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This paper proposes an analytical model for the modular multilevel converter (MMC) based on the theory of harmonic balance, which removes the iteration process for traditional models. The proposed model considers dynamic harmonic interactions between the modulation of converters and passive elements in the MMC. By transferring the equations into frequency-domain as complex Fourier series, a steady-state harmonic model is created with singular coefficients matrix. Then, through the elimination of all DC components in dynamic model, the singular coefficient matrix can be derived to nonsingular one, and the order of it can be reduced. Finally, the typical open-loop analytical model with DC neutral grounded MMC is derived aim, and the time-domain simulations is used to validate the effectiveness of proposed model. The proposed model can be used to accelerate the simulation and analyze the influence of parameters to guide the design of MMC.

Aims To determine the absorption, distribution, metabolism and excretion of abivertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer (NSCLC). Methods Seven patients with advanced NSCLC were given a single 200 mg/83 μCi oral suspension of [14 C]-abivertinib. Blood, urine and faeces were collected. Mass balance of radioactivity, the pharmacokinetics of abivertinib, and the total radioactivity were determined. Metabolite profiling and characterisation were performed. Results The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug-related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII-7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug-related exposure. MII-2 (an abivertinib cysteine-glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug-related radioactivity in faeces. Conclusion Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects. Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization. The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUC0–24h pool), while other circulating metabolites were minor, accounting for less than 10%. Mean Cmax, AUC0–∞, T1/2 and Tmax values for ensartinib in plasma were 185 ng/mL, 3827 h ng/mL, 18.3 h and 3.25 h, respectively. The total radioactivity in plasma was cleared with terminal half-life of 27.2 h. Treatment with ensartinib was well tolerated, and no serious adverse events were reported. It was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces. ClinicalTrials.gov NCT03804541.

This study proposes a misalignment-tolerant integrated inductive power transfer (IPT) system for tram logistics robots and presents an adapted parameter tuning method for the IPT system. A novel dual-purpose coupler, which could undertake the responsibility of power transmission and self-compensation is realised by substituted partially with compensation inductors of inductor–capacitor–capacitor networks, resulting in an integrated and cost-effective system configuration. With the analysis of working principles on the IPT system and considerations of operation conditions on logistics robots, an adapted parameter tuning method is provided to maximise system misalignment tolerance and maintain high efficiency of power transfer. To demonstrate the validity and safety of the proposed system, comparative simulations and security evaluations are conducted by finite element analysis. Besides, the constant-current output characteristic is simulated and proved. Finally, a 60.20 W experimental prototype is built. Results show that the system can operate stably with 87.31% efficiency at well-aligned cases and the power fluctuation is confined below 9% within −120 to 120 mm x-misalignment, −80 to 80 mm y-misalignment, −50 to 12.5 mm z-misalignment, and −30° to 30° rotatory misalignment. It is also verified that the system could operate safely without any secondary side.

Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single‐dose and multidose cohorts and the effects of ABCB1, UGT1A1, and UGT1A9 genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single‐dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high‐fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration‐time data. The genotypes for ABCB1, UGT1A1, and UGT1A9 single‐nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single‐nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single‐dose and multidose studies, respectively. Sitafloxacin AUC and Cmax increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that Cmax was lower in the ABCB1 (rs1045642) mutation group, whereas t1/2 was longer in the UGT1A1 (rs2741049) and UGT1A9 (rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However, ABCB1 (rs1045642), UGT1A1 (rs2741049), and UGT1A9 (rs3832043) genetic polymorphisms are likely to influence the Cmax or t1/2 and thereby merit further clinical evaluation.

This study aims to evaluate the effects of prolonged expressive writing on health outcomes in breast cancer patients undergoing chemotherapy to help understand how the dosage of an expressive writing intervention might moderate its effects. A total of 112 breast cancer patients undergoing chemotherapy were randomly allocated to the expressive writing group (n = 56) or the prolonged expressive writing group (n = 56). The expressive writing group received the standard expressive writing intervention based on Pennebaker’s prompt to write for at least 20 min over four consecutive days (4 sessions). The prolonged expressive writing group used a modified prompt: write for at least 20 min 3 times a week over a 4-week period (12 sessions); patients could choose whether to write on consecutive days or not. All participants were required to write about their stressor-related upsetting or traumatic feelings about breast cancer. Outcomes were assessed and compared at baseline, as well as 1 month, 3 months, and 6 months postintervention. There was no significant difference in the patients’ quality of life, or physical and psychological wellbeing between the expressive writing group and the prolonged expressive writing group at any time point (all p > .05). The quality of life of breast cancer patients significantly decreased in the two groups over time (F = 40.64, p

Due to low investment cost and high reliability, a new scheme called DR-HVDC (Diode Rectifier based HVDC) transmission was recently proposed for grid integration of large offshore wind farms. However, in this scheme, the application of conventional control strategies for stability operation face several challenges due to the uncontrollability of the DR. In this paper, a coordinated control strategy of offshore wind farms using the DR-HVDC transmission technology to connect with the onshore grid, is investigated. A novel coordinated control strategy for DR-HVDC is proposed based on the analysis of the DC current control ability of the full-bridge-based modular multilevel converter (FB-MMC) at the onshore station and the input and output characteristics of the diode rectifier at the offshore. Considering the characteristics of operation stability and decoupling between reactive power and active power, a simplified design based on double-loop droop control for offshore AC voltage is proposed after power flow and voltage–current (I–V) characteristics of the offshore wind farm being analyzed. Furthermore, the impact of onshore AC fault to offshore wind farm is analyzed, and a fast fault detection and protection strategy without relying on communication is proposed. Case studies carried out by PSCAD/EMTDC verify the effectiveness of the proposed control strategy for the start up, power fluctuation, and onshore and offshore fault conditions.

