Non-equilibrium molecular simulations of thin film rupture.

The retraction of thin films, as described by the Taylor-Culick (TC) theory, is subject to widespread debate, particularly for films at the nanoscale. We use non-equilibrium molecular dynamics simulations to explore the validity of the assumptions used in continuum models by tracking the evolution of holes in a film. By deriving a new mathematical form for the surface shape and considering a locally varying surface tension at the front of the retracting film, we reconcile the original theory with our simulation to recover a corrected TC speed valid at the nanoscale.

Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease.

Calciprotein particles (CPP) are nanoscale mineralo-protein aggregates that help stabilize excess mineral in the circulation. We examined the relationship between CPP and bone mineral density in Fabry disease patients. We found an inverse correlation with total hip and femoral neck density, but none with lumbar spine. PURPOSE: Calciprotein particles (CPP) are colloidal mineral-protein complexes made up primarily of the circulating glycoprotein fetuin-A, calcium, and phosphate. They form in extracellular fluid and facilitate the stabilization, transport, and clearance of excess minerals from the circulation. While most are monomers, they also exist in larger primary (CPP-I) and secondary (CPP-II) form, both of which are reported to be raised in pathological states. This study sought to investigate CPP levels in the serum of patients with Fabry disease, an X-linked systemic lysosomal storage disorder that is associated with generalized inflammation and low bone mineral density (BMD). METHODS: We compared serum CPP-I and CPP-II levels in 59 patients with Fabry disease (37 female) with levels in an age-matched healthy adult cohort (n=28) and evaluated their association with BMD and biochemical data obtained from routine clinical review. RESULTS: CPP-I and CPP-II levels were higher in male Fabry disease patients than female sufferers as well as their corresponding sex- and age-matched controls. CPP-II levels were inversely correlated with BMD at the total hip and femoral neck, but not the lumbar spine. Regression analyses revealed that these associations were independent of common determinants of BMD, but at the femoral neck, a significant association was only found in female patients. CONCLUSION: Low hip BMD was associated with high CPP-II in patients with Fabry disease, but further work is needed to investigate the relevance of sex-related differences and to establish whether CPP measurement may aid assessment of bone disease in this setting.

The Intrinsic Fragility of the Liquid-Vapor Interface: A Stress Network Perspective.

The evolution of the liquid-vapor interface of a Lennard-Jones fluid is examined with molecular dynamics simulations using the intrinsic sampling method. Results suggest clear damping of the intrinsic profiles with increasing temperature. Investigating the surface stress distribution, we have identified a linear variation of the space-filling nature (fractal dimension) of the stress clusters at the intrinsic surface with increasing surface tension or, equivalently, with decreasing temperature. A percolation analysis of these stress networks indicates that the stress field is more disjointed at higher temperatures. This leads to more fragile (or poorly connected) interfaces which result in a reduction in surface tension.

Viscuit and the fluctuation theorem investigation of shear viscosity by molecular dynamics simulations: The information and the noise.

The shear viscosity, η, of model liquids and solids is investigated within the framework of the viscuit and Fluctuation Theorem (FT) probability distribution function (PDF) theories, following Heyes et al. [J. Chem. Phys. 152, 194504 (2020)] using equilibrium molecular dynamics (MD) simulations on Lennard-Jones and Weeks-Chandler-Andersen model systems. The viscosity can be obtained in equilibrium MD simulation from the first moment of the viscuit PDF, which is shown for finite simulation lengths to give a less noisy plateau region than the Green-Kubo method. Two other formulas for the shear viscosity in terms of the viscuit and PDF analysis are also derived. A separation of the time-dependent average negative and positive viscuits extrapolated from the noise dominated region to zero time provides another route to η. The third method involves the relative number of positive and negative viscuits and their PDF standard deviations on the two sides for an equilibrium system. For the FT and finite shear rates, accurate analytic expressions for the relative number of positive to negative block average shear stresses is derived assuming a shifted Gaussian PDF, which is shown to agree well with non-equilibrium molecular dynamics simulations. A similar treatment of the positive and negative block average contributions to the viscosity is also shown to match the simulation data very well.

