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Background In March 2020, hydroxychloroquine (HCQ) alone or combined with azithromycin (AZM) was authorized as a treatment for COVID-19 in many countries. The therapy proved ineffective with long QT and deadly cardiac arrhythmia risks, illustrating challenges to determine the new safety profile of repurposed drugs. Objective To investigate proarrhythmic effects and mechanism of HCQ and AZM (combined and alone) with high doses of HCQ as in the COVID-19 clinical trials. Methods Proarrhythmic effects of HCQ and AZM are quantified using optical mapping with voltage-sensitive dyes in ex vivo Langendorff-perfused guinea pig (GP) hearts and with numerical simulations of a GP Luo-Rudy and a human O'Hara-Virag-Varro-Rudy models, for Epi, Endo, and M cells, in cell and tissue, incorporating the drug's effect on cell membrane ionic currents. Results Experimentally, HCQ alone and combined with AZM leads to long QT intervals by prolonging the action potential duration and increased spatial dispersion of action potential (AP) repolarization across the heart, leading to proarrhythmic discordant alternans. AZM alone had a lesser arrhythmic effect with less triangulation of the AP shape. Mathematical cardiac models fail to reproduce most of the arrhythmic effects observed experimentally. Conclusions During public health crises, the risks and benefits of new and repurposed drugs could be better assessed with alternative experimental and computational approaches to identify proarrhythmic mechanisms. Optical mapping is an effective framework suitable to investigate the drug's adverse effects on cardiac cell membrane ionic channels at the cellular level and arrhythmia mechanisms at the tissue and whole-organ level.

Background Early during the current coronavirus disease 19 (COVID-19) pandemic, hydroxychloroquine (HCQ) received a significant amount of attention as a potential antiviral treatment, such that it became one of the most commonly prescribed medications for COVID-19 patients. However, not only has the effectiveness of HCQ remained questionable, but mainly based on preclinical and a few small clinical studies, HCQ is known to be potentially arrhythmogenic, especially as a result of QT prolongation. Objective The purpose of this study was to investigate the arrhythmic effects of HCQ, as the heightened risk is especially relevant to COVID-19 patients, who are at higher risk for cardiac complications and arrhythmias at baseline. Methods An optical mapping technique utilizing voltage-sensitive fluorescent dyes was used to determine the arrhythmic effects of HCQ in ex vivo guinea pig and rabbit hearts perfused with the upper therapeutic serum dose of HCQ (1000 ng/mL). Results HCQ markedly increased action potential dispersion, resulted in development of repolarization alternans, and initiated polymorphic ventricular tachycardia. Conclusion The study results further highlight the proarrhythmic effects of HCQ.

We extend the Maxwell-Stefan (M-S) formulation of irreversible thermodynamics to multicomponent transport in mixed-matrix membranes (MMMs), using a simulation-based rigorous modeling approach (SMA) through finite-element method (FEM) solution of the three-dimensional (3-d) transport problem in full-scale MMMs. In the new approach, we generalize the dual-mode/partial immobilization (DM/PI) theory for the local permeability in glassy polymers to describe multicomponent permeation in pure glassy polymer membranes and MMMs, by reformulating the M-S constitutive equations in the Onsager formalism considering concentration-dependent transport diffusivities and non-uniform concentration gradients across the MMM. In this way, the new M-S formulation explicitly considers effects of intrinsic MMM features such as finite filler particle size and isotherm nonlinearity in the MMM constituent phases, as well as mixture-related effects, such as competitive adsorption and friction amongst permeants, on the calculation of the mixture fluxes (permeabilities). This is achieved without introduction of empirical fitting parameters in the MMM permeability calculation and only requiring single-gas experimental or simulation-based adsorption and permeation data on the individual MMM materials to predict the mixture perm-selectivity in the MMM as a whole. Further, we validate the new approach by using available experimental permeation data for the separation of an equimolar binary mixture of propylene ( C 3 H 6 ) and propane ( C 3 H 8 ) in ZIF‑8/PIM-6FDA-OH MMMs, with the rigorous simulation results showing very good agreement with both experimental single and mixed-gas permeabilities and perm-selectivities.