This study aimed to evaluate the bioequivalence (BE) of 2 formulations of the 10-mg rivaroxaban tablet. The study was a randomized, open-label, 4-period, crossover study that included 28 healthy subjects in fasting or fed conditions. The pharmacokinetic parameters were determined based on the concentrations of rivaroxaban using high-performance liquid chromatography with a tandem mass spectrometer detector. In each of the 4 study periods with fasting or fed conditions, a single dose of test or reference product was administered. Rivaroxaban concentrations in plasma were determined using a validated liquid chromatography with a tandem mass spectrometer detector method. The pharmacokinetic parameters assessed were the area under the plasma concentration-time curve (AUC0-t , AUC0-∞ ), the peak plasma concentration of the drug (Cmax ), time to achieve Cmax , elimination half-life, within-subject variability of test drug, and within-subject variability of reference drug. The geometric mean ratio (90%CI) of the test drug/reference drug for rivaroxaban was 90.38% to 103.60% for AUC0-t in fasting conditions and 90.13% to 100.42% in fed conditions. The AUC0-∞ s were 89.94% to 102.50% and 90.14% to 100.45% under fasting and fed conditions, respectively. The Cmax values were 90.58% to 105.01% and 96.36% to 108.07% in these 2 conditions, respectively. All 90%CIs for test drug/reference drug geometric mean ratio were ≤2.5. The 90%CIs for test/reference AUC ratio and Cmax ratio were within the acceptable range for BE. There were no adverse events encountered during this BE study. The study's results indicated that the 2 formulations of the rivaroxaban tablet were bioequivalent.

LLC resonant converters are widely used in On-board Power Converter but the pumping voltage of traditional LLC converter is unavoidable under light-load conditions due to the existence of parasitic parameter. In this paper, an LLC resonant converter with damping split inductor is proposed to improve the light-load regulation capability. The original resonant inductor is divided into two parts in series. Then, a simple damping resistor connected on one part in parallel and the other part can be integrated into the transformer. Using damping split inductor, significant regulation improvements could be achieved under light-load conditions with not any change in control strategy and almost zero hardware cost. In addition, based on impedance analysis of the resonant tank, the effects of the proposed method are analyzed including voltage gain, soft switching characteristics, suppression of high frequency interference components, and system power loss. Moreover, the detailed design process and optimization conditions of the damping split inductor parameters are carefully illustrated. Eventually, the experimental results demonstrate the characteristics mentioned above for the 96 W prototype at the expense of a maximum increase in device loss of 0.85 W.

Li Li,1 Rongjin Sun,1 Joseph Zenga,2 Heather Himburg,3 Lu Wang,1 Shengnan Duan,1 Jingwen Liu,1 Dinh Bui,1 Zuoxu Xie,1 Ting Du,4 Lijun Xie,1 Taijun Yin,1 Stu Wong,2 Song Gao,4 Ming Hu1 1Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA; 2Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA; 3Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Ming Hu, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA, Email mhu@uh.edu Song Gao, Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA, Email Song.Gao@tsu.eduObjective: We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production.Methods: An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2.Results: A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11– 17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells.Conclusion: In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.Graphical Abstract: Keywords: cyclooxygenase-1, cyclooxygenase-2, turnover number, inflammation, absolute quantification, liquid chromatography with tandem mass spectrometry

Development of new mechanochromic luminescent (MCL) materials from aggregation-induced emission luminogens (AIEgens) has attracted wide attention due to their potential application in multiple areas. However, rational design and crafting of new MCL materials from the simple AIEgens skeleton is still a big challenge because of the undesirable concentration quenching effect. In this study, we have constructed a new class of MCL materials by adding one phenyl as a new rotator and incorporating one pair of electron donor (D) and acceptor (A) into the system of rofecoxib skeleton. This strategy endowed the compounds (

The development of aggregation-induced emission luminogens (AIEgens) has attracted increasing attention due to their potential applications in various areas in recent years. In this study, a facile conversion from aggregation-caused quenching (ACQ) to aggregation-induced emission (AIE) was achieved by an efficient regioisomerization strategy based on the rofecoxib scaffold. Two compounds, named PYR2 and PYR4, were identified as regioisomers of rofecoxib derivatives to show dramatically different fluorescent properties. Compound PYR2 with an ortho-substituted piperidine group showed typical AIE activity while compound PYR4 with a para-piperidine group exhibited typical ACQ behavior. Notably, compound PYR2 showed polymorphism with two forms of crystals. It was also endowed with reversible mechanochromic luminescence and acidochromic properties. The different fluorescent properties were elucidated by UV/Vis absorption spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analyses. Its application as a security ink and in lipid droplets imaging have been demonstrated.

Rice (Oryza sativa) is one of the most important crops worldwide. Heading date is a vital agronomic trait that influences rice yield and adaption to local conditions. Hd3a, a proposed florigen that primarily functions under short-day (SD) conditions, is a mobile flowering signal that promotes the floral transition in rice. Nonetheless, how Hd3a is transported from leaves to the shoot apical meristem (SAM) under SDs remains elusive. Here, we report that FT-INTERACTING PROTEIN9 (OsFTIP9) specifically regulates rice flowering time under SDs by facilitating Hd3a transport from companion cells (CCs) to sieve elements (SEs). Furthermore, we show that the tetratricopeptide repeat (TPR) protein OsTPR075 interacts with both OsFTIP9 and OsFTIP1 and strengthens their respective interactions with Hd3a and the florigen RICE FLOWERING LOCUS T1 (RFT1). This in turn affects the trafficking of Hd3a and RFT1 to the SAM, thus regulating flowering time under SDs and long-day conditions, respectively. Our findings suggest that florigen transport in rice is mediated by different OsFTIPs under different photoperiods and those interactions between OsTPR075 and OsFTIPs are essential for mediating florigen movement from leaves to the SAM.

This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin.Forty-eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200 mg cetagliptin. Positive control (sitagliptin 100 mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study.Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0-1.5 hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses ≥50 mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase-4 (DPP-4) inhibition (≥80%). The plasma concentration giving 50% of maximum drug effect of DPP-4 inhibition for cetagliptin (5.29 ng/mL) was lower than that of sitagliptin (7.03 ng/mL). Active glucagon-like-1 peptide (GLP-1) concentrations were significantly increased in the cetagliptin groups by 2.3- to 3.1-fold at day 1 and 3.1- to 3.6-fold at steady state compared with that of placebo, and active GLP-1 concentrations were increased with increasing dose. Compared with sitagliptin, doses ≥100 mg once daily of cetagliptin produced postprandial increases in active GLP-1 level and induced to long-lasting glucose-lowering efficacy. Cetagliptin was well tolerated across all doses studied.Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin.

