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Under servitization (one paradigm of non-ownership-transfer) business model such as sharing, a manufacturer is responsible not only for product design but also for maintenance. This paper deals with joint decision of product quality and maintenance under servitization. A model minimising total cost is formulated to obtain the optimal product quality, maintenance effort and maintenance times. We find that the total cost first decreases then increases with product quality, maintenance effort and maintenance times. Moderate quality and maintenance effort level are the best for the manufacturer, because too high or too low quality and effort cause too high total cost. However, preventive maintenance should be implemented as many times as possible until the failure cost is reduced to zero as long as each maintenance can save cost. Moreover, in the optimal joint decision, the product quality, maintenance effort and maintenance times are negatively correlated in pairs. In addition, we explore the impact of unit failure cost, product lifecycle, production cost, maintenance cost, and failure intensity on the manufacturer's optimal decisions. In extensions, we further take penalty cost, exponential failure distribution, discount rate, and customer usage into account. This paper provides insight for the manufacturer to jointly consider product design and maintenance under servitization. [ABSTRACT FROM AUTHOR]

Purpose: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method. Methods: The Emax model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with Emax model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4–10 ng/ml. Results: In machine learning model, the Emax from tacrolimus effecting proteinuria in IMN patients was −72.7%, the ET50 was 0.43 months, and the time to achieving 25% Emax, 50% Emax, 75% Emax, and 80% (plateau) Emax of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively. Conclusion: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4–10 ng/ml for at least 1.72 months. [ABSTRACT FROM AUTHOR]

Background: Post-hepatectomy liver failure (PHLF) is a serious complication after hepatectomy and a major cause of death. The current criteria for PHLF diagnosis (ISGLS consensus) require laboratory data of elevated INR level and hyperbilirubinemia on or after postoperative day 5. This study aims to propose a new indicator for the early clinical prediction of PHLF. Methods: The peri-operative arterial lactate concentration level ratios were derived from time points within the 3 days before surgery and within POD1, the patients were divided into two groups: high lactate ratio group (≥ 1) and low lactate ratio group (< 1). We compared the differences in morbidity rates between the two groups. Utilized logistic regression analysis to identify the risk factors associated with PHLF development and ROC curves to compare the predictive value of lactate ratio and other liver function indicators for PHLF. Results: A total of 203 patients were enrolled in the study. Overall morbidity and severe morbidity occurred in 64.5 and 12.8 per cent of patients respectively. 39 patients (19.2%) met the criteria for PHLF, including 15 patients (7.4%) with clinically relevant Post-hepatectomy liver failure (CR-PHLF). With a significantly higher incidence of PHLF observed in the lactate ratio ≥ 1 group compared to the lactate ratio < 1 group (n = 34, 26.8% vs. n = 5, 6.6%, P < 0.001). Multivariable logistic regression analysis revealed that a lactate ratio ≥ 1 was an independent predictor for PHLF (OR: 3.239, 95% CI 1.097–9.565, P = 0.033). Additionally, lactate ratio demonstrated good predictive efficacy for PHLF (AUC = 0.792). Conclusions: Early assessment of peri-operative arterial lactate concentration level ratios may provide experience in early intervention of complications in patients with hepatocellular carcinoma, which can reduce the likelihood of PHLF occurrence and improve patient prognosis. [ABSTRACT FROM AUTHOR]

Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug–drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients. Methods: In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM). Results: Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40– 70, and 70– 100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40– 60, and 60– 100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40– 53, and 53– 100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40– 100 kg schizophrenia patients, respectively. Conclusion: Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients. [ABSTRACT FROM AUTHOR]

A new biflavone (philonotisflavone-3′′′-methyl ether), three diterpenes (lupulin G, lupulin H, lupulin I), a new ecdysteroid (ajugasterone E), and four known compounds were isolated from the whole plant of Ajuga lupulina Maxim. Their structures were determined by spectroscopic analysis, including MS, NMR and ECD spectral data. Compounds 1-3 has DPPH radical scavenging ability, and compound 1 has stronger activity than vitamin C. Compounds 2, 3, 7 and 8 have potential cytotoxic activity against Hela, with IC50 values less than 20.0 μM. Abietane diterpenes 2, 3, 7 and 8 are also found to have NO inhibitory effects with IC50 values less than 40.0 μM. [ABSTRACT FROM AUTHOR]

COVID-19 has caused huge losses to countries around the world, and it will not end in a short time. The lack of motivation for international joint prevention and control is one of the important reasons for the global pandemic of COVID-19. How to improve the efforts and level of international joint prevention and control has become an urgent problem to be solved. Considering the long-term and dynamic nature of international joint prevention and control, the differential game method is used to compare and analyze the optimal decisions of countries in the three scenarios of spontaneous governance, external subsidies and internal cost sharing. The results show that the optimal prevention and control efforts of countries are negatively correlated with discount rates, prevention and control cost coefficients, decay rate and risk factors. It is positively correlated with the impact degree of social benefits, the impact degree of prevention and control efforts on the level of joint prevention and control, the distribution ratio of social benefits, and the impact degree of prevention and control level on social benefits. The prevention and control efforts, joint prevention and control level, social benefits and system benefits under spontaneous governance are the lowest and highest under the internal cost sharing. The internal cost sharing will only be carried out when social benefits distribution ratio obtained reach a certain threshold. This study provides decision-making support for the joint prevention and control of countries to defeat COVID-19 under the normalization of the epidemic. [ABSTRACT FROM AUTHOR]

