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This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC0–24 h of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 μg·h/mL, respectively. For Streptococcus pneumoniae and Staphylococcus aureus, based on the free-drug AUC over MIC ratio (fAUC/MIC) target of 1-log10 cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

The deep reinforcement learning (DRL) technique has gained attention for its potential in designing "virtual network" controllers. This skill utilizes a novel solution that can avoid the specific parameters and system model required in classical dynamic programming algorithms. However, addressing the issue of system uncertainties and performance deterioration remains a challenge. To overcome this challenge, the authors propose a new control prototype using a twin delayed deep deterministic policy gradient (TD3)-based adaptive controller, which replaces the conventional virtual synchronous generator (VSG) module in the modular multilevel converter (MMC) control. In this approach, an adaptive programming module is developed using a critic fuzzy network point of view to determine the optimal control policy. The modification presented in this framework is able to improve the system stability and resist disruptions while retaining the merits of the conventional VSG control model. The proposed approach is implemented and tested using the DRL toolbox in MATLAB/Simulink. [ABSTRACT FROM AUTHOR]

Studies on ESRRB-regulating porcine-induced pluripotent stem cells (piPSCs) converted to trophoblast-like stem cells (TLSCs) contribute to the understanding of early embryo development. However, the epigenetic modification regulation network during the conversion is poorly understood. Here, the global change in histone H3 Lysine 4, 9, 27, 36 methylation and Lysine 27 acetylation was investigated in piPSCs and TLSCs. We found a high modification profile of H3K36me2 in TLSCs compared to that of piPSCs, whereas the profiles of other modifications remained constant. KDM4C, a H3K36me3/2 demethylase, whose gene body region was combined with ESRRB, was upregulated in TLSCs. Moreover, KDM4 inhibitor supplementation rescued the AP-negative phenotype observed in TLSCs, confirming that KDM4C could regulate the pluripotency of TLSCs. Subsequently, KDM4C replenishment results show the significantly repressed proliferation and AP-positive staining of TLSCs. The expressions of CDX2 and KRT8 were also upregulated after KDM4C overexpression. In summary, these results show that KDM4C replaced the function of ESRRB. These findings reveal the unique and crucial role of KDM4C-mediated epigenetic chromatin modifications in determination of piPSCs' fate and expand the understanding of the connection between piPSCs and TSCs. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A randomized, single-dose, three-period, self-crossover controlled extended-infusion clinical trial was conducted with 12 healthy Chinese subjects. Plasma and urine samples were collected to determine doripenem concentrations. Non-compartmental and population PK analysis were performed to characterize the PK of doripenem. The Monte Carlo simulation was employed to optimize dosing regimens based on the probability of target attainment of doripenem against pathogens with different minimum inhibitory concentrations (MIC). All 12 healthy Chinese subjects completed the study, and the doripenem was well tolerated. The study showed linearity relationships in the peak plasma concentration and the area under the concentration-time curve after intravenous infusion of doripenem from 0.25 g to 1.0 g. The cumulative urinary recovery rate of doripenem was 68.1–72.0% within 24 h. PPK modeling showed a two-compartmental model, with first-order elimination presenting the best fit for doripenem PK. Monte Carlo simulation results showed that 1.0 g q12h or 0.5 g q8h was an optimal regimen for pathogens susceptible to doripenem (MIC ≤ 1 mg/L); while high dose and extended infusion (1 g, q8h, 4 h infusion) was proposed for unsusceptible pathogens (2 ≤ MIC ≤ 8 mg/L). In the dose range of 0.25 to 1.0 g, doripenem showed linear pharmacokinetics. Doripenem at 1.0 g with a prolonged infusion time of 4 h was predicted to be effective against pathogens with MICs as high as 8 mg/L. [ABSTRACT FROM AUTHOR]

