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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]

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]

The lack of innovation power in industry-university-research (IUR) cooperation is one of the important reasons leading to low independent innovation ability in China. Considering the long-term and dynamic nature of IUR innovation effort, the differential game method is used to compare and analyse the optimal decision under four scenarios: independent R&D by enterprises and university-research institutes, tax incentives for enterprises by the government, tax incentives and subsidies by the government, and a Stackelberg game considering the internal cost subsidy of enterprises. The results show that government tax incentives can improve the enthusiasm of enterprises for cooperative innovation, while government subsidies can simultaneously improve the enthusiasm of IUR institutes for cooperative innovation and can enhance the overall benefits of both parties and even the system. When certain conditions are met based on the government’s tax incentive and subsidy policies, the innovation effort, cooperative innovation level and benefits in the Stackelberg game are optimal, and Pareto improvement can be achieved. The optimal benefits of enterprises and university-research institutes, the total benefits of the system, and the optimal trajectory of the cooperative innovation level tend to be stable over time in the four game scenarios. [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]

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]

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]

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]

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 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]

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]

A novel magnetic Zn (II) ion-imprinted polymer was prepared by the surface ion-imprinted technique by using magnetic Fe3O4@SiO2microspheres as supporter, methacrylic acid and salicylaldoxime as monomers, ethylene glycol dimethacrylate as the crosslinker. The products were characterized by Fourier transform infrared, X-ray photoelectron spectrometer, vibrating sample magnetometer and scanning electron microscope. The adsorption experiments showed that the imprinted polymer was employed successfully in comparison with non-imprinted polymer. When the temperature was in a range of 291–297 K, the maximum adsorption was about 52.69 mg g−1with an optimal pH 6.0 for an equilibrium time of 40 min. The imprinted polymer possessed high selectivity and specific recognition towards Zn (II). The Langmuir adsorption model was more favourable than the Freundlich or the Temkin adsorption model. Thermodynamic experiment showed that the adsorption was a spontaneous and endothermic process for Zn (II). The mechanism for Zn (II) adsorption on the imprinted polymer was investigated. [ABSTRACT FROM AUTHOR]

A novel magnetic Pb(II) ion-imprinted polymer was prepared via surface ion-imprinting technique by using magnetic Fe3O4@SiO2microspheres as supporter, Pb(II) as template ion, methacrylic acid and salicylaldoxime as monomers, and ethylene glycol dimethacrylate as crosslinker. The product was characterized by FT-IR, VSM, XRD, and SEM. The adsorption experiments showed that the imprinted polymer was employed successfully in comparison with non-imprinted polymer. When the temperature was in a range of 277 K to 291 K the maximum adsorption was about 81.83 mg/g with an optimal pH 6.0. Its relative selectivity coefficient values of Pb(II)/Cu(II), Pb(II)/Zn(II), and Pb(II)/Cd(II) were 2.60, 6.38, and 7.89 times greater than the ones of the magnetic non-imprinted polymer. The Langmuir adsorption model was more favorable for M-IIP than Freundlich or Temkin adsorption models. The Scatchard analysis suggested that M-IIP was processed with two kinds of binding sites with different affinity. Thermodynamic experiment showed that the adsorption was a spontaneous and endothermic process for Pb(II). The mechanism for Pb(II) adsorption on the imprinted polymer was also investigated. [ABSTRACT FROM PUBLISHER]

BulbusFritillariae Cirrhosae(BFC) is widely used in China both for food and folk medicine because of its powerful biological activities. Firstly, this study was designed to examine the antiproliferative activities of the different fractions from BFC in vitro by MTT assay. The results showed that chloroform extracts (CE) and the purified total alkaloids of BFC (TAF) exhibited stronger antiproliferative activity than the other fractions. We further determined the total alkaloids and 3 main alkaloids monomers content of CE and TAF by UV and HPLC-ELSD methods, respectively. Moreover, we assessed the antitumor activity of TAF in vivo and made preliminary investigation of its antitumor mechanism by histological and immunohistochemical staining technique. These results demonstrate that TAF showed significant antitumor activity and low toxicity in vivo. Meanwhile, TAF significantly inhibited tumor angiogenesis and induced apoptosis by improvement of expression level of caspase-3. These results suggest that alkaloids of BFC could hold a good potential for use as an antitumor drug. [ABSTRACT FROM PUBLISHER]