Recent Administration of Iodinated Contrast Renders Core Infarct Estimation Inaccurate Using RAPID Software.

BACKGROUND AND PURPOSE: Automated CTP software is increasingly used for extended window emergent large-vessel occlusion to quantify core infarct. We aimed to assess whether RAPID software underestimates core infarct in patients with an extended window recently receiving IV iodinated contrast. MATERIALS AND METHODS: We reviewed a prospective, single-center data base of 271 consecutive patients who underwent CTA ± CTP for acute ischemic stroke from May 2018 through January 2019. Patients with emergent large-vessel occlusion confirmed by CTA in the extended window (>6 hours since last known well) and CTP with RAPID postprocessing were included. Two blinded raters independently assessed CT ASPECTS on NCCT performed at the time of CTP. RAPID software used relative cerebral blood flow of <30% as a surrogate for irreversible core infarct. Patients were dichotomized on the basis of receiving recent IV iodinated contrast (<8 hours before CTP) for a separate imaging study. RESULTS: The recent IV contrast and contrast-naïve cohorts comprised 23 and 15 patients, respectively. Multivariate linear regression analysis demonstrated that recent IV contrast administration was independently associated with a decrease in the RAPID core infarct estimate (proportional increase = 0.34; 95% CI, 0.12-0.96; P = .04). CONCLUSIONS: Patients who received IV iodinated contrast in proximity (<8 hours) to CTA/CTP as part of a separate imaging study had a much higher likelihood of core infarct underestimation with RAPID compared with contrast-naïve patients. Over-reliance on RAPID postprocessing for treatment disposition of patients with extended window emergent large-vessel occlusion should be avoided, particularly with recent IV contrast administration.

Single trajectory transport coefficients and the energy landscape by molecular dynamics simulations.

The Green-Kubo (GK) method is widely used to calculate the transport coefficients of model liquids by Molecular Dynamics (MD) simulation. A reformulation of GK was proposed by Heyes et al. [J. Chem. Phys. 150, 174504 (2019)], which expressed the shear viscosity in terms of a probability distribution function (PDF) of "single trajectory (ST) viscosities," called "viscuits." This approach is extended here to the bulk viscosity, thermal conductivity, and diffusion coefficient. The PDFs of the four STs expressed in terms of their standard deviations (calculated separately for the positive and negative sides) are shown by MD to be statistically the same for the Lennard-Jones fluid. This PDF can be represented well by a sum of exponentials and is independent of system size and state point in the equilibrium fluid regime. The PDF is not well reproduced by a stochastic model. The PDF is statistically the same as that derived from the potential energy, u, and other thermodynamic quantities, indicating that the transport coefficients are determined quantitatively by and follow closely the time evolution of the underlying energy landscape. The PDFs of out-of-equilibrium supercooled high density states are quite different from those of the equilibrium states.

Shear stress relaxation and diffusion in simple liquids by molecular dynamics simulations: Analytic expressions and paths to viscosity.

The results are reported of an equilibrium molecular dynamics simulation study of the shear viscosity, η, and self-diffusion coefficient, D, of the Lennard-Jones liquid using the Green-Kubo (GK) method. Semiempirical analytic expressions for both GK time correlation functions were fitted to the simulation data and used to derive analytic expressions for the time dependent diffusion coefficient and shear viscosity, and also the correlation function frequency transforms. In the case of the shear viscosity for a state point near the triple point, a sech function was found to fit the correlation function significantly better than a gaussian in the ballistic short time regime. A reformulation of the shear GK formula in terms of a time series of time integrals ("viscuits") and contributions to the viscosity from components based on the initial stress ("visclets") enable the GK expressions to be recast in terms of probability distributions which could be used in coarse grained stochastic models of nanoscale flow. The visclet treatment shows that stress relaxation is statistically independent of the initial stress for equilibrium and metastable liquids, suggesting that shear stress relaxation in liquids is diffusion controlled. By contrast, the velocity autocorrelation function is sensitive to the initial velocity. Weak oscillations and a plateau at intermediate times originate to a greater extent from the high velocity tail of the Maxwell-Boltzmann velocity distribution. Simple approximate analytic expressions for the mean square displacement and the self Van Hove correlation function are also derived.