This work investigates the effect of condensable Hg vapour on the transport of N-2 gas across cobalt oxide silica (CoOxSi) membranes. Experimental results suggest that Hg significantly affects N-2 permeation at 100 and 200 degrees C, though this effect is negligible at 300 degrees C. This effect was found to have a correlation with Hg adsorption on CoOxSi xerogels. In order to understand the Hg effect in the transport phenomena of N-2 permeation, the oscillator model was used to model gas transport through pores with different sizes. By including effective medium theory (EMT), the oscillator model fitted well the experimental results and gave good prediction of mass transfer in ultra-microporous materials with a tri-modal pore size distribution, such as silica membranes. It is postulated that Hg seeks lower level potentials in micro-pores, and therefore Hg molecules tend to block small pores (2.5-4 angstrom from 2.9 angstrom), or reduce the average pore size of larger pores (6.7-7.8 angstrom and 12-14 angstrom). Although N-2 permeation decreased with the presence of Hg, it did not decrease when the Hg load was increased by a factor of ten; this strongly suggests the adsorption of Hg molecules in the smaller pores (2.5-4.0 angstrom), or along the pore wall for the larger pore ranges (6.7-7.8 angstrom and 12-14 angstrom). (C) 2018 Elsevier Ltd. All rights reserved.

We extend effective medium theory (EMT) to composite hollow fiber mixed matrix membranes, considering the asymmetric filler volume fraction profile arising from finite system size. This volume fraction profile leads to strong variation of the driving force (i.e. pseudo-bulk concentration gradient) in the regions adjacent to the composite ends, and to sensitivity of the effective permeability of the composite to the geometrical configuration. The new theory is validated against rigorous simulations of the transport in mixed-matrix membranes (MMMs) using both concentration-independent and concentration-dependent diffusivities in the MMM constituent phases. Both theory and simulations show that flat mixed-matrix membranes (F-MMMs) have higher effective overall permeability than hollow fiber mixed-matrix membranes (HF-MMMs), upon comparison of systems having identical operating conditions, filler phase loading and particle size. Furthermore, we show here that the sensitivity to the geometry vanishes with increase of inner radius of the hollow fiber membrane at fixed thickness, and the effective permeability of a HF-MMM is found to asymptotically approach that of a F-MMM.

In the present paper, the carbon dioxide molecule adsorption through nanoporous carbons has been studied at 248 [K], 298 [K] and 323 [K]. The 3-stage graphite, turbostratic carbon and activated carbon have been taken into account as nanoporous carbon structures with nearly the same simulation box size, i.e. 30 × 30 × 30 [A]. The numerical experiments of the adsorption phenomenon of CO2 molecule have been successfully achieved by user-written massively parallel codes via MPI paradigm which has been carefully examined and evaluated including electrostatic charges, 3-site CO2 molecule and linear scalability issues for the parallel programming purposes. By taking advantage of the parallel programming and efficient algorithm paradigm, very accurate outcomes and highly portable implementations for High Performance Computing (HPC) have been obtained. The effect of nanoscale pore size and its distribution for the above-mentioned nanoporous carbons which are generated via user-written C++ codes, have been studied by means of scalable parallel code. In the first stage, the carbon dioxide at bulk state has been investigated. Afterwards, the adsorption simulations have been achieved on regular and nearly regular nanoporous structures, i.e. 3-stage graphite including 6 [A] and 12 [A] interlayer distances (pore width), receptively. The activated carbon structure which is generated via Reverse Monte Carlo in Pikunic et al. (2003), has been considered for numerical experiments of adsorption as well. The comparison among these nanoporous carbons reveals a cross-over trend beyond a specific Adams constant value and this issue can be found out for the above-mentioned carbons as well as bulk case.

