Assessing in vitro combinations of antifungal drugs against yeasts and filamentous fungi: comparison of different drug interaction models.

Contains fulltext : 48405.pdf (publisher's version ) (Closed access)Non-parametric and parametric approaches of two competing zero-interaction theories--the Loewe additivity and the Bliss independence - were evaluated for analyzing the in vitro interactions of various antifungal drugs. Fifty-one data sets, derived from three drug combinations, tested in triplicate against 17 clinical yeast and mold isolates with a two-dimensional checkerboard microdilution technique, were selected to span from strong synergy to strong antagonism. These were analyzed with the standard FIC index model and modern concentration-effect response surface models: the fully parametric model developed by Greco et al. and the 3-D analysis developed by Prichard et al. The FIC index model is subjective, sensitive to experimental errors and resulted in approximated results and variable conclusions depending on the MIC endpoints determined and interpretation endpoints used. By using the MIC-2 endpoint (lowest drug concentration showing 50% of growth) for calculating the FIC indices, problems due to trailing phenomena were reduced and weak interactions could be detected; higher levels of reproducibility and agreement with the other models were achieved using the MIC-0 and MIC-1 (lowest drug concentration showing 10 and 25% of growth, respectively). High reproducibility was achieved in interpreting the FIC indices when the cutoffs of 0.25 and 4 (for single experiments) and the cutoff of 1 (for replicates) were used for defining the limits of additivity/indifference. Although the fully parametric Greco model did not describe precisely the entire response surface of all antifungal drug interactions, it was able to differentiate synergistic from non-synergistic interactions with a non-unit, reproducible, concentration-independent interaction parameter, including its uncertainty, without requiring replication. The Bliss independence based models resulted in mosaics of synergistic and antagonistic combinations, raising questions about the concentration-dependent nature of antifungal drug interaction. The sum of all statistically significant interactions were used as a summary interaction parameter for the entire response surface, concluding synergy or antagonism when it was positive or negative, respectively. The cutoffs of 100% and 200% were used to distinguish weak and moderate interactions, respectively in 12-16 x 8-12 checkerboard formats. Semi-parametric approaches need particular care as experimental errors are not eliminated from the entire response surface

Centrality dependence of the pseudorapidity density distribution for charged particles in Pb–Pb collisions at sNN=2.76 TeV

AbstractWe present the first wide-range measurement of the charged-particle pseudorapidity density distribution, for different centralities (the 0–5%, 5–10%, 10–20%, and 20–30% most central events) in Pb–Pb collisions at sNN=2.76 TeV at the LHC. The measurement is performed using the full coverage of the ALICE detectors, −5.0<η<5.5, and employing a special analysis technique based on collisions arising from LHC ‘satellite’ bunches. We present the pseudorapidity density as a function of the number of participating nucleons as well as an extrapolation to the total number of produced charged particles (Nch=17165±772 for the 0–5% most central collisions). From the measured dNch/dη distribution we derive the rapidity density distribution, dNch/dy, under simple assumptions. The rapidity density distribution is found to be significantly wider than the predictions of the Landau model. We assess the validity of longitudinal scaling by comparing to lower energy results from RHIC. Finally the mechanisms of the underlying particle production are discussed based on a comparison with various theoretical models

Production of charged pions, kaons and protons at large transverse momenta in pp and Pb–Pb collisions at sNN=2.76 TeV

AbstractTransverse momentum spectra of π±, K± and p(p¯) up to pT=20 GeV/c at mid-rapidity in pp, peripheral (60–80%) and central (0–5%) Pb–Pb collisions at sNN=2.76 TeV have been measured using the ALICE detector at the Large Hadron Collider. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3 GeV/c in central Pb–Pb collisions. Below the peak, pT<3 GeV/c, both ratios are in good agreement with hydrodynamical calculations, suggesting that the peak itself is dominantly the result of radial flow rather than anomalous hadronization processes. For pT>10 GeV/c particle ratios in pp and Pb–Pb collisions are in agreement and the nuclear modification factors for π±, K± and p(p¯) indicate that, within the systematic and statistical uncertainties, the suppression is the same. This suggests that the chemical composition of leading particles from jets in the medium is similar to that of vacuum jets

Centrality, rapidity and transverse momentum dependence of J/ψ suppression in Pb–Pb collisions at sNN=2.76 TeV

AbstractThe inclusive J/ψ nuclear modification factor (RAA) in Pb–Pb collisions at sNN=2.76 TeV has been measured by ALICE as a function of centrality in the e+e− decay channel at mid-rapidity (|y|<0.8) and as a function of centrality, transverse momentum and rapidity in the μ+μ− decay channel at forward-rapidity (2.5<y<4). The J/ψ yields measured in Pb–Pb are suppressed compared to those in pp collisions scaled by the number of binary collisions. The RAA integrated over a centrality range corresponding to 90% of the inelastic Pb–Pb cross section is 0.72±0.06(stat.)±0.10(syst.) at mid-rapidity and 0.58±0.01(stat.)±0.09(syst.) at forward-rapidity. At low transverse momentum, significantly larger values of RAA are measured at forward-rapidity compared to measurements at lower energy. These features suggest that a contribution to the J/ψ yield originates from charm quark (re)combination in the deconfined partonic medium