Measuring heat flux beyond Fourier's law.

We use nonequilibrium molecular dynamics to explore the effect of shear flow on heat flux. By simulating a simple fluid in a channel bounded by tethered atoms, the heat flux is computed for two systems: a temperature driven one with no flow and a wall driven, Couette flow system. The results for the temperature driven system give Fourier's law thermal conductivity, which is shown to agree well with experiments. Through comparison of the two systems, we quantify the additional components of the heat flux parallel and normal to the walls due to shear flow. To compute the heat flux in the flow direction, the Irving-Kirkwood equations are integrated over a volume, giving the so-called volume average form, and they are also manipulated to get expressions for the surface averaged and method of planes forms. The method of planes and volume average forms are shown to give equivalent results for the heat flux when using small volumes. The heat flux in the flow direction is obtained consistently over a range of simulations, and it is shown to vary linearly with strain rate, as predicted by theory. The additional strain rate dependent component of the heat flux normal to the wall is obtained by fitting the strain rate dependence of the heat flux to the expected form. As a result, the additional terms in the thermal conductivity tensor quantified in this work should be experimentally testable.

Evaluation of the EntericBio CPE assay for the detection of carbapenemase-producing organisms.

Carbapenemase-producing organisms (CPOs) represent an increasing threat in healthcare facilities and detection of these organisms in the diagnostic laboratory can be challenging. The EntericBio CPE (EBCPE) real-time PCR assay (Serosep Ltd) was evaluated for the detection of NDM, KPC, OXA-48-like, VIM, IMP and GES carbapenemase genes from a panel of 145 multidrug-resistant organisms (29 NDM, 35 OXA-48, 21 VIM, 4 OXA-23, 3 KPC, 5 NDM+OXA-48, 3 GES-5, 1 OXA-23+NDM, 1 IMI, 2 IMP-1 and 41 multidrug-resistant carbapenemase-negative isolates). The EBCPE assay performed well, with 100 % sensitivity and specificity for the detection of all genotypes included in the assay. Turnaround time and laboratory workflow were improved compared to culture-based assays. Users must remain aware of the limitations of molecular assays for CPO detection to ensure implementation of the most suitable CPO diagnostic pathways.

Incremental viscosity by non-equilibrium molecular dynamics and the Eyring model.

The viscoelastic behavior of sheared fluids is calculated by Non-Equilibrium Molecular Dynamics (NEMD) simulation, and complementary analytic solutions of a time-dependent extension of Eyring's model (EM) for shear thinning are derived. It is argued that an "incremental viscosity," η i , or IV which is the derivative of the steady state stress with respect to the shear rate is a better measure of the physical state of the system than the conventional definition of the shear rate dependent viscosity (i.e., the shear stress divided by the strain rate). The stress relaxation function, C i (t), associated with η i is consistent with Boltzmann's superposition principle and is computed by NEMD and the EM. The IV of the Eyring model is shown to be a special case of the Carreau formula for shear thinning. An analytic solution for the transient time correlation function for the EM is derived. An extension of the EM to allow for significant local shear stress fluctuations on a molecular level, represented by a gaussian distribution, is shown to have the same analytic form as the original EM but with the EM stress replaced by its time and spatial average. Even at high shear rates and on small scales, the probability distribution function is almost gaussian (apart from in the wings) with the peak shifted by the shear. The Eyring formula approximately satisfies the Fluctuation Theorem, which may in part explain its success in representing the shear thinning curves of a wide range of different types of chemical systems.

