Contributions beyond direct random-phase approximation in the binding energy of solid ethane, ethylene, and acetylene.

The random-phase approximation (RPA) includes a subset of higher than second-order correlation-energy contributions, but stays in the same complexity class as the second-order Møller-Plesset perturbation theory (MP2) in both Gaussian-orbital and plane-wave codes. This makes RPA a promising ab initio electronic structure approach for the binding energies of molecular crystals. Still, some issues stand out in practical applications of RPA. Notably, compact clusters of nonpolar molecules are poorly described, and the interaction energies strongly depend on the reference single-determinant state. Using the many-body expansion of the binding energy of a crystal, we investigate those issues and the effect of beyond-RPA corrections. We find the beneficial effect of quartic-scaling exchange and non-ring coupled-cluster doubles corrections. The nonadditive interactions in compact trimers of molecules are improved by using the self-consistent Hartree-Fock orbitals instead of the usual Kohn-Sham states, but this kind of orbital input also leads to underestimated dimer energies. Overall, a substantial improvement over the RPA with a renormalized singles approach is possible at a modest quartic-scaling cost, which encourages further research into additional RPA corrections.

Using Noncovalent Interactions to Test the Precision of Projector-Augmented Wave Data Sets.

The projector-augmented wave (PAW) method is one of the approaches that are widely used to approximately treat core electrons and thus to speed up plane-wave basis set electronic structure calculations. However, PAW involves approximations, and it is thus important to understand how they affect the results. Tests of the precision of PAW data sets often use the properties of isolated atoms or atomic solids. While this is sufficient to identify problematic PAW data sets, little information has been gained to understand the origins of the errors and suggest ways to correct them. Here, we show that the interaction energies of molecular dimers are very useful not only to identify problematic PAW data sets but also to uncover the origin of the errors. Using dimers from the S22 and S66 test sets and other dimers, we find that the error in the interaction energy is composed of a short-range component with an exponential decay and a long-range electrostatic part caused by an error in the total charge density. We propose and evaluate a simple improvable scheme to correct the long-range error and find that even in its simple and readily usable form, it is able to reduce the interaction energy errors to less than half on average for hydrogen-bonded dimers.

Magnetically Induced Binary Ferrocene with Oxidized Iron.

Ferrocene is perhaps the most popular and well-studied organometallic molecule, but our understanding of its structure and electronic properties has not changed for more than 70 years. In particular, all previous attempts of chemically oxidizing pure ferrocene by binding directly to the iron center have been unsuccessful, and no significant change in structure or magnetism has been reported. Using a metal organic framework host material, we were able to fundamentally change the electronic and magnetic structure of ferrocene to take on a never-before observed physically stretched/bent high-spin Fe(II) state, which readily accepts O2 from air, chemically oxidizing the iron from Fe(II) to Fe(III). We also show that the binding of oxygen is reversible through temperature swing experiments. Our analysis is based on combining Mößbauer spectroscopy, extended X-ray absorption fine structure, in situ infrared, SQUID, thermal gravimetric analysis, and energy dispersive X-ray fluorescence spectroscopy measurements with ab initio modeling.

Assessment of random phase approximation and second-order Møller-Plesset perturbation theory for many-body interactions in solid ethane, ethylene, and acetylene.

The relative energies of different phases or polymorphs of molecular solids can be small, less than a kilojoule/mol. A reliable description of such energy differences requires high-quality treatment of electron correlations, typically beyond that achievable by routinely applicable density functional theory (DFT) approximations. At the same time, high-level wave function theory is currently too computationally expensive. Methods employing an intermediate level of approximations, such as Møller-Plesset (MP) perturbation theory and the random phase approximation (RPA), are potentially useful. However, their development and application for molecular solids has been impeded by the scarcity of necessary benchmark data for these systems. In this work, we employ the coupled-cluster method with singles, doubles, and perturbative triples to obtain a reference-quality many-body expansion of the binding energy of four crystalline hydrocarbons with a varying π-electron character: ethane, ethene, and cubic and orthorhombic forms of acetylene. The binding energy is resolved into explicit dimer, trimer, and tetramer contributions, which facilitates the analysis of errors in the approximate approaches. With the newly generated benchmark data, we test the accuracy of MP2 and non-self-consistent RPA. We find that both of the methods poorly describe the non-additive many-body interactions in closely packed clusters. Using different DFT input states for RPA leads to similar total binding energies, but the many-body components strongly depend on the choice of the exchange-correlation functional.