The present study aimed to explore the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on liver functions in patients with nonalcoholic fatty liver disease (NAFLD). A total of 4771 patients with NAFLD were included for analysis by means of nonlinear mixed effect modeling, where the change rates of liver functions were taken as the evaluation indexes so as to eliminate the potential baseline effects. For ALT and AST, the Emax of SGLT-2 inhibitors was −17.8% and −13.9%, respectively, and the ET50 was 6.86 weeks and 10 weeks, respectively. Furthermore, the duration time to achieve 25%, 50%, 75%, and 80% Emax were 2.3 weeks, 6.86 weeks, 20.6 weeks, 27.5 weeks in ALT, 3.4 weeks, 10 weeks, 30 weeks, 40 weeks in AST, respectively. Thus, to realize the plateau period (80% of Emax) of SGLT-2 inhibitors on ALT and AST in patients with NAFLD, 100 mg/day canagliflozin (or 10 mg/day dapagliflozin or 10 mg/day empagliflozin) needs to be taken for 20.6 weeks and 30 weeks, respectively. The present study explored the quantitative effects of SGLT-2 inhibitors on liver functions and recommends a therapeutic regimen in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Background and aims: Preoperative prediction of microvascular invasion (MVI) using a noninvasive method remain unresolved, especially in HBV-related in intrahepatic cholangiocarcinoma (ICC). This study aimed to build and validate a preoperative prediction model for MVI in HBV-related ICC. Methods: Patients with HBV-associated ICC undergoing curative surgical resection were identified. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors of MVI in the training cohort. Then, a prediction model was built by enrolling the independent risk factors. The predictive performance was validated by receiver operator characteristic curve (ROC) and calibration in the validation cohort. Results: Consecutive 626 patients were identified and randomly divided into the training (418, 67%) and validation (208, 33%) cohorts. Multivariate analysis showed that TBIL, CA19-9, tumor size, tumor number, and preoperative image lymph node metastasis were independently associated with MVI. Then, a model was built by enrolling former fiver risk factors. In the validation cohort, the performance of this model showed good calibration. The area under the curve was 0.874 (95% CI: 0.765–0.894) and 0.729 (95%CI: 0.706–0.751) in the training and validation cohort, respectively. Decision curve analysis showed an obvious net benefit from the model. Conclusion: Based on clinical data, an easy model was built for the preoperative prediction of MVI, which can assist clinicians in surgical decision-making and adjuvant therapy. [ABSTRACT FROM AUTHOR]

Although anatomical hepatectomy (AH) is widely used in the treatment of hepatocellular carcinoma (HCC), the prognosis is still unsatisfactory. The present study aimed to evaluate the survival benefit of adjuvant transcatheter arterial chemoembolization (TACE) for patients with HCC after AH. A total of 832 patients were stratified into with adjuvant TACE (443, 53.2%) and without adjuvant TACE group (389, 46.8%) AH. Propensity score matching (PSM) was performed to control for confounding factors, and multivariable Cox regression was performed to determine the independent risk factors. After PSM, the results showed that the adjuvant TACE group had better overall survival (OS) and recurrence-free survival (RFS). Among the patients with tumor recurrence, adjuvant TACE was associated with a high rate of early-stage tumor at recurrence, a lower recurrence rate around the frontal margin and extrahepatic metastases, and a higher rate of receiving curative treatment. Multivariable Cox regression analysis showed that adjuvant TACE was an independent prognostic factor for OS (HR 0.673, P = 0.001) and RFS (HR 0.650, P = 0.001). Patients with HCC after AH can benefit from postoperative adjuvant TACE. Therefore, adjuvant TACE should be considered for patients with a high risk of recurrence. [ABSTRACT FROM AUTHOR]

The binary Ga–Al alloy cathode has been proven to be a prospective candidate for the separation of actinides over lanthanides (Lns) in the dry reprocessing. Therefore, in this work the electrochemical behaviors of U(III) on solid Al, liquid Ga and Ga–Al eutectic alloy cathodes were studied by cyclic voltammetry, and the kinetic properties of U(III)/U on these reactive cathodes were also investigated via electrochemical impedance spectroscopy technique in LiCl–KCl melts. The results showed that the exchange current density (j0) of U(III)/U on the Ga–Al eutectic alloy cathode is the largest, and followed the order: Ga–Al eutectic alloy > Ga > Al. Finally, U was electro-separated on the binary Ga–Al eutectic alloy cathode in a molten salt system containing U and representative Lns (La, Ce, Pr, Nd). The electrolysis products were validated to be Al3U and Ga3U according to XRD and SEM–EDS characterizations. The extraction rate of U was determined to be 88.3% via ICP-OES. This work is of theoretical guidance for high-temperature molten salt electro-separation of An over Ln. [ABSTRACT FROM AUTHOR]

