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 diagnostic value of histopathological examination of ultrasound-guided puncture biopsy samples in extrapulmonary tuberculosis(EPTB). Methods This study was conducted at the Shanghai Public Health Clinical Center.A total of 115 patients underwent ultrasound-guided puncture biopsy,followed by MGIT 960 culture(culture),smear,GeneXpert MTB/RIF(Xpert),and histopathological examination.These assays were performed to evaluate their effectiveness in diagnosing EPTB in comparison to two different diagnostic criteria:liquid culture and composite reference standard(CRS). Results When CRS was used as the reference standard,the sensitivity and specificity of culture,smear,Xpert,and histopathological examination were(44.83%,89.29%),(51.72%,89.29%),(70.11%,96.43%),and(85.06%,82.14%),respectively.Based on liquid culture tests,the sensitivity and specificity of smear,Xpert,and pathological examination were(66.67%,72.60%),(83.33%,63.01%),and(92.86%,45.21%),respectively.Histopathological examination showed the highest sensitivity but lowest specificity.Further,we found that the combination of Xpert and histopathological examination showed a sensitivity of 90.80%and a specificity of 89.29%. Conclusion Ultrasound-guided puncture sampling is safe and effective for the diagnosis of EPTB.Compared with culture,smear,and Xpert,histopathological examination showed higher sensitivity but lower specificity.The combination of histopathology with Xpert showed the best performance characteristics.

68Ga-DOTATATE/18F-FDG two-day low-dose total-body PET/CT imaging is increasingly employed to facilitate the diagnosis,prognosis,and heterogeneity assessment of neuroendocrine neoplasms.We present a consensus on operational guideline for a two-day combined imaging from experts in low-dose/ultra-low-dose total-body PET/CT from several domestic medical institutions.

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure.Methods Thirty patients undergoing cardiac transcathe-ter closure under elective intravenous anesthesia were included in this study.Paired t-tests were performed to com-pare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and mus-cle ARNT-1 like protein-1(BMAL1),cryptochrome1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score be-fore and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery.Results The postoperative mRNA level of CLOCK was higher[1.38±1.23 vs.1.90±1.47;MD(95％CI):0.52(0.20-0.84),t=3.327,P=0.002]and the postoperative mRNA levels of CRY1[1.56±1.50 vs.1.13±0.98;MD(95％CI):-0.43(-0.81--0.05),t=-2.319,P=0.028]and PER2[0.82±0.63 vs.0.50±0.31;MD(95％CI):-0.33(-0.53--0.12),t=-3.202,P=0.003]were lower than the preoperative levels.One week after surgery,the pa-tients presented advanced sleep chronotype[3:03±0:59 vs.2:42±0:37;MD(95％CI):-21(-40--1),t=-2.172,P=0.038],shortened sleep latency[(67±64)min vs.(37±21)min;MD(95％CI):-30.33(-55.28--5.39),t=-2.487,P=0.019],lengthened sleep duration[(436±83)min vs.(499±83)min;MD(95％CI):62.80(26.93-98.67),t=3.581,P=0.001],increased sleep efficiency[(87.59±10.35)％vs.(92.98±4.27)％;MD(95％CI):5.39(1.21-9.58),t=2.636,P=0.013],decreased sleep quality score[1.13±0.78 vs.0.80±0.71;MD(95％CI):-0.33(-0.62--0.05),t=-2.408,P=0.023],and declined PSQI total score[6.60±3.17 vs.4.03±2.58;MD(95％CI):-2.57(-3.87--1.27),t=-4.039,P＜0.001].Body mass index(BMI)(B=-227.460,SE=95.475,t=-2.382,P=0.025),anesthesia duration(B=-47.079,SE=18.506,t=-2.544,P=0.017),and mRNA level of PER2(B=2815.804,SE=1080.183,t=2.607,P=0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine(B=0.067,SE=0.028,t=2.385,P=0.024)independently influenced the PSQI one week after surgery.Conclusions Total intravenous anesthe-sia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Type B insulin resistance syndrome(TBIR)is a rare autoimmune disease caused by the presence of autoantibodies against insulin receptors in the human body,leading to severe refractory hyperglycemia or refractory hypoglycemia.This article reports a case of TBIR patient,summarizes and analyzes its epidemiological characteristics and diagnosis and treatment methods,providing a basis for clinical treatment.

