The breakage pattern of unit particles during the production of oral solid dosage forms (OSD) is closely related to the quality of intermediate or final products. To accurately characterize the particles and study the evolution law of particle breakage, the Bonding model of the discrete element method (DEM) was used to investigate the breakage patterns of model parameters, particle shape and process conditions (loading mode and loading rate) on the dynamic breakage, force-time curve, breakage rate, maximum breakage size ratio and fracture strength of particles. The results showed that the particle breakage force was positively correlated with normal strength and bonded disk scale, negatively correlated with normal stiffness per unit area and tangential stiffness per unit area, and weakly correlated with tangential strength. The particle breakage rate was negatively correlated with the aspect ratio of the particles, and the maximum breakage size ratio was positively correlated with the aspect ratio of the particles; among the three loading modes, the breakage rate of compression breakage model was the largest, the breakage rate of shear breakage model was the second largest, and the breakage rate of wear breakage model was the smallest; the maximum breakage size ratio was positively correlated with the loading rate, the loading mode and the loading rate had no mutual influence on particle breakage rate, but had mutual influence on the maximum breakage size ratio. The research results will provide a theoretical basis for the shift of OSD from batch manufacturing to advanced manufacturing.

Isotemporal substitution model is a powerful tool to explore the real association between physical behavior and health outcomes, which has the potential of the application in large-scale cohort study. This paper systematically introduces the principle of isotemporal substitution model and its implementation method in specific analysis to provide analytical ideas for the epidemiological research related to physical behavior in China. The baseline data of Regional Ethic Cohort Study in Northwest China conducted in Shaanxi province were used to analyze the relationship between physical behavior and cardiovascular disease with single-factor model, partition model and isotemporal substitution model. The advantages and disadvantages of different models were compared, and the advantages of isotemporal substitution model in quantifying physical activity health risk were introduced. Isotemporal substitution model could qualify physical behavior and health outcomes, which has wide application value in epidemiological research.
Humans ; Cohort Studies ; Epidemiologic Studies ; Cardiovascular Diseases ; China/epidemiology*

Objective: To analyse the efficacy of recombinant human growth hormone (rhGH) treatment in children born small for gestational age (SGA) with syndormic and non-syndormic short stature. Methods: The clinical data of 59 children born SGA who were diagnosed as short stature and admitted to the Center of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital from July 2012 to June 2021 were collected and analyzed. According to the 2019 consensus on short stature, they were divided into syndromic group and non-syndromic group. Before treatment and 6, 12, 18 and 24 months after treatment, height standard deviation score (Ht-SDS), difference of height standard deviation (∆Ht-SDS) and homeostasis model assessment-insulin resistance index (HOMA-IR) were compared between groups, while Ht-SDS and HOMA-IR were compared before and after treatment. Independent t test or Kruskal-Wallis test were used for comparison between the 2 groups, and paired t test or Mann-Whitney U test were used for the intra-group comparison. Results: Among the 59 cases, 37 were males and 22 females, aged (5.5±2.3) years. There was no significant difference in Ht-SDS after 12 months of treatment between 2 groups (0.9±0.4 vs. 1.2±0.4, t=1.68, P=0.104) or in height SDS after 24 months of treatment (1.4±0.7 vs. 1.9±0.5, t=1.52, P=0.151). After 12 months of treatment, the insulin resistance index of the non-syndromic group was significantly higher than that of the syndromic group (2.29 (1.43, 2.99) vs. 0.90 (0.55, 1.40), Z=-2.95, P=0.003). There were significant differences in Ht-SDS between 6 months and before treatment, 12 months and 6 months in syndromic type (Z=7.65, 2.83 P<0.001, P=0.020), but all were significant differences in non-syndromic type between 6 months and before treatment, 12 months and 6 months, 18 months and 12 months, 24 months and 18 months (Z=11.95, 7.54, 4.26, 3.83, all P<0.001). Conclusion: The efficacy of rhGH treatment in children born SGA is comparable between syndromic and non-syndromic short stature cases, but non-syndromic children treated with rhGH need more frequent follow-up due to the risk of insulin resistance.
Child ; Female ; Humans ; Male ; Body Height ; Gestational Age ; Human Growth Hormone/therapeutic use* ; Infant, Small for Gestational Age ; Insulin ; Insulin Resistance ; Recombinant Proteins ; Child, Preschool

