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Abstract. Background:. Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. Methods:. This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. Results:. Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUCtau) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. Conclusion:. ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. Registration:. NCT04410965, https://clinicaltrials.gov.

With the development of the pharmaceutical industry, halogenated hydrocarbons, which are the main raw materials and emissions of the pharmaceutical industry, may be defined as atmospheric emerging contaminants due to toxicity and low oxidation of the atmosphere. This study analyzed the volatile organic compounds (VOCs) emissions from four pharmaceutical companies located in the Yangtze River Delta. Samples were taken three times at each of the selected fixed and fugitive sampling sites in each company. Through testing, 141 VOCs were identified. The mean concentration and proportion of halogenated hydrocarbons from the four pharmaceutical companies were the highest of all the industries in the industrial park. They reached 18.9 ppm and 28.8 %, respectively. Fixed emissions of the companies exhibited the mean maximum concentration of dichloromethane and chlorobenzene, which are 11.4 ppm and 250.67 ppb. The mean concentration of fugitive emission of dichloromethane from the four companies in this study is lower than that of pharmaceutical companies in other studies. Newly detected halogenated hydrocarbons, such as 1,1-dichloropropanone and dichloronitromethane, present potential non-cancer and cancer risks to workers. Chlorobenzene was identified as a key potential cancer risk halogenated hydrocarbon the value of which reaches 0.00965. 2,6-dichloropyridine could be a potential emerging contaminant due to its lower MIR value and higher potential cancer risk. The study suggests that relevant pharmaceutical companies focus on the emissions of chlorobenzene and dichloromethane, which may be the atmospheric emerging contaminants for the pharmaceutical industry and focus on improve the treatment of waste gases in workshops and sewage stations.

Ethylene glycol (EG) is a colorless and odorless organic compound, which is an important industrial raw material but harmful to the environment and human health. Thus, it is necessary to develop high-performance sensing materials to monitor EG gas. Herein, sea urchin-shaped ZnO was successfully synthesized by a hydrothermal method. Subsequently, a series of carbon dot (CD)-modified ZnO nanocomposites were successfully prepared using a simple mechanical grinding method. The prepared CDs@ZnO-1 sensor exhibits an excellent response to EG gas, with a response value of 1356.89 to 100 ppm EG at the optimal operating temperature (220 °C). After five cycles of detection, the sensor can still maintain a stable response. The enhanced sensing performance of EG can be attributed to rich oxygen vacancies that are generated on the surface of CDs@ZnO, and the heterojunction formed between p-type CDs and n-type ZnO. This study provides inspiration for the development of high-response semiconductor metal oxide sensors.

Synoptic conditions and microphysical formation mechanisms for hail events form the basis for investigating hail suppression technology. There are few relevant studies on hail formation mechanisms in spring in southern China. Most previous theories on hail formation are primarily based on numerical simulations and lack sufficient validation through observations. The atmospheric circulation, stratification, and hail microphysical properties of a typical spring hail event of Honghe in Yunnan on 28 March 2023 are investigated using meteorological and C-band dual-pol radar data. The hail formation mechanisms are compared with those derived from a cloud model with hail-bin microphysics. Results indicate that the synoptic conditions for the hail process are closely associated with the south branch of the westerly winds, which are caused by the blocking effect of the Tibetan Plateau, and the warm moist air carried by the southwesterlies around the western edge of the South Asian tropical high. Due to the relatively weak thermodynamics in spring, small-sized hail below 10 mm is predominant at the surface, with the maximum hail size reaching 20 mm. The microphysical structure of the hail cloud features a warm base and a highly active warm rain process. The dual-polarization radar products of differential reflectivity (ZDR), specific differential phase (KDP) and correlation coefficient indicate that during the initial stage of hail formation, the hail formation region consisted of spherical-shaped hail and supercooled raindrops. It suggests that hail embryos are formed through the freezing process of small-sized supercooled raindrops. As the hail embryos descend, the radar reflectivity increased and the particle shape tended to become discoid, indicating that the hail undergoes a growth process through collision with supercooled cloud water during the descent. The shape also changes from spherical to plate-like. it is because during the initial stage of hail formation, raindrops carry to the upper levels by updrafts are relatively small and had spherical shapes, causing their freezing process to form nearly spherical hail embryos. These spherical hail embryos collide with supercooled cloud water and form discoid hailstones during the falling process, which is consistent with shapes of hailstones collected at the surface. Numerical simulations show that hail embryos are primarily formed through homogeneous freezing of supercooled raindrops, and the growth of these embryos depends on accretion with supercooled cloud water, which is well consistent with products by dual-pol radar.

ABSTRACT: Objectives: Several linezolid population pharmacokinetic (popPK) models have been established to facilitate optimal therapy; however, their extrapolated predictive performance to other clinical sites is unknown. This study aimed to externally evaluate the predictive performance of published pharmacokinetic models of linezolid in adult patients. Methods: For the evaluation dataset, 150 samples were collected from 70 adult patients (72.9% of which were critically ill) treated with linezolid at our center. Twenty-five published popPK models were identified from PubMed and Embase. Model predictability was evaluated using prediction-based, simulation-based, and Bayesian forecasting-based approaches to assess model predictability. Results: Prediction-based diagnostics found that the prediction error within ±30% (F30) was less than 40% in all models, indicating unsatisfactory predictability. The simulation-based prediction- and variability-corrected visual predictive check and normalized prediction distribution error test indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting with one or two prior observations significantly improved the models’ predictive performance. Conclusion: The published linezolid popPK models showed insufficient predictive ability. Therefore, their sole use is not recommended, and incorporating therapeutic drug monitoring of linezolid in clinical applications is necessary.

