OBJECTIVE To prepare berberine/piperine co-loaded self-microemulsion drug delivery system （BBR/PIP- SMEDDS）， evaluate its physicochemical properties， in vitro release and pharmacokinetic characteristics. METHODS The drug loading mass ratio of berberine （BBR） and piperine （PIP） in the preparation was determined by the everted intestinal sac method. The oil-phase， emulsifier and co-emulsifier were determined by solubility detection， compatibility evaluation and pseudo-ternary phase diagram， respectively. The formulation of blank self-microemulsion drug delivery system （SMEDDS） was optimized and verified by central composite design-response surface methodology with the amount of oil-phase and the mass ratio of emulsifier to co-emulsifier as factors， and the comprehensive score of particle size and Zeta potential as response value. According to the optimal prescription， BBR/PIP-SMEDDS was prepared by adding excessive BBR and PIP raw materials under magnetic stirring， and its physicochemical properties， in vitro release behavior and pharmacokinetic characteristics in rats were investigated. RESULTS The drug loading mass ratio of BBR and PIP was 1∶1. The optimal prescription included oil-phase （ethyl oleate） accounted for 18.54%， emulsifier （Tween-80） accounted for 52.16%， and co-emulsifier （polyethylene glycol 400） accounted for 29.30%. Three verification experiments showed that the average particle size of blank SMEDDS was （16.49±0.49） nm； the Zeta potential was （－16.22±0.77） mV； the comprehensive score was 0.97， the relative deviation of which from the predicted value （0.95） was 2.11%. The prepared BBR/PIP-SMEDDS was an oil-in-water microemulsion， which was a golden yellow oily liquid with a spherical shape. The average particle size was （32.90±0.38） nm， and the Zeta potential was （－19.17±0.70） mV. The encapsulation efficiency of BBR was （90.44±0.88）% ， and the drug loading was （10.18±0.17） mg/g. The encapsulation efficiency of PIP was （87.48±1.13）%， and the drug loading was （9.41±0.17） mg/g. BBR/PIP-SMEDDS had good stability at low temperature （4 ℃ ） in the dark， centri-fugation and dilution. The results of in vitro release showed that the cumulative release percentage of BBR in simulated intestinal fluid for 24 h was significantly higher than that of the raw drug after the preparation of SMEDDS. The pharmacokinetic results in rats showed that the peak concentration and area under the drug- concentration time curve （AUC0－）t of BBR/PIP-SMEDDS were 4.61 and 7.07 times higher than those of the raw drug respectively， and the relative bioavailability was 707.484%. CONCLUSIONS BBR/PIP-SMEDDS is successfully prepared， and the in vitro release and bioavailability of the preparation are greatly improved compared with the raw material.

Objective To establish a HPLC method for the simultaneous determination of artemisinin,arteannuin B,chrysosplenetin and chrysosplenol-D in the water extract of Artemisia annua L.Methods The analysis was performed on Agilent ZORBAX SB-C18(250 mm×4.6 mm,5 μm)column with a mobile phase of acetonitrile(A)-water(B)and the flow rate of 0.8 mL·min-1 in a gradient elution manner.The column temperature was 30℃.The injection volume was 10 μL,and the detection wavelength was 210 nm.Results Artemisinin,arteannuin B,chrysosplenetin and chrysosplenol-D were correlated well linearly with peak area in their respective ranges 1.608 8-16.088 μg(r=0.999 9),0.014 1-0.141 4 μg(r=1),0.185 1-1.850 9 μg(r=0.999 9),0.144 1-1.441 4 μg(r=0.999 9),the average recovery rate(n=6)were 102.44%,97.82%,95.07%,95.55%,and the RSD values were 1.12%,1.44%,1.29%,1.53%.Conclusion This method is convenient and accurate.It has good stability and repeatability,and can be used to simultaneously determine the content of artemisinin,arteannuin B,chrysosplenetin and chrysosplenol-D in the water extract of Artemisia annua L.

Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Objectives:To evaluate the value of electromagnetic navigation assisted percutaneous pedicle screw placement in unilateral biportal endoscopic transforaminal lumbar interbody fusion(UBE-TLIF).Methods:The clinical data of 34 patients with single-level lumbar degenerative diseases treated with UBE-TLIF assist-ed with electromagnetic navigation for percutaneous pedicle screw placement between August 2020 and August 2021 were retrospectively analyzed,and there were 18 males and 16 females,aged 43-73 years(58.4±9.4 years)with body mass index of 24.7±2.9kg/m2;1 case was of L2/3,5 cases were of L3/4,17 cases were of L4/5 and 11 cases were of L5/S1(electromagnetic navigation group).A total of 20 patients treated with UBE-TLIF assisted with C-arm X-ray machine fluoroscopy for percutaneous pedicle screw placement during the same period were selected as the control group,which consisted of 11 males and 9 females,aged 35-73 years(58.1±10.2 years),with body mass index of 26.5±3.8kg/m2;1 case was of L1/2,1 case was of L2/3,3 cases were of L3/4,12 cases were of L4/5 and 3 cases were of L5/S1(C-arm fluoroscopy group).The opera-tive time,fluoroscopy times,screw placement time,screw placement accuracy rate,and complications of the two groups were analyzed.Visual analogue scale(VAS)and Oswestry disability index(ODI)were evaluated be-fore and after surgery.The modified MacNab criteria were used to evaluate the clinical effect at final follow-up.Results:All the patients successfully completed operation.The screw placement time,number of fluo-roscopy times and operative time were 30.4±3.3min,3.6±1.0,173.8±23.9min in electromagnetic navigation group and 44.1±6.lmin,22.8±4.9,190.2±12.5min in C-arm fluoroscopy group,which were significantly lower in the electromagnetic navigation group(P＜0.05).The accuracy of pedicle screw placement was comparable be-tween the two groups(97.1％vs 95％,P＞0.05).There were no serious complications and revision surgery.With a mean follow-up of 17.6(6-27)months,the VAS back pain,VAS leg pain and ODI in both groups were significantly improved compared with those before surgery at all time points after operation(P＜0.05),and there was no significant difference between the two groups at the same time point(P＞0.05).According to MacNab criteria,there was no significant difference between the two groups in the rate of excellent and good results at final follow-up(97.1％vs 95％,P＞0.05).Conclusions:UBE-TLIF assisted with electromagnetic navigation for percutaneous pedicle screw placement is feasible and safety in the treatment of single-level lumbar de-generative disease,with few intraoperative fluoroscopy times,high safety,and satisfactory early results.

Bone organoids can simulate the complex structure and function of the bone tissues, which makes them a frontier technology in organoid researches. Bone organoids show a tremendous potential of applications in bone disease modeling, bone injury repair, and medicine screening. Although advancements have been made so far in constructing bone organoids with functional structures like mineralization, bone marrow, trabecular bone, callus, woven bone, etc, the researches in this field are confronted with numerous challenges such as lack of standardized construction strategies and unified evaluation criteria, which limits their further promotion and application. To standardize researches in bone organoids, the Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, the Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, the Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and the Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine organized related experts to formulate Expert consensus on the construction, evaluation, and application of bone organoids ( version 2024) based on an evidence-based approach. A total of 17 recommendations were put forth, aiming to standardize researches and clinical applications of bone organoids and enhance their value in scientific research and clinical practice.

【Objective】 To reduce the incidence of postoperative intestinal obstruction, we tried to improve surgical techniques by closing the cavity formed during radical cystectomy + ileal passage (Bricker) via laparoscopy to prevent the formation of abdominal hernia. 【Methods】 During Oct.2018 and Feb.2022, 41 patients were involved (conventional group). After standard laparoscopic radical cystectomy + pelvic lymphadenectomy, the ileum channel was established. The right medial retroperitoneum was sutured to cover the mesothelium and end of the ileum channel under open operation or endoscope. The space between the ureter and mesothelium of the ileum channel was sealed, and the end of the ileum channel and both ureters were externalized. During Feb.2022 and Dec.2022, 15 patients were involved (modified group). The right inner and outer lateral peritoneums below the ileal conduit were sutured to "bottom out" the gap between the ileal conduit and the right abdominal wall in addition to standard procedures. The recovery of intestinal function and incidence of bowel obstruction were compared between the two groups. 【Results】 In the conventional group, the intestinal function recovered within 2 to 6 days after surgery, with a median ventilation time of 3 days. Intestinal obstruction occurred in 3 patients, 2 of whom improved after conservative treatment while 1 underwent surgical exploration after ineffective conservative therapy. There were no significant differences in the time of discharge and ventilation between the two groups, but no intestinal obstruction occurred in the modified group. 【Conclusion】 Peritoneal externalization at the end of ileal passage can reduce the incidence of intra-abdominal hernia and postoperative intestinal obstruction, which is worthy of clinical application.