Fractional-order systems generalize classical differential systems and have empirically shown to achieve fine-grain modeling of the temporal dynamics and frequency responses of certain real-world phenomena. Although the study of integer-order memory element (mem-element) emulators has persisted for several years, the study of fractional-order memory elements (FOMEs) has received little attention. To promote the study of the characteristics and applications of mem-element systems in fractional calculus (FC) and memory systems, in this paper, we propose a novel universal interface for constructing floating FOMEs. When the topological structure of the interface remains unchanged, the floating fractional-order memristor (FOMR), fractional-order memcapacitor (FOMC) and fractional-order meminductor (FOMI) emulators can be realized by using the impedance combinations of different passive elements, without any mem-element emulators and mutators. When compared with previously proposed FOMEs, the proposed fractional-order mem-element emulators based on a universal interface not only feature the characteristics of floating terminals and simpler circuit structures, but can also realize all three different types of FOMEs. To explore the dynamical relationships between the mem-elements and the fractional order, we mathematically derive and analyze the maximum and minimum possible values of memductance, memcapacitance and inverse meminductance which accounts for practical design considerations when building FO systems. The memory characteristics of FOMEs are analyzed by varying their orders and stimuli frequencies. The consistency of theoretical analysis, numerical calculation and simulation results validates the correctness of our proposed emulators.

Background and objectives Cetagliptin is a highly selective dipeptidyl peptidase-4 inhibitor under development to treat type 2 diabetes mellitus. This first-in-human study was conducted to characterise the pharmacokinetics, pharmacodynamics and tolerability of single-ascending oral doses of cetagliptin in healthy subjects. In addition, the effect of food on pharmacokinetics was evaluated. Methods Study 1 enrolled 66 healthy subjects in a double-blind, randomised, placebo-controlled, single-dose escalation study; sitagliptin was employed as a positive open-label control. Forty-four subjects were assigned to seven cohorts (cetagliptin 12.5, 25, 50, 100, 200, 300 or 400 mg); 12 subjects were assigned to the placebo group. The remaining ten subjects received sitagliptin 100 mg as the positive control. Blood, urine and faeces were collected for the pharmacokinetic analysis and determination of plasma dipeptidyl peptidase-4 inhibition, active glucagon-like peptide-1, glucose and insulin levels. In Study 2, 14 healthy subjects were assigned to a randomised, open-label, two-period crossover study, and received a single oral dose of cetagliptin 100 mg in the fasted state or after a high-fat meal, with a 14-day washout period between treatments. Blood samples were collected to evaluate the effects of food on the pharmacokinetics of cetagliptin. Results Following administration of a single oral dose, cetagliptin was rapidly absorbed, presenting a median time to maximum concentration of 1.0-3.25 h. The terminal half-life ranged between 25.8 and 41.3 h, which was considerably longer than that of sitagliptin. The area under the plasma concentration-time curve was approximately dose proportional between 25 mg and 400 mg, and the increase in maximum concentration was greater than dose proportional. The unchanged drug was mainly excreted in the urine (27.2-46.2% of dose) and minimally via the faeces (1.4% of dose). Dipeptidyl peptidase-4 inhibition, an increase in active glucagon-like peptide-1 and a slight decrease in blood glucose were observed, whereas insulin was not significantly altered when compared with placebo. The weighted average dipeptidyl peptidase-4 inhibition by cetagliptin 100 mg was higher than that mediated by sitagliptin 100 mg. Cetagliptin was well tolerated up to a single oral dose of 400 mg. No food effects were noted. Conclusions Cetagliptin inhibited plasma dipeptidyl peptidase-4 activity, increased levels of active glucagon-like peptide-1 and was well tolerated at single doses up to 400 mg, eliciting no dose-limiting toxicity in healthy volunteers. Food did not affect the pharmacokinetics of cetagliptin. Clinical trial registration The studies were registered at http://www.chinadrugtrials.org.cn (Nos. CTR20180167 and CTR20181331).

Qingshan Huang,1 Lijun Xie,2 Liyan Huang,2 Weili Wei,2 Haiying Li,2 Yunfang Zhuang,2 Xinxiu Liu,2 Shuqiang Chen,2 Sufang Zhang2 1Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China; 2Department of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of ChinaCorrespondence: Sufang ZhangDepartment of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of ChinaTel/Fax +86-591-87981961Email zsufang@fjmu.edu.cnQingshan HuangMusculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, 100044, People’s Republic of ChinaTel/Fax +86-10-88324471Email hqingshan@pku.edu.cnBackground: High-resolution ultrasound is the first choice for the diagnosis of thyroid nodules, but it is still difficult to distinguish between follicular thyroid carcinoma (FTC) and follicular adenoma (FA). Our research aimed to develop and validate an ultrasonic diagnostic model for differentiating FTC from FA.Methods: This study retrospectively analyzed 196 patients who were diagnosed as FTC (n=83) and FA (n=113). LASSO regression analysis was used to screen clinical and ultrasonic features. Multivariate logistic regression analysis was used to establish the ultrasonic diagnostic model of FTC. Nomogram was used for the visualization of diagnostic models. C-index, ROC, and calibration curves analysis were used to evaluate the accuracy of the diagnostic model. Decision curve analysis (DCA) was used to evaluate the net benefits of the ultrasonic diagnostic model for FTC diagnosis under different threshold probabilities. The bootstrap method was used to verify the ultrasonic diagnostic model.Results: After Lasso regression analysis, 10 clinical and ultrasonic features were used to construct the ultrasonic diagnostic model of FTC. The C-index and AUC of the model were 0.868 and 0.860, respectively. DCA showed that the ultrasonic model had good clinical application value. The C-index in the validation group was 0.818, which was close to the C-index in the model.Conclusion: Ultrasonic diagnostic model constructed with 10 clinical and ultrasonic features can better distinguish FTC from FA.Keywords: follicular thyroid carcinoma, follicular adenoma, diagnostic, ultrasonic

Cyclooxygenase-2 (COX-2) fluorescent probes are promising tools for early diagnosis of cancer. Traditionally, COX-2 probes were designed by connecting two parts, a fluorophore and a COX-2 binding unit, via a flexible linker. Herein, a new class of COX-2-specific fluorescent probes have been developed via one-step modification from rofecoxib by an integrative approach to combine the binding unit and the fluorophore into one. Among them, several new rofecoxib analogues not only exhibited still potent COX-2 binding ability but also exhibited attractive fluorescence properties, such as tunable blue-red emission, solvatochromism, aggression-induced emission behavior, and mechanochromism. Notably, the emission of 2a16 can be switched between green-yellow in the crystalline state and red-orange in the amorphous state by grinding and fuming treatments. Furthermore, the highly fluorescent compound 2a16 (Φf = 0.94 in powder) displayed a much stronger fluorescence imaging of COX-2 in HeLa cancer cells overexpressing COX-2 than RAW264.7 normal cells with a minimal expression of COX-2. Most importantly, 2a16 can light up human cancer tissues from adjacent normal tissues with a much brighter fluorescence by targeting the COX-2 enzyme. These results demonstrated the potential of 2a16 as a new red fluorescent probe for human cancer imaging in clinical applications.