Background: Patients with ulcerative colitis (UC) often exhibit susceptibilities to multiple autoimmune diseases such as Sjogren's syndrome, primary sclerosing cholangitis, systemic lupus erythematosus, and insulin-dependent diabetes mellitus. This propensity likely stems from common pathogenic mechanisms underlying immune-mediated conditions. This report highlights the occurrence of autoimmune thyroid disease during UC exacerbations. Notably, the patient displayed petrified auricles.Case Summary.A 57-year-old male complained of sustained abdominal pain, diarrhea, hematochezia, and mucus for a duration of 20 days. The diagnosis of UC was confirmed via colonoscopy, histopathological examination, and small bowel MRE. Clinical evaluations revealed bilateral ectopic ossification in his ears, which appeared to develop over an unspecified timeframe. Imaging and histological evaluations substantiated the ectopic ossification diagnosis while eliminating the possibility of adrenal insufficiency. The presented case offers a unique instance of bilateral auricular ossification, which is hypothesized to result from hyperthyroidism. Conclusion: Our case report underscores the necessity of enhancing awareness of the rare complications associated with UC. Medical practitioners should recognize the potential overlap of autoimmune thyroid disorders in UC patients. It is imperative to test for thyroid-related antibodies in such individuals, irrespective of overt thyroid dysfunction.

Triethylamine (TEA) is a typical volatile organic compound (VOC) widely present in air and water, produced in industrial production activities, with high toxicity and great harm. Fluorescence detection and resistive sensing are effective methods for detecting pollutants. Here, In-doped interpenetrating twin ZIF-8 and its annealed derivatives have been successfully designed and prepared as a multifunctional TEA sensor. On the one hand, ZIF-8-In exhibits excellent fluorescence emission enhancement at 450 nm in a dose-dependent manner to TEA in water within the concentration range of 1–100 ppm, with a detection limit as low as 1 ppm. On the other hand, the annealed ZIF-8-In derivative is ZnO/In2O3 with a porous hierarchical structure, which is a perfect sensitive material for manufacturing gas sensors. Within the concentration range of 1–100 ppm, the ZnO/In2O3 gas sensor has a high response for 100 ppm TEA, reaching 107.7 (Ra/Rg), and can detect TEA gas as low as 1 ppm. Furthermore, the response of ZnO/In2O3 sensors to TEA is at least 10 times that of the other four VOC gases, demonstrating excellent gas selectivity. This multifunctional sensor can adapt to complex detection situations, demonstrating good application prospects.

Remimazolam, widely used for procedural sedation and general anesthesia, is a new ultra short-acting benzodiazepine for intravenous sedation and anesthesia. We aim to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of remimazolam and its metabolite CNS 7054 in healthy Chinese volunteers using population analysis and suggest an optimal dosing regimen for sedation therapy. Data were collected from a single-center, placebo-controlled, randomized, and dose–escalation clinical pharmacology study. Forty-six healthy volunteers received a single infusion dose of remimazolam, while nine healthy subjects received a continuous infusion of remimazolam. A population PK/PD model was established and RxODE and Shiny in R were used to design the remimazolam dosing regimens. A three-compartment model best described the PK of remimazolam and a two-compartment model with one transit compartment was adopted for CNS 7054. The relationship between exposure and the bispectral index was best described using an effect compartment model with an inhibitory sigmoid model. Additionally, a web-based dashboard was developed to provide individualized dosing regimens, complemented by a graphical illustration of the PK/PD profiles of the proposed dosing regimen. The established population PK/PD model characterized the dose–exposure–response relationship of remimazolam well, which could be applied to optimize individual dosing regimens.

Micafungin (MFG) is a widely used echinocandin antifungal agent for treating invasive candidiasis, particularly in critically ill patients. However, its pharmacokinetics can be highly variable in this population. This systematic review aims to summarize population pharmacokinetic models and provide recommendations for its use in intensive care unit (ICU) patients. Monte Carlo simulations were implemented to compare pharmacokinetic parameters and probability of target attainment (PTA) against various Candida species. A total of 16 studies were included, of which 6 studies were conducted in adult ICU patients. The key covariates were body size, liver function, and sepsis-related organ failure assessment score (SOFA) score. The median MFG clearance in adult ICU patients was 30–51% higher than in adult non-ICU patients. For infections with C. albican with MIC below 0.016 mg/L, micafungin dosages of 100 and 150 mg/d were recommended for adult non-ICU and ICU patients, respectively. For C. tropicalis and C. glabrata, 200 and 250 mg/d were recommended, respectively. However, for C. krusei and C. parapsilosis, none of the tested dosage regimens achieved assumed PTA criteria within MIC ranges of 0.125–0.25 mg/L and 0.125–2 mg/L, respectively. Therefore, MFG dosage regimens in ICU and non-ICU patients should be tailored based on the Candida spp. and their respective MIC values.

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy.

