Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry

Background: Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. Method: A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time <3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. Results: During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in patient samples, but not in spiked calibrator samples. Comparison with LC-MS/MS disclosed a significant bias with higher concentrations measured by LC-MS/MS, while UPLC-MS/MS showed excellent agreement with the commercially available HPLC method. In the LC-MS/MS procedure, comparably wide and left side shifted peaks were noticed. This could be ascribed to in-source fragmentation of conjugate metabolites during electrospray ionisation. Precursor and product ion scans confirmed the assumption that the additional compounds are posaconazole glucuronides. Reducing the cone voltage led to disappearance of the glucuronide peaks. Slight modification of the LC-MS/MS method enabled separation of the main interference, leading to significantly reduced deviation. Conclusions: These results highlight the necessity to reliably eliminate interference from labile drug metabolites for correct TDM results, either by sufficient separation or selective MS conditions. The presented UPLC-MS/MS method provides a reliable and fast assay for TDM of posaconazole. Clin Chem Lab Med 2010; 48:1723-31

Numerical simulations of the Princeton magneto-rotational instability experiment with conducting axial boundaries

We investigate numerically the Princeton magneto-rotational instability (MRI) experiment and the effect of conducting axial boundaries or endcaps. MRI is identified and found to reach a much higher saturation than for insulating endcaps. This is probably due to stronger driving of the base flow by the magnetically rather than viscously coupled boundaries. Although the computations are necessarily limited to lower Reynolds numbers ($\Re$) than their experimental counterparts, it appears that the saturation level becomes independent of $\Re$ when $\Re$ is sufficiently large, whereas it has been found previously to decrease roughly as $\Re^{-1/4}$ with insulating endcaps. The much higher saturation levels will allow for the first positive detection of MRI beyond its theoretical and numerical predictions

Nonlinear excitation of low-n harmonics in reduced magnetohydrodynamic simulations of edge-localized modes

Nonlinear simulations of the early ELM phase based on a typical type-I ELMy ASDEX Upgrade discharge have been carried out using the reduced MHD code JOREK. The analysis is focused on the evolution of the toroidal Fourier spectrum. It is found that during the nonlinear evolution, linearly subdominant low-n Fourier components, in particular the n = 1, grow to energies comparable with linearly dominant harmonics. A simple model is developed, based on the idea that energy is transferred among the toroidal harmonics via second order nonlinear interaction. The simple model reproduces and explains very well the early nonlinear evolution of the toroidal spectrum in the JOREK simulations. Furthermore, it is shown for the n = 1 harmonic, that its spatial structure changes significantly during the transition from linear to nonlinearly driven growth. The rigidly growing structure of the linearly barely unstable n = 1 reaches far into the plasma core. In contrast, the nonlinearly driven n = 1 has a rigidly growing structure localized at the plasma edge, where the dominant toroidal harmonics driving the n = 1 are maximal and in phase. The presented quadratic coupling model might explain the recent experimental observation of strong low-n components in magnetic measurements [Wenninger et al., Non-linear magnetic perturbations during edge localized modes in TCV dominated by low n mode components, submitted to Nuclear Fusion]

Comments on "Volume ignition of mixed fuel" by H. Ruhl and G. Korn (Marvel Fusion, Munich)

In the most recent note on Marvel Fusion's concept for a laser driven pB reactor without compression, Ruhl and Korn consider the volumetric energy balance of fusion reactions vs. bremsstrahlung losses in a mixed fuel (DT and pB) environment and claim the satisfaction of this necessary "ideal ignition" condition. Their results are based, however, on improper assumptions about the deposition of fusion energy in the plasma. Correcting for them, we show that the quoted composition of their fuel (a solid boron composite, binding high concentrations of D, T and p) would actually preclude ignition due to the high bremsstrahlung losses associated with the presence of boron. To facilitate ignition, Ruhl and Korn also consider the reduction of the bremsstrahlung losses by confining the radiation in the optically thin fuel region by high Z walls. They suggest to preload this region with radiation so that the radiation temperature equals approximately that of the plasma constituents $T_{r} \approx T_{e} \approx T_{i}$. We show that in this set-up the radiation energy - neglected in these considerations - would, however, vastly exceed the thermal energy of the plasma and actually dominate the ignition energy requirements.Comment: 6 pages, 1 figur

Testing of the new JOREK stellarator-capable model in the tokamak limit

In preparation for extending the JOREK nonlinear MHD code to stellarators, a hierarchy of stellarator-capable reduced and full MHD models has been derived and tested. The derivation was presented at the EFTC 2019 conference. Continuing this line of work, we have implemented the reduced MHD model (arXiv:1907.12486) as well as an alternative model which was newly derived using a different set of projection operators for obtaining the scalar momentum equations from the full MHD vector momentum equation. With the new operators, the reduced model matches the standard JOREK reduced models for tokamaks in the tokamak limit and conserves energy exactly, while momentum conservation is less accurate than in the original model whenever field-aligned flow is present.Comment: 23 pages, 1 table, 7 figures. Submitted to Journal of Plasma Physic

A three-dimensional reduced MHD model consistent with full MHD

Within the context of a viscoresistive magnetohydrodynamic (MHD) model with anisotropic heat transport and cross-field mass diffusion, we introduce novel three-term representations for the magnetic field (background vacuum field, field line bending and field compression) and velocity ($\vec E\times\vec B$ flow, field-aligned flow and fluid compression), which are amenable to three-dimensional treatment. Once the representations are inserted into the MHD equations, appropriate projection operators are applied to Faraday's law and the Navier-Stokes equation to obtain a system of scalar equations that is closed by the continuity and energy equations. If the background vacuum field is sufficiently strong and the $\beta$ is low, MHD waves are approximately separated by the three terms in the velocity representation, with each term containing a specific wave. Thus, by setting the appropriate term to zero, we eliminate fast magnetosonic waves, obtaining a reduced MHD model. We also show that the other two velocity terms do not compress the magnetic field, which allows us to set the field compression term to zero within the same reduced model. Dropping also the field-aligned flow, a further simplified model is obtained, leading to a fully consistent hierarchy of reduced and full MHD models for 3D plasma configurations. Finally, we discuss the conservation properties and derive the conditions under which the reduction approximation is valid. We also show that by using an ordering approach, reduced MHD equations similar to what we got from the ansatz approach can be obtained by means of a physics-based asymptotic expansion.Comment: 18 pages. This article was published in Physics of Plasma