Objective This study was conducted to evaluate the difference in acid inhibition function among lansoprazole (LPZ), pantoprazole (PPZ), and their respective stereoisomers following single and multiple intravenous doses in healthy Chinese subjects. Materials and methods The dosage groups were set as follows: 30 mg single and multiple intravenous administrations of LPZ or R-LPZ, 40 mg single and multiple intravenous administrations of PPZ or S-PPZ. Subjects received an intravenous infusion of LPZ, R-LPZ, PPZ, or S-PPZ injection in sterile saline solution (100 mL/h, 60 minutes), respectively. The intragastric pH was sampled every second for 24 hours at baseline and for 24 hours after drug administration. The baseline-adjusted pharmacodynamic (PD) parameters include ΔMean (pH), ΔMedian (pH), ΔTpH≥3 (%), ΔTpH≥4 (%), ΔTpH≥6 (%), and ΔAUECph-tτ1-τ2. The PD parameters were evaluated in different time intervals (0 - 24 hours, 0 - 4 hours and 14 - 24 hours). Results After a single dose, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ and PPZ was 56.6 ± 19.6, 53.1 ± 23.3, 35.6 ± 24.9 and 26.8 ± 30.2, respectively. The ΔTpH≥6 (%) was 50.7 ± 26.1, 41.4 ± 26.2, 25.4 ± 24.9 and 22.1 ± 27.6, respectively. The ΔAUECph-τ1-τ was 45,564 ± 16,107, 41,798 ± 16,153, 31,914 ± 17,304 and 20,744 ± 21,500, respectively. Statistically significant differences were found with R-LPZ vs. S-PPZ, R-LPZ vs. PPZ, LPZ vs. S-PPZ and LPZ vs. PPZ. The average TpH≥4 of R-LPZ, LPZ, S-PPZ, and PPZ was (47.2 ± 26.1) minutes, (49.6 ± 19.3) minutes, (56.1 ± 23.7) minutes, and (72.1 ± 27.3) minutes, respectively. Statistically significant differences were found with R-LPZ vs. PPZ (p = 0.009) and LPZ vs. PPZ (p = 0.019). After multiple doses, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ, and PPZ was 71.7 ± 20.2, 63.5 ± 19.4, 59.5 ± 17.8 and 64.0 ± 22.4, respectively. The ΔTpH≥6 (%) was 64.0 ± 22.2, 52.0 ± 19.2, 49.6 ± 20.4 and 50.9 ± 23.8, respectively. The ΔAUECph-τ1-τ was 326,149 ± 94,839, 288,565 ± 93,279, 296,189 ± 83,412 and 300,960 ± 108,057, respectively. No statistically significant differences were found in baseline-adjusted PD parameters during all time periods after multiple doses. Conclusion After a single dose, the mean gastric pH inhibition value of R-LPZ was the highest, followed by LPZ, then S-PPZ and PPZ. R-LPZ and LPZ provided significantly better pH control compared with PPZ and S-PPZ in healthy subjects. The onset time of R-LPZ was the fastest and R-LPZ can provide better acid inhibition during sleeping time. After multiple doses, the mean values in all PD parameters of R-LPZ were the highest, the values of LPZ, S-PPZ, and PPZ were similar. However, no significant difference was found in acid inhibition among these four drugs after multiple doses.

Application of bioactive materials as synthetic bone graft substitutes in regenerative medicine has seen great evolution over the past decades in treating challengeable bone defects. However, balancing the preparation conditions and biological performances of inorganic biomaterials remain a great challenge, especially when there is lack of biomaterial design on how to control component distribution and how pathological bone responds to the biomaterial stimulations and osteogenesis. Here, our objective is to develop yolk-shell Ca-silicate microspheres and to investigate the potential biological performances to overcome the limitations in repair of osteoporotic bone defects. The introduction of β-calcium silicate (CaSiO3 ) or mesoporous bioactive glass (MBG) into self-curing β-dicalcium silicate (Ca2 SiO4 ) cement shell to form spherical granules (CaSiO3 @Ca2 SiO4 , MBG@Ca2 SiO4 ) was to retain the physicochemical property and/or microstructure of each component for optimizing bioactive ion release that could maximize osteostimulation in osteoporosis. We report a scalable shape-controlled mild fabrication protocol to yield the yolk-shell granules, endowing to different phases in yolk layer and interconnected macropore networks in the closely packed granule scaffolds. This unique heterostructure preparation is governed by coaxially aligned bilayer nozzle, inorganic powders and biocompatible binders. Extensive in vitro and in vivo evaluation showed that the CaSiO3 @Ca2 SiO4 and MBG@Ca2 SiO4 granules exhibited many superior properties such as controllable ion release, improved biodegradation and enhanced osteogenic capability in comparison with the pure Ca2 SiO4 @Ca2 SiO4 , thereby opening new mild-condition approach in fabricating osteogenesis-tailored silicate biomaterials for bone regenerative medicine, especially for efficient reconstruction of challenging pathological bone defects.

We have developed the new core-shell bioceramic CSi-Sr4@CaP-px microspheres with tuning porous shell layer so that the biodegradation of both CSi-Sr4 core and CaP shell is readily adjusted synergistically. This is for the first time, to the best of our knowledge, that the bioceramic scaffolds concerning gradient distribution and microstructure-tailoring design is available for tailoring biodegradation and ion release (bioactivity) to optimizing osteogenesis. Furthermore, it is possibly helpful to develop new bioactive scaffold system for time-dependent tailoring bioactivity and microporous structure to significantly enhance bone regeneration and repair applications, especially in some non-load-bearing arbitrary 3D anatomical bone and teeth defects.

