Drug-induced liver injury （DILI） is the main cause of failures in drug development and the withdrawal of approved drugs from the market， and therefore， there is an increasing demand for accurate prediction and in vitro testing. However， the two-dimensional cell culture system of hepatocytes is not suitable for the toxicity study of long-term drug use due to the fact that it cannot accurately simulate and reproduce the real environment and micro-ecosystem of hepatocytes in vivo. In view of this， there is an urgent need for liver models with higher predictability to assess the hepatotoxicity of drugs in drug development and the safety evaluation of active compounds. This article reviews the construction and application of three-dimensional in vitro hepatocyte culture systems for DILI， in order to provide a reference for their effective implementation in DILI analysis.

OBJECTIVE To investigate the effects of multiple doses of Shugan jieyu capsules on the pharmacokinetics of voriconazole,rivaroxaban and apixaban in rats.METHODS Male SD rats were randomly divided into voriconazole group(30 mg/kg),rivaroxaban group(2 mg/kg),apixaban group(0.5 mg/kg),Shugan jieyu capsules+voriconazole group(145 mg/kg+30 mg/kg),Shugan jieyu capsules+rivaroxaban group(145 mg/kg+2 mg/kg),Shugan jieyu capsules+apixaban group(145 mg/kg+0.5 mg/kg),with 6 rats in each group.After the rats in each group were consecutively administered solvent(0.5%sodium carboxymethyl cellulose solution)or Shugan jieyu capsules by intragastric gavage for 8 days,they were respectively given voriconazole,rivaroxaban and apixaban solution by intragastric gavage on the 8th day.Blood samples were then collected at different time points(in voriconazole group,rivaroxaban group and corresponding drug combination groups,blood was collected before administration and at 0.17,0.34,0.5,0.75,1,1.5,2,3,4,5,6,8,10 and 12 hours post-administration;in apixaban group and corresponding drug combination group,blood was collected before administration and at 0.08,0.17,0.25,0.34,0.5,0.75,1,3,5,7,10 and 12 hours post-administration).Ultra-high performance liquid chromatography-tandem mass spectrometry method was employed to determine the mass concentrations of voriconazole,rivaroxaban and apixaban in rat plasma.The main pharmacokinetic parameters of these drugs were calculated using a non-compartmental model,and the comparisons were made between groups.RESULTS Compared with single drug group,after multiple administrations of Shugan jieyu capsules,AUC0-t,AUC0-∞ and cmax of voriconazole were significantly decreased,while CLz/F was significantly increased,and tmax was also significantly prolonged(P＜0.05).For rivaroxaban and apixaban,their tmax values were both significantly prolonged(P＜0.05).However,there were no statistically significant differences in the other pharmacokinetic parameters between the two groups(P＞0.05).CONCLUSIONS The combination of Shugan jieyu capsules can decrease the exposure,increase the clearance,and delay the peak concentration of oral voriconazole.However,it does not affect the exposure levels of rivaroxaban and apixaban,but it does delay the time to reach peak concentration for both drugs.

AIM: To explore the pharmacokinetic interactions between sorafenib and dapagliflozin in rats and to provide some theoretical basis for the rational clinical use of the two drugs. METHODS: An ultra -performance liquid chromatography-tandem mass spectrometry (UPLC / MS / MS) method was developed for the simultaneous determination of sorafenib and dapagliflozin. Male SD rats were randomly divided into 5 groups (6 rats in each group), including 100 mg / kg sorafenib group, 0.5 mg / kg dapagliflozin group, 1 mg / kg dapagliflozin group, and 100 mg/kg sorafenib combined with 0.5 mg/kg dapagliflozin group and 100 mg/kg sorafenib combined with 1 mg / kg dapagliflozin group, for sorafenib and dapagliflozin drug interaction study. All samples were analyzed using a validated UPLC/ MS/MS method, and the main pharmacokinetic parameters were calculated by compartment model. RESULTS: 1 mg/kg dapagliflozin increased the C