Background and Objective: Tacrolimus, a calcineurin inhibitor widely used as a potent immunosuppressant to prevent graft rejection, exhibits nonlinear kinetics in patients with kidney transplantation and nephrotic syndrome. However, whether nonlinear drug metabolism occurs in adult patients undergoing liver transplantation remains unclear, as do the main underlying mechanisms. Therefore, here we aimed to further confirm the characteristics of nonlinearity through a large sample size, and determine the potential influence of nonlinearity and its possible mechanisms.Methods: In total, 906 trough concentrations from 176 adult patients (150 men/26 women; average age: 50.68 ± 9.71 years, average weight: 64.54 ± 11.85 kg after first liver transplantation) were included in this study. Population pharmacokinetic analysis was performed using NONMEM®. Two modeling strategies, theory-based linear compartmental and nonlinear Michaelis–Menten (MM) models, were evaluated and compared. Potential covariates were screened using a stepwise approach. Bootstrap, prediction-, and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine model stability and predictive performance. Finally, Monte Carlo simulations based on the superior model were conducted to design dosing regimens.Results: Postoperative days (POD), Aspartate aminotransferase (AST), daily tacrolimus dose, triazole antifungal agent (TAF) co-therapy, and recipient CYP3A5*3 genotype constituted the main factors in the theory-based compartmental final model, whereas POD, Total serum bilirubin (TBIL), Haematocrit (HCT), TAF co-therapy, and recipient CYP3A5*3 genotype were important in the nonlinear MM model. The theory-based final model exhibited 234 L h−1 apparent plasma clearance and 11,000 L plasma distribution volume. The maximum dose rate (Vmax) of the nonlinear MM model was 6.62 mg day−1; the average concentration at steady state at half-Vmax (Km) was 6.46 ng ml−1. The nonlinear MM final model was superior to the theory-based final model and used to propose dosing regimens based on simulations.Conclusion: Our findings demonstrate that saturated tacrolimus concentration-dependent binding to erythrocytes and the influence of daily tacrolimus dose on metabolism may partly contribute to nonlinearity. Further investigation is needed is need to explore the causes of nonlinear pharmacokinetic of tacrolimus. The nonlinear MM model can provide reliable support for tacrolimus dosing optimization and adjustment in adult patients undergoing liver transplantation.

It continues to be a challenge to design innovative NiCoP composite anode materials to further improve rate capacity. In this work, bimetallic flower-like NiCoP encapsulated in an N-doped carbon shell (designated as NiCoP@NC) as a high-rate capable anode material for lithium-ion batteries (LIBs) was successfully designed and synthesized. The novel structure design combines the advantages of flower-like NiCoP (core) and N-doped carbon (shell). Flower-like NiCoP offers numerous interface and redox reaction sites for improving lithium storage, while the N-doped carbon shell effectively buffers volume expansion and enhances electrical conductivity. The synergistic effect between NiCoP and the N-doped carbon shell proposes a marvelous high-rate capacity (320 mA h/g even at 5 A/g) and a good cycle life with high reversible capacity (369.8 mA h/g for 700 cycles at 3 A/g with 81% retention). An investigation of kinetics performance shows that the introduction of the N-doped carbon shell enhances the charge transfer, and the pseudocapacitive behavior dominates the rapid Li+ storage of the NiCoP@NC electrode.

ABSTRACT: Objectives: Effective antifungal therapy is important to reduce mortality in patients with invasive fungal infections (IFIs). Numerous factors affect pharmacokinetic/pharmacodynamic (PK/PD) parameters in critically-ill patients. To guide individualised administration in critically-ill patients, it is of great significance to determine the population pharmacokinetics of caspofungin. Methods: A prospective study in 42 ICU patients with IFIs was conducted in China. A population pharmacokinetic model of caspofungin was established using a non-linear mixed-effects model, which was utilised to investigate the effects of demographic indices, liver function and kidney function on pharmacokinetics. Additionally, appropriate dosages of caspofungin under various scenarios were determined based on MICs and probability of target attainment (PTA) at specific dosages. Results: In critically-ill Chinese patients, clearance (CL), volume of distribution (V) and area under the curve at steady-state (AUCss) of caspofungin were 0.32 L/h, 6.77 L and 135.47 mg•h/L, respectively. Blood albumin and total bilirubin levels were factors affecting CL, while body weight was the only factor affecting V among Chinese people with relatively low weight compared with other populations. A maintenance dose of 50 mg caspofungin achieved a high PTA for treating IFIs caused by Candida albicans (MIC ≤ 0.06 mg/L) and Candida glabrata (MIC ≤ 0.125 mg/L). The maintenance dose of caspofungin should be adjusted to 70–200 mg for IFIs caused by C. albicans (MIC, 0.06–0.125 mg/L). For IFIs caused by Candida parapsilosis, an MIC > 0.03 mg/L is associated with a very low PTA, but higher doses of caspofungin or alternative antifungals need to be further studied. Conclusion: The population pharmacokinetic model established here described well the PK/PD characteristics of caspofungin in critically-ill Chinese patients. These results could guide the formulation of individualised caspofungin dosing regimens for critically-ill patients.