Cyclooxygenase-2 (COX-2) fluorescent probes are promising tools for early cancer diagnosis. Traditionally, COX-2 probes were designed by connecting two parts, a fluorophore and a COX-2 binding unit, via a flexible linker. Herein, a new class of COX-2-specific fluorescent probes have been developed by one-step modification from rofecoxib by an integrative approach to combining the fluorophore and binding units into one. Among them, several new rofecoxib analogues not only retained their COX-2 binding ability but also exhibited attractive fluorescent properties, such as tunable Blue-Red emission, solvatochromism, AIE behavior and mechanochromism. Notably, the emission of 2a16 can be switched between greenish-yellow in the crystalline state to red-orange in the amorphous state by grinding and fuming treatments. Furthermore, the highly fluorescent compound 2a16 (Фf = 0.94 in powder) displayed much stronger fluorescent imaging of COX-2 in HeLa cancer cells overexpressing COX-2 than RAW264.7 normal cells with minimal expressing of COX-2. Most importantly, 2a16 can light up human cancer tissues from adjacent normal tissues with much brighter fluorescence by targeting COX-2 enzyme. These results illustrate the potential of 2a16 as a new red fluorescent probe for human cancer imaging in clinical applications.

SY-004, a dual-acting full glucokinase activator, is under development to provide a dose-dependent improvement of glucose control. This study aimed to assess the tolerability, safety, and pharmacokinetic and pharmacodynamic properties of SY-004 in healthy Chinese adults.Two study participants were administered 2 mg of SY-004 in the 2-mg cohort, whereas 6 study participants were randomized with 4 study participants receiving SY-004 and 2 receiving placebo in the 20-mg cohort. In each of other 3 dose cohorts (40, 80, and 120 mg), 12 participants were randomized in a 10:2 ratio to receive single oral SY-004 capsules or placebos. Drug concentrations, glucose and insulin levels, and safety data were assessed and analyzed. Noncompartmental analysis was used to determine SY-004 pharmacokinetic parameters.SY-004 was generally well tolerated. Nine of the 44 study participants reported 17 treatment-related adverse events, and most treatment-related adverse events were mild. SY-004 had approximately dose-proportional increases in systemic exposure. The mean tSY-004, a new potential glucokinase activator, had favorable safety profiles and good PK characteristics. The glucose-lowering effects were slightly dose related. The SY-004 data in healthy Chinese adults supports further development.gov identifier: NCT03171623.

BACKGROUND: Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants. METHODS: Total radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [(14)C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration. RESULTS: The safety and tolerability of a single oral dose of 110 mg/50 µCi [(14)C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a T(max) of 4.0 h; however, TRA was cleared slowly in vivo, with a mean terminal elimination phase (half-life, T(1/2)) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively. CONCLUSIONS: Almonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized in vivo before excretion and is excreted as a parent drug and metabolites mainly via feces. TRIAL REGISTRATION: The trial registration number: CTR20192291.

Sufang Zhang,1,* Liyan Huang,1,* Qingshan Huang,2,* Weili Wei,1 Lijun Xie,1 Jinshu Zeng,1 Qiuyang Gu,1 Ling Chen,1 Shuqiang Chen1 1Department of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuqiang ChenDepartment of Ultrasound, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of ChinaTel/Fax +86-591-87981961Email chenshu0518@163.comPurpose: Ultrasonography as the first choice for thyroid nodules is still difficult to distinguish between solid follicular thyroid neoplasm (FTN) and solid nodular goiter (NG). We tried to investigate the value of relative size (M/S, M: the maximum diameter of target nodule, S: the maximum diameter of the largest of the remaining nodules) that may help to differentiate FTN from NG.Methods: T test and chi-square test were used to retrospectively analyze the differences of the clinical and ultrasonographic characteristics between FTN and NG in 422 cases in our hospital. T test was used to analyze the difference of M/S value in the two kinds of nodules. ROC was used to evaluate the accuracy of M/S value in distinguishing the two.Results: There were statistically significant differences in age, echogenicity, calcification, peripheral halo and blood supply between the two. The M/S value is not only significantly different in the two kinds of nodules but also can be used as a quantitative indicator to guide ultrasound diagnosis. ROC analysis showed that the cutoff point and AUC of M/S value were 1.94 and 0.709, respectively.Conclusion: In the ultrasound diagnosis of multiple thyroid nodules, the M/S value can better distinguish FTN and NG. We need to be aware of FTN when the M/S value of the nodule is greater than 2.Keywords: follicular thyroid neoplasm, nodular goiter, size, ultrasonography

Purpose Primary hepatic angiosarcoma is a very rare and highly malignant tumor with poor prognosis. It is difficult to diagnose because of the lack of typical clinical features, and the treatment protocols for PHA are also not clear. Therefore, this study wants to find out the clinical characteristics and surgical treatments of primary hepatic angiosarcoma. Methods Among 8990 patients diagnosed with primary malignant tumor of the liver from January 2000 to December 2019 in our hospital, only four patients were diagnosed with primary hepatic angiosarcoma. The demographics, clinical manifestation, past history, serology test results, MRI features, pathology, treatment modality and prognosis of four patients were collected and analyzed. Results Three of four patients had no clinical symptoms, while one patient's symptom was abdominal pain. The levels of tumor markers of all four patients were within the normal reference range and serological tests were negative for hepatitis B and C virus. The MRI imaging findings of all four patients were mixed mass with highly disordered vascular characteristics. All four patients were misdiagnosed preoperatively. One patient who underwent hepatic lobectomy was still alive for about 18 months after surgery. One patient who underwent hepatic lobectomy has survived for only 6 months due to severe pneumonia. The other two patients who received transarterial chemoembolization survived 16 months and 11 months respectively. Conclusion The clinical symptoms of primary hepatic angiosarcoma are not typical, and primary hepatic angiosarcoma is easily misdiagnosed. The typical imaging manifestations are structural disorder and heterogeneous tumor. Hepatic lobectomy and transarterial chemoembolization may be important surgical treatments to improve the prognosis of patients.

