Objective To evaluate the effects of high-fat diet on the pharmacokinetics of metronidazole in Chinese healthy adult subjects.Methods This program is designed according to a single-center,randomized,open,single-dose trial.Forty-seven healthy subjects were assigned to receive single dose of metronidazole tablets 200 mg in either fasting and high-fat diet state,and blood samples were taken at different time points,respectively.The concentrations of metronidazole in plasma were determined by high performance liquid chromatography-mass spectromentry.Results The main pharmacokinetic parameters of metronidazole in fasting state and high-fat diet state were as follows:Cmax were(4 799.13±1 195.32)and(4 044.17±773.98)ng·mL-1;tmax were 1.00 and 2.25 h;t1/2 were(9.11±1.73)and(9.37±1.79)h;AUC0_t were(5.59±1.19)x 104 and(5.51±1.18)x 104 ng·mL-1·h;AUC0_∞ were(5.79±1.33)x 104 and(5.74±1.32)× 104 ng·mL-1·h.Compared to the fasting state,the tmaxof the drug taken after a high fat diet was delayed by 1.25 h(P＜0.01),Cmax,AUC0_t,AUC0-∞ were less or decreased in different degrees,but the effects were small(all P＞0.05).Conclusion High-fat diet has little effects on the pharmacokinetic parameters of metronidazole,which does not significantly change the degree of drug absorption,but can significantly delay the time to peak.

Objective To study the pharmacokinetic characteristics of etoricoxib tablets in healthy Chinese subjects and to evaluate the bioequivalence and safety of the test and reference formulations.Methods In a randomised,single-dose,two-period,two-sequence crossover trial,28 healthy subjects were enrolled under the fasting and fed conditions,respectively,who received a single oral dose of 60 mg of etoricoxib tablets in the test or reference formulation.The concentration of etoricoxib in plasma was detected by LC-MS/MS,and the main pharmacokinetic parameters were calculated to evaluate bioequivalence and using WinNonlin 8.2 software.Results The main pharmacokinetic parameters of the test and reference preparations were as follows:The fasting condition Cmax of etoricoxib were(1 176.96±287.95)and(1 164.93±189.65)ng·mL-1;AUC0-t were(18 651.95±6 100.27)and(19 241.39±6 107.48)ng·h·mL-1;and AUC0-∞ were(19 939.15±7 553.27)and(20 536.31±7 223.40)ng·h·mL-1.The fed condition Cmax of etoricoxib were(913.50±184.72)and(878.59±164.35)ng·mL-1;and AUC0-t were(19 085.22±5 155.01)and(18 669.54±4 508.21)ng·h·mL-1;AUC0-∞ were(20 103.77±5 567.02)and(19 528.05±4 989.74)ng·h·mL-1.The 90％confidence intervals for the geometric mean ratios of the main pharmacokinetic parameters in the fasting and fed conditions fell between 80.00％and 125.00％.The incidence of adverse events in the fasting and fed conditions were 28.57％and 21.43％,respectively.Conclusion Two kinds of etoricoxib tablets are bioequivalent,and have similar safety in healthy Chinese subjects.