Abstract Background We aim to develop a population pharmacokinetics (PopPK) model of vancomycin for the treatment of septicemia in infants younger than one year. Factors influence of the PK was investigated to optimize vancomycin dosing regimen. Methods The nonlinear mixed effects modelling software (NONMEM) was used to develop the PopPK model of vancomycin. The stability and predictive ability of the final model were assessed by using normalized prediction distribution errors (NPDE) and bootstrap methods. The final model was subjected to Monte Carlo simulation in order to determine the optimal dose. Results A total of 205 trough and peak concentrations in 94 infants (0–1 year of age) with septicemia were analyzed. The interindividual variability of the PK parameter was described by the exponential model. Residual error was better described by the proportional model than the mixed proportional and addition models. Serum creatinine concentration and body weight are the major factors that affect the PK parameters of vancomycin. The clearance was shown to be higher when ceftriaxone was co-treated. More than two model evaluation methods showed better stability than the base model, with superior predictive performance, which can develop individualized dosing regimens for clinical reference. Through prediction of final model, the trough concentration was more likely

Aims: The aims of the study were to 1) establish a population pharmacokinetic (Pop-PK) model for busulfan in Chinese pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and then estimate busulfan exposure and 2) explore the association between busulfan exposure and clinical outcomes.Methods: A total of 128 patients with 467 busulfan concentrations were obtained for Pop-PK modeling using nonlinear mixed effect model (NONMEM) software. Sixty-three patients who received the 16-dose busulfan conditioning regimen were enrolled to explore the correlations between clinical outcomes and the busulfan area under the concentration–time curve (AUC) using the Cox proportional hazards regression model, Kaplan–Meier method and logistic regression.Results: The typical values for clearance (CL) and distribution volume (V) of busulfan were 7.71 L h−1 and 42.4 L, respectively. The allometric normal fat mass (NFM) and maturation function (Fmat) can be used to describe the variability in CL, and the fat-free mass (FFM) can be used to describe the variability in V. Patients with AUCs of 950–1,600 µM × min had 83.7% (95% CI: 73.3–95.5) event-free survival (EFS) compared with 55.0% (95% CI: 37.0–81.8) for patients with low or high exposure (p = 0.024). The logistic regression analysis results showed no association between transplant-related toxicities and the busulfan AUC (p > 0.05).Conclusions: The variability in busulfan CL was related to the NFM and Fmat, while busulfan V was related to the FFM. Preliminary analysis results suggested that a busulfan AUC of 950–1,600 µM × min was associated with better EFS in children receiving the 16-dose busulfan regimen.

Pharmacokinetic characterization plays a vital role in drug discovery and development. Although involving numerous laboratory animals with error-prone, labor-intensive, and time-consuming procedures, pharmacokinetic profiling is still irreplaceable in preclinical studies. With physiologically based pharmacokinetic (PBPK) modeling, the in vivo profiles of drug absorption, distribution, metabolism, and excretion can be predicted. To evaluate the application of such an approach in preclinical investigations, the plasma pharmacokinetic profiles of seven commonly used probe substrates of microsomal enzymes, including phenacetin, tolbutamide, omeprazole, metoprolol, chlorzoxazone, nifedipine, and baicalein, were predicted in rats using bottom-up PBPK models built with in vitro data alone. The prediction’s reliability was assessed by comparison with in vivo pharmacokinetic data reported in the literature. The overall predicted accuracy of PBPK models was good with most fold errors within 2, and the coefficient of determination (R2) between the predicted concentration data and the observed ones was more than 0.8. Moreover, most of the observation dots were within the prediction span of the sensitivity analysis. We conclude that PBPK modeling with acceptable accuracy may be incorporated into preclinical studies to refine in vivo investigations, and PBPK modeling is a feasible strategy to practice the principles of 3Rs.

The cardiotoxicity of anti-cancer drugs presents as a challenge to both clinicians and patients. Significant advances in cancer treatments have improved patient survival rates, but have also led to the chronic effects of anti-cancer therapies becoming more prominent. Additionally, it is difficult to clinically predict the occurrence of cardiovascular toxicities given that they can be transient or irreversible, with large between-subject variabilities. Further, cardiotoxicities present a range of different symptoms and pathophysiological mechanisms. These notwithstanding, mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling offers an important approach to predict cardiotoxicities and offering precise cardio-oncological care. Efforts have been made to integrate the structures of physiological and pharmacological networks into PK-PD modeling to the end of predicting cardiotoxicities based on clinical evaluation as well as individual variabilities, such as protein expression, and physiological changes under different disease states. Thus, this review aims to report recent progress in the use of PK-PD modeling to predict cardiovascular toxicities, as well as its application in anti-cancer therapies.

Rivaroxaban has been widely used to prevent and treat various thromboembolic diseases for more than a decade. However, whether a lower dose of rivaroxaban is required for Asians is still debatable. This review aimed to explore the potential ethnic difference in pharmacokinetic/pharmacodynamic (PK/PD) characteristics between Asians and Caucasians. A systematic search was conducted and twenty-four studies were identified, of which 10 were conducted on Asian adults, 11 on predominantly Caucasian adults, and 3 on Caucasian pediatrics. The apparent clearance (CL/F) of rivaroxaban in Caucasian adults with non-valvular atrial fibrillation (6.45–7.64 L/h) was about 31–43% higher than that in Asians (4.46–5.98 L/h) taking 10~20 mg rivaroxaban every 24 h. Moreover, there was no obvious difference in CL/F among Japanese, Chinese, Thai, and Irani people. Regarding PK/PD relationship, prothrombin time was linked to rivaroxaban concentration in a linear or near-linear manner, and Factor Xa activity was linked with the Emax model. The exposure–response relationship was comparable between Asians and Caucasians. Renal function has a significant influence on CL/F, and no covariate was recognized for exposure–response relationship. In conclusion, a lower dose of rivaroxaban might be required for Asians, and further studies are warranted to verify this ethnic difference to facilitate optimal dosing regimens.

