Physiologically based pharmacokinetic modelling of cefoperazone in paediatrics.

AIMS: Cefoperazone is commonly used off-label in the treatment of bacterial meningitis and sepsis in children, and the pharmacokinetic (PK) data are limited in this vulnerable population. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict pediatric cefoperazone exposure for rational dosing recommendations. METHODS: A cefoperazone PBPK model for adults was first constructed using Simcyp V22 simulator. Subsequently, the model was extended to children based on the built in age-dependent physiological parameters, while the drug characteristics remained unchanged. The verified pediatric PBPK model was then utilized to assess the rationality of the common dosing regimens for children at different age groups. RESULTS: Cefoperazone PBPK model included elimination via biliary excretion, glomerular filtration, and organic anion transporter 3 (OAT3)-mediated tubular secretion. 95.2% of the observed mean concentrations and 100% of the area under the plasma drug concentration-time curve (AUC) and peak concentration (Cmax) in adults were within a twofold range of model mean predictions. Good predictive accuracy was also observed in children, including neonates. 50 mg/kg q12h cefoperazone demonstrated effective target attainment in virtual term neonates (<1 month) when the MIC was ≤1 mg/L, adhering to the stringent PK/PD target of 75% fT > MIC. 37.5 mg/kg q12h cefoperazone achieved the common 50% fT > MIC target for an MIC ≤ 0. 25 mg/L in virtual pediatric patients ranging from 1 month to 18 years of age. CONCLUSIONS: A pediatric PBPK model was developed for cefoperazone, and it could serve as the basis for deriving rational dosing regimens in children.

Evaluation of Various Approaches to Estimate Transplacental Clearance of Vancomycin for Predicting Fetal Concentrations using a Maternal-Fetal Physiologically Based Pharmacokinetic Model.

BACKGROUND: Evaluating drug transplacental clearance is vital for forecasting fetal drug exposure. Ex vivo human placenta perfusion experiments are the most suitable approach for this assessment. Various in silico methods are also proposed. This study aims to compare these prediction methods for drug transplacental clearance, focusing on the large molecular weight drug vancomycin (1449.3 g/mol), using maternal-fetal physiologically based pharmacokinetic (m-f PBPK) modeling. METHODS: Ex vivo human placenta perfusion experiments, in silico approaches using intestinal permeability as a substitute (quantitative structure property relationship (QSPR) model and Caco-2 permeability in vitro-in vivo correlation model) and midazolam calibration model with Caco-2 scaling were assessed for determining the transplacental clearance (CLPD) of vancomycin. The m-f PBPK model was developed stepwise using Simcyp, incorporating the determined CLPD values as a crucial input parameter for transplacental kinetics. RESULTS: The developed PBPK model of vancomycin for non-pregnant adults demonstrated excellent predictive performance. By incorporating the CLPD parameterization derived from ex vivo human placenta perfusion experiments, the extrapolated m-f PBPK model consistently predicted maternal and fetal concentrations of vancomycin across diverse doses and distinct gestational ages. However, when the CLPD parameter was derived from alternative prediction methods, none of the extrapolated maternal-fetal PBPK models produced fetal predictions in line with the observed data. CONCLUSION: Our study showcased that combination of ex vivo human placenta perfusion experiments and m-f PBPK model has the capability to predict fetal exposure for the large molecular weight drug vancomycin, whereas other in silico approaches failed to achieve the same level of accuracy.

A perspective of ecological civilization: research on the spatial coupling and coordination of the energy-economy-environment system in the Yangtze River Economic Belt.