Objective To investigate the effects and mechanisms of lncRNA OIP5-AS1 on cell proliferation and apoptosis in esophageal squamous cell carcinoma(ESCC).Methods TE-1 cells were randomly divided into control(normal culture),si-NC(transfected with si-NC),si-OIP5-AS1(transfected with si-OIP5-AS1),si-OIP5-AS1+NC inhibitor(transfected with si-OIP5-AS1,NC inhibitor),si-OIP5-AS1+miR-129 inhibitor(transfected with si-OIP5-ASS1,miR-129 inhibitor),NC mimic(transfected with NC mimic),miR-129 mimic(transfected with miR-129 mimic),miR-129 mimic+Vector(transfected with miR-129 mimic,Vector),miR-129 mimic+KRAS[transfected with miR-129 mimic,Kirsten rat sarcoma virus oncogene(KRAS)]groups.The expression of OIP5-AS1 and miR-129 in each group was detected by real-time fluorescence quantitative polymerase chain reaction assay.The expression levels of KRAS,N-cadherin,Vimentin and E-cadherin in cells were detected by Western blot assay.Cell proliferation was detected by cell counting kit-8(CCK-8),and apoptosis was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL)assay.Results The expression levels of OIP5-AS1 in cells of control,si-NC,si-OIP5-AS1,si-OIP5-AS1+NC inhibitor,si-OIP5-AS1+miR-129 inhibitor groups were 1.00±0.13,0.98±0.12,0.25±0.04,0.25±0.02 and 0.89±0.08;the expression levels of miR-129 were 1.00±0.15,0.97±0.07,2.06±0.17,2.04±0.11 and 1.22±0.15;72 h absorbance values(OD)were 1.16±0.12,1.11±0.09,0.58±0.03,0.58±0.05 and 0.94±0.10.The KRAS protein expression levels of NC mimic,miR-129 mimic,miR-129 mimic+Vector,and miR-129 mimic+KRAS groups were 1.08±0.07,0.41±0.06,0.40±0.06,1.03±0.10;the 72 h OD values were 1.17±0.10,0.59±0.03,0.60±0.04 and 0.90±0.05,respectively.si-NC group was compared with si-OIP5-AS1 group,si-OIP5-AS1+NC inhibitor group was compared with si-OIP5-AS1+miR-129 inhibitor group,NC mimic group was compared with miR-129 mimic group,miR-129 mimic+Vector group was compared with miR-129 mimic+KRAS group,the differences of the above indexes were statistically significant(all P＜0.05).Conclusion OIP5-AS1 can promote ESCC cell proliferation and epithelial mesenchymal transformation by regulating miR-129 targeting KRAS.

Objective To evaluate the bioequivalence of metronidazole tablet and reference formulation in Chinese healthy subjects.Methods A single-dose,two-cycle,randomized,open,self-crossover trial was designed with 48 healthy subjects randomly assigned to fasting or postprandial group.For each group,a single oral dose of metronidazole tablet(200 mg)or a reference preparation(200 mg)per cycle were enrolled.The concentration of metronidazole in plasma was measured by high performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS).The non-compartmental model was applied to calculate the pharmacokinetic parameters for bioequivalence analysis via SAS 9.3 software.Results The main pharmacokinetic parameters of test and reference metronidazole tablets in the fasting group were as follows,the Cmax were(4 855.00±1 383.97)and(4 799.13±1 195.32)ng·h·mL-1;the AUC0-t were(54 834.68±12 697.88)and(55 931.35±11 935.28)ng·h·mL-1;the AUC0-∞ were(56 778.09±13 937.76)and(57 922.83±13 260.54)ng·h·mL-1;the Tmax were respectively 1.17 and 1.00 h;t1/2 were(8.99±1.76)and(9.11±1.73)h,respectively.The ratio of the geometric mean and its 90％confidence intervals(CI)of Cmax,AUC0-t and AUC0-∞ were all within the equivalent interval of 80.00％-125.00％.As for postprandial conditions,the main pharmacokinetic parameters of test and reference metronidazole tablets were as follows,the Cmax were(4 057.08±655.08)and(4 044.17±773.98)ng·h·mL-1;the AUC0-t were(55 956.42±12 228.12)and(55 121.04±11 784.55)ng·h·mL-1;the AUC0-∞ were(58 212.83±13 820.00)and(57 350.38±13 229.46)ng·h·mL-1;the Tmax were 2.50 and 2.25 h;the t1/2 were(9.37±1.68)and(9.37±1.79)h,respectively.The ratio of the geometric mean and 90％CI of Cmax,AUC0-t and AUC0-∞ were all within the equivalent interval of 80.00％-125.00％.Conclusion The two preparations were bioequivalent to Chinese healthy adult volunteers under both fasting and fed conditions.

