OBJECTIVE To investigate the effects of clopidogrel on the pharmacokinetics and pharmacodynamics of ciprofol in rats. METHODS Eighteen male SD rats were randomly divided into control group， clopidogrel normal-dose group and clopidogrel high-dose group， with 6 rats in each group. Among them， rats in the normal-dose group and high-dose group were given 7.5 mg/kg and 15 mg/kg clopidogrel by gavage， respectively， and rats in the control group were given the same volume of 0.5% sodium carboxymethyl cellulose solution， once a day， for 14 consecutive days. Afterward， 2.4 mg/kg ciprofol was injected by tailvein and blood samples were collected from the inner canthus of the eye at 2， 4， 8， 12， 16， 20， 30， 45 and 60 min after the end of the administration. During this period， the duration of the loss of righting reflex （LORR） in rats was counted. After the proteins were precipitated by acetonitrile， the rat plasma sample was analyzed by LC-MS/MS using deuterated ciprofol as the internal standard， Symmetry C18 as the chromatographic column， and acetonitrile-0.01% ammonia solution containing 5 mmol/L ammonium acetate （gradient elution） as the mobile phase to detect the concentration of ciprofol in the plasma. The pharmacokinetic parameters in rats were calculated by using DAS 2.0 software. RESULTS Compared with control group， area under the drug concentration-time curve and mean residence time of ciprofol increased or prolonged significantly， while plasma clearance decreased significantly in clopidogrel normal-dose and high-dose groups； the duration of LORR in rats was prolonged by 19.5% and 23.9%， with statistical difference （P＜0.05）. However， there was no statistically significant difference in the pharmacokinetic parameters or LORR duration of ciprofol between the different dose groups of clopidogrel （P＞0.05）. CONCLUSIONS Clopidogrel could inhibit the metabolism of ciprofol in rats and prolong the duration of LORR.

OBJECTIVE To investigate the effects of clopidogrel on the pharmacokinetics and pharmacodynamics of ciprofol in rats. METHODS Eighteen male SD rats were randomly divided into control group， clopidogrel normal-dose group and clopidogrel high-dose group， with 6 rats in each group. Among them， rats in the normal-dose group and high-dose group were given 7.5 mg/kg and 15 mg/kg clopidogrel by gavage， respectively， and rats in the control group were given the same volume of 0.5% sodium carboxymethyl cellulose solution， once a day， for 14 consecutive days. Afterward， 2.4 mg/kg ciprofol was injected by tailvein and blood samples were collected from the inner canthus of the eye at 2， 4， 8， 12， 16， 20， 30， 45 and 60 min after the end of the administration. During this period， the duration of the loss of righting reflex （LORR） in rats was counted. After the proteins were precipitated by acetonitrile， the rat plasma sample was analyzed by LC-MS/MS using deuterated ciprofol as the internal standard， Symmetry C18 as the chromatographic column， and acetonitrile-0.01% ammonia solution containing 5 mmol/L ammonium acetate （gradient elution） as the mobile phase to detect the concentration of ciprofol in the plasma. The pharmacokinetic parameters in rats were calculated by using DAS 2.0 software. RESULTS Compared with control group， area under the drug concentration-time curve and mean residence time of ciprofol increased or prolonged significantly， while plasma clearance decreased significantly in clopidogrel normal-dose and high-dose groups； the duration of LORR in rats was prolonged by 19.5% and 23.9%， with statistical difference （P＜0.05）. However， there was no statistically significant difference in the pharmacokinetic parameters or LORR duration of ciprofol between the different dose groups of clopidogrel （P＞0.05）. CONCLUSIONS Clopidogrel could inhibit the metabolism of ciprofol in rats and prolong the duration of LORR.

OBJECTIVE To study the pharmacokinetic characteristics of ciprofol in pregnant and fetal rats， and provide reference for the application of ciprofol in cesarean section. METHODS Eight pregnant rats were selected. A single dose of 2.4 mg/kg of ciprofol was administered via the tail vein. One fetal rat was selected at 2， 4， 8， 12， 16， 25， 35， 45， 60， and 90 minutes respectively after ciprofol administration. Subsequently， whole blood samples were collected simultaneously from both the pregnant rats and fetal rats. HPLC-MS/MS method was used to determine the concentration of ciprofol in the bodies of pregnant and fetal rats. The ratios of fetal-to-maternal blood concentrations （F/M ratios） at each time point were calculated， and the F/M-time curves were plotted. Subsequently， non-compartmental pharmacokinetic parameters were computed using DAS 2.0 software. RESULTS Compared with pregnant rats， cmax， AUC0-90 min and AUC0-∞ of ciprofol in fetal rats were decreased significantly， while MRT was increased significantly （P＜0.05）. The F/M curve of ciprofol initially increased and then decreased， and between 0.16- 0.84， reaching a maximum value of 0.84 at 45 minutes. CONCLUSIONS Ciprofol can penetrate the placental barrier， and there are significant differences in pharmacokinetic parameters between pregnant and fetal rats. Moreover， the exposure level of ciprofol in fetal rats is much lower than that in pregnant rats. Therefore， ciprofol shows promise as an ideal anesthetic agent for cesarean section delivery.