Improving the detection of carbapenemase-producing organisms (CPO) in a low-prevalence setting: evaluation of four commercial methods and implementation of an algorithm of testing.

PURPOSE: Carbapenemase-producing organisms (CPOs) can be resistant to almost all ß-lactams and represent an increasing threat in healthcare facilities. Detection of these organisms in routine diagnostic laboratories is difficult; here we evaluate four commercially available CPO detection assays and assess their suitability for the clinical laboratory. METHODOLOGY: A panel of 95 clinical multidrug-resistant organisms (22 NDM, 24 OXA-48, 19 VIM, 4 OXA-23, 3 KPC, 4 NDM+OXA-48, 1 OXA23+NDM, 1 IMI, 1 IMP-1, 9 ESBL, 3 derepressed AmpC and 4 inducible AmpC producers) were tested by the RESIST-3 O.K.N., RapidEC CarbaNP, Acuitas Resistome and Xpert Carba-R assays.Results/Key Findings. The commercial assays performed well, with high sensitivities (96.2-100 %) and specificities (all, 100 %). The RapidEC CarbaNP and Acuitas Resistome were able to detect the broadest range of carbapenemase genotypes. The RESIST-3 O.K.N. and Xpert CarbaR had the shortest turnaround times, whilst the RapidEC CarbaNP was the only assay included in this study that could detect previously undescribed genotypes. CONCLUSION: Using an algorithm of the RapidEC CarbaNP, followed by either the RESIST-3 O.K.N. (Enterobacteriaceae) or the Xpert Carba-R (Pseudomonas aeruginosa and Acinetobacter spp.) on suspect CPOs allowed rapid in-house detection and genotyping of a high proportion of CPOs, reducing turnaround time by up to 7 days.

Towards the Irving-Kirkwood limit of the mechanical stress tensor.

The probability density functions (PDFs) of the local measure of pressure as a function of the sampling volume are computed for a model Lennard-Jones (LJ) fluid using the Method of Planes (MOP) and Volume Averaging (VA) techniques. This builds on the study of Heyes, Dini, and Smith [J. Chem. Phys. 145, 104504 (2016)] which only considered the VA method for larger subvolumes. The focus here is typically on much smaller subvolumes than considered previously, which tend to the Irving-Kirkwood limit where the pressure tensor is defined at a point. The PDFs from the MOP and VA routes are compared for cubic subvolumes, V=ℓ3. Using very high grid-resolution and box-counting analysis, we also show that any measurement of pressure in a molecular system will fail to exactly capture the molecular configuration. This suggests that it is impossible to obtain the pressure in the Irving-Kirkwood limit using the commonly employed grid based averaging techniques. More importantly, below ℓ≈3 in LJ reduced units, the PDFs depart from Gaussian statistics, and for ℓ=1.0, a double peaked PDF is observed in the MOP but not VA pressure distributions. This departure from a Gaussian shape means that the average pressure is not the most representative or common value to arise. In addition to contributing to our understanding of local pressure formulas, this work shows a clear lower limit on the validity of simply taking the average value when coarse graining pressure from molecular (and colloidal) systems.

Parenteral iron polymaltose changes i:c-terminal FGF23 ratios in iron deficiency, but not in dialysis patients.