Colistin methanesulfonate (CMS) is an important treatment option for infections caused by carbapenem-resistant Gram-negative organisms (CROs). This study evaluated the pharmacokinetic/pharmacodynamic (PK/PD) profiles and safety of CMS in Chinese subjects following a recommended dosage. A total of 12 healthy Chinese subjects received CMS injections at 2.5 mg/kg once every 12 h for 7 consecutive days. The PK/PD profiles of the active form of CMS, colistin, against CROs were analyzed with the Monte Carlo simulation method. No serious adverse events were observed. The average steady-state plasma concentrations of CMS and colistin were 4.41 ± 0.75 μg/mL and 1.27 ± 0.27 μg/mL, and the steady-state exposures (AUC0–12,ss) were 52.93 ± 9.05 h·μg/mL and 15.28 ± 3.29 h·μg/mL, respectively. Colistin, at its minimum inhibitory concentration (MIC) of 0.5 μg/mL, has >90% probability to reduce CROs by ≥1 log. The PK/PD breakpoints for the ≥1 log kill were ≥MIC90 for carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa, but were ≤MIC50 for carbapenem-resistant Acinetobacter baumannii. The recommended dose regimen of CMS for 7 consecutive days was safe in Chinese subjects. The systemic exposure of colistin showed a high probability of being sufficient for most CROs, but was not sufficient for some carbapenem-resistant A. baumannii. [ABSTRACT FROM AUTHOR]

Fe-Si-Cr soft magnetic powder cores (SMCs), with high electrical resistivity, magnetic permeability, saturation magnetic induction, and good corrosion resistance, are widely applied to inductors, filters, choke coils, etc. However, with the development of electronic technology with high frequency and high power density, the relative decline in the magnetic properties limits the high-frequency application of SMCs. In this paper, the phosphating process and polyimide (PI) insulation coating is applied to Fe-Si-Cr SMCs to reduce the core loss, including hysteresis loss and eddy current loss. The microstructure and composition of Fe-Si-Cr powders were analyzed by SEM, XRD, and Fourier-transform infrared spectra, respectively. The structural characteristics of the Fe-Si-Cr @ phosphate layer @ PI layer core–shell double coating were studied, and the best process parameters were determined through experiments. For SMCs with 0.4 wt% content of PI, the relative permeability is greater than 68%, and the core loss is the lowest, 7086 mW/cm3; annealed at 500 °C, the relative permeability is greater than 57%, and the core loss is the lowest, 6222 mW/cm3. A 0.4 wt% content of PI, annealed at 500 °C, exhibits the ideal magnetic properties: μe = 47 H/m, P = 6222 mW/cm3. [ABSTRACT FROM AUTHOR]

Cefoperazone/sulbactam (CPZ/SUL) is a β-lactam and β-lactamase inhibitor combination therapy for the treatment of respiratory tract infections. Using data from a prospective, multiple-center, open-label clinical trial in 54 patients with hospital-acquired pneumonia or ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii (Ab), we showed that a combined PK/PD index %(T > MICcpz*T > MICsul) is a more appropriate PK/PD index against Ab, compared to the PK/PD index (%T > MIC) for a single drug. For a 2 h infusion, the PK/PD cutoff of CPZ/SUL (2 g/1 g, q8h) for clinical and microbiological efficacy was 4/2 and 1/0.5 mg/L, respectively. The corresponding cumulative fraction of response was 46.5% and 25.3%, respectively. Results based on the combined PK/PD index were quite similar to that based on the joint probability of target attainment. The two drugs have interaction from the viewpoint of PK/PD. When the dose of one drug was too high, the PK/PD cutoff was often determined by another drug in which the dose was maintained. In most cases, sulbactam exerted the main effect against infection by Ab in the complex CPZ/SUL, which was similar to the literature reports. When the MIC of CPZ was 8, 16, or 32 mg/L, a CPZ/SUL 2 g/1 g (q8h), 2 g/2 g (q8h), or 2 g/2 g (q6h) (infusion was all 3 h) was recommended, respectively. A clinical efficacy and safety study to confirm simulation results is warranted. [ABSTRACT FROM AUTHOR]