The concept of sustainable economic development as the core promotes socio-economic progress and rapid economic development. Nevertheless, in the new era of China, the contradiction between socio-economic development and environmental sustainability is still prominent. In order to deal with the coordinated development relationship among regional economy, energy, and environment, this paper constructs an energy-economy-environment (3E) index system from the perspective of green development and ecological integrity. On this basis, the distance-based coupling coordinated degree (CCD) model and dynamically comprehensive coordination degree model were used to evaluate the coupling coordinated development levels of 11 provinces (cities) along the Yangtze River Economic Belt (YREB) from 2008 to 2017. Then, a spatial econometric model was used to explore the spatial effects of the regional 3E system of the YREB. The results indicated that (1) the overall coordination of the 3E system in the provinces (cities) along the YREB shows an increasing trend. However, change paths varied with the provinces (cities) due to the influence of regional policies; (2) the CCD of the 3E system in the YREB differed spatially significantly, showing a stepped distribution of "high in the east and low in the west"; (3) the 3E system in the YREB had a positive spatial correlation and showed the characteristics of aggregation, with Jiangsu and Zhejiang provinces mainly showing "high-high" agglomeration and Sichuan showing "high-low" aggregation, while the rest of the provinces had the characteristics of random distribution in terms of spatial effects. The research process and results show that combining the ecological civilization concept and the CCD model can provide the vision and indicators for evaluating and researching the regional 3E system.

Stochastic equation of motion approach to fermionic dissipative dynamics. II. Numerical implementation.

This paper provides a detailed account of the numerical implementation of the stochastic equation of motion (SEOM) method for the dissipative dynamics of fermionic open quantum systems. To enable direct stochastic calculations, a minimal auxiliary space (MAS) mapping scheme is adopted, with which the time-dependent Grassmann fields are represented by c-number noises and a set of pseudo-operators. We elaborate on the construction of the system operators and pseudo-operators involved in the MAS-SEOM, along with the analytic expression for the particle current. The MAS-SEOM is applied to study the relaxation and voltage-driven dynamics of quantum impurity systems described by the single-level Anderson impurity model, and the numerical results are benchmarked against those of the highly accurate hierarchical equations of motion method. The advantages and limitations of the present MAS-SEOM approach are discussed extensively.

Stochastic equation of motion approach to fermionic dissipative dynamics. I. Formalism.

In this work, we establish formally exact stochastic equation of motion (SEOM) theory to describe the dissipative dynamics of fermionic open systems. The construction of the SEOM is based on a stochastic decoupling of the dissipative interaction between the system and fermionic environment, and the influence of environmental fluctuations on the reduced system dynamics is characterized by stochastic Grassmann fields. Meanwhile, numerical realization of the time-dependent Grassmann fields has remained a long-standing challenge. To solve this problem, we propose a minimal auxiliary space (MAS) mapping scheme with which the stochastic Grassmann fields are represented by conventional c-number fields along with a set of pseudo-levels. This eventually leads to a numerically feasible MAS-SEOM method. The important properties of the MAS-SEOM are analyzed by making connection to the well-established time-dependent perturbation theory and the hierarchical equations of motion theory. The MAS-SEOM method provides a potentially promising approach for the accurate and efficient simulation of fermionic open systems at ultra-low temperatures.

A semiclassical initial-value representation for quantum propagator and boltzmann operator.

Starting from the position-momentum integral representation, we apply the correction operator method to the derivation of a uniform semiclassical approximation for the quantum propagator and then extend it to approximate the Boltzmann operator. In this approach, the involved classical dynamics is determined by the method itself instead of given beforehand. For the approximate Boltzmann operator, the corresponding classical dynamics is governed by a complex Hamiltonian, which can be described as a pair of real Hamiltonian systems. It is demonstrated that the semiclassical Boltzmann operator is exact for linear systems. A quantum propagator in the complex time is thus proposed and preliminary numerical results show that it is a reasonable approximation for calculating thermal correlation functions of general systems. © 2018 Wiley Periodicals, Inc.

Stochastic Representation of Non-Markovian Fermionic Quantum Dissipation.