BACKGROUND/OBJECTIVES: Iron and phosphate are both vital to many biological cellular processes with central roles in energy metabolism, cellular proliferation and nucleic acid synthesis. Regulatory pathways in some of these metabolic pathways may intersect at fibroblast growth factor 23 (FGF23), a major phosphate regulatory hormone. Iron is reported to induce hypophosphataemia in rare cases, and recent reports suggest that iron deficiency may upregulate FGF23 synthesis by mechanisms involving hypoxia-inducible factor 1α (HIF1α). Our objective was to evaluate the effect of administration of intravenous iron polymaltose on intact and c-terminal FGF23 (i:cFGF23) ratios in two independent cohorts of patients, iron-deficient but non-inflamed patients and haemodialysis (HD)-dependent patients, and to examine the balance of synthesis and degradation. SUBJECTS/METHODS: We studied biochemical effects of intravenous iron polymaltose on both iFGF23 and cFGF23 fragments and their ratios in two patient groups: iron-deficient patients with normal renal function (ID-norm) and HD patients receiving iron supplementation (HD-ESKD) at a single institution. Patients were tested at baseline, day 4 and day 12 post iron administration. RESULTS: Parenteral iron polymaltose resulted in increased i:cFGF23 ratios in ID-norm patients where circulating cFGF23 levels decreased with no appreciable effect on iFGF23, whereas no significant changes in i:cFGF23 ratios were observed in HD-ESKD patients following intravenous administration of 100mg iron polymaltose. CONCLUSIONS: Dysregulation of intracellular FGF23-processing mechanisms may be related to iron deficiency per se rather than iron repletion with iron polymaltose. In ID-norm, i:cFGF23 ratios altered with iron administration without significant clinical alterations in mineral parameters, implying that other regulatory mechanisms may be important. Finally, iron supplementation in HD-ESKD patients does not appear to significantly affect i:cFGF23 ratios already disturbed by a chronic inflammatory or functionally iron-deficient state.

A Langevin model for fluctuating contact angle behaviour parametrised using molecular dynamics.

Molecular dynamics simulations are employed to develop a theoretical model to predict the fluid-solid contact angle as a function of wall-sliding speed incorporating thermal fluctuations. A liquid bridge between counter-sliding walls is studied, with liquid-vapour interface-tracking, to explore the impact of wall-sliding speed on contact angle. The behaviour of the macroscopic contact angle varies linearly over a range of capillary numbers beyond which the liquid bridge pinches off, a behaviour supported by experimental results. Nonetheless, the liquid bridge provides an ideal test case to study molecular scale thermal fluctuations, which are shown to be well described by Gaussian distributions. A Langevin model for contact angle is parametrised to incorporate the mean, fluctuation and auto-correlations over a range of sliding speeds and temperatures. The resulting equations can be used as a proxy for the fully-detailed molecular dynamics simulation allowing them to be integrated within a continuum-scale solver.

Equilibrium fluctuations of liquid state static properties in a subvolume by molecular dynamics.

System property fluctuations increasingly dominate a physical process as the sampling volume decreases. The purpose of this work is to explore how the fluctuation statistics of various thermodynamic properties depend on the sampling volume, using molecular dynamics (MD) simulations. First an examination of various expressions for calculating the bulk pressure of a bulk liquid is made, which includes a decomposition of the virial expression into two terms, one of which is the Method of Planes (MOP) applied to the faces of the cubic simulation cell. Then an analysis is made of the fluctuations of local density, temperature, pressure, and shear stress as a function of sampling volume (SV). Cubic and spherical shaped SVs were used within a spatially homogeneous LJ liquid at a state point along the melting curve. It is shown that the MD-generated probability distribution functions (PDFs) of all of these properties are to a good approximation Gaussian even for SV containing only a few molecules (∼10), with the variances being inversely proportional to the SV volume, Ω. For small subvolumes the shear stress PDF fits better to a Gaussian than the pressure PDF. A new stochastic sampling technique to implement the volume averaging definition of the pressure tensor is presented, which is employed for cubic, spherical, thin cubic, and spherical shell SV. This method is more efficient for less symmetric SV shapes.

A localized momentum constraint for non-equilibrium molecular dynamics simulations.

