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.

Objective:To evaluate the interaction between remimazolam and propofol for sedation during hysteroscopy.Methods:American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ patients, aged 20-45 yr, with body mass index of 18-28 kg/m 2, scheduled for elective hysteroscopy, were included. The test was conducted in two steps. Up-and-down sequential allocation was used to determine the median effective dose (ED 50) of remimazolam (group A) and propofol (group B). The ED 50 obtained in A and B groups were then used as the standard to determine the combination regimen in group C (0.25×ED 50 of remimazolam+ 0.75×ED 50 of propofol as the initial dose), in group D (0.5×ED 50 of remimazolam+ 0.5×ED 50 of propofol as the initial dose), and in group E (0.75×ED 50 of remimazolam+ 0.25×ED 50 of propofol as the initial dose). Up-and-down sequential allocation was used to determine the ED 50 of propofol when propofol and remimazolam were combined in C, D and E groups. The interaction between the sedative effects of two drugs was analyzed using the isobolographic analysis method, and the interaction coefficient and synergistic dose ratio of two drugs were calculated. Results:The ED 50 of remimazolam was 0.180 mg/kg in group A, and the ED 50 of propofol was 1.167 mg/kg in group B. The results of isobolographic analysis showed that remimazolam and propofol had a synergistic effect. When remimazolam 0.045, 0.090 and 0.135 mg/kg were combined with propofol 0.546, 0.288 and 0.160 mg/kg, the interaction coefficients were 1.393, 1.339 and 1.127 respectively. The synergistic dosage ratio of remimazolam and propofol was 1.0∶(3.2 to 12.0). Conclusions:Remimazolam and propofol have a synergistic effect on sedation when used for hysteroscopy, and the dose ratio is 1.0∶(3.2-12.0).

Objective:To evaluate the efficacy of esketamine combined with different doses of remimazolam for induction of general anesthesia in pediatric patients.Methods:One hundred and sixty pediatric patients of either sex, aged 3-6 yr, of American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ, with body mass index of 13-20 kg/m 2, undergoing elective general anesthesia under a laryngeal mask, were divided into 4 groups ( n=40 each) by the random number table method: esketamine combined with propofol group (KP group) and esketamine combined with different doses of remimazolam group (0.2, 0.3, 0.4 mg/kg) groups (KR1 group, KR2 group, KR3 group). Esketamine 0.8 mg/kg was intravenously injected in the preanesthesia room. After entering the operating room, propofol 2.5 mg/kg was intravenously injected in KP group, and remimazolam 0.2, 0.3 and 0.4 mg/kg were intravenously injected in KR1, KR2 and KR3 groups, respectively. When the child lost consciousness and the Modified Observer′s Assessment of Alertness/Sedation Scale score<1, sufentanil and mevacurium were intravenously injected. When the Modified Observer′s Assessment of Alertness/Sedation Scale score≥1, rescue sedation was performed, and 3 min later the laryngeal mask airway was inserted. The onset time of sedation, response to laryngeal mask airway placement, rescue sedation, hypotension, tachycardia, bradycardia, bucking, hiccup, injection pain and apnea were recorded, and the increase rate of perfusion index (PI) was calculated. Results:No response to laryngeal mask implantation occurred in the four groups. Compared with KP group, the onset time of sedation was significantly prolonged, the incidence of hypotension, bradycardia, injection pain and apnea was decreased, the incidence of tachycardia was increased, and the increase rate of PI was decreased in KR1, KR2 and KR3 groups, and the rate of rescue sedation and incidence of bucking were increased in KR1 and KR2 groups ( P<0.05). Compared with KR1 group, the onset time of sedation was significantly shortened in KR2 group and KR3 group, and the rate of rescue sedation and incidence of bucking were decreased in KR3 group ( P<0.05). Compared with KR2 group, the onset time of sedation was significantly shortened, and the rate of rescue sedation was decreased in KR3 group ( P<0.05). There was no significant difference in the increase rate of PI, hypotension, bradycardia, tachycardia, injection pain and apnea among KR1, KR2 and KR3 groups ( P>0.05). There was no significant difference in the incidence of hiccup among the four groups ( P>0.05). Conclusions:Esketamine 0.8 mg/kg combined with remimazolam 0.4 mg/kg can be safely and effectively used for anesthesia induction and has milder inhibition of respiration and circulation as compared with esketamine combined with propofol in pediatric patients.