Quantum Brownian motion plays a fundamental role in many areas of modern physics. In the path-integral formulation, environmental fluctuations can be characterized by auxiliary stochastic fields. Intriguingly, for fermionic environments the stochastic fields must be Grassmann valued so as to memorize the order of the random forces exerted on the system. Such nonclassical fields cannot be represented by conventional means. We propose a strategy to map the Grassmann-number fields to conventional c-number noises and a set of quantized pseudolevels. The resulting stochastic equation of motion (SEOM) enables direct stochastic simulation of the fermionic dissipative dynamics. The SEOM gives exact physical observables of noninteracting systems, and yields accurate approximate results for interacting systems. The practicality and accuracy of the proposed strategy and the SEOM are exemplified by numerical studies conducted on a single-impurity Anderson model.

Stochastic simulation of anharmonic dissipation. II. Harmonic bath potentials with quadratic couplings.

The workhorse simulating the dissipative dynamics is mainly based on the harmonic bath potentials together with linear system-bath couplings, but a realistic bath always assumes anharmonicity. In this work, we extend the linear dissipation model to include quadratic couplings and suggest a stochastic simulation scheme for the anharmonic dissipation. We show that the non-Gaussian noises induced by the anharmonic bath can be rigorously constructed, and the resulting stochastic Liouville equation has the same form as that for the linear dissipation model. As a preliminary application, we use this stochastic method to investigate the vibration-induced symmetry breaking in two-level electronic systems and find that the characteristic function of the non-Gaussian noises determines the absorption and fluorescence spectra.

A unified view of hierarchy approach and formula of differentiation.

The stochastic differential equation is a powerful tool for describing the dynamics of a dissipative system in which noise characterizes the influence of the environment. For the Ornstein-Uhlenbeck noise, both the formula of differentiation and the hierarchy approach provide efficient numerical simulations, with the stochastic differential equation transformed into a set of coupled, linear ordinary differential equations. We show that while these two deterministic schemes result in different sets of equations, they can be regarded as two representations of an underlying linear-dynamics. Moreover, by manipulating the involved Ornstein-Uhlenbeck noise, we propose a unified algorithm that may reduce to the hierarchy approach or the formula of differentiation in different limits. We further analyze the numerical performance of this algorithm and find that the hierarchy approach appears to be more efficient for our numerical model studies.

Exciton interference revealed by energy dependent exciton transfer rate for ring-structured molecular systems.

The quantum interference is an intrinsic phenomenon in quantum physics for photon and massive quantum particles. In principle, the quantum interference may also occur with quasi-particles, such as the exciton. In this study, we show how the exciton quantum interference can be significant in aggregates through theoretical simulations with hierarchical equations of motion. The systems under investigation are generalized donor-bridge-acceptor model aggregates with the donor consisting of six homogeneous sites assuming the nearest neighbor coupling. For the models with single-path bridge, the exciton transfer time only shows a weak excitation energy dependence. But models with double-path bridge have a new short transfer time scale and the excitation energy dependence of the exciton transfer time assumes clear peak structure which is detectable with today's nonlinear spectroscopy. This abnormality is attributed to the exciton quantum interference and the condition for a clear observation in experiment is also explored.

Stochastic simulation of anharmonic dissipation. I. Linear response regime.

Over decades, the theoretical study of the quantum dissipative dynamics was mainly based on the linear dissipation model. The study of the nonlinear dissipative dynamics in condensed phases, where there exist an infinite number of bath modes, is extremely difficult even if not impossible. This work put forward a stochastic scheme for the simulation of the nonlinear dissipative dynamics. In the linear response regime, the second-order cumulant expansion becomes exact to reproduce the effect of the bath on the evolution of the reduced system. Consequently, a Hermitian stochastic Liouville equation is derived without explicit treatment of the bath. Stochastic simulations for an anharmonic model illustrate that the dynamics dissipated by anharmonic bath exhibits substantial difference on temperature dependence compared to that with the Caldeira-Leggett model.

Exciton Seebeck effect in molecular systems.