Background: Compared with epithelial ovarian cancer, borderline ovarian tumor has earlier onset age and better prognosis. Ovarian serous surface papillary borderline tumor (SSPBT) is a special subtype of ovarian serous borderline tumor, which is rare in clinic. It is easy to be misdiagnosed as malignant before operation. SSPBT usually occurs in women of childbearing age. The operation of preserving fertility can have a higher pregnancy rate. Therefore, preoperative ultrasound for qualitative diagnosis of SSPBT is of great significance in the selection of surgical methods and treatment. There are few reports on the imaging of SSPBT, and the multimodal ultrasound features of SSPBT combined with conventional ultrasound, two-dimensional and three-dimensional contrast-enhanced ultrasound have not been reported. The purpose of this article is to explore the multimodal ultrasonic characteristics of ovarian SSPBT, combining its clinical and pathological features.Result: The conventional ultrasound of ovarian SSPBT was characterized by large patchy substantial masses wrapped around the ovary.Large flaky dense fine anechoic areas could be seen in the parenchyma,accompanied by speckle strong echo with different degrees.Peritoneal implants were observed in 3 cases(60%)and ascites were found in 4 cases(80%).On further contrast-enhanced ultrasonography,with reference to the myometrium,the tumor on 2D-CEUS showed synchronous or delayed eccentric and inhomogeneous enhancement,and subsided earlier than the uterine wall.The tortuously running tumor trophoblast vessels from the periovarian of the affected side could be further observed clearly and stereospecially on 3D-CEUS.Angiographic rising time(RT),time to peak(TTP),peak intensity(PI),area under the curve(AUC)and half time of descending peak intensity(HT)were significantly different from those of the myometrium(PConclusion: There are characteristic manifestations of ovarian SSPBT on multimodal ultrasound,which are closely related to the pathological structure.Multimodal ultrasound has important reference value in the diagnosis of ovarian SSPBT.

Objective: To explore the diagnostic efficiency of ultrasound for the identification of periprosthetic joint infection (PJI) and aspetic loosening.Methods: 50 patients with joint pain after total hip arthroplasty, who were all clinically diagnosed as aseptic prosthesis loosening or PJI, were examined by ultrasonography combined with C-reactive protein, erythrocyte sedimentation rate, bacterial culture and pathology.Results: Thirty-eight of the 50 cases were PJI (group A) , and twelve cases were aseptic loosening (group B) . Fourteen patients with extra-capsular effusion were diagnosed as PJI, while none appeared extra-capsular effusion effusion in group B. 34 cases PJI obtained joint fluid, which was more than group B (7/11) (P < 0.05). The average depth of joint effusion of group B (19.83 ± 8.9mm), was significantly less than group A (25.97±15.25mm) (P < 0.05). In group A , 21 cases (55.26%) had grade 2-3 synovial blood flow signal,which was higher than group B (8.3%) (P < 0.05). Under the circumstance that PJI was diagnosed: (1) There was a sinus tract or extra-capsular effusion; or (2) Joint fluid depth was ≥ 17.0 mm; or (3) Grade 2-3 synovial blood flow signal was detected,the positive predictive value of ultrasound diagnosis of PJI was 92.1% (35/38)，and the accuracy of aseptic loosening was 83.3% (10/12) (P < 0.05).Conclusions: Ultrasound has significant value in the differential diagnosis of PJI and aspetic loosening.

The electric deep well pump in the deck machinery is the key equipment on the liquid cargo ship, and it is the prerequisite for the formation of related operational capabilities. However, due to the special structure of the electric deep well pump, the sensor configuration needs to be optimized for monitoring and diagnosis, in order to control the monitoring cost and improve the efficiency of information acquisition. In this paper, the structural characteristics of multi-span slender shaft transmission and coaxial transmission-conveying system of deep well pump are analysed, and the excitation principles of rotary excitation source and fluid excitation source during the operation of deep well pump are studied. Then the vibration acceleration data at the response points obtained from transient response analysis were used to optimize the sensor configuration based on mutual information.

Background Rheumatoid Arthritis (RA) is a chronic inflammatory condition characterized by autoantibodies development and an elevated spectrum of pro-inflammatory cytokines. Previous reports highlighted a relationship between IL-21and the pathogenesis of RA. Although elevated IL-21 levels have been reported in RA patients, the association of common IL-21 genetic variants with a predisposition to RA development in the Chinese population lacks. Materials and methods Five hundred and fourteen Chinese subjects (healthy controls: 303 and rheumatoid arthritis patients: 211) were enrolled in the study. Clinical data of patients were collected from medical records, and patients were treated as per the guidelines. Common single nucleotide polymorphisms in the IL-21 gene (rs907715, rs2221903, rs2055979 and rs6822844) were genotyped by TaqMan SNPs genotyping method. IL-21 level in plasma of RA patients and healthy subjects was measured by ELISA. Results The plasma level of IL-21 was significantly higher in subjects with rheumatoid arthritis relative to healthy controls (p r = 0.61, p p p Conclusion IL-21 plays a crucial function in rheumatoid arthritis pathogenesis. IL-21 rs2055979 polymorphism is associated with IL-21 plasma levels and is predisposed to RA development in the Chinese population.

The adaptability of renewable energy connected to the VSC-HVDC grid will become an important issue affecting grid operation. In particular, the complex interaction between renewable power generation and the power grid brings new challenges to the renewable power generation and VSC-HVDC grid to achieve fault ride-through. Therefore, it is necessary to study the fault ride-through strategies of the VSC-HVDC grid-renewable power generation combined system. According to the operating characteristics and adaptability of renewable energy clusters connected to the VSC-HVDC grid under different faults, this paper proposes technical requirements for high- / low-voltage fault ride-through of renewable power plants that are connected to the grid in island operation, and analyzes key technologies for renewable power generation dealing with AC faults at the sending end of the grid in island integration mode. It is expected to realize joint fault ride-through of renewable energy and VSC-HVDC, thereby increasing the availability of the system, contributing to the safe and stable operation of renewable energy and VSC-HVDC grid, providing technical support for the planning of large-scale renewable energy delivery methods, and effectively guiding the planning and design of renewable energy and VSC-HVDC grid