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.

Objective:To evaluate the effects of heparin on focal adhesion kinase (FAK)/Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil-containing protein kinase (ROCK) signaling pathways during acute lung injury (ALI) in septic mice.Methods:Thirty SPF healthy adult male C57BL/6J mice, aged 6-8 weeks, weighing 20-23 g, were assigned into 3 groups ( n=10 each) using a random number table method: control group (group C), ALI group, and heparin group (group H). Septic ALI model was prepared by intraperitoneal injection of lipopolysaccharide 15 mg/kg, while group C received the equal volume of normal saline. In group H, heparin sodium solution 10 U was injected via the tail vein at 30 min before developing the model. The equal volume of normal saline was injected in C and ALI groups. Venous blood samples were collected from the eyeballs under deep anesthesia at 24 h after lipopolysaccharide injection. The mice were subsequently sacrificed and lung tissues were obtained for determination of the serum concentrations of interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (using enzyme-linked immunosorbent assay), wet/dry lung weight (W/D) ratio, expression of vascular endothelial adhesion factor 1 (VCAM-1) (by immunohistochemical staining) and expression of FAK, phosphorylated FAK (p-FAK), RhoA, GTP-bound RhoA (RhoA-GTP) and ROCK (by Western blot) and for examination of the pathological changes. The lung injury was assessed and scored. Results:Comparison with group C, the serum concentrations of IL-1β, IL-6 and TNF-α, W/D ratio and lung injury scores were significantly increased, and the expression of VCAM-1, p-FAK, RhoA-GTP and ROCK was up-regulated in ALI group ( P<0.05). Compared with ALI group, the serum concentrations of IL-1β, IL-6 and TNF-α, W/D ratio and lung injury scores were significantly decreased, and the expression of VCAM-1, p-FAK, RhoA-GTP and ROCK was down-regulated in H group ( P<0.05). Conclusions:The mechanism through which heparin mitigates ALI is associated with the inhibition of the FAK/RhoA/ROCK signaling pathway in septic mice.

Objective:To identify the risk factors, and develop and validate a risk prediction model for abnormal bone mass in end-stage renal disease (ESRD) patients.Methods:It was a retrospective cross-sectional study. The clinical and laboratory data of ESRD patients who were hospitalized in the Department of Nephrology, Zhongda Hospital Affiliated to Southeast University from January 2022 to May 2023 were collected retrospectively. The patients were randomly divided into training and validation cohorts at a ratio of 7∶3. They were further divided into normal and abnormal bone mass groups according to the T value measured by dual-energy X-ray absorptiometry (DXA). Then, backward stepwise regression and least absolute shrinkage and selection operator (LASSO) were respectively used to develop the risk prediction model for abnormal bone mass in ESRD patients. Akaike information criterion (AIC), bayesian information criterion (BIC), and accuracy were used to evaluate the performance of these two models, after which the preferable model was selected. Moreover, the receiver operating characteristic (ROC) curve, calibration curve, Hosmer-Lemeshow test, and decision curve analyses (DCA) were applied to evaluate the diagnostic performance of the preferable model. Finally, a dynamic nomogram for individual assessment was constructed based on the preferable model.Results:A total of 254 ESRD patients were enrolled, including 160 (63.0%) males, 161 (63.4%) hemodialysis patients, and 202 (79.5%) patients with abnormal bone mass. There was no significant difference in the prevalence of abnormal bone mass between training group ( n=178) and validation group ( n=76) (79.2% vs. 80.3%, χ2=0.036, P=0.849). The final variables and variable parameters included in the LASSO and stepwise regression models were the same, which were five variables: age, body mass index, hypertension, diabetes, and osteocalcin. Both models also had the same AIC, BIC, and accuracy in the training group, which were 113.45, 132.54, and 0.837, respectively. Therefore, the LASSO model and the stepwise regression model performed consistently in this study and could be considered as the same model, hereafter referred to as the Model. The Model's area under the ROC curve in the training and validation groups was 0.923 (95% CI 0.884-0.963) and 0.809 (95% CI 0.675-0.943), respectively. The optimal cutoff for the training group was 0.858, with a sensitivity of 0.801, a specificity of 0.973 and an accuracy of 0.837; when this cutoff value was taken, the validation group's sensitivity was 0.689, specificity was 0.800, and accuracy was 0.711. The Model demonstrated excellent performance in the calibration curve, Hosmer-Lemeshow test ( P>0.05), and DCA. Finally, based on the five predictors of the Model, a dynamic nomogram was created for clinicians to enter baseline clinical parameters for early identification of high-risk patients with abnormal bone mass. Conclusions:A dynamic nomogram for abnormal bone mass in ESRD patients is constructed with good predictive performance based on the prediction model, which can be used as a practical approach for the personalized early screening and auxiliary diagnosis of the potential risk factors and assist physicians in making a personalized diagnosis for patients.