Evidence supports linezolid therapeutic drug monitoring as the exposure–response relationship has been identified for toxicity among patients receiving linezolid, but the data to establish the upper limit are limited and the published toxicity thresholds range widely. The purpose of this study was to determine the linezolid exposure–toxicity thresholds to improve the safety of linezolid. This is a multicenter retrospective study of adult patients treated with linezolid from 2018 to 2019. The population pharmacokinetic model of linezolid was established based on 270 plasma concentrations in 152 patients, which showed creatinine clearance and white cell count are covariates affecting the clearance of linezolid, and serum albumin is the covariate affecting the volume of distribution. Classification and regression tree analysis was used to determine the linezolid exposure thresholds associated with an increased probability of toxicity. Among 141 patients included for toxicity analysis, the rate of occurring toxicity was significantly higher among patients with an AUC0-24, d1 ≥163 mg h/L, AUC0-24, d2 ≥207 mg h/L, AUC0-24, ss ≥210 mg h/L, and Cmin,d2 ≥6.9 mg/L, Cmin,ss ≥6.9 mg/L, while no threshold was discovered for Cmin, d1. Those exposure thresholds and duration of linezolid treatment were independently associated with linezolid-related toxicity in the logistic regression analyses. In addition, the predictive performance of the AUC0-24 and Cmin thresholds at day 2 and steady state were close. Considering that the AUC estimation is cumbersome, Cmin threshold at 48 h and steady state with a value of ≥6.9 mg/L is recommended to improve safety, especially for patients with renal insufficiency and patients with low serum albumin.

In order to adjust to the change of the large-scale deployment of photovoltaic (PV) power generation and fully exploit the potentialities of an integrated energy distribution system (IEDS) in solar energy accommodation, an evaluation method on maximum hosting capacity of solar energy in IEDS based on convex relaxation optimization algorithm is proposed in this paper. Firstly, an evaluation model of maximum hosting capacity of solar energy for IEDS considering the electrical-thermal comprehensive utilization of solar energy is proposed, in which the maximization of PV capacity and solar collector (SC) capacity are fully considered. Secondly, IEDS’s potential in electricity, heat, and gas energy coordinated optimization is fully exploited to enhance the hosting capacity of solar energy in which the electric distribution network, heating network, and natural gas network constraints are fully modeled. Then, an enhanced second-order cone programming (SOCP)-based method is employed to solve the proposed maximum hosting capacity model. Through SOCP relaxation and linearization, the original nonconvex nonlinear programming model is converted into the mixed-integer second-order cone programming model. Meanwhile, to ensure the exactness of SOCP relaxation and improve the computation efficiency, increasingly tight linear cuts of distribution system and natural gas system are added to the SOCP relaxation. Finally, an example is given to verify the effectiveness of the proposed method. The analysis results show that the maximum hosting capacity of solar energy can be improved significantly by realizing the coordination of an integrated multi-energy system and the optimal utilization of electricity, heat, and gas energy. By applying SOCP relaxation, linearization, and adding increasingly tight linear cuts of distribution system and natural gas system to the SOCP relaxation, the proposed model can be solved accurately and efficiently.

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations.Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b.Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations.Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

Both sodium alginate and polyethyleneimine (PEI) have a good ability to adsorb heavy metal ions. PEI and sodium alginate were used as important precursors to synthesize positively charged carbon nanoparticles (p-CNDs) with hydroxyl and carboxyl, and negatively charged carbon nanoparticles (n-CNDs) with amino, respectively. The carbon nanoparticles (CNDs) aerogel with a large specific surface area and rich functional groups were constructed by self-assembled p-CNDs and n-CNDs via electrostatic attraction for adsorption of heavy metal ions in water. The results show that CNDs aerogel has good adsorption properties for Pb2+ (96%), Cu2+ (91%), Co2+ (86%), Ni2+ (82%), and Cd2+ (78%). Furthermore, the fluorescence emission intensity of CNDs aerogel will gradually decrease with the increase in the adsorption rate, indicating that it can detect the adsorption process synchronously. In addition, the cytotoxicity test reveals that CNDs have good biocompatibility and will not cause secondary damage to biological cells.

Background: Numerous vancomycin population pharmacokinetic models in neonates have been published; however, their predictive performances remain unknown. This study aims to evaluate their external predictability and explore the factors that might affect model performance.Methods: Published population pharmacokinetic models in neonates were identified from the literature and evaluated using datasets from two clinical centers, including 171 neonates with a total of 319 measurements of vancomycin levels. Predictive performance was assessed by prediction- and simulation-based diagnostics and Bayesian forecasting. Furthermore, the effect of model structure and a number of identified covariates was also investigated.Results: Eighteen published pharmacokinetic models of vancomycin were identified after a systematic literature search. Using prediction-based diagnostics, no model had a median prediction error of ≤ ± 15%, a median absolute prediction error of ≤30%, and a percentage of prediction error that fell within ±30% of >50%. A simulation-based visual predictive check of most models showed there were large deviations between observations and simulations. After Bayesian forecasting with one or two prior observations, the predicted performance improved significantly. Weight, age, and serum creatinine were identified as the most important covariates. Moreover, employing a maturation model based on weight and age as well as nonlinear model to incorporate serum creatinine level significantly improved predictive performance.Conclusion: The predictability of the pharmacokinetic models for vancomycin is closely related to the approach used for modeling covariates. Bayesian forecasting can significantly improve the predictive performance of models.