【Objective】 To establish a blood quality monitoring indicator system, in order to continuously improve blood quality and standardized management. 【Methods】 Based on the research of literature and standards, and guided by the key control points of blood collection and supply process, the blood quality monitoring indicator system was developed. Through two rounds of Delphi expert consultation, the indicator content was further revised and improved according to expert opinions after six months of trial implementation. The indicator weight was calculated by questionnaire and analytic hierarchy process. 【Results】 A blood quality monitoring indicator system covering the whole process of blood collection and supply was constructed, including five primary indicators, namely blood donation service, blood component preparation, blood testing, blood supply and quality control, as well as 72 secondary indicators, including definitions, calculation formulas, etc. Two rounds of expert consultation and two rounds of feasibility study meeting were held to revise 17 items and the weight of each indicator was obtained through the analytic hierarchy process. After partial adjustments, a blood quality monitoring indicator system was formed. 【Conclusion】 A blood quality monitoring indicator system covering the whole process of blood collection and supply has been established for the first time, which can effectively evaluate the quality management level of blood banks and coordinate blood quality control activities of blood banks in Shandong like pieces in a chess game, thus improving the standardized management level

【Objective】 To objectively evaluate the quality control level of blood testing process in blood banks through quantitative monitoring and trend analysis, and to promote the homogenization level and standardized management of blood testing laboratories in blood banks. 【Methods】 A quality monitoring indicator system covering the whole process of blood collection and supply, including blood donation service, blood component preparation, blood testing, blood supply and quality control was established. The questionnaire Quality Monitoring Indicators for Blood Collection and Supply Process with clear definition of indicators and calculation formulas was distributed to 17 blood banks in Shandong province. Quality monitoring indicators of each blood bank from January to December 2022 were collected, and 31 indicators in terms of blood testing were analyzed using SPSS25.0 software. 【Results】 The proportion of unqualified serological tests in 17 blood bank laboratories was 55.84% for ALT, 13.63% for HBsAg, 5.08% for anti HCV, 5.62% for anti HIV, 18.18% for anti TP, and 1.65% for other factors (mainly sample quality). The detection unqualified rate and median were (1.23±0.57)% and 1.11%, respectively. The ALT unqualified rate and median were (0.74±0.53)% and 0.60%, respectively. The detection unqualified rate was positively correlated with ALT unqualified rate (r=0.974, P<0.05). The unqualified rate of HBsAg, anti HCV, anti HIV and anti TP was (0.15±0.09)%, (0.05±0.04)%, (0.06±0.03)% and (0.20±0.05)% respectively. The average unqualified rate, average hemolysis rate, average insufficient volume rate and the abnormal hematocrit rate of samples in 17 blood bank laboratories was 0.21‰, 0.08‰, 0.01‰ and 0.02‰ respectively. There were differences in the retest concordance rates of four HBsAg, anti HCV and anti HIV reagents, and three anti TP reagents among 17 blood bank laboratories (P<0.05). The usage rate of ELISA reagents was (114.56±3.30)%, the outage rate of ELISA was (10.23±7.05) ‰, and the out of range rate of ELISA was (0.90±1.17) ‰. There was no correlation between the out of range rate, outrage rate and usage rate (all P>0.05), while the outrage rate was positively correlated with the usage rate (r=0.592, P<0.05). A total of 443 HBV DNA positive samples were detected in all blood banks, with an unqualified rate of 3.78/10 000; 15 HCV RNA positive samples were detected, with an unqualified rate of 0.13/10 000; 5 HIV RNA positive samples were detected, with an unqualified rate of 0.04/10 000. The unqualified rate of NAT was (0.72±0.04)‰, the single NAT reaction rate [(0.39±0.02)‰] was positively correlated with the single HBV DNA reaction rate [ (0.36±0.02) ‰] (r=0.886, P<0.05). There was a difference in the discriminated reactive rate by individual NAT among three blood bank laboratories (C, F, H) (P<0.05). The median resolution rate of 17 blood station laboratories by minipool test was 36.36%, the median rate of invalid batch of NAT was 0.67%, and the median rate of invalid result of NAT was 0.07‰. The consistency rate of ELISA dual reagent detection results was (99.63±0.24)%, and the median length of equipment failure was 14 days. The error rate of blood type testing in blood collection department was 0.14‰. 【Conclusion】 The quality monitoring indicator system for blood testing process in Shandong can monitor potential risks before, during and after the experiment, and has good applicability, feasibility, and effectiveness, and can facilitate the continuous improvement of laboratory quality control level. The application of blood testing quality monitoring indicators will promote the homogenization and standardization of blood quality management in Shandong, and lay the foundation for future comprehensive evaluations of blood banks.

