A positive interaction between inhibitors of protein synthesis and cefepime in the fight against methicillin-resistant Staphylococcus aureus

Quinupristin-dalfopristin (Q-D) synergizes with cefepime for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Here, we studied whether the synergism was restricted to MRSA and if it extended to non-beta-lactam cell wall inhibitors or to other inhibitors of protein synthesis. Three MRSA and two methicillin-susceptible S. aureus (MSSA) strains were tested, including an isogenic pair of mecA −/mecA + S. aureus Newman. The drug interactions were determined by fractional inhibitory concentration (FIC) indices and population analysis profiles. The antibacterial drugs that we used included beta-lactam (cefepime) and non-beta-lactam cell wall inhibitors (D-cycloserine, fosfomycin, vancomycin, teicoplanin), inhibitors of protein synthesis (Q-D, erythromycin, chloramphenicol, tetracycline, linezolid, fusidic acid), and polynucleotide inhibitors (cotrimoxazole, ciprofloxacin). The addition of each protein inhibitor to cefepime was synergistic (FIC ≤ 0.5) or additive (FIC > 0.5 but < 1) against MRSA, but mostly indifferent against MSSA (FIC ≥ 1 but ≤ 4). This segregation was not observed after adding cotrimoxazole or ciprofloxacin to cefepime. Population analysis profiles were performed on plates in the presence of increasing concentrations of the cell wall inhibitors plus 0.25 × minimum inhibitory concentration (MIC) of Q-D. Cefepime combined with Q-D was synergistic against MRSA, but D-cycloserine and glycopeptides were not. Thus, the synergism was specific to beta-lactam antibiotics. Moreover, the synergism was not lost against fem mutants, indicating that it acted at another level. The restriction of the beneficial effect to MRSA suggests that the functionality of penicillin-binding protein 2A (PBP2A) was affected, either directly or indirectly. Further studies are necessary in order to provide a mechanism for this positive interactio

Quantum Hall effect in exfoliated graphene affected by charged impurities: metrological measurements

Metrological investigations of the quantum Hall effect (QHE) completed by transport measurements at low magnetic field are carried out in a-few-$\mu\mathrm{m}$-wide Hall bars made of monolayer (ML) or bilayer (BL) exfoliated graphene transferred on $\textrm{Si/SiO}_{2}$ substrate. From the charge carrier density dependence of the conductivity and from the measurement of the quantum corrections at low magnetic field, we deduce that transport properties in these devices are mainly governed by the Coulomb interaction of carriers with a large concentration of charged impurities. In the QHE regime, at high magnetic field and low temperature ($T<1.3 \textrm{K}$), the Hall resistance is measured by comparison with a GaAs based quantum resistance standard using a cryogenic current comparator. In the low dissipation limit, it is found quantized within 5 parts in $10^{7}$ (one standard deviation, $1 \sigma$) at the expected rational fractions of the von Klitzing constant, respectively $R_{\mathrm{K}}/2$ and $R_{\mathrm{K}}/4$ in the ML and BL devices. These results constitute the most accurate QHE quantization tests to date in monolayer and bilayer exfoliated graphene. It turns out that a main limitation to the quantization accuracy, which is found well above the $10^{-9}$ accuracy usually achieved in GaAs, is the low value of the QHE breakdown current being no more than $1 \mu\mathrm{A}$. The current dependence of the longitudinal conductivity investigated in the BL Hall bar shows that dissipation occurs through quasi-elastic inter-Landau level scattering, assisted by large local electric fields. We propose that charged impurities are responsible for an enhancement of such inter-Landau level transition rate and cause small breakdown currents.Comment: 14 pages, 9 figure

A positive interaction between inhibitors of protein synthesis and cefepime in the fight against methicillin-resistant Staphylococcus aureus.