Purpose: Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) remains controversial, especially for tumors larger than 5 cm. We compared the short- and long-term outcomes of laparoscopic and open liver resection (OLR) for large HCC. Methods: Patients with large HCC after curative hepatectomy were enrolled. To compare the short-term outcomes, propensity score matching (PSM) and inverse probability treatment weighting (IPTW) were performed to reduce the effect of confounding factors, respectively. Subsequently, Cox-regression analyses were conducted to identify the independent risk factors associated with decreased recurrence-free survival (RFS) and poor overall survival (OS). Result: There were 265 patients enrolled in the final analysis: 146 who underwent OLR and 119 who underwent LLR. There was no significant difference between the OLR and LLR groups according to PSM and IPTW analysis (all P > 0.05). Multivariable analysis revealed that LLR was not independently associated with poorer OS (HR 1.15, 95% CI 0.80–1.67, P = 0.448) or RFS (HR 1.22, 95% CI 0.88–1.70, P = 0.238). Conclusion: There were no significant differences in perioperative complications or long-term prognosis between LLR and OLR for large HCC, which provides evidence for standard laparoscopic surgical practice with adequate surgeon experience and careful patient selection. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that pediatric tuina, a modality of traditional Chinese medicine (TCM), might have beneficial effects on the symptoms of attention deficit hyperactivity disorder (ADHD), such as overall improvements in concentration, flexibility, mood, sleep quality, and social functioning. This study was conducted to understand the facilitators and barriers in the delivery of pediatric tuina by parents to children with ADHD symptoms. Methods: This is a focus group interview embedded in a pilot randomized controlled trial on parent-administered pediatric tuina for ADHD in preschool children. Purposive sampling was employed to invite 15 parents who attended our pediatric tuina training program to participate voluntarily in three focus group interviews. The interviews were audio-recorded and transcribed verbatim. The data were analyzed through template analysis. Results: Two themes were identified: (1) facilitators of intervention implementation and (2) barriers to intervention implementation. The theme of the facilitators of intervention implementation included the subthemes of (a) perceived benefits to children and parents, (b) acceptability to children and parents, (c) professional support, and (d) parental expectations of the long-term effects of the intervention. The theme of barriers to intervention implementation included the subthemes of (a) limited benefits for children's inattention symptoms, (b) manipulation management difficulties, and (c) limitations of TCM pattern identification. Conclusion: Perceived beneficial effects on the children's sleep quality and appetite and parent–child relationships, as well as timely and professional support, mainly facilitated the implementation of parent-administered pediatric tuina. Slow improvements in the children's inattention symptoms and the possible inaccuracies of online diagnosis were the dominant barriers of the intervention. Parents have high expectations for the provision of long-term professional support during their practice of pediatric tuina. The intervention presented here can be feasibly used by parents. [ABSTRACT FROM AUTHOR]

Taking the upper sub-member of Sha 4 in Well Fanye 1 and Well Niuye 1 in Dongying Sag, Jiyang Depression, Bohai Bay Basin as a typical example, this paper adopts the method of combining macro and micro laminar characterization and complementing each other. The characteristics of laminar development are studied by means of fine description of rock thin sections by cores and electron microscopic observation Reconstruction of the Bohai Bay Basin in sand four period of ancient sedimentary environment, it is concluded that the sand on the four period of development of four complete filling sedimentary cycle. Using Milankovitch cycles method, reveals the ancient climate control mechanism of lithofacies, formed by organic laminae under hot and humid climate and a small amount of calcite laminated lithofacies, in hot and humid climate, the lithofacies is mainly composed of organic lamina and a small amount of calcite lamina, while in cold and dry climate, the lithofacies is mainly composed of calcite lamina, and the lithofacies is mainly composed of organic lamina, silty lamina and gypsum lamina. Micro-laminar research is an important scientific issue in unconventional oil and gas eology. It can provide basic data for unconventional oil and gas exploration, such as the types, distribution and extension of laminar, especially the determination of sampling targets. Different laboratory samples can be analyzed according to the laminar types. [ABSTRACT FROM AUTHOR]

What Is Known and Objectives: The present study aimed to predict the effect of sirolimus on disease activity in patients with systemic lupus erythematosus (SLE) using machine learning and to recommend appropriate sirolimus dosage regimen for patients with SLE. Methods: The Emax model was selected for machine learning, where the evaluation indicator was the change rate of systemic lupus erythematosus disease activity index from baseline value. Results: A total 103 patients with SLE were included for modelling, where the Emax, ET50 were −53.9%, 1.53 months in the final model respectively, and the evaluation of the final model was good. Further simulation found that the follow‐up time to achieve 25%, 50%, 75% and 80% (plateau) Emax of sirolimus effecting on disease activity in patients with SLE were 0.51, 1.53, 4.59 and 6.12 months, respectively. In addition, the sirolimus dosage was flexible and adjusted according to drug concentration, where the intersection of sirolimus concentration range included in this study was about 8–10 ng/ml. What Is New and Conclusions: This study was the first time to predict the effect of sirolimus on disease activity in patients with SLE and in order to achieve better therapeutic effect maintaining a concentration of 8–10 ng/ml sirolimus for at least 6.12 months was necessary. [ABSTRACT FROM AUTHOR]

What is Known and Objectives: The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients. Methods: This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients. Results: Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10–16, 16–30, and 30–40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10–16, 16–25, 25–30, and 30–40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10–40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10–24 and 24–40 kg, respectively. What is New and Conclusions: This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients. [ABSTRACT FROM AUTHOR]