【Objective】 To establish an effective quality monitoring indicator system for blood quality control in blood banks, in order to analyze the quality control indicators for blood collection and supply, and evaluate blood quality control process, thus promoting continuous improvement and standardizing management of blood quality control in blood banks. 【Methods】 A quality monitoring indicator system covering the whole process of blood collection and supply, including blood donation services, component preparation, blood testing, blood supply and quality control was established. The Questionnaire of Quality Monitoring Indicators for Blood Collection and Supply Process was distributed to 17 blood banks in Shandong, which clarified the definition and calculation formula of indicators. The quality monitoring indicator data from January to December 2022 in each blood bank were collected, and 20 quality control indicators data were analyzed by SPSS25.0 software. 【Results】 The average pass rate of key equipment monitoring, environment monitoring, key material monitoring, and blood testing item monitoring of 17 blood banks were 99.47%, 99.51%, 99.95% and 98.99%, respectively. Significant difference was noticed in the pass rate of environment monitoring among blood banks of varied scales(P<0.05), and the Pearson correlation coefficient (r) between the total number of blood quality testing items and the total amount of blood component preparation was 0.645 (P<0.05). The average discarding rates of blood testing or non-blood testing were 1.14% and 3.36% respectively, showing significant difference among blood banks of varied scales (P<0.05). The average discarding rate of lipemic blood was 3.07%, which had a positive correlation with the discarding rate of non testing (r=0.981 3, P<0.05). There was a statistically significant difference in the discarding rate of lipemic blood between blood banks with lipemic blood control measures and those without (P<0.05). The average discarding rate of abnormal color, non-standard volume, blood bag damage, hemolysis, blood protein precipitation and blood clotting were 0.20%, 0.14%, 0.06%, 0.06%, 0.02% and 0.02% respectively, showing statistically significant differences among large, medium and small blood banks(P<0.05).The average discarding rates of expired blood, other factors, confidential unit exclusion and unqualified samples were 0.02%, 0.05%, 0.003% and 0.004%, respectively. The discarding rate of blood with air bubbles was 0.015%, while that of blood with foreign body and unqualified label were 0. 【Conclusion】 The quality control indicator system of blood banks in Shandong can monitor weak points in process management, with good applicability, feasibility, and effectiveness. It is conducive to evaluate different blood banks, continuously improve the quality control level of blood collection and supply, promote the homogenization and standardization of blood quality management, and lay the foundation for comprehensive evaluation of blood banks in Shandong.