Helicobacter Species and Their Association with Gastric Pathology in a Cohort of Dogs with Chronic Gastrointestinal Signs.

Prevalence of individual Helicobacter species, data evaluating their association with gastric pathology and comparison of accuracy of diagnostic techniques are limited. The aims of this study were to determine the prevalence of gastric Helicobacter species, their association with gastric pathology, and to compare diagnostic techniques. Gastric biopsies from 84 privately-owned dogs with chronic gastrointestinal signs were obtained endoscopically. Helicobacters were detected using PCR, cytology, urease test, and histopathology. PCR detected helicobacters in 71.4% of dogs. Helicobacter heilmannii sensu stricto (s.s.) was the predominant species. Mixed infection was detected in 40% of PCR positive dogs. Gastritis was diagnosed in 38.5% of Helicobacter positive and 47.4% of Helicobacter negative dogs. Mono-infection was associated with 2.4 times increased odds of having more severe inflammation compared to mixed infection. Erosions and ulcers were common endoscopic lesions. Cytology had sensitivity/specificity of 88.3/91.7%. Association between infection and lymphoid follicular hyperplasia was demonstrated.

Ferroelectric 2D ice under graphene confinement.

We here report on the direct observation of ferroelectric properties of water ice in its 2D phase. Upon nanoelectromechanical confinement between two graphene layers, water forms a 2D ice phase at room temperature that exhibits a strong and permanent dipole which depends on the previously applied field, representing clear evidence for ferroelectric ordering. Characterization of this permanent polarization with respect to varying water partial pressure and temperature reveals the importance of forming a monolayer of 2D ice for ferroelectric ordering which agrees with ab-initio and molecular dynamics simulations conducted. The observed robust ferroelectric properties of 2D ice enable novel nanoelectromechanical devices that exhibit memristive properties. A unique bipolar mechanical switching behavior is observed where previous charging history controls the transition voltage between low-resistance and high-resistance state. This advance enables the realization of rugged, non-volatile, mechanical memory exhibiting switching ratios of 106, 4 bit storage capabilities and no degradation after 10,000 switching cycles.

Random-Phase Approximation in Many-Body Noncovalent Systems: Methane in a Dodecahedral Water Cage.

The many-body expansion (MBE) of energies of molecular clusters or solids offers a way to detect and analyze errors of theoretical methods that could go unnoticed if only the total energy of the system was considered. In this regard, the interaction between the methane molecule and its enclosing dodecahedral water cage, CH4···(H2O)20, is a stringent test for approximate methods, including density functional theory (DFT) approximations. Hybrid and semilocal DFT approximations behave erratically for this system, with three- and four-body nonadditive terms having neither the correct sign nor magnitude. Here, we analyze to what extent these qualitative errors in different MBE contributions are conveyed to post-Kohn-Sham random-phase approximation (RPA), which uses approximate Kohn-Sham orbitals as its input. The results reveal a correlation between the quality of the DFT input states and the RPA results. Moreover, the renormalized singles energy (RSE) corrections play a crucial role in all orders of the many-body expansion. For dimers, RSE corrects the RPA underbinding for every tested Kohn-Sham model: generalized-gradient approximation (GGA), meta-GGA, (meta-)GGA hybrids, as well as the optimized effective potential at the correlated level. Remarkably, the inclusion of singles in RPA can also correct the wrong signs of three- and four-body nonadditive energies as well as mitigate the excessive higher-order contributions to the many-body expansion. The RPA errors are dominated by the contributions of compact clusters. As a workable method for large systems, we propose to replace those compact contributions with CCSD(T) energies and to sum up the remaining many-body contributions up to infinity with supermolecular or periodic RPA. As a demonstration of this approach, we show that for RPA(PBE0)+RSE it suffices to apply CCSD(T) to dimers and 30 compact, hydrogen-bonded trimers to get the methane-water cage interaction energy to within 1.6% of the reference value.