BackgroundDepending on the renal function of patients and many other influencing factors, studies on vancomycin pharmacokinetics show significant inter- and intra-individual variability. The present study was conducted using a population pharmacokinetics method to investigate the pharmacokinetic parameters and identified their influencing covariates for intravenous vancomycin in adult kidney transplant recipients.MethodsThe drug monitoring data included 56 adult renal transplant recipients who received intravenous vancomycin as prophylactic medication. The analysis was performed by a population approach with NONMEM. Data were collected mainly during the first week after transplantation. Monitoring of vancomycin trough concentration in blood was initiated mainly 3–5 days after the initial administration.ResultsThe one-compartment open model was optimal and adequately described the data. Body weight (WT) and estimated glomerular filtration rate (GFR) were identified as significant covariates of the pharmacokinetic parameters CL and V of intravenous vancomycin in the kidney transplant patients. The typical values of vancomycin CL and V were 2.08 L h-1 and 63.2 L, respectively. A dosage strategy scheme according to model results was also designed.ConclusionBoth WT and GFR of the kidney transplant patients positively influence the pharmacokinetic parameters CL and V for intravenous vancomycin. Our population pharmacokinetic model provides a reference for vancomycin dosage adjustment in kidney transplant recipients.

Preclinical studies have shown that anti-cytokine therapies could alter drug dispositions through affecting cytochrome P450 synthesis; however, evidence and case reports evaluating clinical relevance of this interaction are scarce. This is the first reported case of interaction between cyclosporine (CsA) and etanercept in a 42-year-old male patient with ankylosing spondylitis and immunoglobulin A nephropathy in whom cytokine levels were monitored both before and after CsA initiation. The initiation of etanercept led to at least 2.5-folds increase in total clearance of CsA. After comprehensive assessment and stepwise exclusion of alternative causes, it was considered that inflammation resolution with etanercept administration has highly induced clearance of CsA, probably mediated by interleukin-2. The case has shown that co-administration of CsA and anti-cytokine therapies such as etanercept needs close monitoring of trough levels. Physicians and pharmacists should be aware of similar interactions especially when the biological therapy is initiated or discontinued and for patients undergoing acute inflammation phase. Monitoring cytokine levels should be considered when drug-cytokine interaction is suspected.

With the development of the times, more and more pollutants such as dyes produced by industry have inevitably caused harm to human health. Dyes are complex and stable in structure, and traditional methods of physically and chemically processing dyes have been proven to be inefficient. The heterogeneous photocatalytic technology has been widely regarded as one of the most promising processes for the treatment of harmful organic wastewater. In this paper, copper oxide (CuO) nanomaterials were synthesized via a hydrothermal method and it was found that the stirring temperature can regulate its morphology and structure, which in turn affects the optical, electrical and catalytic properties of the final product. By controlling the stirring temperature, CuO nanomaterials in the range of ∼30–500 nm were obtained. The as-prepared composites were characterized using x-ray diffraction, transmission electron microscope, scanning electron microscopy, and ultraviolet-visible spectroscopy techniques, among others. After a possible mechanism was proposed according to the above data, the photocatalytic performance of the CuO nanomaterials was evaluated by measuring the decomposition rate of rhodamine B (RhB) solutions. The results indicated that the CuO obtained at 100 °C exhibited excellent photocatalytic activity in comparison to other samples, with around 93% degradation of the RhB solution after 80 min. Finally, the recycling performance of the CuO nanomaterials was also tested and found to be extremely stable, with a high degradation level of 78% maintained after five cycles. In conclusion, the CuO nanomaterials are efficient catalysts for the complete degradation of RhB.

Paving thickness and evenness are two key factors that affect the paving operation quality of earth-rock dams. However, in the recent study, both of the key factors characterising the paving quality were measured using finite point random sampling, which resulted in subjectivity in the detection and a lag in the feedback control. At the same time, the on-site control of the paving operation quality based on experience results in a poor and unreliable paving quality. To address the above issues, in this study, a novel assessment and feedback control framework for the paving operation quality based on the observe–orient–decide–act (OODA) loop is presented. First, in the observation module, a cellular automaton is used to convert the location of the bulldozer obtained by monitoring devices into the paving thickness of the levelling layer. Second, in the orient module, the learning automaton is used to update the state of the corresponding and surrounding cells. Third, in the decision module, an overall path planning method is developed to realise feedback control of the paving thickness and evenness. Finally, in the act module, the paving thickness and evenness of the entire work unit are calculated and compared to their control thresholds to determine whether to proceed with the next OODA loop. The experiments show that the proposed method can maintain the paving thickness less than the designed standard value and effectively prevent the occurrence of ultra-thick or ultra-thin phenomena. Furthermore, the paving evenness is improved by 21.5% as compared to that obtained with the conventional paving quality control method. The framework of the paving quality assessment and feedback control proposed in this paper has extensive popularisation and application value for the same paving construction scene.

