Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients.Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83–17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens.Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml.Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

Background: Tic disorders (TDs), including Tourette syndrome, are childhood-onset neuropsychiatric disorders characterized by motor and/or vocal tics that commonly affect children’s physical and mental health. The pathogenesis of TDs may be related to abnormal neurotransmitters in the cortico-striatal-thalamo-cortical circuitry, especially dopaminergic, glutamatergic, and serotonergic neurotransmitters. The purpose of this study was to preliminarily investigate the differences in the three types of neurotransmitters in plasma and urine between children with TD and healthy children. Methods: We collected 94 samples of plasma and 69 samples of urine from 3–12-year-old Chinese Han children with TD before treatment. The plasma and urine of the same number of healthy Chinese Han children, matched for age and sex, participating in a physical examination, were collected. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the three types of neurotransmitters in the above samples. Results: The plasma levels of norepinephrine, glutamic acid, and γ-aminobutyric acid, and the urine levels of normetanephrine and 5-hydroxyindoleacetic acid were higher in the TD children than in healthy children. The area under the curve (AUC) values of the above neurotransmitters in plasma and urine analyzed by receiver operating characteristic curve analysis were all higher than 0.6, with significant differences. Among them, the combined AUC of dopamine, norepinephrine, normetanephrine, glutamic acid, and γ-aminobutyric acid in the 8–12-year-old subgroup was 0.930, and the sensitivity and specificity for TD were 0.821 and 0.974, respectively (p = 0.000). Conclusions: There are differences in plasma and urine neurotransmitters between TD children and healthy children, which lays a foundation for further research on the pathogenesis of TD.

This article introduces the existing research and deficiencies of domestic and foreign scholars in the corporate governance of corporate safety production, as well as the application research based on evolutionary game theory in various fields. Based on evolutionary game theory, from the perspective of limited rationality and stakeholders, a systematic study of the corporate governance structure's behavior in safety production is proposed, so as to establish a multiparty dynamic game model of corporate governance structure for corporate safety production. Safety production provides a new perspective, reduces the occurrence of safety production accidents, and guarantees the orderly progress of safety production activities. IntroductionCorporate governance refers to the system of checks and balances formed between the company's internal board of directors, the board of supervisors and the management level [1] . In view of the important influence of the board of directors, the board of supervisors and the managerial level on the safe production and operation of enterprises, domestic and foreign scholars have conducted in-depth research on the board of directors, board of supervisors and managers in the corporate governance structure under the framework of entrustment-agent. More fruitful research results. Representative research results are as follows: John G etc. [2] consider the factors of supervision, supervision cost and supervision success rate, establish a game-supervised game model of the board of directors, and find that high salary can better control the manager through calculation. Human behavior. In his book, Zhang Weiying [3] established a supervisory cost function for managers' lazy behavior and non-slack behavior, and obtained the best supervision of the board of directors. Deng Yingjie etc [4] built a monitoring cost model based on the goal of maximizing revenue and minimizing total cost, and analyzed the supervision model of the board of directors on the behavior of state-owned enterprise managers. Yao Haixin etc [5] used the game theory analysis method to analyze the supervision function of the board of directors from the perspective of active supervision. The study found that the board of directors played an active supervisory function to promote the growth of the company's value and protect shareholders' rights and interests. Yu Dong [6] comprehensively considers the influence of manager abuse of power and board supervision on company performance and shareholder returns, constructs a game model, verifies the effectiveness of board supervision on managers, and finds a game equilibrium between board and managers. Hu Can etc [7] based on the determination of the behavior selection strategy of the board of directors, the management level and the board of supervisors, comprehensively consider the factors of wages, supervision, business performance and other factors, and build a complete information static game model of the board of directors, the management level and the board of supervisors, research ...