We investigate the exciton dynamics under temperature difference with the hierarchical equations of motion. Through a nonperturbative simulation of the transient absorption of a heterogeneous trimer model, we show that the temperature difference causes exciton population redistribution and affects the exciton transfer time. It is found that one can reproduce not only the exciton population redistribution but also the change of the exciton transfer time induced by the temperature difference with a proper tuning of the site energies of the aggregate. In this sense, there exists a site energy shift equivalence for any temperature difference in a broad range. This phenomenon is similar to the Seebeck effect as well as spin Seebeck effect and can be named as exciton Seebeck effect.

Three-dimensional agricultural water scarcity assessment based on water footprint: A study from a humid agricultural area in China.

The comprehensive assessments of quantitative and qualitative water scarcity have been agreed upon in many parts of the world. However, most of the previous studies on water scarcity focus on quantitative water scarcity and arid regions. In this study, based on the water footprint theory, we proposed three-dimensional agricultural water scarcity indexes by simultaneously considering water quantity and water quality, blue water scarcity, green water scarcity, and grey water scarcity. With the help of CROPWAT 8.0, we calculated the three-dimensional agricultural water scarcity index of Liuyang City, a humid region in China, from 2010 to 2019. Meanwhile, the STIRPAT model was used to investigate the effect of human and natural factors on the agricultural water scarcity index. The results show that: (1) During the study period, the agricultural water resources had a shortage of water quantity in Liuyang City, and the blue water scarcity index (WSIblue) exceeded the water shortage threshold in drought years. The green water scarcity index (WSIgreen) exceeded the water shortage threshold from April to July in most years; while the grey water scarcity index (WSIgrey) did not exceed the threshold, which means there was no water qualitative water scarcity during the study period. (2) The natural meteorological conditions have the greatest influence on the three-dimensional scarcity index, among which meteorological factors inhibit the WSIblue and WSIgrey, and promote the WSIgreen. (3) Green water contributes significantly to crop growth, accounting for 42 % of the crop's total water footprint. According to the change law of the green water scarcity index on the monthly scale to guide agricultural production, it plays an important role in regional water resources management. This study is expected to provide scientific suggestions for alleviating regional water resources pressure by considering virtual water use.

Measurement of water resources carrying capacity in Gugang Town of Central China based on human-water-agriculture framework.

More research has revealed that central China is one of the most vulnerable areas to a water crisis because of limited and unequally distributed water resources as well as rising water demands. Also, climate change is expected to reduce water resources dramatically, resulting in increased competition among users and severe water shortages for irrigated agriculture. The township, the most basic level of the Chinese government system, urgently needs to compare water allocation based on different management strategies to define the most optimized water management plan. The concept of a "human-water-agriculture" evaluation system was proposed in this study to couple and coordinate human well-being, sustainable water resource use, and agricultural development in Gugang Town, China. Within this framework, twenty-five indicators were chosen from the criterion layers to assess and optimize the carrying capacity of water resources for historical periods and the future year 2030. The results showed that the WRCC was bearable in previous years, except for 2018 when the percentage of water shortage reached 19.5 % because of a sharp reduction in dynamic surface water availability. The static surface water, represented by the water restored in hilly ponds in village and town areas, was discovered to account for up to 17 % of the total amount for the dry year. The WRCC would be overburdened in 2030, with 61.6 % and 18.1 % water-deficient underwater supply at 90 % and 75 % guarantee rates, respectively. The WRCC states that effective optimization of agricultural water allocation for crops to maximize economic benefits with limited water consumption could significantly improve human and agricultural systems. This study investigated a route for studying WRCC in village and town areas, providing theoretical and practical guidelines for local water-adapted development.

Rapid start-up of autotrophic shortcut nitrification system in SBR and microbial community analysis.