Modern explosion protection equipment, protected by traditional explosion protection technology (as defined by the international electrotechnical commission (IEC) publication IEC60079-ff series standards) and electrical/electronic/programmable electronic (E/E/PE) safety-related systems, is becoming ever more complex in coal mine development and petrochemical industry; thus, the possibility of failures in their operation is also growing. It is well-known that E/E/PE safety-related systems can be used to actively control dangerous sources, with real and expected levels of reliability, if they have been qualified according to the IEC61508-ff series standards. To uniformly evaluate the safety integrity level (SIL) of the explosion protection function of traditional explosion protection technology and E/E/PE safety-related system technology, this study analyzed the ability of these types of protection to remove the ignition risk residual, evaluating the failure rates of safety devices. The key objective of this paper is the presentation of a new equipment protection level (EPL) assessment method for explosion protection equipment based on a functional safety assessment. The method is applied to a variable frequency drive (VFD) system, and the results show that the EPL of the explosion protection equipment evaluated by this method is consistent with the EPL corresponding to the traditional explosion protection type of the IEC60079-ff series standard. Meanwhile, the flexible configuration of explosion protection safety devices and E/E/PE safety-related systems enables explosion protection equipment of different EPL levels to be designed. [ABSTRACT FROM AUTHOR]

The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Inhibitors, such as CHIR99021 and XAV939 targeting the WNT signaling pathway, have been added in a culture medium to modify the cell regulatory network. However, potential side effects of inhibitors could confine the pluripotency and practicability of piPSCs. This study aimed to investigate the roles of AXIN, one component of the WNT pathway in piPSCs. Here, porcine AXIN1 and AXIN2 genes were knocked-down or overexpressed. Digital RNA-seq was performed to explore the mechanism of cell proliferation and apoptosis. We found that (1) overexpression of the porcine AXIN2 gene significantly reduced survival and negatively impacted the pluripotency of piPSCs, and (2) knockdown of AXIN2, a negative effector of the WNT signaling pathway, enhanced the expression of genes involved in cell cycle but reduced the expression of genes related to cell differentiation, death, and apoptosis. [ABSTRACT FROM AUTHOR]

(1) Background: in early 2020, COVID-19 broke out. Driven by people's psychology of conformity, panic, group polarization, etc., various rumors appeared and spread wildly, and the Internet became a hotbed of rumors. (2) Methods: the study selected Weibo as the research media, using topic models, time series analysis, sentiment analysis, and Granger causality testing methods to analyze the social media texts related to COVID-19 rumors. (3) Results: in study 1, we obtained 21 topics related to "COVID-19 rumors" and "outbreak rumors" after conducting topic model analysis on Weibo texts; in study 2, we explored the emotional changes of netizens before and after rumor dispelling information was released and found people's positive emotions first declined and then rose; in study 3, we also explored the emotional changes of netizens before and after the "Wuhan lockdown" event and found positive sentiment of people in non-Wuhan areas increased, while negative sentiment of people in Wuhan increased; in study 4, we studied the relationship between rumor spread and emotional polarity and found negative sentiment and rumor spread was causally interrelated. (4) Conclusion: These findings could help us to intuitively understand the impact of rumors spread on people's emotions during the COVID-19 pandemic and help the government take measures to reduce panic. [ABSTRACT FROM AUTHOR]

Effective management of an urban solid waste system (USWS) is crucial for balancing the tradeoff between economic development and environment protection. A factorial ecological-extended physical input-output model (FE-PIOM) was developed for identifying an optimal urban solid waste path in an USWS. The FE-PIOM integrates physical input-output model (PIOM), ecological network analysis (ENA), and fractional factorial analysis (FFA) into a general framework. The FE-PIOM can analyze waste production flows and ecological relationships among sectors, quantify key factor interactions on USWS performance, and finally provide a sound waste production control path. The FE-PIOM is applied to managing the USWS of Fujian Province in China. The major findings are: (i) waste is mainly generated from primary manufacturing (PM) and advanced manufacturing (AM), accounting for 30% and 38% of the total amount; (ii) AM is the biggest sector that controls the productions of other sectors (weight is from 35% to 50%); (iii) the USWS is mutualistic, where direct consumption coefficients of AM and PM are key factors that have negative effects on solid waste production intensity; (iv) the commodity consumption of AM and PM from other sectors, as well as economic activities of CON, TRA and OTH, should both decrease by 20%, which would be beneficial to the sustainability of the USWS. [ABSTRACT FROM AUTHOR]