Objective To construct SpyCatcher-mi3 nanoparticle vaccine delivery vectors,evaluate their role in enhancing the immunogenicity of the ovalbumin CD8+T-cell epitope peptide,OVA257-264,and determine its protective effect in a model which mice were immunized and subcutaneously challenged with E.G7-OVA tumor cells.Methods SpyCatcher-mi3 proteins were expressed by E.coli and purified by affinity chromatography and anion exchange chromatography sequentially.OVA257-264-SpyTag peptide was obtained by synthesis.The OVA257-264-mi3 nanoparticles were produced by the SpyTag/SpyCatcher system.The toxicity of OVA257-264-mi3 was evaluated using hemolysis assay,CCK-8 assay and mouse experiment.A total of 42 female SPF-grade C57BL/6 mice(6～8 weeks old,18～20 g)were randomly divided into OVA257-264-mi3,OVA257-264,and control groups,with 14 mice in each group.Then the mice in each group were immunized on days 0,14 and 28.In 14 d after the last immunization,the amounts of spot-forming cells(SFCs,indicating IFN-γ secreting cells in splenic lymphocytes)were determined using ELISpot assay to evaluate their immunogenicity.After the immunized mice were subcutaneously implanted with E.G7-OVA tumor cells,the antitumor effect of the vaccine in prophylactic xenograft tumor model was evaluate by observing tumor volumes with a caliper and tumor growth with MRI.Results Both SpyCatcher-mi3 and OVA257-264-mi3 could be self-assembled to form homogeneous and stable nanoparticles,with an average particle size of about 43.8 and 91.3 nm,respectively.The OVA257-264-mi3 was safe for in vitro and in vivo toxicity evaluation.The number of IFN--y secreting cells per 1 × 106 splenic lymphocytes reached 253 in the OVA257-264-mi3 group of mice,significantly higher than that in the OVA257-264 group and the Control group(P＜0.05).The tumor volume of mice in the OVA257-264-mi3 group was about 151.1 mm3 on day 22,which was significantly smaller than that of the OVA257-264 group and the Control group(P＜0.05),and the survival rate during the observation period reached 60％,which was significantly higher than that of the OVA257-264 groups(P＜0.05).Conclusion Nanoparticle vaccine OVA257-264-mi3 is successfully constructed,and it shows enhancing effect on the immunogenicity of the antigen epitope peptide,and exerts protective effect on prophylactic xenograft tumor model,providing a theoretical basis for the research of tumor neoantigen vaccines.

Objective To investigate the correlation between lipid-related index and diabetic kidney disease(DKD)by observing the expression levels of lipid-related index in different stages of DKD.Methods A total of 265 patients with type 2 diabetes mellitus(T2DM)were divided into the T2DM group(n=106)and the DKD group(n=159).According to estimated glomerular filtration rate(eGFR)level,the DKD group was sub-divided into the DKD-G2 group(n=59),the DKD-G3 group(n=59)and the DKD-G4 group(n=41).Data of triglycerides(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),apolipoprotein A(Apo A),Apo B and urinary albumin/urinary creatinine ratio(UACR)were collected.Gomerular filtration rate(eGFR),triglyceride-glucose index(TyG),visceral adiposity index(VAI)and atherogenic index of plasma(AIP)were calculated.The differences of TyG,VAI and AIP between different groups and their correlation with eGFR and UACR were analyzed.Multiple linear regression analysis of DKD renal injury factors was conducted.Receiver operating characteristic(ROC)curves were drawn to evaluate the predictive efficiency of TyG,VAI,and AIP.Results The levels of TyG,VAI and AIP were significantly higher in the DKD group compared to the T2DM group,and these indices exhibited an increasing trend with disease progression(P＜0.05).Furthermore,there was a negative correlation between TyG,VAI,AIP and eGFR(r=-0.396,-0.425,-0.519,P＜0.01),and a positive correlation between UACR and eGFR(r=0.482,0.479 and 0.583,P＜0.01)in DKD patients.Multiple linear regression results showed that VAI and AIP were independent risk factors for eGFR,and TG,HDL-C,LDL-C,Apo B and VAI were influencing factors of UACR(P＜0.05).The ROC curve analysis revealed that the areas under the curves for TyG,VAI and AIP were 0.902(0.866-0.937),0.969(0.953-0.986)and 0.958(0.937-0.979)respectively.Conclusion The levels of TyG,VAI and AIP are correlated with the progression of DKD,and have predictive value for the occurrence and development of DKD.These biomarkers can be used as a biological indicator to evaluate the occurrence and development of DKD.