Shortcut nitrification is crucial for application of autotrophic nitrogen removal which is beneficial for treating carbon-limited wastewater. In this experiment, rapid start-up of autotrophic shortcut nitrification system was studied in a small sequencing batch reactor (SBR) built in laboratory with intermittent aeration operation mode. The influent was artificially simulated inorganic domestic wastewater (the ammonium nitrogen concentration was 35.19-57.54 mg/L), the pH value was 7.6-7.8, the hydraulic loading was 1L, the operating temperature was 24.3-28.3 °C, and the dissolved oxygen (DO) was 2-4 mg/L and 0.5-0.9 mg/L at the stage of complete nitrification sludge domestication and shortcut nitrification sludge domestication. High-throughput sequencing technology was used to analyse the composition and changes of microbial populations in sludge. The experimental results showed that on the 24th day of the experiment, shortcut nitrification was started successfully, the accumulation rate of nitrite was 81.63% and the removal efficiency of ammonium nitrogen was 99.25%; the richness of the main denitrifying bacteria phylum Proteobacteria increased from 30.21% to 42.85%; the richness of Nitrosomonas (ammonia oxidizing bacteria, AOB) increased from 0.37% to 22.43%, and at the species level, AOB was the salt-tolerant bacteria Nitrosomonas. europaea; the richness of Nitrospira (nitrite oxidizing bacteria, NOB) decreased from 2.59% to 0.47%.

Geometric correlations and infrared spectrum of adenine-uracil hydrogen bonds in CDCl(3) solution.

Hybrid QM/MM molecular dynamics simulations have been carried out for the Watson-Crick base pair of 9-ethyl-8-phenyladenine and 1-cyclohexyluracil in deuterochloroform solution at room temperature. Trajectories are analyzed paying special attention to the geometric correlations within the N-HN and N-HO hydrogen bonds in the base pair. Even though the two hydrogen bonds are only approximately linear and the heterocycles are tilted with respect to each other, hydrogen bond and N-H lengths follow a simple empirical correlation based on Pauling's valence bond order model. In order to describe the IR line shape of the two NH-stretching vibrations, the correlation between their fundamental transition frequencies and the hydrogen bond lengths is exploited. This facilitates efficient evaluation of the fluctuating transition frequencies along the QM/MM trajectory which allows the determination of the line shape function.

Effects of Pr and Yb Dual Doping on the Thermoelectric Properties of CaMnO3.

There has been research on CaMnO3 with natural abundance, low toxicity, and low cost as promising candidates for n-type thermoelectric (TE) materials. In this paper, Ca1-2xPrxYbxMnO3 with different Pr and Yb contents (x = 0, 0.01, 0.02, 0.03, 0.04 and 0.05) were synthesized by means of coprecipitation. With X-ray diffraction (XRD), scanning electron microscopy (SEM), and high-resolution transmission electron microscopy (HRTEM), researchers characterized the phase structure and morphology of all the samples. The oxidation states of manganese were determined by X-ray photoemission spectroscopy (XPS). The role of Ca-site dual doping in the TE properties was also investigated. Increasing the Pr and Yb contents leads to decreases in the electrical resistivity and Seebeck coefficient, leading to a power factor of 3.48 × 10-4 W·m-1·K-2 for x = 0.04 at 773 K, which is its maximum. Furthermore, the thermal conductivity (κ) decreases with increasing x, and κ = 1.26 W m-1·K-1 is obtained for x = 0.04 at 973 K. Ca0.92Pr0.04Yb0.04MnO3 exhibit a ZT (thermoelectric figure of merit) value of 0.24 at 973 K, approximately 3 times more than that of the pristine CaMnO3. Thus, the reported method is a new strategy to enhance the TE performance of CaMnO3.

Unraveling the correlated dynamics of the double hydrogen bonds of nucleic acid base pairs in solution.

Quantum mechanics/molecular mechanics hybrid simulations (CPMD/GROMOS) of nonlinear infrared spectra are performed for a modified adenine-uracil base pair in CDCl(3) solution. Employing a mapping between hydrogen bond distances and fundamental as well as overtone transition frequencies on the basis of on-the-fly snapshot potential energy curves, energy gap correlation functions are established. These correlation functions are utilized to determine pump-probe and two-dimensional photon echo spectra. Analysis of the latter yields off-diagonal peaks signifying correlated fluctuations of the N-H···N and N-H···O hydrogen bonds.