Objective:To investigate the effect of acupoint stimulation assisted anesthesia on the agitation during recovery and the levels of serum opioids (Opiorphin) and amyloid A (SAA) in elderly patients after hip fracture surgery.Methods:Eighty-six older patients who underwent hip fracture surgery in Shaoxing Second Hospital from February 2020 to September 2021 were randomly divided into the routine group and the research group, each with 43 patients. They were given acupoint sham stimulation and acupoint stimulation respectively, and the general indexes of the two groups, recovery quality, cognitive function and changes in serum Opiorphin and SAA levels were compared.Results:There were no differences in operation time, anesthesia time, recovery time and intraoperative blood transfusion between the two groups ( P>0.05). The dosage of remifentanil in the research group was significantly lower than that in the routine group: (270.64 ± 17.62) μg vs. (291.82 ± 23.34) μg, P<0.05. The incidence of agitation during the recovery period in the research group was significantly lower than that in the routine group: 13.95% (6/43) vs. 48.84% (21/43), P<0.05. The mini-mental state examination (MMSE) scores in the research group at 12, 24 and 48 h after operation were significantly higher than those in the routine group: (22.80 ± 2.04) scores vs. (19.31 ± 3.61) scores, (24.92 ± 2.44) scores vs. (21.49 ± 3.58) scores, (26.73 ± 2.57) scores vs. (24.23 ± 3.95) scores, there were statistical differences ( P<0.05). The serum Opiorphin level at 24 h after operation in the research group was higher than that in the routine group: (32.74 ± 8.57) mg/L vs. (25.40 ± 6.36) mg/L; and the SAA level was lower than that in the routine group: (157.36 ± 10.24) mg/L vs. (204.37 ± 15.56) mg/L, there were statistical differences ( P<0.05). Conclusions:Acupoint stimulation adjuvant anesthesia can reduce the occurrence of agitation during the recovery period of elderly patients with hip fracture, reduce the dosage of anesthetics, reduce postoperative cognitive impairment, regulate serum Opiorphin and SAA levels, and help early postoperative recovery.

Objective:To investigate the difference in left ventricular dysfunction between type 2 diabetes mellitus (T2DM) patients with hyperlipidemia and those without hyperlipidemia, and analyze the application value of three-dimensional speckle tracking technology.Methods:The clinical data of 70 patients with T2DM admitted to Heji Hospital Affiliated to Changzhi Medical College from January 2020 to June 2021 were retrospectively analyzed. Among these patients, 35 patients had hyperlipidemia and 35 patients had no hyperlipidemia. At the same time, 40 healthy subjects who concurrently underwent health checkups in the same hospital were included as healthy controls. All subjects underwent routine cardiac ultrasound and 3D-STE examinations. General clinical information and left ventricular function-related parameters, including global longitudinal strain, global circumferential strain, global area strain, and global radial strain were compared between healthy controls and T2DM patients with hyperlipidemia and those without hyperlipidemia.Results:The proportion of left ventricular remodeling increased in T2DM patients without hyperlipidemia, and the proportion of left ventricular hypertrophy was the highest in T2DM patients with hyperlipidemia. Global longitudinal strain and global circumferential strain in T2DM patients without hyperlipidemia were (-16.97 ± 2.59)% and (-17.41 ± 2.50)%, respectively, which were significantly higher than (-18.86 ± 2.46)% and (-18.71 ± 2.92)% in healthy controls ( t = 0.95, 0.57, both P < 0.05). Global longitudinal strain, global circumferential strain, and global area strain in T2DM patients with hyperlipidemia were (-14.98 ± 3.15)%, (-15.80 ± 3.16)%, (-27.17 ± 4.54)%, respectively, which were significantly higher than (-18.86 ± 2.46)%, (-18.71 ± 2.92)%, (-30.62 ± 4.02)% in healthy controls ( t = 0.46, 1.37, 0.98, all P < 0.05) and (-16.97 ± 2.59)%, (-17.41 ± 2.50)%, (-30.06 ± 3.59)% in T2DM patients without hyperlipidemia ( t = 0.37, 1.02, 0.77, all P < 0.05). Global radial strain in T2DM patients with hyperlipidemia was significantly higher than [(51.49 ± 8.94)%, t = 1.35, P < 0.05] in healthy controls and [(47.71± 8.46)%, t = 0.98, P < 0.05] in T2DM patients without hyperlipidemia. In patients with T2DM, fasting blood glucose and hyperlipidemia were independently correlated with all strain-related parameters. Conclusion:Hyperlipidemia can aggravate left ventricular remodeling and dysfunction in patients with T2DM and 3D-STE is one of the examination methods for subclinical left ventricular remodeling and dysfunction in T2DM patients with or without hyperlipidemia.