Objective:To investigate the clinical application value of the new tracer mitoxantrone hydrochloride in imaging of cervical lymph nodes and identifying of parathyroid, recurrent laryngeal nerve during thyroid cancer radical surgery.Methods:A prospective controlled study was conducted between January 2022 and April 2024 at Tianjin First Central Hospital, recruiting 180 patients with thyroid cancer, including 54 males and 126 females, aged from 26 to 69 years. The patients were randomly divided into three groups: the mitoxantrone hydrochloride lymph node tracing group (MHI group), the nanocarbon lymph node tracing group (nanocarbon group), and the control group without lymph node tracers, with 60 cases in each group. All patients underwent total thyroid resection and regional lymph node dissection. The number of detected lymph nodes and positive metastatic lymph nodes and surgical field clarity scores and the identification rate of parathyroid glands and the instances of inadvertent excision were compared between the groups. Serum calcium and parathyroid hormone (PTH) levels at different perioperative time points and treatment-related complications were analyzed. One-way ANOVA, chi-square test and two independent sample non-parametric tests, were employed for statistical analyses.Results:The mean operation time, neck drainage volume and hospital stay in the MHI group and the nanocarbon group were respectively significantly lower than those in the control group ( P<0.05). The mean staining intensity score, tracer success rate and surgical field clarity score in MHI group were respectively significantly higher than those in nanocarbon group ( P<0.05). The mean numbers of dissected lymph nodes positive metastatic nodes and identification rates of parathyroid glands in MHI group were respectively significantly higher than those in both the nanocarbon and control groups ( P<0.05). The rates of inadvertent parathyroid excision in both MHI group and nanocarbon group were significantly lower than those in control group ( P<0.05). On postoperative day 1 and day 5, mean serum calcium and PTH levels in MHI group were respectively significantly higher than those in nanocarbon group and control groups. However, on postoperative day 1, there was no difference in mean serum calcium levels between the nanocarbon group and the control group ( P>0.05), though PTH level in the nanocarbon group was higher than that in the control group. By postoperative day 5, both serum calcium and PTH levels were higher in the nanocarbon group compared to the control group ( P<0.05). On postoperative days 30, there were no differences in serum calcium and PTH levels between the MHI group and the nanocarbon group ( P>0.05). The risks of facial numbness, hand and foot tetany and choking during drinking were lower in both the MHI and nanocarbon groups compared to the control group ( P<0.05). Conclusion:MHI demonstrates advantages in rapid targeted delivery and clear staining of the surgical field during regional lymph node dissection in radical thyroidectomy for thyroid cancer, effectively reducing the risk of collateral damage to the recurrent laryngeal nerve and parathyroid glands.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

Objective:This study aimed to explore the clinical value of myostatin(MST) and follistatin(FST) as biological biomarkers in evaluating sarcopenia in elderly women.Methods:This was a retrospective cross-sectional study that enrolled 350 females aged 20-89 years who underwent physical examinations in Shanghai Huadong Hospital in 2021. Demographic characteristics, muscle mass, fat mass, bone mineral density, hand grip strength, gait speed, and serum indices of MST and FST were collected.Results:The serum levels of MST did not change significantly with age. However, the serum levels of FST increased with age. In women aged≥60 years, MST was positively correlated with total lean mass and appendicular skeletal muscle index(ASMI; r=0.236, P=0.041; r=0.289, P=0.014), while FST was negatively correlated with ASMI( r=-0.265, P=0.030). In multivariate stepwise regression analysis, after adjusting for age, body mass index, hip bone mineral density, and total fat mass, only FST was independently correlated with ASMI( β=-0.238, P=0.006), while MST was not correlated with ASMI. The receiver operating characteristic curve was plotted using muscle mass reduction as the state variable and serum FST level as the test variable. The area under the curve was 0.753. And when the FST cutoff value was 17.49 ng/mL, the maximum Jordan index was 0.46, with a sensitivity of 77.3% and a specificity of 68.7%. Women aged ≥60 years were divided into three groups based on serum FST levels. Compared to the upper third of the serum FST level group, the low third of the FST level group had a significantly reduced risk of suffering from sarcopenia( OR=0.098, P =0.036). Conclusions:Serum FST lever has a better correlation with muscle mass among elderly women, making it a promising biomarker for evaluating muscle mass.