prospectively examine the role of clinical, laboratory, echocardiographic, and electrophysiological variables as predictors of appropriate initial implantable cardioverter-defibrillator (ICD) therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) or death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) population.BackgroundThere is limited information regarding the determinants of appropriate ICD therapy in patients with reduced ventricular function after a myocardial infarction.MethodsWe used secondary analysis in one arm of a multicenter randomized clinical trial in patients with a previous myocardial infarction and reduced left ventricular function.ResultsWe analyzed baseline and follow-up data on 719 patients enrolled in the ICD arm of the MADIT-II study. Appropriate ICD therapy was observed in 169 subjects. Clinical, laboratory, echocardiographic, and electrophysiological variables, along with measures of clinical instability such as interim hospitalization for congestive heart failure (IH-CHF) and interim hospitalization for coronary events (IH-CE), were examined with proportional hazards models and Kaplan-Meier time-to-event curves before and after first interim hospitalization. Interim hospitalization-CHF, IH-CE, no beta-blockers, digitalis use, blood urea nitrogen (BUN) >25, body mass index (BMI) ≥30 kg/m2, and New York Heart Association functional class >II were associated with increased risk for appropriate ICD therapy for VT, VF, or death. In a multivariate (stepwise selection) analysis, IH-CHF was associated with an increased risk for the end point of either VT or VF (hazard ratio [HR] 2.52, 95% confidence interval [CI] 1.69 to 3.74, p < 0.001) and for the combined end point of VT, VF, or death (HR 2.97, 95% CI 2.15 to 4.09, p < 0.001). Interim hospitalization-CE was associated with an increased risk for VT, VF, or death (HR 1.66, 95% CI 1.09 to 2.52, p = 0.02).ConclusionsThese results provide important mechanistic information, suggesting that worsening clinical condition and cardiac instability, as reflected by an IH-CHF or IH-CE, are subsequently associated with a significant increase in the risk for appropriate ICD therapy (for VT/VF) and death

Observation of metastable states in spinor Bose-Einstein condensates

Bose-Einstein condensates have been prepared in long-lived metastable excited states. Two complementary types of metastable states were observed. The first is due to the immiscibility of multiple components in the condensate, and the second to local suppression of spin-relaxation collisions. Relaxation via re-condensation of non-condensed atoms, spin relaxation, and quantum tunneling was observed. These experiments were done with F=1 spinor Bose-Einstein condensates of sodium confined in an optical dipole trap.Comment: 3 figures included in paper, fourth figure separat

Personal values, social capital, and higher education student career decidedness: a new 'protean'-informed model

This study investigates the role of personal values as motivational antecedents for understanding HE student career decidedness among university business school (UBS) students. We propose a new ‘protean’ informed HE student career decidedness model for theorizing how both personal values and social capital mediators (student social capital; personal, social and enterprise skills; access to resources) help in the student-centric and self-directed processes of career decision-making. A mixed methods study combines a (stage 1) survey of 308 UBS students from five (UK) university business schools, with results from (stage 2) four student focus groups, and (stage 3) two staff-student interactive seminars. From an employability perspective, arguably, the ultimate responsibility for becoming a ‘protean graduate’ rests with each UBS student, whilst the obligation of HE staff is to effectively facilitate and nurture all possible personal growth and skills development opportunities

Gamma-rays from cascades in close massive binaries containing energetic pulsars

Some massive binaries should contain energetic pulsars which inject relativistic leptons from their inner magnetospheres and/or pulsar wind regions. If the binary system is compact enough, then these leptons can initiate inverse Compton (IC) $e^\pm$ pair cascades in the anisotropic radiation field of a massive star. $\gamma$-rays can be produced in the IC cascade during its development in a pulsar wind region and above a shock in a massive star wind region where the propagation of leptons is determined by the structure of a magnetic field around the massive star. For a binary system with specific parametres, we calculate phase dependent spectra and fluxes of $\gamma$-rays escaping as a function of the inclination angle of the system and for different assumptions on injection conditions of the primary leptons (their initial spectra and location of the shock inside the binary). We conclude that the features of $\gamma$-ray emission from such massive binaries containing energetic pulsars should allow to obtain important information on the acceleration of particles by the pulsars, and on interactions of a compact object with the massive star wind. Predicted $\gamma$-ray light curves and spectra in the GeV and TeV energy ranges from such binary systems within our Galaxy and Magellanic Clouds should be observed by future AGILE and GLAST satellites and low threshold Cherenkov telescopes such as MAGIC, HESS, VERITAS or CANGAROO III.Comment: 17 pages, 14 figures, MNRAS, accepte

Finite covers of random 3-manifolds

A 3-manifold is Haken if it contains a topologically essential surface. The Virtual Haken Conjecture posits that every irreducible 3-manifold with infinite fundamental group has a finite cover which is Haken. In this paper, we study random 3-manifolds and their finite covers in an attempt to shed light on this difficult question. In particular, we consider random Heegaard splittings by gluing two handlebodies by the result of a random walk in the mapping class group of a surface. For this model of random 3-manifold, we are able to compute the probabilities that the resulting manifolds have finite covers of particular kinds. Our results contrast with the analogous probabilities for groups coming from random balanced presentations, giving quantitative theorems to the effect that 3-manifold groups have many more finite quotients than random groups. The next natural question is whether these covers have positive betti number. For abelian covers of a fixed type over 3-manifolds of Heegaard genus 2, we show that the probability of positive betti number is 0. In fact, many of these questions boil down to questions about the mapping class group. We are lead to consider the action of mapping class group of a surface S on the set of quotients pi_1(S) -> Q. If Q is a simple group, we show that if the genus of S is large, then this action is very mixing. In particular, the action factors through the alternating group of each orbit. This is analogous to Goldman's theorem that the action of the mapping class group on the SU(2) character variety is ergodic.Comment: 60 pages; v2: minor changes. v3: minor changes; final versio