Globalagliatin, a glucokinase activator, plays a vital role in glucose homeostasis. The aim of this study was to assess the safety, pharmacokinetics, and pharmacodynamics of globalagliatin in Chinese patients with type 2 diabetes. In this dose-titration study, 24 patients were randomized (3:1 ratio) to receive globalagliatin or placebo. The 28-day titration was divided into two stages, each comprising 12 subjects. In stage I (low-dose), globalagliatin or placebo was administered at ascending doses of 20, 40, 80, and 120 mg once daily, increased at weekly intervals. As the treatment was well tolerated, stage II (high-dose) was initiated, with ascending doses of 80, 160, 240, and 320 mg. Safety, pharmacokinetic and pharmacodynamic analysis were conducted. Following once-daily titration with ascending doses of globalagliatin of 20–120 mg (stage I) and 80–320 mg (stage II) for 7 days, globalagliatin caused mildly high incidences of hypoglycemia and hypertriglyceridemia. The mean maximum plasma concentration (Cmax) of globalagliatin increased from 7.76 to 138.13 ng/mL (stage I), and 29.36 to 471.50 ng/mL (stage II), which occurred at 3–5 h post-dose. A steady state was achieved after 7 days of once-daily dosing in stage I and stage II, respectively. Mean area under the plasma-concentration curve for steady-state 24-h interval (AUC0-24) increased from 106.13 to 2461.95 ng·h/mL (stage I) and 369.71 to 9218.38 ng·h/mL (stage II). Fasting plasma glucose (FPG) decreased continuously during the titration period. Compared with the placebo, high-dose globalagliatin significantly increased the reductions in FPG, the area under the curve of 24-h glucose levels, and glycated albumin, with least-squares mean changes (relative to baseline) of − 4.08 mmol/L (95% CI − 5.05 to − 3.12) (P

Purpose To evaluate the tolerability, safety, pharmacokinetics and drug interaction of cefotaxime sodium-tazobactam sodium injection (6:1) in Chinese healthy subjects. The results of the safety and pharmacokinetic studies supported further clinical trials. Method A randomized, single-blind, ascending dose, placebo-controlled, single-center study was conducted. Sixty healthy subjects (38 males, 22 females) participated in this study. For the single-dose part, 0.47, 1.17, 2.34, 3.51, and 4.68 g of cefotaxime sodium-tazobactam sodium injection (6:1) was administered. For the multiple-dose part, the subjects were administered 2.34 and 3.51 g cefotaxime sodium-tazobactam sodium injection (6:1) three times a day for 7 consecutive days. For the drug interaction part, the subjects received 2.0 g cefotaxime sodium and 0.34 g tazobactam sodium alone and in combination. Results Most adverse events and adverse drug reactions were mild. Moderate rash was considered a serious adverse event because of prolongation of hospitalization. The main pharmacokinetic parameters of cefotaxime and tazobactam had no significance difference between the 1.17, 2.34, and 3.51 g dose cohorts and between genders. There was no difference in trough concentrations on days 6, 7, and 8. The R C max and R AUC were (0.921 ± 0.070) and (0.877 ± 0.057) for cefotaxime, and (0.913 ± 0.046) and (0.853 ± 0.060) for tazobactam, respectively. Following the administration of cefotaxime and tazobactam alone and in combination, the 90% confidence intervals of the geometric mean ratios for C max and AUC were within the predetermined range of 80-125%. In the single-dose part, the renal cumulative excretion ratios were (51.7 ± 6.2)% for cefotaxime, and (84.3 ± 8.1)% for tazobactam. There was no significant difference in the maximum excretion rates and cumulative excretion ratios for cefotaxime and tazobactam, alone or in combination. Conclusions Cefotaxime sodium-tazobactam sodium injection (6:1) was well-tolerated at doses of 0.47 to 4.68 g. The pharmacokinetics of cefotaxime and tazobactam were reported as linear over a dose range of 1.17-3.51 g. Cefotaxime was partially excreted via urine, whereas tazobactam was mainly excreted via urine. There was no significant accumulation after administration over 7 consecutive days. The pharmacokinetics and excretion of cefotaxime and tazobactam were not affected by the co-administration of cefotaxime-tazobactam.

Objective This study evaluated different influences of 14 single nucleotide polymorphisms (SNPs) and demographic factors leading to individual differences in the antihypertensive efficacy of felodipine in healthy Chinese subjects. Materials and methods 24 subjects were sequenced for candidate SNPs. Plasma samples were obtained as clinical trial protocol, and were determined by a HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNonlin 6.0. Statistical analysis was mainly performed by SPSS 22.0. A multiple linear regression model provided different weight coefficients of different demographic and genetic factors. Results The trend of Cmax is almost consistent with AUCss increase, but tmax of individuals is different; the antihypertensive effect of felodipine is individually different. A significant association was observed between systolic blood pressure decrease (ΔSBP) and SNPs of CACNA1C, CACNA1D, GNB3 respectively, while CACNA1C and CACNA1 were associated with diastolic blood pressure decrease (ΔDBP). CYP3A5 rs766746 and CYP3A4 rs2242480 were linked with Cmax and AUCss, and ABCB1 rs1045642 was associated with T1/2. Significant relationships were shown between AUCss and ΔSBP (p = 0.022) as well as Cmax and ΔSBP (p = 0.015). Conclusion The efficacy of felodipine is individually different, influenced especially by CACNA1C rs1051375 and ABCB1 rs1045642. ΔDBP is associated with ΔSBP in multiple-dosing of felodipine in healthy Chinese subjects.

Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects.Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization.The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUCIt was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces.ClinicalTrials.gov NCT03804541.