The management of clinical application of antimicrobial drugs is an important part of the pharmaceutical management and pharmacy services in medical institutions.Based on national policies and regulations,this standard focuses on the whole life cycle of antimicrobial drugs in medical institutions.It is developed based on the principles of scientific validity,universality,guidance and operability,formed by sorting out problems,collecting opinions,expert argumentation and deliberation.It is the first group standard to standardize the clinical application management of antimicrobial drugs.This paper introduces and analyzes the team composition,problem sorting and compilation process,and various elements of the standard in the process of formulating the standard,and provide a reference for the majority of peers who use it.

Objective:To investigate the evaluation efficacy and predictive prognostic value of alpha-fetoprotein (AFP) response in tyrosine kinase inhibitors (TKIs) in combination with PD-1 inhibitors (α-PD-1) for intermediate-to-advanced hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 205 patients with intermediate-to-advanced HCC who were admitted to 9 medical centers, including Mengchao Hepatobiliary Hospital of Fujian Medical University et al, from March 2020 to July 2022 were collected. There were 178 males and 27 females, aged (52±12)years. Based on AFP response at 6-8 weeks after treatment, patients were divided into the AFP response group (AFP level decreased by ≥50% compared to baseline) and the AFP no response group (AFP level decreased by <50% compared to baseline). Observation indicators: (1) AFP response evaluation of anti-tumor efficacy; (2) comparison of patient prognosis; (3) analysis of factors affecting patient prognosis. Measurement data with normal distrubution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range) and M( Q1, Q3). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. The Kaplan-Meier method was used to draw survival curve and calculate survival rate, and the Log-Rank test was used for survival analysis. The COX proportional risk model was used for univariate analysis and the COX stepwise regression model was used for multivariate analysis. Results:(1) AFP response evaluation of anti-tumor efficacy. Before treatment, all 205 patients were positive of AFP, with a baseline AFP level of 1 560(219,3 400)μg/L. All 205 patients were treated with TKIs in combination with α-PD-1, and the AFP level was 776(66,2 000)μg/L after 6 to 8 weeks of treatment. Of the 205 patients, 88 cases were classified as AFP response and 117 cases were classified as AFP no response. According to the response evaluation criteria in solid tumors version 1.1, the objective response rate (ORR) and disease control rate (DCR) were 42.05%(37/88) and 94.32%(83/88) in patients of the AFP response group and 16.24% (19/117) and 64.10% (75/117) in patients of the AFP no response group, showing significant differences between them ( χ2=16.846, 25.950, P<0.05). According to the modified response evaluation criteria in solid tumors, the ORR and DCR were 69.32% (61/88) and 94.32% (83/88) in patients of the AFP response group and 33.33% (39/117) and 64.10% (75/117) in patients of the AFP no response group, showing significant differences between them ( χ2=26.030, 25.950, P<0.05). (2) Comparison of patient prognosis. All 205 patients were followed up for 12.4(range, 2.4-34.0)months after treatment. The median progression free survival time and total survival time were 5.5 months and 17.8 months, respectively. The 1-year, 2-year progression free survival rates were 20.8% and 7.2%, and the 1-year, 2-year overall survival rates were 68.7% and 31.5%, respectively. The median progression free survival time, 1-year and 2-year progression free survival rates were 9.7 months, 39.6% and 14.2% in patients of the AFP response group and 3.7 months, 7.8% and 2.0% in patients of the AFP no response group, showing a significant difference in progression free survival between them ( χ2=43.154, P<0.05). The median overall survival time, 1-year and 2-year overall survival rates were not reached, 85.2% and 56.3% in patients of the AFP response group and 14.6 months, 56.3% and 14.5% in patients of the AFP no response group, showing a significant difference in overall survival between them ( χ2=33.899, P<0.05). (3) Analysis of factors affecting patient prognosis. Results of multivariate analysis showed that invasion of large blood vessels, extrahepatic metastasis, combined hepatic artery intervention therapy, and AFP response were independent factors influencing progression free survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1 ( hazard ratio=1.474, 1.584, 0.631, 0.367, 95% confidence interval as 1.069-2.033, 1.159-2.167, 0.446-0.893, 0.261-0.516, P<0.05), and Eastern Cooperative Oncology Group score, invasion of large blood vessels, extrahepatic metastasis, and AFP response were independent factors influencing overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1 ( hazard ratio= 1.347, 1.914, 1.673, 0.312, 95% confidence interval as 1.041-1.742, 1.293-2.833, 1.141-2.454, 0.197-0.492, P<0.05). Conclusions:AFP response at 6-8 weeks after treatment can effectively evaluate anti-tumor efficacy of TKIs in combination with α-PD-1 for intermediate-to-advanced HCC. AFP response is the independent factor influencing progression free survival and overall survival in patients with intermediate-to-advanced HCC who were treated with TKIs in combination with α-PD-1.