Objective: To understand social anxiety of Tibetan adolescents aged 10-15 years old in high altitude areas and its correlation with sleep duration, so as to provide a reference and support for social anxiety prevention and mental health interventions for Tibetan adolescents in high altitude areas. Methods: A total of 2 426 Tibetan adolescents from the Lhasa, Chamdo, and Nagchu regions of Tibet were surveyed. From April to June 2022, basic demographics, social anxiety, and sleep status were obtained and analyzed using class based, stratified whole group sampling, and the correlations detected between the two were analyzed by logistic regression analysis. Results: The average social anxiety score of Tibetan adolescents aged 10-15 years in high altitude areas was (6.51±4.32), and the detection rate of social anxiety was 5.23%. The mean sleep duration was (7.42±1.18) hours/day. The differences were statistically significant when compared across gender, overweight/obesity status, level of physically activity, and sleep duration ( χ 2=19.44, 14.39, 7.83, 7.21, P <0.05). After adjusting for relevant variables, the Logistic regression analysis showed that sleep deprivation among boys ( OR =2.91, 95% CI =1.82-4.61), sleep deprivation among girls ( OR = 3.51 , 95% CI =2.01-6.04), and overall sleep deprivation among Tibetan adolescents ( OR =3.12, 95% CI =1.91-4.58) were positively associated with social anxiety( P <0.01). Conclusions A positive association was found between social anxiety and sleep deprivation, indicating that social anxiety is an issue among Tibetan adolescents living in high altitude regions. Sufficient sleep duration plays a positive protective role in reducing social anxiety among Tibetan adolescents in high altitude areas, and the findings provide a reference for future mental health interventions.

Objective Establishing intelligent nursing clinical decision support system to improve the safety, quality and efficiency of clinical nursing work. Methods Guided by the HIMSS EMRAM Analytics stage 7 evaluation standard, the nursing decision support system is continuously improved through the establishment of knowledge bases such as nursing plans and nursing conventions. Results By comparing the writing time of nursing documents, the correct rate of nursing diagnosis, and the incidence of nursing risk events before and after the used of the system, the results showed that after the used of the nursing decision-making support system, whole hospital′s writing time could save 222.5 hours per day, improved accuracy of nursing diagnosis from 68.33％ (205/300)to 90.67％ (272/300), the difference was statistical significace (χ2=45.907, P<0.05). Decreased incidents, hospital-wide, on falls from 0.127‰(80/631702) to 0.071‰(45/638715),and on pressure ulcer form 0.064‰ (41/631702)to 0.028‰(18/638715), the difference was statistical significace (χ2=13.004～15.071, P<0.05). Conclusion Nursing clinical decision support system is the trend of hospital informatization and is worthy of clinical application.

OBJECTIVE:To establish the method for simultaneous determination of tenacissoside A,tenacissoside H and tenacissoside I in Marsdenia tenacissima. METHODS:UPLC-MS/MS method was adopted. The determination was performed on a Phenomenex Kinetex XB-C18column with mobile phase consisted of 0.1% formic acid solution-acetonitrile(gradient elution)at the flow rate of 0.2 mL/min. The column temperature was set at 40 ℃,and sample size was 5 μ L. Multiple reaction monitoring (MRM)mode was adopted with electrospray ion source as ion source,using positive ion scanning. Source jet voltage was 5 500 V,nebulizer pressure was 60 psi,heating pressure was 60 psi,curtain pressure was 20 psi and cone temp was set at 600 ℃. RESULTS:The linear ranges of tenacissoside A,tenacissoside H and tenacissoside I were 0.1-10 ng/mL(r=0.999 7),0.025-10 ng/mL(r=0.999 5),0.025-10 ng/mL(r=0.998 9),respectively;limited of quantation were 0.1,0.025,0.025 ng/mL,limited of detection were 0.05,0.012 5,0.012 5 ng/mL,respectively;RSDs of precision,stability and reproducibility tests were<4.0%. The recoveries were 97.67%-99.00%(RSD=0.47%,n=6),95.00%-101.67%(RSD=2.59%,n=6),96.67%-103.33%(RSD=2.83%, n=6). CONCLUSIONS:The method is simple,precise,stable and reproducible,and can be used for simultaneous determination of tenacissoside A,tenacissoside H and tenacissoside I in M.tenacissima.