Quinupristin-dalfopristin (Q-D) synergizes with cefepime for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Here, we studied whether the synergism was restricted to MRSA and if it extended to non-beta-lactam cell wall inhibitors or to other inhibitors of protein synthesis. Three MRSA and two methicillin-susceptible S. aureus (MSSA) strains were tested, including an isogenic pair of mecA (-)/mecA (+) S. aureus Newman. The drug interactions were determined by fractional inhibitory concentration (FIC) indices and population analysis profiles. The antibacterial drugs that we used included beta-lactam (cefepime) and non-beta-lactam cell wall inhibitors (D-cycloserine, fosfomycin, vancomycin, teicoplanin), inhibitors of protein synthesis (Q-D, erythromycin, chloramphenicol, tetracycline, linezolid, fusidic acid), and polynucleotide inhibitors (cotrimoxazole, ciprofloxacin). The addition of each protein inhibitor to cefepime was synergistic (FIC ≤ 0.5) or additive (FIC &gt; 0.5 but &lt; 1) against MRSA, but mostly indifferent against MSSA (FIC ≥ 1 but ≤ 4). This segregation was not observed after adding cotrimoxazole or ciprofloxacin to cefepime. Population analysis profiles were performed on plates in the presence of increasing concentrations of the cell wall inhibitors plus 0.25 × minimum inhibitory concentration (MIC) of Q-D. Cefepime combined with Q-D was synergistic against MRSA, but D-cycloserine and glycopeptides were not. Thus, the synergism was specific to beta-lactam antibiotics. Moreover, the synergism was not lost against fem mutants, indicating that it acted at another level. The restriction of the beneficial effect to MRSA suggests that the functionality of penicillin-binding protein 2A (PBP2A) was affected, either directly or indirectly. Further studies are necessary in order to provide a mechanism for this positive interaction

A 30 GHz 5-TeV Linear Collider

We present parameters for a linear collider with a $3$ to $5$ TeV center-of-mass energy that utilizes conventional rf technology operating at a frequency around 30 GHz. We discuss the scaling laws and assumed limitations that lead to the parameters described and we compare the merits and liabilities of different technological options including rf power source, accelerator structure, and final focus system design. Finally, we outline the components of the collider while specifying the required alignment and construction tolerances

METHODOLOGICAL INVESTIGATION OF VIBRATION EFFECTS ON PERFORMANCE OF THREE TASKS

ABSTRACT Twenty young Navy e n l i s t e d male volunteers were f i r s t rehearsed and then t e s t e d before, during. and a f t e r whole-body v i b r a t i o n . Fourteen were t e s t e d only a t 8 Hz, and six were t e s t e d a t 8 Hz/0.21 g rms, 16 HzI0.43 &amp; rms and 32 HzI0.85 &amp; rms. using t h r e e paper-and-pencil t a s k s involving v i s u a l , motor, and c o g n i t i v e s k i l l s . The t a s k s were &quot;Spoke&quot;. a speed of tapping test; &quot;Aiming&quot;, a test of f i n e motor coordination; and &quot;Coding&quot;, involving mental computation. Results showed an approximately equal decrement e f f e c t a c r o s s conditions i n t h e Spoke and Coding (but not Aiming) tests t h a t conforms w i t h t h e frequency function embodied i n t h e c u r r e n t i n t e r n a t i o n a l standard ( I S 0 2631:1978) on human exposure t o v i b r a t i o n ; but t h a t a modicum of previous v i b r a t i o n experience may be necessary before r e l i a b l e d a t a are obtained i n t h i s kind of t e s t i n g . t i o n of t h e c u r r e n t standard are b r i e f l y discussed. Implications f o r methodology and f o r t h e applica

A posteriori error analysis and adaptive non-intrusive numerical schemes for systems of random conservation laws

In this article we consider one-dimensional random systems of hyperbolic conservation laws. We first establish existence and uniqueness of random entropy admissible solutions for initial value problems of conservation laws which involve random initial data and random flux functions. Based on these results we present an a posteriori error analysis for a numerical approximation of the random entropy admissible solution. For the stochastic discretization, we consider a non-intrusive approach, the Stochastic Collocation method. The spatio-temporal discretization relies on the Runge--Kutta Discontinuous Galerkin method. We derive the a posteriori estimator using continuous reconstructions of the discrete solution. Combined with the relative entropy stability framework this yields computable error bounds for the entire space-stochastic discretization error. The estimator admits a splitting into a stochastic and a deterministic (space-time) part, allowing for a novel residual-based space-stochastic adaptive mesh refinement algorithm. We conclude with various numerical examples investigating the scaling properties of the residuals and illustrating the efficiency of the proposed adaptive algorithm