In response to the failure of traditional administrative methods to manage transboundary polluted areas, this study uses Stackelberg game theory to construct a three‐party dynamic game model from the perspective of government participation. The results show that the central government will only subsidize local governments when the environmental benefits obtained reach a certain threshold, prompting the local governments to increase pollution control efforts to improve environmental benefits. From the perspective of pollutant emission reduction and environmental benefits, the collaborative governance model is superior to both spontaneous governance and the central government‐led model. Finally, the validity of the conclusion is verified. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to detect the association between P-selectin autoantibody positive and response to steroid treatment in newly diagnosed immune thrombocytopenia (ITP) patients. Methods: The data from 105 newly diagnosed adult ITP patients administered with first-line of steroid treatment from October 2016 to May 2021 were retrospectively analyzed. Treatment responses were evaluated within 3 months after the onset of treatment. Results: Among the 105 patients, 80.00% (84/105) of patients presented with platelet glycoprotein-specific antibody positive; 44.76% (47/105) patients were anti-P-selectin positive, while 35.24% (37/105) were anti-P-selectin negative. No significant difference in overall response was observed between patients who were anti-P-selectin positive and those who were anti-P-selectin negative (74.47% vs. 89.19, χ2 = 2.910, p = 0.088). But patients who were anti-P-selectin negative had significantly higher complete response rate, compared to those who were anti-P-selectin positive (72.97% vs. 48.94%, χ2 = 4,965, p = 0.026). Logistic regression analysis revealed that anti-GP IIb/IIIa positive (OR = 3.114, p = 0.010, 95% CI: 1.313–7.388) and anti-P-selectin positive (OR = 0.309, p = 0.036, 95% CI: 0.127–0.753) were two factors that could affect patients' response. Conclusions: Our study found that ITP patients with anti-GP IIb/IIIa may have a higher response to steroid treatment, but anti-P-selectin-mediated-ITP might be less responsive to steroid treatment. In adults with ITP, the presence of anti-P-selectin autoantibodies is a predictive factor for poor response to steroid treatment. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to explore the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on urine albumin to creatinine ratio (UACR) in type 2 diabetes mellitus (T2DM) patients and to recommend appropriate medication care scheme. Methods. 8371 T2DM patients from four dapagliflozin studies and two canagliflozin studies were collected for analyzing with nonlinear mixed effect model (NONMEM). The change rates of UACR from baseline were intended to be evaluation indicators. Results. In the present study, there was no significant difference in the effects on UACR using dapagliflozin or canagliflozin treatment in T2DM patients. The maximal effect ( E max ) and the treatment duration of reaching half of E max (ET50) from SGLT-2 inhibitors on UACR in T2DM patients were -19.2% and 0.448 weeks, respectively. Further, the treatment duration to reach 25%, 50%, 75%, and 80% E max was 0.150 weeks, 0.448 weeks, 1.344 weeks, and 1.792 weeks, respectively. Namely, for achieving the plateau period (80% of E max ) of SGLT-2 inhibitors on UACR in T2DM patients, 10 mg/day dapagliflozin (or 100 mg/day canagliflozin) should be taken for at least 1.792 weeks. Conclusions. To our knowledge, the present study explored the effects of SGLT-2 inhibitors on UACR in T2DM patients, meanwhile, recommended appropriate medication care scheme for the first time. [ABSTRACT FROM AUTHOR]

It has been established that star polymers with a large number of arms display both the conventional chain relaxation and a slower interchain relaxation due to the formation of hard cores, which is called the local structural relaxation. Here, we demonstrate that this unique relaxation property of multi-arm stars leads to unusual rheological behaviors. We study the response of star polymer melts with various arm numbers to start-up shear flow via nonequilibrium molecular dynamics simulation. Our simulation results indicate that the stress-strain response of multi-arm star polymer melts differs from that of star polymers with a small number of arms in both quantitative and qualitative manners. While the multi-arm star polymer melts exhibit an overshoot peak in the stress-strain curve both at relatively small and sufficiently large shear rates, two overshoot peaks appear when the flow strength is comparable to the relaxation time of the star polymers. This double stress overshoot is absent in linear polymers and star polymers with a small number of arms and is evidently related to the presence of the local structural relaxation in star polymers with a large number of arms. We present a detailed analysis of the conformational and dynamical properties of star polymer melts under start-up shear to gain a molecular understanding of their stress response. [ABSTRACT FROM AUTHOR]

As global environmental problems are becoming more severe, how to efficiently reduce carbon emissions has become an urgent problem to be solved. Manufacturers and retailers can effectively reduce carbon emissions through low‐carbon efforts, and doing so is important for the sustainable development of low‐carbon supply chains. This paper develops a general framework that considers how bounded rationality and fairness concerns affect the manufacturer's and retailer's low‐carbon effort decisions and discusses the evolutionary stable strategy (ESS) and the evolution process of the manufacturer's and retailer's low‐carbon efforts. The ESS shows that the manufacturer and the retailer will increase their low‐carbon efforts when the initial unit profit is higher. Otherwise, a smaller initial unit profit will reduce their low‐carbon efforts. This paper also analyzes different attributes of fairness concerns and finds that advantageous fairness concerns increase low‐carbon efforts, whereas disadvantageous fairness concerns reduce low‐carbon efforts. In addition, fairness concerns will speed up the manufacturer's and retailer's low‐carbon efforts to ESSs. When the manufacturer and retailer choose the "no effort" strategy, they will stop investing quickly, but when they choose the "effort" strategy, they will not invest quickly. This paper can provide decision support for using the low‐carbon effort investment strategy by supply chain members. [ABSTRACT FROM AUTHOR]