Objective: Systematically summarize the research progress of clinical trials of gastric cancer oncology drugs and the overview of marketed drugs in China from 2012 to 2021, providing data and decision-making evidence for relevant departments. Methods: Based on the registration database of the drug clinical trial registration and information disclosure platform of Food and Drug Administration of China and the data query system of domestic and imported drugs, the information on gastric cancer drug clinical trials, investigational drugs and marketed drugs from January 1, 2012 to December 31, 2021 was analyzed, and the differences between Chinese and foreign enterprises in terms of trial scope, trial phase, treatment lines and drug type, effect and mechanism studies were compared. Results: A total of 114 drug clinical trials related to gastric tumor were registered in China from 2012 to 2021, accounting for 3.7% (114/3 041) of all anticancer drug clinical trials in the same period, the registration number showed a significant growth rate after 2016 and reached its peak with 32 trials in 2020. Among them, 85 (74.6%, 85/114) trials were initiated by Chinese pharmaceutical enterprise. Compared with foreign pharmaceutical enterprise, Chinese pharmaceutical enterprise had higher rates of phase I trials (35.3% vs 6.9%, P=0.001), but the rate of international multicenter trials (11.9% vs 67.9%, P<0.001) was relatively low. There were 76 different drugs involved in relevant clinical trials, of which 65 (85.5%) were targeted drugs. For targeted drugs, HER2 is the most common one (14 types), followed by PD-1 and multi-target VEGER. In the past ten years, 3 of 4 marketed drugs for gastric cancer treatment were domestic and included in the national medical insurance directory. Conclusions: From 2012 to 2021, China has made some progress in drug research and development for gastric carcinoma. However, compared with the serious disease burden, it is still insufficient. Targeted strengthening of research and development of investment in many aspects of gastric cancer drugs, such as new target discovery, matured target excavating, combination drug development and early line therapy promotion, is the key work in the future, especially for domestic companies.
China ; Gastrointestinal Agents/therapeutic use* ; Gastrointestinal Neoplasms ; Humans ; Pharmaceutical Preparations ; United States ; United States Food and Drug Administration

Objective: To investigate the distribution of HIV-1 genetic subtypes and pretreatment drug resistance (PDR) among men who have sex with men (MSM) from 19 cities of 6 provinces in China. Methods: From April to November 2019, 574 plasma samples of ART-naive HIV-1 infected MSM were collected from 19 cities in Hebei, Shandong, Jiangsu, Zhejiang, Fujian, and Guangdong provinces, total ribonucleic acid (RNA) was extracted and amplified the HIV-1 pol gene region by nested polymerase chain reaction (PCR) after reverse transcription. Then sequences were used to construct a phylogenetic tree to determine genetic subtypes and submitted to the Stanford drug resistance database for drug resistance analysis. Results: A total of 479 samples were successfully amplified by PCR. The HIV-1 genetic subtypes included CRF01_AE, CRF07_BC, B, CRF55_01B, CRF59_01B, CRF65_cpx, CRF103_01B, CRF67_01B, CRF68_01B and unrecognized subtype, which accounted for 43.4%, 36.3%, 6.3%, 5.9%, 0.8%, 0.8%, 0.4%, 0.4%, 0.2% and 5.5%, respectively. The distribution of genetic subtypes among provinces is statistically different (χ²=44.141, P<0.001). The overall PDR rate was 4.6% (22/479), the drug resistance rate of non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors were 3.5% (17/479), 0.8% (4/479) and 0.2% (1/479), respectively. The PDR rate of recent infections was significantly higher than that of long-term infections (χ²=4.634, P=0.031). Conclusions: The HIV-1 genetic subtypes among MSM infected with HIV-1 from 19 cities of 6 provinces in China are diverse, and the distribution of subtypes is different among provinces. The overall PDR rate is low, while the PDR rate of recent infections was significantly higher than that of long-term infections, suggesting the surveillance of PDR in recent infections should be strengthened.
China/epidemiology* ; Cities ; Drug Resistance ; Drug Resistance, Viral/genetics* ; Female ; Genotype ; HIV Infections/epidemiology* ; HIV Seropositivity/drug therapy* ; HIV-1/genetics* ; Homosexuality, Male ; Humans ; Male ; Phylogeny ; Reverse Transcriptase Inhibitors/therapeutic use* ; Sexual and Gender Minorities