An Investigation into the Prevalence of Migraine and Its Prophylactic Treatment Patterns in the Czech Republic: An Observational Study.

PURPOSE: A national primary and secondary healthcare-level study in the Czech Republic has not yet been conducted to evaluate the prevalence of migraine. We analyzed the current treatment patterns (acute and prophylactic) in migraine patients and the number of migraine patients potentially eligible for treatment with recent calcitonin gene-related peptide (CGRP) pathway-targeted therapies. METHODS: This retrospective study utilized the Ministry of the Interior Health Insurance Fund claims database of the Czech Republic wherein every citizen is insured. Migraine patients with or without aura, and potentially on triptan therapy were included in this study (index years 2012-2016). The prevalence approach included all patients (new and old) present in each index year. Prophylactic therapies were followed f0or three and seven years prior to the index year, including the index year, until 2010. The incidence approach included all patients first diagnosed in each index year. Prophylactic therapies were followed for the next three years, including the index year, until 2017 following incidence approach. The primary endpoint of this study was to determine the rate of migraine prevalence and diagnosis for each index year during the period 2012-2016. The study also evaluated prophylactic and acute treatment patterns and comorbidities among patients in 2016. RESULTS: The rate of migraine prevalence was 1% and the rate of diagnosis was 0.2-0.4%. By prevalence approach, approximately 39% of the patients were on prophylactics, and 11.2% and 21.6% of the patient population had two prior treatment failures (three- and seven-year recall period, respectively). Antiepileptics (26%) and beta blockers (15.8%) were the most prescribed prophylactics, and sumatriptan was the predominant triptan used (12%) for acute treatment. CONCLUSION: Taking into account the number of inhabitants in the Czech Republic (10.7 million), there could be up to 23,000 adult patients eligible for novel CGRP therapies.

Anomalous Freezing of Low-Dimensional Water Confined in Graphene Nanowrinkles.

Various properties of water are affected by confinement as the space-filling of the water molecules is very different from bulk water. In our study, we challenged the creation of a stable system in which water molecules are permanently locked in nanodimensional graphene traps. For that purpose, we developed a technique, nitrocellulose-assisted transfer of graphene grown by chemical vapor deposition, which enables capturing of the water molecules below an atomically thin graphene membrane structured into a net of regular wrinkles with a lateral dimension of about 4 nm. After successfully confining water molecules below a graphene monolayer, we employed cryogenic Raman spectroscopy to monitor the phase changes of the confined water as a function of the temperature. In our experiment system, the graphene monolayer structured into a net of fine wrinkles plays a dual role: (i) it enables water confinement and (ii) serves as an extremely sensitive probe for phase transitions involving water via graphene-based spectroscopic monitoring of the underlying water structure. Experimental findings were supported with classical and path integral molecular dynamics simulations carried out on our experimental system. Results of simulations show that surface premelting of the ice confined within the wrinkles starts at ∼200 K and the melting process is complete at ∼240 K, which is far below the melting temperature of bulk water ice. The processes correspond to changes in the doping and strain in the graphene tracked by Raman spectroscopy. We conclude that water can be confined between graphene structured into nanowrinkles and silica substrate and its phase transitions can be tracked via Raman spectral feature of the encapsulating graphene. Our study also demonstrated that peculiar behavior of liquids under spatial confinement can be inspected via the optical response of atomically thin graphene sensors.

Random Phase Approximation Applied to Many-Body Noncovalent Systems.