Objective:To evaluate the accuracy of continuous photoplethysmography algorithms for atrial fibrillation diagnosis and atrial fibrillation burden evaluation via wearable devices.Methods:This study was a self-controlled prospective cohort study. A total of 254 consecutive inpatients were recruited from the Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University from September 2022 to November 2022. All participants were required to wear two devices at the same time: (1) an electrocardiogram (ECG) watch for acquisition of photoplethysmography (watch-recorded-photoplethysmography, W-PPG) and electrocardiogram (watch-recorded-electrocardiogram, W-ECG); (2) an ECG patch for acquisition of electrocardiogram (patch-recorded-electrocardiogram, P-ECG). The results were measured in 30 s data segments and individual participants, separately, which were calculated for sensitivity and specificity by comparing them with the results of expert-read ECG according to the receiver operating characteristic curve. Four groups were separated according to the proportion of the atrial fibrillation burden, and the difference of atrial fibrillation burden from algorithm and expert-read ECG was calculated.Results:All 254 subjects completed the study. The mean age of participants was (63.04±11.04) years old, 99 (38.98%) of them were female, and 97 (38.19%) patients had persistent atrial fibrillation. Expert-read ECG results were taken as standard criteria in all calculations. The P-ECG algorithm had a sensitivity of 94.86% (95% CI: 94.81%-94.91%) and a specificity of 99.30% (95% CI: 99.28%-99.31%) when measured in data segments. The W-PPG algorithm had a sensitivity of 96.07% (95% CI: 95.97%-96.18%) and a specificity of 98.62% (95% CI: 98.59%-98.65%). When measured in terms of individual participants, the P-ECG algorithm had a sensitivity of 92.55% (95% CI: 87.57%-95.71%) and a specificity of 96.39% (95% CI: 93.45%-98.09%), while the W-PPG algorithm had a sensitivity of 93.71% (95% CI: 88.75%-96.67%) and a specificity of 89.62% (95% CI: 85.61%-92.65%). When measured in terms of a single acquisition of W-ECG records, the W-ECG algorithm had a sensitivity of 92.04% (95% CI: 88.14%-94.78%) and a specificity of 96.19% (95% CI: 94.35%-97.47%). For atrial fibrillation burden assessment, the difference between the W-PPG analysis results and the expert-read ECG results was less than 2% in all burden distribution intervals. Conclusions:Continuous photoplethysmography algorithm applied to wearable devices to detect atrial fibrillation is a feasible strategy. Taking expert-read ECG results as standard, continuous monitoring of PPG by a smartwatch is highly accurate for atrial fibrillation diagnosis and can also be used to effectively complete atrial fibrillation burden assessment.

Objective:To explore the role of mechanical hemodynamic support (MHS) in mapping and catheter ablation of patients with hemodynamically unstable ventricular tachycardia (VT), report single-center experience in a cohort of consecutive patients receiving VT ablation during MHS therapy, and provide evidence-based medical evidence for clinical practice.Methods:This was a retrospective cohort study. Patients with hemodynamically unstable VT who underwent catheter ablation with MHS at Beijing Anzhen Hospital, Capital Medical University between August 2021 and December 2023 were included. Patients were divided into rescue group and preventive group according to the purpose of treatment. Their demographic data, periprocedural details, and clinical outcomes were collected and analyzed.Results:A total of 15 patients with hemodynamically unstable VT were included (8 patients in the rescue group and 7 patients in the preventive group). The acute procedure was successful in all patients. One patient in the rescue group had surgical left ventricular assist device (LVAD) implantation, remaining 14 patients received extracorporeal membrane oxygenation (ECMO) for circulation support. ECMO decannulation was performed in 12 patients due to clinical and hemodynamic stability, of which 6 patients were decannulation immediately after surgery and the remaining patients were decannulation at 2.0 (2.5) d after surgery. Two patients in the rescue group died during the index admission due to refractory heart failure and cerebral hemorrhage. During a median follow-up of 30 d (1 d to 12 months), one patient with LVAD had one episode of ventricular fibrillation at 6 months after discharge, and no further episodes of ventricular fibrillation and/or VT occurred after treatment with antiarrhythmic drugs. No malignant ventricular arrhythmia occurred in the remaining 12 patients who were followed up.Conclusions:MHS contributes to the successful completion of mapping and catheter ablation in patients with hemodynamically unstable VT, providing desirable hemodynamic status for emergency and elective conditions.