The Cretaceous has been considered a "high-fire" world accompanied by widespread by-products of combustion in the rock record. The mid-Cretaceous oceanic anoxic event 1b (OAE1b) is marked by one of the major perturbations in the global carbon cycle characterized by deposition of organic-rich sediments in both marine and terrestrial settings. However, our understanding is still limited on changes in wildfire activity during OAE1b period. Here, we carried out a comprehensive analysis, including organic carbon isotope (δ13C org), total organic carbon (TOC), coal petrology, trace elements, and pyrolytic polycyclic aromatic hydrocarbons (pyroPAHs), of coal seams of the middle Aptian to early Albian Shahezi Formation from borehole SK-2 in Songliao Basin, Northeast China. Two negative δ13C org excursions in the Shahezi Formation can be corresponded with the 113/Jacob and Kilian sub-events of OAE1b. Moreover, the intensive peatland wildfires have been identified during the sub-event periods of OAE1b based on the co-occurrence of high abundance of charcoal and pyroPAHs at that time. In addition, Sr/Ba, Sr/Cu and Sr/Rb ratios demonstrate that enhanced peatland wildfires were controlled by dryer climate conditions owing to episodic northward migration of arid zones in East Asia related with rising global temperature during the sub-events of OAE1b. The climate-driven extensive wildfire activity in the mid-latitude terrestrial ecosystems can be a contributing factor for OAE1b through the increased flux of nutrients fuelling primary producers in the lake and marine environments and leading to more speculative anoxia to allow the deposition of organic-rich sediments. Our results provide essential understanding of the importance of wildfires in driving mechanism of oceanic anoxic events (OAEs) in Earth's history. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) act as tumor promoters or suppressors in various types of cancer. Previous investigations suggest that ceramide synthase 6 (CERS6) antisense RNA 1 (CERS6‐AS1) acts as an oncogene in breast cancer; however, its role in colorectal cancer is unknown. This study aimed to explore the molecular mechanism of CERS6‐AS1 in colorectal cancer. Gene expression in colorectal cancer was examined using reverse transcription‐quantitative polymerase chain reaction and western blot analyses. The viability and proliferation of colorectal cancer cells were measured by Cell Counting Kit‐8 assays and colony formation assays. The migratory and invasive capacities of the colorectal cancer cells were assessed by Transwell assay. Cell stemness was examined by sphere‐formation assay. Mechanistically, RNA pull‐down assays, RNA immunoprecipitation assays, and luciferase reporter assays were performed to explore the relationship among CERS6‐AS1, miR‐15b‐5p and spectrin beta, non‐erythrocytic 2 (SPTBN2). Moreover, a xenograft tumor model was established to investigate the role of CERS6‐AS1 in vivo. We found that CERS6‐AS1 and SPTBN2 were highly expressed in colorectal cancer tissues and cells. CERS6‐AS1 depletion inhibited cell viability, proliferation, migration, and invasion; the epithelial‐mesenchymal transition process and stemness. It suppressed xenograft tumor growth in colorectal cancer. Moreover, SPTBN2 levels were positively regulated by CERS6‐AS1 and negatively regulated by miR‐15b‐5p in colorectal cancer cells. Rescue assays revealed that SPTBN2 reversed the inhibitory effect of CERS6‐AS1 deficiency on the malignant behaviors of colorectal cancer cells. Overall, the lncRNA CERS6‐AS1 facilitates malignant phenotypes of colorectal cancer cells by targeting miR‐15b‐5p to upregulate SPTBN2. [ABSTRACT FROM AUTHOR]

The dose-dependent pharmacological response to dapagliflozin in patients with type 2 diabetes mellitus (T2DM) with regard to weight loss remain unknown. The aim of the present study was to investigate the effects of dapagliflozin on weight loss in patients with T2DM. A total of 8,545 patients with T2DM from 24 randomized controlled trials reported in the literature were selected for inclusion in the study. Data from these trials were analyzed using maximal effect (Emax) models with nonlinear mixed effects modeling; the evaluation index was the body weight change rate from baseline values. Patients treated with 2.5 mg/day dapagliflozin exhibited an Emax of -3.04%, and the time taken for therapy to reach half of the Emax (ET50) was estimated to be 30.8 weeks for patients treated with this dose. Patients treated with 5, 10 and 20 mg/day dapagliflozin exhibited Emax values of -6.57, -4.12 and -3.23%, respectively, and their ET50 values were estimated to be 27.3, 20.4 and 4.23 weeks, respectively. The data indicated ideal linear relationships between individual predictions and observations, suggesting the optimal fitting of the final models. The present study is the first systematic analysis of the effect of dapagliflozin on weight loss in patients with T2DM. The application of dapagliflozin at 5 mg/day exhibited a greater weight loss effect compared with the other doses used, and the weight loss onset time shortened as the dose of dapagliflozin increased. [ABSTRACT FROM AUTHOR]

Aims. The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations. Methods. 20,019 patients with T2DM were enrolled. The maximal effect ( E max ) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM). Results. For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max , and treatment duration to reach half of the maximal effects (ET50) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight. Conclusions. This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively. [ABSTRACT FROM AUTHOR]

What is known and objectives: Dapagliflozin was the first oral treatment approved in type 1 diabetes mellitus (T1DM) patients, simultaneously improving body weight. However, the time course and dose effect of dapagliflozin on loss of weight in T1DM patients was still unknown. The present study aimed to investigate quantitative relationship between dapagliflozin and loss of weight in T1DM patients based on Model‐based Meta‐analysis. Methods: Five dapagliflozin dosage groups, two of them were 5 mg/day and three of them were 10 mg/day, 1612 T1DM patients were analysed with maximal effect (Emax) model, and evaluation index was change rate of body weight from baseline value. Results: In these T1DM patients, dosages were not incorporated into model, indicating no significant dose‐response relationship between 5 and 10 mg/day affecting loss of weight. Emax and the treatment duration to reach half of the maximal effects (ET50) of dapagliflozin influencing loss of weight in T1DM patients were −4.9% and 10.4 weeks, and the duration to achieve 25%, 50%, 75%, and 80% (plateau) of Emax were 3.5, 10.4, 31.2, and 41.6 weeks. What is new and conclusions: It was the first time to explore quantitative relationship between dapagliflozin and loss of weight in T1DM patients. To achieve the plateau period in loss of weight, 5 mg/day dapagliflozin was required for at least 41.6 weeks. [ABSTRACT FROM AUTHOR]