The random phase approximation (RPA) has received considerable interest in the field of modeling systems where noncovalent interactions are important. Its advantages over widely used density functional theory (DFT) approximations are the exact treatment of exchange and the description of long-range correlation. In this work, we address two open questions related to RPA. First, we demonstrate how accurately RPA describes nonadditive interactions encountered in many-body expansion of a binding energy. We consider three-body nonadditive energies in molecular and atomic clusters. Second, we address how the accuracy of RPA depends on input provided by different DFT models, without resorting to self-consistent RPA procedure, which is currently impractical for calculations employing periodic boundary conditions. We find that RPA based on the SCAN0 and PBE0 models, that is, hybrid DFT, achieves an overall accuracy between CCSD and MP3 on a data set of molecular trimers from Rezác et al. ( J. Chem. Theory. Comput. 2015 , 11 , 3065 ). Finally, many-body expansion for molecular clusters and solids often leads to a large number of small contributions that need to be calculated with high precision. We therefore present a cubic-scaling (or self-consistent field (SCF)-like) implementation of RPA in atomic basis set, which is designed for calculations with high numerical precision.

Efficient and accurate description of adsorption in zeolites.

Accurate theoretical methods are needed to correctly describe adsorption on solid surfaces or in porous materials. The random phase approximation (RPA) with singles corrections scheme and the second order Møller-Plesset perturbation theory (MP2) are two schemes, which offer high accuracy at affordable computational cost. However, there is little knowledge about their applicability and reliability for different adsorbates and surfaces. Here, we calculate adsorption energies of seven different molecules in zeolite chabazite to show that RPA with singles corrections is superior to MP2, not only in terms of accuracy but also in terms of computer time. Therefore, RPA with singles is a suitable scheme for obtaining highly accurate adsorption energies in porous materials and similar systems.

Indacaterol/Glycopyrronium versus Salmeterol/Fluticasone in Patients with COPD-A Cost-Effectiveness Analysis in the Czech Republic.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) represents an illness with significant healthcare and societal impacts. Fixed combinations of long-acting beta-agonists (LABA) and inhaled corticosteroids have been used for COPD treatment as the standard of care for many years. A daily dose of indacaterol and glycopyrronium (IND/GLY) at 110/50 µg has recently been gaining attention due to its improved efficacy and tolerability versus the standard of care.The study aims to evaluate the cost-effectiveness of once daily IND/GLY vs. twice daily salmeterol/fluticasone propionate (SFC) at 50/500 µg in COPD patients. METHODS: A microsimulation model in MS Excel was adapted to the Czech setting. Effectiveness data and disease severity stages were obtained from the FLAME study, which is a head-to head trial comparing IND/GLY vs. SFC. Quality of life data were derived from a literature review. Costs (medication, monitoring and complications) were taken from published Czech sources. The incremental cost-effectiveness ratio (ICER) was expressed as cost per quality-adjusted life year (QALY) gained. Costs and outcomes were discounted at 3 %. A lifetime horizon was used for the analysis. Cost-effectiveness was studied from the perspective of a health care system in the Czech Republic. RESULTS: Mean QALYs were higher in the IND/GLY arm (difference 0.167 QALYs). The ICER of IND/GLY compared with SFC was €13,628 per QALY gained. Deterministic sensitivity analyses and probabilistic sensitivity analyses confirmed the base-case result to be robust. CONCLUSIONS: From the perspective of the Czech health care system, managing COPD using IND/GLY is cost-effective in this analysis because the base-case is clearly below the willingness-to-pay threshold in the Czech Republic, which is automatically set at 3 times GDP/capita (approximately €44,000/ QALY). This is the first available economic analysis utilizing FLAME study results in the Central East European (CEE) countries showing IND/ GLY as a highly cost-effective investment into COPD patients.

Fast and accurate quantum Monte Carlo for molecular crystals.