Circulating microRNAs (miRNAs, miRs) have great potential as cardiac biomarkers and they are also being explored for their roles in intercellular communication and gene expression regulation. The analysis of circulating miRNAs in response to exercise would provide a deeper understanding of the molecular response to physical activity and valuable information for clinical practice. Here, eight male college students were recruited to participate in cardiopulmonary exercise testing (CPET) and 1 h acute exercise training (AET). Blood samples were collected and serum miRNAs involved in angiogenesis, inflammation and enriched in muscle and/or cardiac tissues were analyzed before and after cardiopulmonary exercise and acute exercise. The miRNAs we detected were miR-1, miR-20a, miR-21, miR-126, miR-133a, miR-133b, miR-146, miR155, miR-208a, miR-208b, miR-210, miR-221, miR-222, miR-328, miR-378, miR-499, and miR-940. We found that serum miR-20a was decreased significantly after CPET and serum miR-21 was increased after AET. In addition, no robust correlation was identified between the changes of these miRNAs and makers of cardiac function and exercise capacity, which indicates a distinct adaptation of these miRNAs to exercise. Future studies are highly needed to define the potential use of these circulating miRNAs as useful biomarkers of exercise training, and disclose the biological function of circulating miRNAs as physiological mediators of exercise-induced cardiovascular adaptation.

ObjectivesThe population pharmacokinetic (popPK) characteristics of total mycophenolic acid (tMPA) have been investigated in various ethnic populations. However, investigations of popPK of unbound MPA (uMPA) are few. Thus, a popPK analysis was performed to: (1) characterize the PK of uMPA and tMPA and its 7-O-mycophenolic acid glucuronide (MPAG) metabolite in kidney transplant patients cotreated with cyclosporine (CsA), and (2) identify the clinically significant covariates that explain variability in the dose–exposure relationship.MethodsA total of 740 uMPA, 741 tMPA, and 734 total MPAG (tMPAG) concentration–time data from 58 Chinese kidney transplant patients receiving MPA in combination with CsA were analyzed using NONMEM® software with the stochastic approximation expectation maximization (SAEM) followed by the important sampling (IMP) method. The influence of covariates was tested using a stepwise procedure.ResultsThe PK of uMPA and unbound MPAG (uMPAG) were characterized by a two- and one-compartment model with first-order elimination, respectively. A linear protein binding model was used to link uMPA and tMPA. Apparent clearance (CL/F) and central volume of distribution (VC/F) of uMPA (CLuMPA/F and VCuMPA/F, respectively) and protein binding rate constant (kB) were estimated to be 851 L/h [relative standard error (RSE), 7.1%], 718 L (18.5%) and 53.4/h (2.3%), respectively. For uMPAG, the population values (RSE) of CL/F (CLuMPAG) and VC/F (VCuMPAG/F) were 5.71 L/h (4.4%) and 29.9 L (7.7%), respectively. Between-subject variability (BSVs) on CLuMPA/F, VCuMPA/F, CLuMPAG/F, and VCuMPAG/F were 51.0, 80.0, 31.8 and 48.4%, respectively, whereas residual unexplained variability (RUVs) for uMPA, tMPA, and uMPAG were 47.0, 45.9, and 22.0%, respectively. Significant relationships were found between kB and serum albumin (ALB) and between CLuMPAG/F and glomerular filtration rate (GFR). Additionally, model-based simulation showed that changes in ALB concentrations substantially affected tMPA but not uMPA exposure.ConclusionsThe established model adequately described the popPK characteristics of the uMPA, tMPA, and MPAG. The estimated CLuMPA/F and unbound fraction of MPA (FUMPA) in Chinese kidney transplant recipients cotreated with CsA were comparable to those published previously in Caucasians. We recommend monitoring uMPA instead of tMPA to optimize mycophenolate mofetil (MMF) dosing for patients with lower ALB levels.

ObjectiveThe aim of the present study was to investigate the absorption routes as well as the potential application of the oral transmucosal delivery of risperidone orodispersible film (ODF) using physiologically based pharmacokinetic modeling.MethodsThe pharmacokinetic study after intragastric (i.g.), supralingual, and sublingual administration of risperidone ODF was conducted in Beagle dogs. Then a mechanic absorption model which combined Oral Cavity Compartment Absorption and Transit (OCCAT) model with Advanced Compartment Absorption and Transit (ACAT) model for predicting the absorption routes of risperidone ODF in vivo was constructed using GastroPlus™. A sensitivity analysis was performed to investigate the impact of oral residence time on the in vivo absorption of risperidone ODF. Based on the fraction of intraoral absorption, the potential of the oral transmucosal delivery of risperidone were predicted.ResultsThere were no statistical differences in the AUC0–t (P = 0.4327), AUC0-∞ (P = 0.3278), Cmax (P = 0.0531), and Tmax (P = 0.2775) values among i.g., supralingual, and sublingual administration of risperidone ODF in Beagle dogs. The predicted absorption percentage via oral mucosa at oral residence time of 2 min, 5 min, and 10 min was 7.0%, 11.4%, and 19.5%, respectively. No obvious difference was observed for the bioavailability of risperidone ODF within 10 min of oral residence time. The PBPK absorption model for risperidone could be simplified to include ACAT model solely. ConclusionThe main absorption route for risperidone ODF was the gastrointestine. The absorption percentage via oral mucosa was almost negligible due to the physicochemical properties of risperidone although ODF dissolved completely in the oral cavity of Beagle dogs within 2 min.