A look into the future of in-building networks: roadmapping the fiber invasion

Optical fiber-based in-building network solutions can outperform in the near future copper- and radiobased solutions both regarding performance and costs. POF solutions are maturing, and can already today be cheaper than Cat-5e solutions when ducts are shared with electricity cabling. Advanced signal modulation techniques allow high-capacity services over POF. With their extra features of multi-wavelength transport and routing, fiber solutions offer a higher network throughput and flexibility, and improved sustainability

Validation and clinical application of a multiplex high performance liquid chromatography - tandem mass spectrometry assay for the monitoring of plasma concentrations of 12 antibiotics in patients with severe bacterial infections.

Unpredictable pharmacokinetics of antibiotics in patients with life-threatening bacterial infections is associated with drug under- or overdosing. Therapeutic drug monitoring (TDM) may guide dosing adjustment aimed at maximizing antibacterial efficacy and minimizing toxicity. Rapid and accurate analytical methods are key for real-time TDM. Our objective was to develop a robust high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) for multiplex quantification of plasma concentrations of 12 antibiotics: imipenem/cilastatin, meropenem, ertapenem, cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam, amoxicillin, flucloxacillin, rifampicin, daptomycin. A single extraction procedure consisting in methanol plasma protein precipitation and H &lt;sub&gt;2&lt;/sub&gt; O dilution was used for all analytes. After chromatographic separation on an Acquity UPLC HSS-T3 2.1 × 50 mm, 1.8 µm (Waters®) column, quantification was performed by electro-spray ionisation-triple quadrupole mass spectrometry with selected reaction monitoring detection. Antibiotics were divided in two pools of calibration according to the frequency of analyses requests in the hospital routine antibiotic TDM program. Stable isotopically-labelled analogues were used as internal standards. A single analytical run lasted less than 9 min. The method was validated based on FDA recommendations, including assessment of extraction yield (96-113.8%), matrix effects, and analytical recovery (86.3-99.6%). The method was sensitive (lower limits of quantification 0.02-0.5 µg/mL), accurate (intra/inter-assay bias -11.3 to +12.7%) and precise (intra/inter-assay CVs 2.1-11.5%) over the clinically relevant plasma concentration ranges (upper limits of quantification 20-160 µg/mL). The application of the TDM assay was illustrated with clinical cases that highlight the impact on patients' management of an analytical assay providing information with short turn-around time on antibiotic plasma concentration. This simple, robust high-throughput multiplex HPLC-MS/MS assay for simultaneous quantification of plasma concentrations of 12 daily used antibiotics is optimally suited for clinically efficient real-time TDM

Coordination Dynamics of Upper Limbs in Swimming: Effects of Speed and Fluid Flow Manipulation

Purpose: Motor outputs are governed by dynamics organized around stable states and spontaneous transitions: we seek to investigate the swimmers’ motor behavior flexibility as a function of speed and aquatic environment manipulations. Method: Eight elite male swimmers partook an eight-level incremental test (4% increment from 76% to 104% of their mean speed on 200 m front crawl) in a quasi-static aquatic environment (pool). Swimmers then partook another incremental test at similar effort in a dynamic aquatic environment (swimming flume) up to maximal speed. Stroke rate (SR), index of coordination (IdC) and intersegmental coupling of the upper limbs were computed from the inertial sensors located on the upper limbs and the sacrum. Results: With speed increase, SR values presented a steeper linear increase in the pool than in the flume. IdC values increased also in the pool but remained stable in the flume. Individual SR and IdC vs. speed increase displayed second-order polynomial dynamics, indicative of adaptive flexibility with a range of extremum values more restricted in the flume. Finally, a reduction of the in-phase coordination pattern was noted with flume speed increase. Conclusions: Action possibilities were strongly constrained in the flume at the highest speeds as the fluid flow led to discontinuity in the propulsive actions of the upper limbs and lack of in-phase inter-segmental coordination. This highlights that the behavioral flexibility was restricted in the flume in comparison to the pool, in which the exploitation of opportunities for action involved a larger number of degrees of freedom in the movement