Objective Objective To evaluate the effects and safety of total glucosides of paeony (TGP) in the treatment of patients with Sjogren syndrome.Methods The Cochrane Library,PubMed,EMBASE,CBM,VIP,CNKI,Wanfang databases were searched from their establishments up to September 30,2015.We used the method recommended by the Cochrane collaboration to perform a meta-analysis of randomized controlled trails (RCTs) of total glucosides of peony in the treatment of patients with Sjogren syndrome.Two reviewers analyzed these data independently.The Cochrane Collaboration's software RevMan 5.3 was used for meta-analysis.Results A total of 573 patients in 10 studies were finally included,and were divided into different subgroups.The results of subgroup-analysis showed that:①Schimer test:TGP group had a higher effective rate than the blank control group [MD=2.41,95%CI (0.08,4.74)],lower effective rate than Chinese herbal medicine [MD=-2.55,95%CI (-3.88,-1.22);②Salivary flow:TGP group had a lower effective rate than the control group [SMD=-0.87,95%CI (-1.20,-0.54)].③Rheumatic factors (RF):TGP group had a higher effective rate than Chinese herbal medicine [SMD=0.44,95%CI (0.06,0.82)] and Chinese patent drug [SMD=0.74,95%CI (0.36,1.12)],lower effective rate than the blank control group [SMD=2.23,95%CI (-2.79,-1.67);④ C-reactive protein (CRP):TGP group had a higher effective rate than the control group [MD=4.51,95%CI (1.75,7.26)];⑤IgG:TGP group had a higher effective rate than Chinese patent drug group [MD=2.73,95%CI (1.63,3.84)],lower effective rate than the blank control group [MD=-3.90,95%CI (-5.67,-2.13),but no statistical difference was noted when compared with Chinese herbal medicine and Western medicine groups;⑥ESR:TGP group had a higher effective rate than Chinese herbal medicine group [MD=12.73,95%CI (3.62,21.84)] and Chinese patent drug group [MD=7.82,95%CI (5.39,10.24)],lower effective rate than the blank control group [MD=-7.13,95%CI (-12.70,-1.56) and Western medicine group [MD=-12.19,95%CI (-24.19,-0.19)];⑦Safety:8 studies reported adverse effects in 41 patients.TGP group had a higher adverse reaction rate than the control group [OR=3.23,95%CI (1.60,6.50)].Conclusion Current evidence demonstrates that TGP can effectively improve CRP,but its effects on Salivary flow,Schimer test,IgG,ESR,RF were not significant.However,the heterogeneity and high risk of bias in the reports involved in this study limits the reliability of this conclusion.

A 61-year-old female patient with stomach discomfort received omeprazole enteric coated tablet 40 mg once daily.On day 3 of administration of omeprazole, she presented sporadic erythema and stopped the medicine by herself.Three days after drug withdrawal, her symptom of erythema improved.She received omeprazole enteric coated tablet at the previous dosage again.Two days after taking medicine again, the patient developed rash all over her body, severe diarrhea and vomiting, acute renal injury and allergic shock in succession.She was diagnosed as severe allergic reaction due to omeprazole.The patient received the treatments of antianaphylaxis, maintaining the function of circulatory system, fluid infusion, and continuous veno venous hemodiafiltration.But the therapeutic effect was poor.The patient died on the second day after giving up the treatment which decided by her family members.

A 61-year-old female patient with stomach discomfort received omeprazole enteric coated tablet 40 mg once daily.On day 3 of administration of omeprazole, she presented sporadic erythema and stopped the medicine by herself.Three days after drug withdrawal, her symptom of erythema improved.She received omeprazole enteric coated tablet at the previous dosage again.Two days after taking medicine again, the patient developed rash all over her body, severe diarrhea and vomiting, acute renal injury and allergic shock in succession.She was diagnosed as severe allergic reaction due to omeprazole.The patient received the treatments of antianaphylaxis, maintaining the function of circulatory system, fluid infusion, and continuous veno venous hemodiafiltration.But the therapeutic effect was poor.The patient died on the second day after giving up the treatment which decided by her family members.