Objective:To understand the current situation of anxiety and depression in patients with atrial fibrillation who are going to undergo radiofrequency ablation and their family members and analyze the influencing factors.Methods:Using the convenient sampling method, a total of 197 patients with atrial fibrillation and their family members who were admitted to Arrhythmia Center of Beijing Anzhen Hospital Affiliated to Capital Medical University and planned to undergo radiofrequency ablation from October to December 2020 were selected as the research objects. The general information questionnaire, Generalized Anxiety Disorder (GAD-7) and Patient Health Questionaire-9 items (PHQ-9) were used to investigate them. Binomial logistic regression analysis was used to investigate the influencing factors of anxiety and depression in patients with atrial fibrillation who were going to undergo radiofrequency ablation and their family members.Results:The PHQ-9 score of 197 patients with atrial fibrillation undergoing radiofrequency ablation was (3.9±3.8) , the GAD-7 score was (2.7±3.1) , the detection rate of depressive symptom was 34.5% (68/197) and the detection rate of anxiety symptom was 20.3% (40/197) . The PHQ-9 score of family members of patients was (1.9±3.0) , the GAD-7 score was (1.8±2.9) , the detection rate of anxiety symptom was 15.2% (30/197) and the detection rate of depressive symptoms was 16.2% (32/197) . Binomial Logistic regression analysis showed that the number of attacks in the past 1 month was greater than or equal to 4 times and the duration of atrial fibrillation episodes in the past 1 month was greater than or equal to 6 hours as the influencing factors of depressive symptoms ( P<0.05) . The number of seizures more than or equal to 4 in the past month was the influencing factor of anxiety symptoms of patients ( P<0.05) . The anxiety state of patients was the influencing factor of anxiety symptoms of family members ( P<0.05) . Conclusions:The current situation of anxiety and depression in patients with atrial fibrillation who are going to undergo radiofrequency ablation and their family members is not optimistic. The recent frequent attack of atrial fibrillation is the influencing factor of anxiety and depression symptoms of patients and the anxiety state of patients is the influencing factor of anxiety symptoms of family members. Medical staff should also pay attention to the anxiety and depression of patients with atrial fibrillation who are going to undergo radiofrequency ablation and their family members and give effective interventions as soon as possible.

Objective:To evaluate the efficacy of sugammadex for the reversal of residual neuromuscular blockade after laparoscopic radical gastrectomy in elderly patients.Methods:Sixty patients of both sexes, aged 65-85 yr, with body mass index of 20-26 kg/m 2, of American Society of Anesthesiologists physical status Ⅰ-Ⅲ, undergoing elective laparoscopic radical gastrectomy under general anesthesia, were divided into 2 groups ( n=30 each) by a random number table method: sugammadex group (S group) and neostigmine group (N group). Rocuronium 0.3-0.6 mg·kg -1·h -1 was intravenously infused during operation, and the muscle relaxation was monitored by a Veryark-TOF monitor, maintaining TOF ratio=0 and counting 1 or 2 after tonic stimulation.Rocuronium was discontinued when the peritoneum was closed.The patients were admitted to the PACU after operation.When the muscle relaxation monitoring T 2 appeared, sugammadex 2 mg/kg was intravenously injected in S group, and neostigmine 0.03 mg/kg plus atropine 0.015 mg/kg was intravenously injected in N group.The tracheal tube was removed after the patient′s consciousness and spontaneous breathing recovered.Before anesthesia (T 1) and 5 and 30 min after tracheal extubation (T 2, 3), arterial blood samples were collected for blood gas analysis, PaO 2 and PaCO 2 were recorded, and ultrasound was used to measure the diaphragm end-inspiratory thickness, end-expiratory thickness and mobility of diaphragm muscle at the above time points.The diaphragm thickening fraction was calculated.The time of T 2 appeared, time of extubation, time of postanesthesia care unit (PACU) stay, postoperative hospital stay, and residual neuromuscular blockade (TOF ratio <0.9) and hypoxemia occurred within 30 min after extubation were recorded.The pulmonary complications within 7 days after operation were recorded. Results:Compared with group N, PaO 2 was significantly increased and PaCO 2 was decreased at T 2, 3, the mobility of diaphragm muscle and diaphragm thickening fraction were increased at T 2, the tracheal extubation time, time of PACU stay and postoperative hospital stay were shortened, the residual neuromuscular blockade and hypoxemia occurred after extubation and incidence of pulmonary complications after operation were decreased ( P<0.05), and no significant change was found in the time of T 2 appeared in group S ( P>0.05). Conclusion:Sugammadex can quickly and effectively reverse the residual neuromuscular blockade after laparoscopic radical gastrectomy, which is helpful for early postoperative recovery in elderly patients.