The high shear wet granulation(HSWG) process of Chinese medicine has a complicated mechanism. There are many influencing factors that contribute to this process. In order to summarize the manufacturability of different kinds of materials in HSWG, this paper constructed a material library composed of 11 materials, including 4 Chinese medicine extracts and 7 pharmaceutical excipients. Each material was described by 22 physical parameters. Several binders were employed, and their density, viscosity and surface tension were characterized. Combining empirical constraints and the principle of randomization, 21 designed experiments and 8 verification experiments were arranged. The partial least squares(PLS) algorithm was used to establish a process model in prediction of the median granule size based on properties of raw materials and binders, and process parameters. The surface tension and density of binders, as well as the maximum pore saturation were identified as key variables. In the latent variable space of the HSWG process model, all materials could be divided into three categories, namely the Chinese medicine extracts, the diluents and the disintegrants. The granulation of Chinese medicine extracts required low viscosity and low amount of binder, and the resulted granule sizes were small. The diluent powders occupied a large physical space, and could be made into granules with different granule sizes by adjusting the properties of binders. The disintegrants tended to be made into large granules under the condition of aqueous binder. The combination use of material database and multivariate modeling method is conducive to innovate the knowledge discovery of the wet granulation process of Chinese medicine, and provides a basis for the formulation and process design based on material attributes.
Drug Compounding ; Excipients ; Medicine, Chinese Traditional ; Particle Size ; Powders ; Tablets ; Technology, Pharmaceutical

Objective:To investigate the influence of particle size on density of binary powder mixture of traditional Chinese medicine （TCM）， and to provide reference for formulation design of TCM preparations. Method:Three groups of binary powder mixtures with different particle size ratio （α） were constructed， namely Oroxyli Semen-microcrystalline cellulose PH102 （MCC PH102） （α=0.071 7）， Stellariae Radix-MCC PH200 （α=0.158 7） and Angelicae Sinensis Radix-MCC KG802 （α=0.840 6）. Binary powder mixtures with nine mass ratios （90∶10， 80∶20， 70∶30， 60∶40， 50∶50， 40∶60， 30∶70， 20∶80 and 10∶90） were prepared for each group， and 27 binary powder mixtures containing TCM were obtained. The particle size distribution， density and other parameters of six single materials and 27 binary powder mixtures were characterized. Based on the packing theory and multivariate analysis， the effects of particle size related parameters on the filling structure and density of the binary powder mixtures were elucidated. Result:The α of Angelicae Sinensis Radix-MCC KG802 binary mixture system was larger than the replacement rate （α_r=0.741 0）， and its density had a good linear relationship with the mass ratio， which conformed to the replacement mechanism. The α of Oroxyli Semen-MCC PH102 binary mixture system was smaller than the critical ratio （α_c=0.154 0）， and its density was nonlinear with the mass ratio of components， which conformed to the filling mechanism. The α of Stellariae Radix-MCC PH200 binary mixture system was between α_c and α_r， its density was affected by both of replacement mechanism and filling mechanism. Based on the partial least squares （PLS） model， the variable importance in the projection （VIP） analysis further proved that the mixing mass ratio （VIP value=1.62）， α （VIP value=1.13） and D₁₀ （the corresponding particle size when the particle size distribution accumulated to 10%， VIP value=1.06） were the key factors affecting the density of binary powder mixtures of TCM. Conclusion:In the binary powder mixtures of TCM， the linearity relationship between density and mass ratio is largely depended on particle size difference of components.

According to the commonly used tablet compressibility, compactability and tabletability equation, the influence of pressure range on the fitting results and parameters of different compression equations was studied, and the optimal pressure range of different equations was determined. Plastic material microcrystalline cellulose (MCC) PH102, brittle material spray dried lactose and Chinese medicine Sanqi were used as experimental objects, the compression curves of tablets were obtained by the combination of dies with different diameters. For Heckel equation, the shape of Heckel section of different materials is not uniform, and the specified linear fitting range cannot be obtained, therefore, different distances between fitting pressure starting point and starting point were set to observe the influence of pressure range on R² of Heckel equation. The Kawakita equation, Gurnham equation, Ryshkewitch-Duckworth (R-D) equation and Power equation are fitted in three different pressure ranges of 15-200, 15-300 and 15-400 MPa, respectively. In order to find the best linear region of Heckel equation, the 3D scatter diagram of "starting point of pressure, pressure range and R²" is drawn. The best linear pressure ranges of Heckel curves of MCC, lactose and Sanqi were 20-170, 20-220 and 10-90 MPa, respectively. It is proved that the 3D scatter diagram is an effective method to find the linear range of Heckel equation. The change of pressure range has little influence on the curve fitting effect and compression parameters of Kawakita equation, Gurnham equation and Ryshkewitch-Duckworth equation. The low pressure range of 15-200 MPa can meet the fitting requirements of Kawakita equation, Gurnham equation, R-D equation and Power equation for different materials. Therefore, only by optimizing the pressure range, can the good fitting effect be ensured and the obtained compression parameters be more reliable and interpretable.