Objective To optimize the extraction process of flavonoids from Plantago asiatica L.rich in plantagoside by response surface methodology,and to explore the protective effect and mechanism of plantain flavonoids on H2O2-damaged L02 cells.Methods The effects of various parameters,including ethanol concentration,extraction temperature and the liquid-solid ratio on the yield of flavonoids from P.asiatica and the transfer rate of plantagoside were studied by single factor experiment.The central composite design(CCD)and response surface methodology(RSM)were employed on this basic to screen the optimized extraction conditions,which yielded the highest extraction rate of flavonoids from P.asiatica and the maximum transfer rate of plantagoside.The protective effect of flavonoids from P.asiatica on H2O2-damaged L02 cells was assessed through the analysis of cell survival rate,apoptosis rate,mitochondrial membrane potential,malondialdehyde(MDA)and glutathione(GSH)levels,oxide dismutase(SOD)concentration,and the expression levels of HO-1,Nrf2,and SOD proteins.Results The results showed that the highest yield of extraction rate of flavonoids from P.asiatica(1.82％)and the maximum transfer rate of plantagoside(35.01％)were achieved under the optimized extraction condition:extraction temperature of 80 ℃,ethanol concentration of 65％and liquid-solid ratio of 15:1.Flavonoids from P.asiatica extracted under these parameters significantly reduced the apoptosis rate(P<0.001)and the degree of mitochondrial membrane potential damage(P<0.001),increased the expressions of SOD and GSH(P<0.001),and reduced the MDA level(P<0.01,P<0.001)in H2O2-damaged L02 cells at concentrations ranging from 25 to 100 μg·mL-1.In addition,100 μg·mL-1 flavonoids from P.asiatica were found to regulate the expressions of HO-1,Nrf2 and SOD in H2O2-damaged L02 cells.These flavonoids decrease the expressions of HO-1 and Nrf2 proteins,while enhance the expression of SOD protein in H2O2-damaged L02 cells(P<0.05,P<0.01).Conclusion The extraction process for flavonoids from P.asiatica,which was optimized using the response surface method,is operationally simple and yields a high transfer rate of the key active component,plantagoside.This approach offers valuable insights for the actual production of flavonoids from P.asiatica.Besides,flavonoids from P.asiatica could reduce oxidative stress level in H2O2-damaged liver cells,which exhibited a certain protective effect on L02 cells against oxidative damage.This study provides a foundational basis for the development and application of flavonoids from P.asiatica as liver-protective health supplements.

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.

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.

AIM:To investigate the effects of ginkgetin on neurological deficit and angiogenesis induced by cerebral ischemia/reperfusion(I/R)and its underlying mechanism.METHODS:Sixty SD rats were randomly allocated into three groups:sham group,I/R model group,and ginkgetin(40 mg/kg)treatment(I/R+ginkgetin)group,with twenty rats in each group.The middle cerebral artery occlusion/reperfusion(MCAO/R)rat model was employed to simulate cere-bral I/R,and ginkgetin was administered continuously for 7 days following reperfusion.The cerebral infarction volume was quantified using TTC staining.Neuronal density in the ischemic penumbra was assessed through Nissl staining and immu-nohistochemistry for neuron-specific nuclear protein(NeuN).Microvessel density and angiogenesis in the ischemic pen-umbra of each group were analyzed using CD31 labeling and BrdU/von willebrand factor(vWF)double labeling immuno-fluorescence staining.Western blot analysis was performed to determine the levels of heat shock protein 70(HSP70),vas-cular endothelial growth factor(VEGF),and hypoxia inducible factor-1α(HIF-1α)in the ischemic penumbra.RE-SULTS:Compared with the I/R model group,the cerebral infarction volume was significantly reduced in ginkgetin treat-ment group(P<0.01),the number of neurons,the microvessel density,angiogenesis and the expression levels of HIF-1α,VEGF,and HSP70 in the ischemic penumbra were significantly increased(P<0.01).CONCLUSION:Ginkgetin exhibits the potential to augment angiogenesis and facilitate neurological function recovery in MCAO rats,while concur-rently upregulating the expression of HSP70,VEGF,and HIF-1α within the ischemic penumbra.

As a new clinical trial mode,decentralized & digitalized clinical trial(DCT)is based on digital health equipment and uses internet and artificial intelligence technologies to complete the screening,registration,randomization,intervention,evaluation and follow-up of subjects,which is helpful to improve efficiency and reduce trial costs.The DCT mode has been applied to evaluate the treatment and management effects of cardiovascular diseases such as atrial fibrilla-tion,heart failure,coronary heart disease,and hypertension,showing broad development prospects and application space.This article will provide a brief introduction to representative DCT in the global cardiovascular disease field,and look for-ward to the application prospects of this model,providing reference and guidance for accelerating the development of cardio-vascular DCT in China.