Multi-level converters are widely used in various industrial applications. Among various space vector modulation (SVM) schemes, the multi-level SVM scheme based on two-level space vector pulse width modulation (SVPWM) is recognised as a simplified multi-level SVM scheme, which can reduce the computation complexity. However, this scheme is still complicated when the number of the voltage levels is large. This paper proposes a modified SVM scheme that can further simplify the multi-level SVM scheme based on two-level SVPWM. The proposed SVM scheme can directly determine the two-level hexagon where the reference voltage vector is located by calculating a simple formula. The whole modulation process can be completed by only three steps. Meanwhile, the proposed method is generic for any n-level converter without adding much calculation, which greatly simplifies the modulation process. Experimental results have been provided, which verify the effectiveness and generality of the proposed SVM scheme for two types of multi-level converters. [ABSTRACT FROM AUTHOR]

In this work, a two-phase system composed of hydrophobic ionic liquid (IL) and water phases was introduced to prepare copper sulfide (CuS) nanoparticles. It was found that CuS particles generated from the interfaces of carboxyl-functionalized IL and sodium sulfide (Na2S) aqueous solution were prone to aggregate into nanoplates and those produced from the interfaces of carboxyl-functionalized IL and thioacetamide (TAA) aqueous solution tended to aggregate into nanospheres. Both the CuS nanoplates and nanospheres exhibited a good absorption ability for ultraviolet and visible light. Furthermore, the CuS nanoplates and nanospheres showed highly efficient photocatalytic activity in degrading rhodamine B (RhB). Compared with the reported CuS nanostructures, the CuS nanoparticles prepared in this work could degrade RhB under natural sunlight irradiation. Finally, the production of CuS from the interfaces of hydrophobic IL and water phases had the advantages of mild reaction conditions and ease of operation. [ABSTRACT FROM AUTHOR]

In low and medium voltage power conversion systems, multilevel converters are becoming more and more attractive due to improved power density. However, the complexity of topology and control is a big challenge for the application of multilevel converters. In this paper, a four-level (4L) hybrid flying capacitor (FC) T-type converter has been researched in detail. The topological advantage of the converter is displayed in comparison to existing four-level converters. According to the feature of the topology, the operating status has been analyzed and the reason for the voltage jump is researched in detail during the dead-time period. A strategy to reduce voltage jump by adjusting the switching states has be presented. The FC voltages can be balanced by selecting the appropriate switching states. The relationships between the fluctuations of FC voltages and the modulation index and power factor (PF) have been analyzed by simulation results. The performance of the 4L converter has been investigated in MATLAB/Simulink as well as on a down-scaled laboratory prototype. [ABSTRACT FROM AUTHOR]

The large mining height fully mechanized top-coal caving mining technique has developed rapidly and become the most extensively used mining method for ultra-thick coal seams. The arching of coal/gangue and the drawing out of gangue are peculiar phenomena in the process of fully mechanized top-coal caving mining, which not only affects the recovery of top-coal, but also affects the quality of the coal. This paper studies the arching phenomenon in top-coal caving mining process of ultra-thick coal seam. A series of laboratory granular material simulation experiments were performing and a top-coal arching model in the framework of mechanics was established to explore the formation characteristic of arches and their effects to top-coal loss. Then the countermeasures against the arches and technology path of intelligent mining based on improving top-coal recovery were put forward and performed in practice. The results show that the recovery ratio of top-coal has increased nearly 6%, and increased the production efficiency at the same time. The research on arching mechanism and removing strategies of dynamic random arches effectively improves the efficiency of fully mechanized top-coal caving mining in ultra-thick coal seams, and provides the foundation for the realization of intelligent top-coal caving mining technology. [ABSTRACT FROM AUTHOR]