A chemical investigation of Sophora flavescens Ait. identified 6 compounds. On the basis of spectroscopic data, they were determined to be flavonoids and their analogues, among which were two previously undescribed compounds, sophoflavanone G (1) and sophoflavanone H (2). The inhibitory effects of new compounds against five human tumour cell lines were evaluated in vitro by MTT assays, which revealed potential inhibitory effects with IC50 values < 20 mM, in particular, compound 1 has shown significant cytotoxicity for several tumour cells with IC50 values around 20 mM, which was similar to cisplatin and potential to be used as tumour drugs. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: Four previously undescribed ent‐abietane diterpenoids (1—4), along with eleven known analogues (5—15), were isolated from the roots of wild Euphorbia fischeriana. Their gross structures were determined via extensive spectroscopic data, and the absolute configurations were elucidated by means of single‐crystal X‐ray diffraction analysis, Rh2(OCOCF3)4‐induced CD spectrum and ECD calculations. Their cervical carcinoma inhibition activities counteract HeLa cells were screened by MTT assay, and the structure‐activity relationships were further examined. The results demonstrated that 2 (IC50 value at 3.75 μmol/L) was more potent than cisplatin. The underlying mechanism study revealed that 2 could distinctly induce apoptosis accompanied by increasing reactive oxygen species (ROS) production, Ca2+ influx and decreasing mitochondrial membrane potential. Furthermore, signal pathways including MAPKs/AKT might play a significant role in 2‐induced cervical cancer cells death. [ABSTRACT FROM AUTHOR]

This study aimed to explore the quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients using model-based meta-analysis (MBMA). Literatures were retrieved from the public database and data from these trials were extracted. The quantitative efficacy of L-carnitine on fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients were evaluated by maximal effect (Emax) models with nonlinear mixed effects modeling (NONMEM). In the model of FPG, Emax and treatment duration to reach half of the maximal effects (ET50) were −9.8% and 36.1 weeks, respectively. In the model of HbA1c, Emax and ET50 were −19.6% and 106 weeks, respectively. In addition, the durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on FPG were 13, 36.1, 118, 160, and 390 weeks, respectively. The durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on HbA1c were 38, 106, 334, 449, and 1058 weeks, respectively. It was the first time to provide valuable quantitative information for efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients. [ABSTRACT FROM AUTHOR]

Coal, especially the inertinite in it, is highly sensitive to climate changes, showing an obvious response to paleoclimate conditions, in particular, to paleo-oxygen concentration (pO2). In this study, the inertinite abundance data of typical coal-forming periods in China were systematically collected and analyzed. Its characteristics and control factors were studied, and its evolution was established. Based on inertinite abundance data, pO2 evolution curves of various coal-forming periods in China were established, which fluctuated between 15% and 30% during the entire Phanerozoic. The inertinite abundance in coal deposits during Paleozoic in China was basically consistent with that of other areas of the world, while it was quite different globally from the Mesozoic to the Cenozoic. The results show that the inertinite abundance in coal deposits is controlled by pO2 and other factors including climatic zones, plant differentiation, sedimentary environments, and tectonic activities. The inertinite abundance in coal deposits in China during the Jurassic was high, suggesting dry paleoclimate of inland China. [ABSTRACT FROM AUTHOR]

In this study, plasma electrolytic oxidation (PEO) process was applied to AA1060 aluminum alloy in an alkaline‐based electrolyte with different concentrations of EDTA‐2Na. The investigation of coatings was concentrated on sparks, phase, structure, morphology, and corrosion resistance. The whole process presented a "soft spark" regime which proved by the reduction of light and acoustic emission with increase of current. The results of SEM and EDS showed that more discharge channels were found under surface and the proportion of silicon in the inner layer increased for the sample treated in solution with 5 g/L EDTA‐2Na, which was attributed to D type discharge causing some light emission invisible on sample surface. The polarization test presented a better corrosion resistance with the increase of EDTA‐2Na. However, EIS measurement showed a bigger corrosion resistance for outer layer of sample prepared with the addition concentration up to 3 g/L that meant outer layer played a more critical role in terms of corrosion resistance. [ABSTRACT FROM AUTHOR]

What is known and objectives: Tacrolimus is used to treat patients with lupus nephritis; however, its time course and dose effect on proteinuria in lupus nephritis patients remain unknown. The purpose of this study was to determine the time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients via model‐based meta‐analysis (MBMA). Methods: PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov databases were systematically searched for information on the efficacy of tacrolimus against proteinuria in lupus nephritis patients. Useful data were extracted to build a model for the population studied using a non‐linear mixed‐effect model (NONMEM). This model was applied to simulate time course of tacrolimus on proteinuria using Monte Carlo simulations. Results: Ten clinical studies that recruited 222 patients with lupus nephritis were included. Based on various diagnostic plots, we found that the established model described the observed data reasonably well. In addition, the typical Emax and ET50 of tacrolimus for 24‐hour proteinuria in lupus nephritis patients were −5.88 g and 0.37 months, respectively. The baseline value of 24‐hour proteinuria affected Emax. No significant dose‐response relationship was observed in the range of tacrolimus concentration used in the present study (3‐10 ng/mL), indicating that the effect of tacrolimus on proteinuria depends on effective concentration range and not the dose. However, the time course relationship was obvious; the efficacy of tacrolimus increased over time, reaching a plateau (80% Emax) at approximately 1.48 months from the beginning of treatment. What is new and conclusion: When the concentration range of tacrolimus is maintained at 3‐10 ng/mL, at least 1.48 months of treatment is required to achieve a better outcome with regard to proteinuria in lupus nephritis patients. [ABSTRACT FROM AUTHOR]