Computer simulation plays a central role in modern-day materials science. The utility of a given computational approach depends largely on the balance it provides between accuracy and computational cost. Molecular crystals are a class of materials of great technological importance which are challenging for even the most sophisticated ab initio electronic structure theories to accurately describe. This is partly because they are held together by a balance of weak intermolecular forces but also because the primitive cells of molecular crystals are often substantially larger than those of atomic solids. Here, we demonstrate that diffusion quantum Monte Carlo (DMC) delivers subchemical accuracy for a diverse set of molecular crystals at a surprisingly moderate computational cost. As such, we anticipate that DMC can play an important role in understanding and predicting the properties of a large number of molecular crystals, including those built from relatively large molecules which are far beyond reach of other high-accuracy methods.

A model of natural degradation of 17-α-ethinylestradiol in surface water and identification of degradation products by GC-MS.

Over the past decade, the environment has been polluted by a wide spectrum of exogenous chemicals and environmental analysis has become one of the most progressive parts of analytical research. The aim of this work was to determine the kinetics of natural degradation, and to identify the degradation products of the massively used estrogenic drug, 17-α-ethinylestradiol. The photodegradation, oxidation and thermostability conditions were selected according to ICH requirements for pharmaceutical stability testing. A simple 72-h photodegradation study in purified water exhibited significant first-order kinetics with the kinetic constant k = 0.0303 h-1, and degradation halftime 22.8 h. The basic halftime could be reduced to 17.1 h by the addition of sea salt, and increase in temperature. Monohydroxy, dihydroxy and dehydrogenated derivatives of ethinylestradiol with intact steroidal structure were identified as major degradation products resulting from simple photodegradation. The addition of an oxidative agent significantly accelerated the degradation rate; combined with higher temperature, the degradation halftime was reduced to 1.1 h with the first-order kinetic constant k = 0.632 h-1. TOC analysis showed a notable decrease of organic mass (18% in 3 days) during oxidation experiments, and confirmed the degradation of steroidal structure.

Cost-of-illness analysis and regression modeling in cystic fibrosis: a retrospective prevalence-based study.

BACKGROUND: Economic data pertaining to cystic fibrosis (CF), is limited in Europe generally, and completely lacking in Central and Eastern Europe. We performed an analysis of all direct costs associated with CF relative to key disease features and laboratory examinations. METHODS: A retrospective prevalence-based cost-of-illness (COI) study was performed in a representative cohort of 242 CF patients in the Czech Republic, which represents about 65 % of all Czech CF patients. Medical records and invoices to health insurance companies for reference year 2010 were analyzed. RESULTS: The mean total health care costs were €14,486 per patient, with the majority of the costs going towards medicinal products and devices (€10,321). Medical procedures (€2676) and inpatient care (€1829) represented a much smaller percentage of costs. A generalized linear model showed that the strongest cost drivers, for all cost categories, were associated with patient age and lung disease severity (assessed using the FEV1 spirometric parameter), when compounded by chronic Pseudomonas aeruginosa airway infections. Specifically, maximum total costs are around the age 16 years; a FEV1 increase of 1 % point represented a cost decrease of: 0.9 % (medicinal products), 1.7 % (total costs), 2.8 % (procedures) and 7.0 % (inpatient care). CONCLUSIONS: COI analysis and regression modeling using the most recent data available can provide a better understanding of the overall economic CF burden. A comparison of our results with other methodologically similar studies demonstrates that although overall costs may differ, FEV1 can nonetheless be utilized as a generally transferrable indicator of the relative economic impact of CF.

Lattice energies of molecular solids from the random phase approximation with singles corrections.

We use the random phase approximation (RPA) method with the singles correlation energy contributions to calculate lattice energies of ten molecular solids. While RPA gives too weak binding, underestimating the reference data by 13.7% on average, much improved results are obtained when the singles are included at the GW singles excitations (GWSE) level, with average absolute difference to the reference data of only 3.7%. Consistently with previous results, we find a very good agreement with the reference data for hydrogen bonded systems, while the binding is too weak for systems where dispersion forces dominate. In fact, the overall accuracy of the RPA+GWSE method is similar to an estimated accuracy of the reference data.

Placental passage of olomoucine II, but not purvalanol A, is affected by p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins (ABCCs).

1. Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date. 2. In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A. 3. Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area.

Singles correlation energy contributions in solids.

The random phase approximation to the correlation energy often yields highly accurate results for condensed matter systems. However, ways how to improve its accuracy are being sought and here we explore the relevance of singles contributions for prototypical solid state systems. We set out with a derivation of the random phase approximation using the adiabatic connection and fluctuation dissipation theorem, but contrary to the most commonly used derivation, the density is allowed to vary along the coupling constant integral. This yields results closely paralleling standard perturbation theory. We re-derive the standard singles of Görling-Levy perturbation theory [A. Görling and M. Levy, Phys. Rev. A 50, 196 (1994)], highlight the analogy of our expression to the renormalized singles introduced by Ren and coworkers [Phys. Rev. Lett. 106, 153003 (2011)], and introduce a new approximation for the singles using the density matrix in the random phase approximation. We discuss the physical relevance and importance of singles alongside illustrative examples of simple weakly bonded systems, including rare gas solids (Ne, Ar, Xe), ice, adsorption of water on NaCl, and solid benzene. The effect of singles on covalently and metallically bonded systems is also discussed.

Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro.

Dinaciclib is a novel cyclin-dependent kinase inhibitor (CDKI) with significant activity against various cancers in vitro and in vivo. ABC efflux transporters play an important role in drug disposition and are responsible for multidrug resistance in cancer cells. Inhibitors and substrates of these transporters may participate in pharmacokinetic drug-drug interactions (DDIs) that alter drug disposition during pharmacotherapy. To assess such risks associated with dinaciclib we evaluated its possible effects on efflux activities of ABCB1, ABCC1 and ABCG2 transporters in vitro. Monolayer transport, XTT cell proliferation, ATPase and intracellular accumulation assays were employed. Here, we show that the transport ratio of dinaciclib was far higher across monolayers of MDCKII-ABCB1 and MDCKII-ABCG2 cells than across MDCKII parental cell layers, demonstrating that dinaciclib is a substrate of ABCB1 and ABCG2. In addition, overexpression of ABCB1, ABCG2 and ABCC1 conferred resistance to dinaciclib in MDCKII cells. In ATPase assays, dinaciclib decreased stimulated ATPase activity of ABCB1, ABCG2 and ABCC1, confirming it has interactive potential toward all three transporters. Moreover, dinaciclib significantly inhibited ABCC1-mediated efflux of daunorubicin (EC50=18 µM). The inhibition of ABCC1 further led to a synergistic effect of dinaciclib in both MDCKII-ABCC1 and human cancer T47D cells, when applied in combination with anticancer drugs. Taken together, our results suggest that ABC transporters can substantially affect dinaciclib transport across cellular membranes, leading to DDIs. The DDIs of dinaciclib with ABCC1 substrate chemotherapeutics might be exploited in novel cancer therapies.

The accurate calculation of the band gap of liquid water by means of GW corrections applied to plane-wave density functional theory molecular dynamics simulations.

Knowledge about the intrinsic electronic properties of water is imperative for understanding the behaviour of aqueous solutions that are used throughout biology, chemistry, physics, and industry. The calculation of the electronic band gap of liquids is challenging, because the most accurate ab initio approaches can be applied only to small numbers of atoms, while large numbers of atoms are required for having configurations that are representative of a liquid. Here we show that a high-accuracy value for the electronic band gap of water can be obtained by combining beyond-DFT methods and statistical time-averaging. Liquid water is simulated at 300 K using a plane-wave density functional theory molecular dynamics (PW-DFT-MD) simulation and a van der Waals density functional (optB88-vdW). After applying a self-consistent GW correction the band gap of liquid water at 300 K is calculated as 7.3 eV, in good agreement with recent experimental observations in the literature (6.9 eV). For simulations of phase transformations and chemical reactions in water or aqueous solutions whereby an accurate description of the electronic structure is required, we suggest to use these advanced GW corrections in combination with the statistical analysis of quantum mechanical MD simulations.