A method which controls momentum evolution in a sub-region within a molecular dynamics simulation is derived from Gauss's principle of least constraint. The technique for localization is founded on the equations by Irving and Kirkwood [J. Chem. Phys. 18, 817 (1950)] expressed in a weak form according to the control volume (CV) procedure derived by Smith et al. [Phys. Rev. E. 85, 056705 (2012)]. A term for the advection of molecules appears in the derived constraint and is shown to be essential in order to exactly control the time evolution of momentum in the subvolume. The numerical procedure converges the total momentum in the CV to the target value to within machine precision in an iterative manner. The localized momentum constraint can prescribe essentially arbitrary flow fields in non-equilibrium molecular dynamics simulations. The methodology also forms a rigorous mathematical framework for introducing coupling constraints at the boundary between continuum and discrete systems. This functionality is demonstrated with a boundary-driven flow test case.

The method of planes pressure tensor for a spherical subvolume.

Various formulas for the local pressure tensor based on a spherical subvolume of radius, R, are considered. An extension of the Method of Planes (MOP) formula of Todd et al. [Phys. Rev. E 52, 1627 (1995)] for a spherical geometry is derived using the recently proposed Control Volume formulation [E. R. Smith, D. M. Heyes, D. Dini, and T. A. Zaki, Phys. Rev. E 85, 056705 (2012)]. The MOP formula for the purely radial component of the pressure tensor is shown to be mathematically identical to the Radial Irving-Kirkwood formula. Novel offdiagonal elements which are important for momentum conservation emerge naturally from this treatment. The local pressure tensor formulas for a plane are shown to be the large radius limits of those for spherical surfaces. The radial-dependence of the pressure tensor computed by Molecular Dynamics simulation is reported for virtual spheres in a model bulk liquid where the sphere is positioned randomly or whose center is also that of a molecule in the liquid. The probability distributions of angles relating to pairs of atoms which cross the surface of the sphere, and the center of the sphere, are presented as a function of R. The variance in the shear stress calculated from the spherical Volume Averaging method is shown to converge slowly to the limiting values with increasing radius, and to be a strong function of the number of molecules in the simulation cell.

Neurointerventions in children: radiation exposure and its import.

BACKGROUND AND PURPOSE: Neurointerventions in children have dramatically improved the clinical outlook for patients with previously intractable cerebrovascular conditions, such as vein of Galen malformations and complex arteriovenous fistulas. However, these complex and sometimes lengthy procedures are performed under fluoroscopic guidance and thus unavoidably expose vulnerable pediatric patients to the effects of ionizing radiation. Recent epidemiologic evidence from a national registry of children who underwent CT scans suggests a higher-than-expected incidence of secondary tumors. We sought to calculate the predicted risk of secondary tumors in a large cohort of pediatric neurointerventional patients. MATERIALS AND METHODS: We reviewed our cohort of pediatric neurointerventions, tabulated radiation dose delivered to the skin, and calculated the range of likely brain-absorbed doses by use of previously developed mathematical models. The predicted risk of secondary tumor development as a function of brain-absorbed dose in this cohort was then generated by use of the head CT registry findings. RESULTS: Maximal skin dose and brain-absorbed doses in our cohort were substantially lower than have been previously described. However, we found 1) a statistically significant correlation between radiation dose and age at procedure, as well as number and type of procedures, and 2) a substantial increase in lifetime predicted risk of tumor above baseline in the cohort of young children who undergo neurointerventions. CONCLUSIONS: Although neurointerventional procedures have dramatically improved the prognosis of children facing serious cerebrovascular conditions, the predicted risk of secondary tumors, particularly in the youngest patients and those undergoing multiple procedures, is sobering.

Large vessel calcification in Takayasu arteritis.

We report the novel case of a young woman with Takayasu arteritis, with extensive large vessel disease. The case demonstrates that while mechanisms of vascular calcification are poorly understood, inflammation per se might be sufficient to mediate increased mineral stress leading to vessel calcification, even in the absence of renal impairment.