To determine the absorption, distribution, metabolism and excretion of abivertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer (NSCLC).Seven patients with advanced NSCLC were given a single 200 mg/83 μCi oral suspension of [The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug-related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII-7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug-related exposure. MII-2 (an abivertinib cysteine-glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug-related radioactivity in faeces.Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

The study explored the correlations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) gene polymorphisms with susceptibility and the condition of primary nephrotic syndrome. A total of 200 patients with primary nephrotic syndrome in Qilu hospital were collected as disease group, and 200 healthy people were selected as control group. Genomic deoxyribonucleic acids (DNAs) of nucleated cells in the peripheral blood were extracted to detect the gene polymorphisms of TNF-α (rs1799724 and rs1800629) and IL-10 (rs1800872 and rs141219090). Allele distributions at rs1799724 (P=0.003) and rs1800629 (P=0.011) of TNF-α gene and at rs1800872 (P=0.033) of IL-10 gene in disease group were different from those in control group. In the disease group, allele C frequency at rs1799724 and allele A frequency at rs1800629 of TNF-α gene and allele T frequency at rs1800872 of IL-10 gene were higher. There were differences between rs1799724 (P=0.007) and rs1800629 (P=0.002) of TNF-α gene. In addition, there was a difference in the frequency of the dominant model of TNF-α gene rs1800629 between disease group and control group (P=0.035), and the frequency of dominant model GG+GA was remarkably lower in the disease group. Additionally, TT genotype at rs1799724 of TNF-α gene was obviously related to the plasma TNF-α level (P

The development of aggregation induced emission luminogens (AIEgens) has attracted increasing attention in recent years as the potential of their application in various areas, including data storage and bioimaging has been realised. However, most of the AIEgens have large conjugation systems which were obtained via lengthy synthetic processes. Herein, we have successfully developed a new pair of far-red fluorescent molecules (λmax = 652 nm, 688 nm), ROF1 and ROF2, which were designed and derivatized from rofecoxib by one-step reaction. Specifically, ROF1 with a para-piperidine shows a classical aggregation caused quenching (ACQ) effect. In contrast, by shifting the piperidine group from para-to ortho-position, the ROF2 exhibits typical AIE behavior. Based on the analyses of single-crystal X-ray data, the AIE property of ROF2 could be ascribed to the highly twisted molecular conformation and loose packing modes caused by the ortho-position of piperidine. These findings allow us to have a better understanding of the impact of the substituent position on the AIE properties. Moreover, the fluorescence of ROF2 was sensitive to multi-stimulus, such as grinding, immersing (solvating), heating and altering pH value, which enabled its potential application in data storage, security ink and pH sensing. In biological experiments, ROF2 could selectively image lipid droplets (LDs) in living HeLa cells. In summary, the regio-isomerization effect used in this article successfully developed a promising AIEgen, ROF2, and provided a principle for the design of new AIEgens.

Large-scale wind farms integrated with multi-terminal direct current (MTDC) system decouples the frequency between the wind farms and the receiving end, resulting in weakened frequency regulation ability of the onshore AC grid. Recently a new topology is proposed, called diode rectifier based HVDC, which recouples the wind farm and onshore AC system due to its characteristics, where offshore AC voltage changes with the DC voltage of HVDC system. A coordinated power control strategy for frequency regulation participation is proposed in this paper for offshore wind farms connected with diode-rectifier based high voltage direct current (HVDC) system. Considering the primary frequency and inertia response control, variable power supplementary control is implemented in wind turbines, and a telecommunication-less method of frequency event detection via detection of offshore AC voltage is proposed, avoiding communication delay and communication failure. Simulations using EMTDC/PSCAD show that frequency dip can be accurately detected by the AC voltage of offshore wind farm, and wind farm can quickly compensate active power.

Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects. Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study. Following a single oral dose of tylerdipine of 5–30 mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas Cmax exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (RAUC) of less than 1.65. All adverse events were assessed as mild or moderate. Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5–30 mg increased in a greater than dose-proportional manner, while Cmax exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing. CTR20140862 and CTR20150660.

For quantitative assaying tylerdipine hydrochloride, and its two primary metabolites (M2 and M4) in human urine, two sensitive and accurate LC-MS/MS methods were firstly developed and validated, where multiple reaction monitoring (MRM) was applied under positive electrospray ionization mode for tylerdipine and negative electrospray ionization mode for M2/M4, respectively. Urinary proteins were precipitated using acetonitrile, and deuterated isotopes of tylerdipine and M4 ([D5]‑tylerdipine and [D6]-M4) were used as internal standards. Triton X-100, a good surfactant, was used to prevent the adsorption. An Agilent Poroshell 120 column was employed for chromatographic separation of the analytes with the mobile phases of 2 mM ammonium formate solution (containing 0.1% formic acid) and acetonitrile (45:55 for tylerdipine and 75:25 for the M2/M4, v/v). Flow rate was 0.3 mL/min. Calibration curves for tylerdipine, M2 and M4 in urine were linear over the ranges of 0.02–10 ng/mL, 2–1500 ng/mL and 0.5–200 ng/mL, respectively. The precision, accuracy, specificity and stability of two methods all evaluated and achieved the acceptable criteria. The LC-MS/MS methods were successfully applied to assay urinary excretion of tylerdipine and the metabolites in healthy Chinese subjects who orally received a single dose of 20 mg tylerdipine tablet. Generally, the urinary excretion of the two primary metabolites accounted for 11.7% of the total dose of tylerdipine in healthy Chinese subjects, while little tylerdipine was recovered in urine.

A low-temperature superconducting quantum interference device (low-Tc SQUID) can improve the depth of exploration. However, a low-Tc SQUID may lose its lock owing to oscillations in the current or the occurrence of spikes when the transmitter is switched off. If a low-Tc SQUID loses its lock, it becomes impossible for the low-Tc SQUID TEM system to function normally and stably for a long period of time. This hinders the practical use of the system. In field experiments, the transmitting current is accurately measured, the voltage overshoot and current spike data are recorded, and the gradient of the primary magnetic field at the center of the transmitting loop is calculated. After analyzing the results of field experiments, it was found that when the gradient of the primary magnetic field far exceeds the slew rate of a low-Tc SQUID, the low-Tc SQUID loses its lock. Based on the mechanisms of the transmitting oscillation, an RC serial and multi-parallel capacity snubber circuit used to suppress such oscillation is proposed. The results of simulation and field experiments show that, when using a 100 m×100 m transmitting loop, the gradient of the primary magnetic field is suppressed from 101.4 to 2.4 mT/s with a transmitting current of 40 A, and from 29.6 to 1.4 mT/s with a transmitting current of 20 A. Therefore, it can be concluded that the gradient of the primary magnetic field is below the slew rate of a low-Tc SQUID after adopting the proposed RC serial and multi-parallel capacity snubber circuit. In conclusion, the technique proposed in this paper solves the problem of a lost lock of a low-Tc SQUID, ensuring that the low-Tc SQUID TEM system functions stably for a long period of time, and providing technical assurance for ground TEM exploration at an additional depth.