Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software

AbstractPurposeTo use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin.MethodsA phenytoin pharmacokinetic model was used in the Simcyp™ population-based ADME simulator, simulating 100 children age 2–10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model.ResultsLoading with doses of 18mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10μg/mL), therapeutic in 62/100 (C2h 10–20μg/mL), and supra-therapeutic in 16/100 (C2h>20μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20mg/kg increased the mean C2h from 16.0 to 17.9μg/mL, and the mean AUC from 145 to 162μg/mL/h. A C2h>30μg/mL was predicted in 4% and 8% of children in the 18 and 20mg/kg doses, with 3% predicted to have a C2h>40μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20mg/kg loading) gives the highest percentages of 10–20μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%.ConclusionUse of PBPK modelling suggests that children receiving the 20mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate

Comment on `Parameter-dependent unitary transformation approach for quantum Rabi model'

We discuss the elementary errors in D.G. Zhang's [New. J. Phys. 23, 093014 (2021)] claimed exact solution of the quantum Rabi model. The erroneous solution is seen to be nothing more than the combined solution of the simpler Jaynes-Cummings and anti-Jaynes-Cummings models obtained by neglecting terms in the model Hamiltonian.Comment: 5 pages, 1 figure, submitted to New. J. Phys. October 14, 202

On bubble clustering and energy spectra in pseudo-turbulence

3D-Particle Tracking (3D-PTV) and Phase Sensitive Constant Temperature Anemometry in pseudo-turbulence--i.e., flow solely driven by rising bubbles-- were performed to investigate bubble clustering and to obtain the mean bubble rise velocity, distributions of bubble velocities, and energy spectra at dilute gas concentrations ($\alpha \leq2.2$%). To characterize the clustering the pair correlation function $G(r,\theta)$ was calculated. The deformable bubbles with equivalent bubble diameter $d_b=4-5$ mm were found to cluster within a radial distance of a few bubble radii with a preferred vertical orientation. This vertical alignment was present at both small and large scales. For small distances also some horizontal clustering was found. The large number of data-points and the non intrusiveness of PTV allowed to obtain well-converged Probability Density Functions (PDFs) of the bubble velocity. The PDFs had a non-Gaussian form for all velocity components and intermittency effects could be observed. The energy spectrum of the liquid velocity fluctuations decayed with a power law of -3.2, different from the $\approx -5/3$ found for homogeneous isotropic turbulence, but close to the prediction -3 by \cite{lance} for pseudo-turbulence

Physics of Rheologically-Enhanced Propulsion: Different Strokes in Generalized Stokes

Shear-thinning is an important rheological property of many biological fluids, such as mucus, whereby the apparent viscosity of the fluid decreases with shear. Certain microscopic swimmers have been shown to progress more rapidly through shear-thinning fluids, but is this behavior generic to all microscopic swimmers, and what are the physics through which shear-thinning rheology affects a swimmer's propulsion? We examine swimmers employing prescribed stroke kinematics in two-dimensional, inertialess Carreau fluid: shear-thinning "Generalized Stokes" flow. Swimmers are modeled, using the method of femlets, by a set of immersed, regularized forces. The equations governing the fluid dynamics are then discretized over a body-fitted mesh and solved with the finite element method. We analyze the locomotion of three distinct classes of microswimmer: (1) conceptual swimmers comprising sliding spheres employing both one- and two-dimensional strokes, (2) slip-velocity envelope models of ciliates commonly referred to as "squirmers" and (3) monoflagellate pushers, such as sperm. We find that morphologically identical swimmers with different strokes may swim either faster or slower in shear-thinning fluids than in Newtonian fluids. We explain this kinematic sensitivity by considering differences in the viscosity of the fluid surrounding propulsive and payload elements of the swimmer, and using this insight suggest two reciprocal sliding sphere swimmers which violate Purcell's Scallop theorem in shear-thinning fluids. We also show that an increased flow decay rate arising from shear-thinning rheology is associated with a reduction in the swimming speed of slip-velocity squirmers. For sperm-like swimmers, a gradient of thick to thin fluid along the flagellum alters the force it exerts upon the fluid, flattening trajectories and increasing instantaneous swimming speed.Comment: 22 pages, 28 figure

A systematic correlation between two-dimensional flow topology and the abstract statistics of turbulence

Velocity differences in the direct enstrophy cascade of two-dimensional turbulence are correlated with the underlying flow topology. The statistics of the transverse and longitudinal velocity differences are found to be governed by different structures. The wings of the transverse distribution are dominated by strong vortex centers, whereas, the tails of the longitudinal differences are dominated by saddles. Viewed in the framework of earlier theoretical work this result suggests that the transfer of enstrophy to smaller scales is accomplished in regions of the flow dominated by saddles.Comment: 4 pages, 4 figure

Pilot scale microwave sorting of porphyry copper ores: Part 2: pilot plant trials

An experimental pilot plant was constructed, commissioned and operated at a major porphyry copper mine to understand the challenges of microwave infrared thermal (MW-IRT) sorting at scale and to compare batch laboratory performance with pilot-scale continuous sortability performance. A method was developed to define the 95% confidence intervals on pilot plant operating windows from experiments on 50 to 150 fragments performed in a laboratory based replica of the pilot scale microwave treatment system. It appeared that the laboratory testing methodology predicted the sortability of the ores fairly well. For the 11 ore types and three size classes (-76.2+50.8mm, -50.8+25.4mm and -25.4+12.7mm) tested over 233 pilot plant experiments, approximately 42% of the better optimised pilot plant runs predicted copper recovery to within ±5% copper recovery and approximately 84% of the runs to within ±10%. These figures were improved to approximately 50% predicted to within ±5% and approximately 90% to within ±10% if the -25.4+12.7mm size class was omitted. It was demonstrated that laboratory testing better predicted pilot plant sorting performance and provided a narrower operating window when a larger sample size (>50 fragments) was considered due to improved representivity. It is, therefore, fully expected that better predictions would result from larger laboratory sample sizes than those tested during any future testing campaigns. To date, approximately 15,500 tonnes of ore has been processed through the pilot-scale test facility, generating significant engineering know-how and demonstrating MW-IRT sorting at a scale in the order of that required by the mining industry

Histidine Targeting Heterobimetallic Ruthenium(II)-Gold(I) Complexes

Inspired by the preferential, allosteric binding of RAPTA-T and auranofin to the nucleosome core particle, we describe the design and synthesis of a series of heterobimetallic ruthenium(II)-gold(I) complexes with varying spacer lengths ranging from four to eight polyethylene glycol units. Evaluation of their cytotoxicity reveals IC50 values in the low micromolar range against cisplatin sensitive and resistant human ovarian carcinoma (A2780, A2780cisR) and nontumoral human embryonic kidney (HEK293) cell lines. Binding studies monitored via mass spectrometry revealed an affinity for histidine residues on a fragment of the amyloid beta-protein (residues 1-16, employed as a model system), which is in accordance with the binding sites of parent drugs, RAPTA-C and auranofin, to the nucleosome core particle