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population. The study population consisted of 80 neonates in the neonatal intensive care unit (ICU) from which 165 trough and peak concentrations of vancomycin were obtained. Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin. The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errors and the bootstrap method. Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin. The average clearance was 0.309 L/h for a neonate with Scr of 23.3 μmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15 μmol/L, current guideline recommendations would likely not achieve therapeutic area under the concentration-time curve over 24 h/minimum inhibitory concentration (AUC24h/MIC) ≥ 400. The exceptions to this are British National Formulary (2016–2017), Blue Book (2016) and Neofax (2017). Recommended dose regimens for neonates with different Scr levels and postmenstrual ages were estimated based on Monte Carlo simulations and the established model. These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.

The use of a dual-gated tunable absorber in graphene-based hyperbolic metamaterial (GHMM) in the near-infrared frequency range was investigated. The horizontal and vertical parts for relative permittivity of GHMM, which consists of monolayer graphene and conventional dielectric, were tuned using the chemical potential. To obtain a large absorption, GHMM was placed on top of a stacked structure containing dielectric and graphene layers and a copper reflector was placed at the bottom. The dual-gated absorber had multiband absorption, which was tuned using the chemical potential of graphene and GHMM. This study focuses on the variation of the absorption with change in the chemical potential and dielectric thickness. The results show that multiband absorption could be attained when chemical potential and dielectric thickness was changed. Broadband absorption could be generated when the frequency ranged from 215 THz to 250 THz. This phenomenon may be valuable for a variety of important applications including optical communication technology and near-infrared stealth communication.

In this paper ITO thin films were deposited on alumina substrates by ultrasonic spray pyrolysis. The NO2 sensing properties of ITO thin films were investigated. The results show ITO thin films have good sensitivity to nitrogen dioxide.

Among the various metal oxide additives tested, the complex of CuO is outstanding in promoting the sensing propoerties of an SnO2 sensor for H2S in air. The SnO2 sensors loaded with 5 wt. % CuO is extremely sensitive to H2S at 200 C° and below, while it is almost unsensitive to many other gases. The response to H2S is rather slow but the recovery is very rapid. Tha added CuO particles interact electronically with the surface of SnO2 (p-n junctions) to make the sensor highly resistive, while the interaction is disconnected when CuO is sulfurized to CuS in the H2S containing atmosphere, leading to a drastic decrease in electrical resistance. The H2S sensing properties, particularly the rate of response of CuO/SnO2 sensors are influenced by the CuO loadings andoperating temperature as well as the thickness of Cuo loading film.

In this paper the characteristics of a CuO-BaTiO3 based CO2 gas sensor was investigated. The sensitivity of the CuO-BaTiO3 based CO2 sensor was influenced by doping various metal elements such as Au, Ag, Pt, Pd, Ce, Mg, Sr, La, Zn, Fe and Bi, which were added as a pure metal or in the form of metal oxides. It was found that Ag is the most suitable additive among all substances tested. The Ag-doped CO2 gas sensor has better sensitivity and lower operating temperature, with a detection concentration range of from 100 ppm to 10%. The sensor also shows good stability.

ZnGa2O4 nano crystals were prepared by an improved coprecipitation method, which we call ‘spray coprecipitation’. XRD results shows the resulting crystal size using the new method is under 10nm, whereas the powder prepared by ordinary coprecipitation is about 30nm. XRD results also shows ZnO peaks exists in ZnGa2O4 powder prepared by traditional coprecipitation, but disappears in ZnGa2O4 nano crystal prepared by spraying coprecipitation. SEM and TEM were used to analysis the structural characteristics of ZnGa2O4 nano crystals. The gas sensitive characteristics of ZnGa2O4 nano crystals are reported.

Regional citrate anticoagulation (RCA) is gaining popularity in continous renal replacement therapy (CRRT) for critically ill patients. The risk of citrate toxicity is a primary concern during the prolonged process. The aim of this study was to assess the pharmacokinetics of citrate in critically ill patients with AKI, and used the kinetic parameters to predict the risk of citrate accumulation in this population group undergoing continuous veno-venous hemofiltration (CVVH) with RCA.Critically ill patients with AKI (n = 12) and healthy volunteers (n = 12) were investigated during infusing comparative dosage of citrate. Serial blood samples were taken before, during 120 min and up to 120 min after infusion. Citrate pharmacokinetics were calculated and compared between groups. Then the estimated kinetic parameters were applied to the citrate kinetic equation for validation in other ten patients' CVVH sessions with citrate anticoagulation.Total body clearance of citrate was similar in critically ill patients with AKI and healthy volunteers (648.04±347.00 L/min versus 686.64±353.60 L/min; P = 0.624). Basal and peak citrate concentrations were similar in both groups (p = 0.423 and 0.247, respectively). The predicted citrate curve showed excellent fit to the measurements.Citrate clearance is not impaired in critically ill patients with AKI in the absence of severe liver dysfunction. Citrate pharmacokinetic data can provide a basis for the clinical use of predicting the risk of citrate accumulation.ClinicalTrials.gov Identifier NCT00948558.