【Objective】 To establish an effective quality indicator monitoring system, scientifically and objectively evaluate the quality management level of blood banks, and achieve continuous improvement of quality management in blood bank. 【Methods】 A quality monitoring indicator system that covers the whole process of blood collection and supply was established, the questionnaire of Quality Monitoring Indicators for Blood Collection and Supply Process with clear definition of indicators and calculation formulas was distributed to 17 blood banks in Shandong. Statistical analysis of 21 quality monitoring indicators in terms of blood donation service (10 indicators), blood component preparation (7 indicators ), and blood supply (4 indicators) from each blood bank from January to December 2022 were conducted using SPSS25.0 software The differences in quality monitoring indicators of blood banks of different scales were analyzed. 【Results】 The average values of quality monitoring indicators for blood donation service process of 17 blood banks were as follows: 44.66% (2 233/5 000) of regular donors proportion, 0.22% (11/50) of adverse reactions incidence, 0.46% (23/5 000) of non-standard whole blood collection rate, 0.052% (13/25 000) of missed HBsAg screening rate, 99.42% (4 971/5 000) of first, puncture successful rate, 86.49% (173/200) of double platelet collection rate, 66.50% (133/200) of 400 mL whole blood collection rate, 99.25% (397/400) of donor satisfaction rate, 82.68% (2 067/2 500) of use rate of whole blood collection bags with bypass system with sample tube, and 1 case of occupational exposure in blood collection.There was a strong positive correlation between the proportion of regular blood donors and the collection rate of 400 mL whole blood (P<0.05). The platelet collection rate, incidence of adverse reactions to blood donation, and non-standard whole blood collection rate in large blood banks were significantly lower than those in medium and small blood banks (P<0.05). The average quality monitoring indicators for blood component preparation process of 17 blood banks were as follows: the leakage rate of blood component preparation bags was 0.03% (3/10 000), the discarding rate of lipemic blood was 3.05% (61/2 000), the discarding rate of hemolysis blood was 0.13%(13/10 000). 0.06 case had labeling errors, 8 bags had blood catheter leaks, 2.76 bags had blood puncture/connection leaks, and 0.59 cases had non-conforming consumables. The discarding rate of hemolysis blood of large blood banks was significantly lower than that of medium and small blood banks (P<0.05), and the discarding rate of lipemic blood of large and medium blood banks was significantly lower than that of small blood banks (P<0.05). The average values of quality monitoring indicators for blood supply process of 17 blood banks were as follows: the discarding rate of expired blood was 0.023% (23/100 000), the leakage rate during storage and distribution was of 0.009%(9/100 000), the discarding rate of returned blood was 0.106% (53/50 000), the service satisfaction of hospitals was 99.16% (2 479/2 500). The leakage rate of blood components during storage and distribution was statistically different with that of blood component preparation bags between different blood banks (P<0.05). There were statistically significant differences in the proportion of regular blood donors, incidence of adverse reactions, non-standard whole blood collection rate, 400 mL whole blood collection rate, double platelet collection rate, the blood bag leakage rate during preparation process, the blood components leakage rate during storage and distribution as well as the discarding rate of lipemic blood, hemolysis blood, expired blood and returned blood among large, medium and small blood banks (all P<0.05). 【Conclusion】 The establishment of a quality monitoring indicator system for blood donation services, blood component preparation and blood supply processes in Shandong has good applicability, feasibility and effectiveness. It can objectively evaluate the quality management level, facilitate the continuous improvement of the quality management system, promote the homogenization of blood management in the province and lay the foundation for future comprehensive evaluation of blood banks.

Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype–phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between TSHR genotypes and clinical phenotypes. Methods: In total, 367 patients with CH were recruited for TSHR variant screening using whole-exome sequencing. The effects of the variants were evaluated by in-silico programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity. Results: Among the 367 patients with CH, 17 TSHR variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic TSHR variants. In vitro experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with TSHR biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with DUOX2 biallelic variants. Conclusions We found a high frequency of TSHR variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by TSHR biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by TSHR biallelic variants is relatively mild. Our study expands the TSHR variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.

Objective To explore the role of TMAO from gut microbiota in non-alcoholic fatty liver disease(NAFLD),we detected the serum level of TMAO and its precursor metabolites in NAFLD,as well as the expression level of Eubacterium rectum,Bacteroidetes multiforme,Lactobacillus and bifidobacterium in the intestinal flora.Methods We collected 118 subjects and divided into NAFLD group(86 cases)and healthy control group(32 cases)randomly.We also detected the serum level of TMAO and its precursor metabolites in subjects by high performance liquid chromatography tandem mass spectrometry detection(LC-MS),and the expression of target bacterial DNA was detected by qRT-PCR.Results Serum TMAO,TMA and choline levels were significantly increased in NAFLD(P<0.05),and liver fat content was positively correlated with TMAO(P<0.05).The expression level of Lactobacillus and Eubacterium rectum in NAFLD group were increased(P<0.05);the expression level of Bifidobacterium and Bacteroides multiform were decreased(P<0.05).The serum TMAO level was positively correlated with Eubacterium rectum(r=0.280,P<0.05),and negatively correlated with Bifidobacterium(r=-0.332,P<0.05).Conclusion The level of TMAO in serum shows a positive correlation with NAFLD.The structure of intestinal flora in individuals with NAFLD is altered and linked to TMAO.This suggests that the intestinal flora may have a significant impact on the development of NAFLD through TMAO.