We present a new theory to estimate fluxes and effective transport conductances of binary mixtures through a membrane comprising a nonuniform porous medium with both pore size and pore length distributions, using the Onsager formulation at the single pore level. The theory defines a conductance of each species that is dependent on the concentration gradients of the various species, and on using effective medium theory determines the fluxes and concentration profiles self-consistently in the porous medium. The transport of CH4/H2 mixtures in a silica membrane having a known pore size distribution is examined using this theory, and the results compared with those from rigorous simulations, showing good agreement. It is found that an optimal network coordination number exists at which species fluxes are a maximum, due to the opposing effects of increasing porosity and mean pore length with increase in coordination number. Further, network fluxes decrease with increase in pore dispersion, indicating that uniform pore size is optimal. A species and pressure-dependent optimal temperature is also predicted, due to the competing effects of increase in diffusivity and decrease in adsorption on increasing temperature. It is seen that the CH4 selectivity is very sensitive to temperature, and undergoes a cross-over, with the membrane being more selective to CH4 at low temperature and to H2 at high temperature. In general, the selectivity is very sensitive to the distribution of pore volume, and for bimodal pore networks, undergoes a sharp transition at the percolation threshold, when the smaller pore size is impermeable to the larger species, CH4. The approach offers a convenient adaption of effective medium theory to multicomponent systems with nonlinear isotherms, overcoming drawbacks of existing theory.

Current models for transport in dispersions, while grounded in well-established effective medium theory (EMT), rely on the assumption of uniformity of the driving force. As consequence, theoretical approaches cannot accommodate driving force inhomogeneities as well as variations over the space occupied by the dispersed phase particles, and existing EMT-based models therefore fail to represent finite particle size effects. Moreover, because transport coefficients are generally considered uniform, such models largely pertain to the Henry's law region. Here, using the context of permeation in mixed-matrix membranes (MMMs), we introduce a self-consistent theory for transport in dispersion-based composites, which captures effects of isotherm nonlinearity and dispersant size without introducing fitting parameters, and accurately predicts concentration-dependent permeabilities. The model is validated against rigorous 3d simulations of transport in filler-polymer composite MMMs, with excellent agreement between theoretical results and those from simulation. Both model and simulations confirm isotherm nonlinearities to have a very significant effect on effective MMM permeability, which is found to be more sensitive to isotherm nonlinearity in the filler phase than in the continuous phase. These effects disappear when the filler phase is much more permeable than the continuous phase, although additional system size effects related to exclusion regions at the ends due to finite particle size lead to decrease in permeability with increase in particle size even for linear isotherms.

Grand Canonical Monte Carlo (GCMC) simulations have been conducted to investigate the interaction between phenol and a commercial activated carbon cloth KIP1200 in aqueous solution. The nanostructure of KIP1200 has been extracted using Hybrid Reverse Monte Carlo (HRMC) simulations based on experimental measurements of XRD-based structure factor, and shows the presence of pore spaces inaccessible to both phenol and nitrogen. The impact of empirical force fields (EDIP and Erhart-Albe) on the structural parameters and adsorption capacity, as well as pore accessibility is investigated via molecular simulations and materials informatics employing lattice and Voronoi decomposition algorithms. While the Erhart-Albe force field leads to more amorphous structures and inaccessible pores, the EDIP force field creates more lamellar structures with sharp edges and narrow pore width. The molecular state of adsorbed phenol in these structures is markedly different, with the narrower pore spaces of the EDIP-based structure providing stronger interaction between phenol molecules and carbon structure than for water. The calculated X-ray intensities and adsorption isotherms for the simulation-based structure are in good agreement with corresponding experimental results. The simulated solvation state of phenol has been verified by experiments, and demonstrates the existence of inter-layer spaces inaccessible to phenol for both force fields.