【Objective】 To investigate the influence of dyslipidemia during pregnancy on postpartum glucose and lipid metabolism in gestational diabetes mellitus(GDM) patients. 【Methods】 A total of 416 GDM women were recruited. They were followed up and completed postpartum reexamination. According to the specific normal reference value of pregnant lipid level, those GDM women were divided into two groups: normal lipid group(n = 82) and dyslipidemia group (n = 334) .The general demographic data of 4-12 weeks after delivery were collected. OGTT, insulin and lipids level were measured, and the differences of postpartum glucose and lipid metabolism parameters between the two groups were compared. 【Results】 The abnormal rate of glucose metabolism in the early postpartum period of GDM women was 38.5%, and the incidence of dyslipidemia was 34.4%. The levels of postpartum TC, TG and LDL-c in the dyslipidemia group during pregnancy were significantly higher than those in the group with normal blood lipid during pregnancy, and the proportion of postpartum dyslipidemia in patients with high TG and high LDL-c during pregnancy was significantly higher. Correlation analysis showed that TG and HDL-c during pregnancy were positively correlated and negatively correlated with postpartum fasting blood glucose and HOMA-IR, respectively. 【Conclusion】 The dyslipidemia during pregnancy in patients with GDM is related to the disorder of glucose and lipid metabolism in the early postpartum period.

Objective:To study the effect of different hormone ratios on the callus induction of roots,stems and leaves of Polygala tenuifolia,and determine and analyze the amount of flavonoids in roots,stems and leaves of P. tenuifolia. Method:With MS as the basic medium and roots,stems and leaves of P. tenuifolia sterile seedings as explants,the effects of 2,4-D,NAA and 6-BA on callus induction and flavonoid accumulation in different parts of roots,stems and leaves of P. tenuifolia were determined by orthogonal test. Result:2,4-D,NAA and 6-BA had significant effects on the callus induction rate of roots,stems and leaves of P. tenuifolia. The optimal callus induction combination of leaves was MS+3.0 mg·L^-1 2,4-D+1.0 mg·L^-1 NAA+1.5 mg·L^-1 6-BA,the optimal callus induction combination of stems was MS+1.0 mg·L^-1 2,4-D+3.0 mg·L^-1 NAA+1.5 mg·L^-1 6-BA,the optimal callus induction combination for roots was MS+1.0 mg·L^-1 2,4-D+1.0 mg·L^-1 NAA+1.0 mg·L^-1 6-BA. And 2,4-D,NAA and 6-BA had significant effects on flavonoid accumulation in the stem callus of P. tenuifolia,and MS+3.0 mg·L^-1 2,4-D+1.0 mg·L^-1 NAA+0.5 mg·L^-1 6-BA was the best flavonoid accumulation combination.NAA,6-BA had significant effects on flavonoid accumulation in the leave callus of P. tenuifolia,while 2,4-D had no significant effect,and MS+3.0 mg·L^-1 2,4-D+2.0 mg·L^-1 NAA+1.0 mg·L^-1 6-BA was the optimal flavonoid accumulation combination,the three hormones had no significant effect on the accumulation of flavonoids in the root callus of P. tenuifolia,and MS+2.0 mg·L^-1 2,4-D+1.0 mg·L^-1 NAA+1.5 mg·L^-1 6-BA was the best flavonoid accumulation combination. Conclusion:Under the conditions,the callus induction rate of roots,stems and leaves of P. tenuifolia is 100%, especially, the callus of P. tenuifolia leaves was the optimal,which is followed by P. tenuifolia stems and P. tenuifolia roots. Under the conditions,the amount of flavonoids in roots,stems and leaves of P. tenuifolia reach 21.31,24.56,23.61 mg·g^-1,respectively.