Several main active components of Centella asiatica (L.) Urban, including triterpenoids, volatile oils, polyacetylenes and so on, have been reviewed. The efficacy of Centella asiatica (L.) Urban, especially in cosmetics, has been described. On this basis, the application status of Centella asiatica (L.) Urban in cosmetics has been introduced, and the broad application prospect of Centella asiatica (L.) Urban in cosmetics has been prospected. [ABSTRACT FROM AUTHOR]

The present study was to quantitate and compare the efficacy of metformin on weight in different disease states using model-based meta-analysis (MBMA). Randomized controlled trials (RCT) of metformin effects on weight in different disease states were collected by searching the public databases. The change rate of weight from baseline was selected as the efficacy indicator. A total 21 RCTs containing 1885 patients including patients with type 2 diabetes mellitus, patients with antipsychotic induced weight gain, patients with obesity, were included into the present study. After deducting placebo effect, the maximal effect (Emax) of metformin on weight in patients with type 2 diabetes mellitus, patients with antipsychotic induced weight gain, patients with obesity were −6.86%, −8.82%, and −4.14%, respectively. The treatment duration to reach half of the maximal effect (ET50) were 107, 45.5, and 15.1 weeks, respectively. Within the metformin dose range from 21 RCTs, no significant dose–response relationship was observed. However, the time–course relationship is obvious for efficacy of metformin on weight. The present study firstly provided quantitative information for metformin effects on weight in different disease states, including patients with type 2 diabetes mellitus, patients with antipsychotic induced weight gain, patients with obesity. [ABSTRACT FROM AUTHOR]

The present study aimed to establish a population pharmacokinetics model of tacrolimus and further optimize the initial dosing regimen of tacrolimus in pediatric and adolescent patients with lupus nephritis (LN). Pediatric and adolescent patients with LN were recruited between August 2014 and September 2019 at the Children's Hospital of Fudan University (Shanghai, China). Relevant information was used to set up a population pharmacokinetics model with a Nonlinear Mixed Effect Model and the initial dosage regimen was simulated with the Monte Carlo method. Body weight and co-administration of wuzhi capsule were indicated to influence tacrolimus clearance in pediatric and adolescent patients with LN, and at the same body weight, the rate of tacrolimus clearance in patients without vs. with co-administration of wuzhi capsule was 1:0.71. In addition, in patients who were not administered wuzhi capsule, an initial dosage regimen of 0.15 mg/kg/day was recommended for a body weight of 10-23 kg and 0.10 mg/kg/day for 23-60 kg; in patients who were administered wuzhi capsule, an initial dosage regimen of 0.10 mg/kg/day was recommended for a body weight of 10-23 kg and 0.05 mg/kg/day for 23-60 kg. To the best of our knowledge, the present study was the first to establish a population pharmacokinetics model of tacrolimus in order to determine the optimal initial dosage regimen of tacrolimus in pediatric and adolescent patients with LN. [ABSTRACT FROM AUTHOR]

Objective To analyze the risk factors of traumatic subdural effusion (TSE) transforming into chronic subdural hematoma (CSDH). Methods A total of 75 patients with TSE after traumatic brain injury (TBI) were included from December 2017 to July 2019. CT or MRI reexamination during treatment and follow-up were performed to observe whether CSDH was transformed and relevant influencing factors were analyzed. Univariate and multivariate Logistic regression analyses were performed to screen the risk factors for the transformation of TSE into CSDH. Results Logistic regression analysis showed that the higher effusion density (OR = 6.021, 95% CI: 1.047-34.631; P = 0.044), subdural effusion increases for a long time (OR = 1.253, 95% CI: 1.002-1.568; P = 0.048), the thicker effusion (OR = 2.080, 95% CI: 1.267-3.414; P = 0.004) and brain atrophy (OR = 35.392, 95% CI: 1.397-896.474; P = 0.031) were risk factors for the transformation of TSE into CSDH. Conclusions The subdural effusion increases for a long time, higher effusion density, thicker effusion and brain atrophy are the risk factors associated with the transformation of TSE into CSDH. [ABSTRACT FROM AUTHOR]

Bone marrow transplants (BMT) are an established therapeutic strategy for patients with severe aplastic anemia, acute lymphoblastic leukemia, acute myeloid leukemia or chronic myeloid leukemia. However, the successful application of BMT is limited by graft-vs.-host disease (GVHD). Ciclosporin has been widely used for treating GVHD in pediatric patients who underwent BMT. The present study aimed to optimize the dosage of ciclosporin for safety and effectiveness based on population pharmacokinetics. A non-linear mixed-effects model was used to analyze the clinical data of pediatric patients who underwent BMT between September 2016 and September 2019 at the Children's Hospital of Fudan University. Monte Carlo simulations were used to identify the optimal dose of ciclosporin. The final population pharmacokinetic model indicated that body weight and days post-transplant influenced the clearance of ciclosporin in pediatric patients who underwent BMT. The present study indicated that the optimal initial dose of ciclosporin for pediatric patients weighing 5-30 kg who underwent BMT was 6 mg/kg/day split into 2 doses. [ABSTRACT FROM AUTHOR]