Objective To investigate the disease assessment and prognosis value of serum copeptin level in patients with acute cerebral infarction (ACI). Methods One hundred first diagnosed ACI patients were selected as ACI group. According to the National Institutes of Health stroke score (NIHSS), the ACI patients were divided into mild (NIHSS<7 scores), moderate (NIHSS 7-15 scores) and severe (NIHSS>15 scores). Sixty cases of healthy subjects were selected as control group. The serum copeptin level was measured by double antibody sandwich enzyme linked immunosorbent assay method in control group and ACI group (onset within 24 h). The NIHSS, Alberta stroke program early CT score (ASPECTS) and modified Rankin score (mRS) onset within 24 h and 14 d were evaluated in patients with ACI, and the mRS 90 d and 180 d after ACI were evaluated. The neurological impairment was assessed by mRS 180 d after ACI, mRS ≤ 2 scores was good prognosis, ≥ 3 scores was poor prognosis. The correlation was analyzed. Results Among the 100 patients with ACI, mild was in 52 cases, moderate in 34 cases, and severe in 14 cases; good prognosis was in 79 cases and poor prognosis in 21 cases. The serum copeptin levels within 24 h of ACI in mild, moderate and severe patients of ACI group were significantly higher than that in control group:(4.82 ± 1.25), (6.39 ± 2.21) and (9.28 ± 3.82) pmol/L vs. (1.95 ± 0.28) pmol/L. The serum copeptin level within 24 h of ACI in moderate patients was significantly higher than that in mild patients, in severe patients was significantly higher than that in moderate patients, and there were statistical differences (P<0.05). Within 24 h of ACI , the ASPECTS in moderate and severe patients were significantly lower than that in mild patients:(10.02 ± 2.10) and (6.24 ± 3.05) scores vs. (12.16 ± 0.84) scores, in severe patients was significantly lower than that in moderate patients, and there were statistical differences (P<0.05). The NIHSS in moderate and severe patients were significantly higher than that in mild patients:(10.68 ± 3.14) and (16.20 ± 4.26) scores vs. (4.35 ± 1.52) scores, in severe patients was significantly higher than that in moderate patients, and there were statistical differences (P<0.05). The serum copeptin levels within 24 h of ACI and NIHSS in each time point in good prognosis patients were significantly lower than those in poor prognosis patients:(3.52 ± 1.26) pmol/L vs. (8.68 ± 3.06) pmol/L and (5.68 ± 2.11) scores vs. (15.36 ± 3.25) scores, (4.85 ± 1.86) scores vs. (12.60 ± 3.89) scores, (3.68 ± 1.21) scores vs. (6.35 ± 2.96) scores, (2.16 ± 0.75) scores vs. (5.21 ±1.96) scores, and the ASPECTS within 24 h of ACI was significantly higher than that in poor prognosis patients:(11.38 ± 2.21) scores vs. (7.86 ± 2.49) scores, and there were statistical differences (P<0.05). The single factor Logistic regression analysis results showed that the age, ASPECTS, NIHSS and serum copeptin level were the influencing factors of severity of illness in patients with ACI (OR = 1.21, 5.36, 5.61 and 6.62;95%CI 0.99-1.39, 3.34-9.21, 2.86-7.52 and 1.38-12.64;P=0.04, 0.01, 0.01 and 0.00), and the influencing factors of poor prognosis (OR=1.32, 5.21, 4.86 and 6.82;95%CI 0.84-1.43, 3.52-8.39, 2.62-5.35 and 2.67-11.85;P=0.04, 0.01, 0.01 and 0.00). ROC analysis results showed that the area under curve of NIHSS, serum copeptin level and ASPECTS in predicting poor prognosis in patients with ACI were 0.926, 0.863 and 0.624. In the mild, moderate and severe patients, the serum copeptin level was negative correlated with ASPECTS ( r=-0.682,-0.594 and-0.572;P<0.01), and the serum copeptin level was positively correlated with NIHSS ( r = 0.652, 0.614 and 0.586; P<0.01). Conclusions The serum copeptin level in patients with ACI is significantly elevated. The serum copeptin level is positively correlated with neurologic impairment severity and prognosis in patients with ACI, and it has important significance in evaluating pathogenetic condition and prognosis.