PURPOSE/OBJECTIVE(S) Nearly half of all patients with ventricular tachycardia (VT) become refractory to standard-of-care anti-arrhythmic medications and catheter ablation. Stereotactic body radiotherapy (SBRT) has emerged as a well-tolerated and effective new treatment for VT. Since arrhythmogenic lesions are undetectable on CT scans, the practice of SBRT target volume delineation is not yet formalized. Many single-institution protocols involve only verbal discussion between electrophysiologists and radiation oncologists or manual re-orientation of surface renderings from electrophysiologic (EP) studies to correlate with the planes on CT scan. We present a novel software, "Rhythm-RT", that synthesizes data from EP studies and heart contours from radiation planning to automatically generate a preliminary target volume. MATERIALS/METHODS Along with DICOM files containing contours, Rhythm-RT can process electroanatomic mapping (EAM) data from CARTO (Biosense Webster, Irvine, CA) and EnSite Precision (Abbott, St. Paul, MN) as well as ablation navigation data from EnSite Precision. All input data are plotted in the reference coordinate system of the CT simulation scan. The user is able to translate and rotate imported EP spatial information for co-registration with contoured cardiac substructures. Rhythm-RT then identifies the cardiac substructure closest to the sites of low voltage from EAM or inadequate previous ablation on which to generate an SBRT gross target volume (GTV), adapted to the myocardial shape and transmural thickness of the cardiac substructure. The GTV is exported as a DICOM file which can be integrated with other contoured structures in the original radiation planning system. RESULTS From October 2019 to February 2021, 7 males and 1 female with VT (53-84 years of age, ejection fraction 10-65%, and 0-7 previous catheter ablations) were treated using Rhythm-RT to guide cardiac SBRT planning. Compared to existing methods of delineating GTV crudely by free-hand, Rhythm-RT visualizes EP spatial information superimposed on heart contours. The area of myocardium selected as GTV, based on proximity to relevant EP signals, is computationally derived rather than inferred and liable to human error. Final GTV modification with the help of an experienced electrophysiologist is still recommended. When structural heart disease is multifocal, he/she may provide insight on which areas are more likely to cause arrhythmia. Adjustment of the GTV boundary may also be informed by direct observations during EP procedures that are not reflected in procedure equipment logs. CONCLUSION Rhythm-RT is a software that improves the accuracy and efficiency of target volume delineation in cardiac SBRT. Additional patient enrollment on our institutional protocol utilizing this technology is ongoing, along with outcomes analysis and expansion of input data versatility to include all EP and radiation planning systems.

We use grand canonical Monte Carlo simulation to investigate the adsorption of a CO2/N2 mixture in neutral and charged (7, 7) carbon nanotube (CNT) arrays. It is found that both the adsorption of CO2, and the CO2/N2 selectivity are either enhanced or reduced when the charges are positive or negative. The CO2/N2 selectivity in a CNT bundle carrying +0.05e charge with intertube distance of 0.335 nm exceeds 1000 for pressures up to 15 bar, which is remarkably high. It is seen that strong electrostatic interactions from neighbouring CNTs enhance the adsorption of CO2 over N2, and while the adsorption of CO2 has complex dependence on intertube distance, the CO2/N2 selectivity decreases with intertube spacing. We propose a quantitative performance coefficient as an aid to assessing the efficiency of CNT bundles to separate CO2 from flue gas, and show that a +0.05e charged bundle with intertube distance of 0.335 nm provides the best performance. Further, it is found that water vapor in flue gas imposes negligible effect on the adsorption of CO2 and its selectivity over N2 in the neutral and positively charged (7, 7) CNT bundles, but dramatically reduces the adsorption of CO2 and N2 in negatively charged bundles.

The majority of thoracic aortic aneurysms (TAA) in the pediatric population are due to post repair etiology (iatrogenic). Although rare, underlying inheritable disease and congenital cardiac anomalies represent the most common non-iatrogenic cause of TAA among patients in this age group (1–21 years of age). Herein, we present a case series of 9aortic aneurysms with varying underlying etiology. We discuss the molecular genetic basis of these syndromes in conjunction with the radiological findings and histological description utilizing the newly published consensus criteria article.