Sirolimus is already used in the treatment of tuberous sclerosis complex (TSC), however, with narrow therapeutic range and considerable inter- and intra-individual pharmacokinetic variability, making it hard to develop an appropriate sirolimus initial dosage regimen, especially in children with TSC. The aim of this study was to recommend the optimal sirolimus initial dosing regimen in pediatric patients with TSC. Underlying physiological and genetic factors were collected to explore the effects on clinical sirolimus concentrations by establishing a nonlinear mixed effect (NONMEM) model, and to further simulate the optimal sirolimus initial dosing regimen using Monte Carlo method in pediatric patients with TSC. The once-daily regimen and the twice-daily regimen were recommended, respectively. For once-daily regimen, the dosages of 0.10, 0.07, 0.05, 0.04, 0.03 mg/kg/day were recommended for children with weights of 5–10, 10–20, 20–30, 30–50, and 50–60 kg, respectively. For twice-daily regimen, the dosages of 0.04, 0.03, 0.02 mg/kg/day (the daily dose was divided evenly into two doses) were recommended for children with weights of 5–20, 20–40, 40–60 kg, respectively. The initial dosages of sirolimus in children with TSC were recommended for the first time. [ABSTRACT FROM AUTHOR]

The present study aimed to optimize the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on population pharmacokinetics and pharmacogenomics. Demographic characteristics, concomitant medication, laboratory data, pharmacogenomics were collected to build the model and Monte Carlo was used to simulate the optimization of initial dosing scheme. Weight, the polymorphisms of CYP3A5, and concomitant medication of wuzhi-capsule were included into the covariates affecting tacrolimus clearance. In addition, with the same weight, there was difference in tacrolimus clearance in patients who carry CYP3A5*3/*3 and no coadministration of wuzhi-capsule, patients who carry CYP3A5*1 allele and no coadministration of wuzhi-capsule, patients who carry CYP3A5*3/*3 and coadministration of wuzhi-capsule, patients who carry CYP3A5*1 allele and coadministration of wuzhi-capsule, and their clearance ratios were 1:1.5:0.697:1.0455, respectively. Based on the differences of clearance in the above cases, we simulated different dosing regimens and obtained the optimal initial dose in each case. The present study recommended the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule. [ABSTRACT FROM AUTHOR]

Ceramic coatings were prepared on 6061 Al alloy in a mixed electrolyte with/without MgO powders at different treatment durations. The results of energy dispersive spectroscopy (EDS) and X‐ray diffraction (XRD) showed that MgO powder was incorporated into the coatings, and Mg species gradually aggregated into coating inside as prolonging the oxidation time. Scanning electron microscopy (SEM) showed that MgO additive had a certain effect on the microstructures and coating thickness. The corrosion behavior tests evaluated by potentiodynamic polarization tests and electrochemical impedance spectroscopy (EIS) in 3.5 wt% NaCl solution suggested that at the same treatment time, the addition of MgO powders can improve the corrosion resistance of the coating, and the Mg‐rich layer can affect the corrosion resistance of the coating. The tests of mechanical properties showed that the addition of MgO powders improved the stability and hardness of the coating. [ABSTRACT FROM AUTHOR]

The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics. Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus. Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus in these patients. With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively. In addition, the initial dose for each condition is recommended. The initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the CYP3A5 genotype. In addition, lower initial doses are recommended with concurrent use of WZ. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is induced by various triggers, including genetic factors, infections, autoimmune diseases, lymphoma or other malignancies. Cyclosporin is one of the clinical treatments for HLH. However, cyclosporin has considerable inter- and intra-individual variabilities in pharmacokinetics and also displays a narrow therapeutic window, making it difficult to define an optimal dose for HLH treatment. This study is aimed to establish cyclosporin population pharmacokinetic (PPK) model of pediatric HLH patients and formulate an initial dose regimen for personalized medicine. Pediatric HLH patients between June 2014 and March 2019 from Children's Hospital of Fudan University were analyzed using NONMEM. Dose recommended was investigated using Monte Carlo simulations. The final cyclosporin PPK model was: CL/F = 91×(WT/70)0.75×(1+ Piperacillin–Tazobactam × θP–T); V/F = 4250×(WT/70), where WT, and θP–T were weight, and the coefficient of the Piperacillin–Tazobactam, respectively. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the first cyclosporin PPK model in pediatric HLH patients was established and the model could be used to predict individualized initial dosing regimens in children with HLH. [ABSTRACT FROM AUTHOR]

1. Numerous tacrolimus population pharmacokinetic (PPK) models in pediatric liver transplantation patients have been established to define an optimal dose schedule. However, the applicability of extrapolating these PPK models to our clinical center remains unknown. The goals of the present study was to evaluate model external predictiveness and establish a new model applicable to traditional therapeutic drug monitoring data. 2. Published PPK models were collected from the literature and assessed using our real-world dataset including 41 pediatric liver transplantation patients via the individual prediction error method. The establishment of a new model was characterized using non-linear mixed-effects modeling. 3. Nine published pediatric liver transplantation PPK models were identified, three of which could be applied to our real-world dataset. However, these models were dissatisfactory in terms of individual prediction error and hence, inadequate for extrapolation. Finally, a new model applicable to our real-world dataset was established as follows: CL/F = 22.9 × (WT/70)0.75 × (1 − WZ × 0.264) × (1 − FCZ × 0.338) × (1 + ASPI × 0.281) × (POD/41)0.0486 L/h; V/F = 906 × (WT/70) L. Where WT, WZ, FCZ, ASPI and POD were weight, Wuzhi capsule, fluconazole, aspirin and post-transplantation day, respectively. In conclusion, published models were inadequate for application to our real-world dataset. The present study produced a new model applicable to our real-world study data. [ABSTRACT FROM AUTHOR]