Objective:To examine the associations of BMI and waist circumference (WC) with the risk of chronic kidney disease (CKD) and its subtypes in adults in China.Methods:The data from the China Kadoorie Biobank were used. After excluding those with cancer, coronary heart disease, stroke, or CKD at baseline survey, 480 430 participants were included in this study. Their body height and weight, and WC were measured at baseline survey. Total CKD was defined as diabetic kidney disease (DKD), hypertensive nephropathy (HTN), glomerulonephritis (GN), chronic tubulointerstitial nephritis (CTIN), obstructive nephropathy (ON), CKD due to other causes, and chronic kidney failure. Cox proportional hazards regression model was used to estimate the associations between exposure factors and risks of outcomes.Results:During a follow-up period of (11.8±2.2) years, 5 486 cases of total CKD were identified, including 1 147 cases of DKD, 340 cases of HTN, 1 458 cases of GN, 460 cases of CTIN, 598 cases of ON, 418 cases of CKD due to other causes, and 1 065 cases of chronic kidney failure. After adjusting for socio-demographic factors, lifestyle factors, baseline prevalence of hypertension and diabetes, and WC and compared to participants with normal BMI (18.5-23.9 kg/m 2), the hazard ratios ( HRs) of total CKD for underweight (<18.5 kg/m 2), overweight (24.0-27.9 kg/m 2), and obese (≥28.0 kg/m 2) were 1.42 (95% CI: 1.23-1.63), 1.00 (95% CI: 0.93-1.08) and 0.98 (95% CI: 0.87-1.10), respectively. Stratification analysis by WC showed that BMI was negatively associated with risk for total CKD in non-central obese participants (WC: <85.0 cm in men and <80.0 cm in women) ( HR=0.97, 95% CI: 0.96-0.99), while the association was positive in central obese participants (≥90.0 cm in men and ≥85.0 cm in women) ( HR=1.03, 95% CI: 1.01-1.05). The association between BMI and GN was similar to that of total CKD. BMI was associated with an increased risk for HTN, with a HR of 1.12 (95% CI: 1.06-1.18) per 1.0 kg/m 2 higher BMI. After adjusting for potential confounders and BMI, compared to participants with non-central obesity, the HRs for pre-central obesity (WC: 85.0-89.9 cm in men and 80.0-84.9 in women) and central obesity were 1.26 (95% CI: 1.16-1.36) and 1.32 (95% CI: 1.20-1.45), respectively. With the exception of HTN and CTIN, WC was positively associated with risks for all CKD subtypes. Conclusions:BMI-defined underweight and central obesity were independent risk factors for total CKD, and BMI and WC had different associations with risks for disease subtypes.

In order to standardize the clinical nursing care for patients with atherosclerotic carotid artery stenosis,this"Expert Consensus on Clinical Nursing Norms for Atherosclerotic Carotid Artery Stenosis"(hereinafter referred to as the"Consensus")was composed.On the basis of the guidelines and consensus for the diagnosis and treatment of carotid artery stenosis and the evidence-based nursing practice at home and abroad in the past 10 years,a total of 51 medical experts engaged in vascular surgery and related fields were invited to revise and improve the first draft,and finally the final version was formed.The"Consensus"includes the following five contents:common surgical methods,preoperative nursing care,preoperative preparation,postoperative nursing care,and discharge education.This"Consensus"is scientific and practical to a certain extent,which can provide practical guidance in the clinical nursing practice for patients with atherosclerotic carotid artery stenosis and can ensure patient safety as well.