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 explore the association between the G71R polymorphism of the UGT1A1 gene and neonatal hyperbilirubinemia. Methods:DNA was extracted from blood samples of 61 neonates with severe neonatal hyperbilirubinemia(severe neonatal hyperbilirubinemia group), 60 neonates with hyperbilirubinemia(hyperbilirubinemia group) and 62 healthy neonates(control group), the G71R mutation of UGT1A1 gene was analyzed by direct sequencing. Results:In severe neonatal hyperbilirubinemia group, there were 17 cases of homozygous mutation(A/A), 23 cases of heterozygous mutation(A/G) , and 21 cases of wild type(G/G) , with 28.87% homozygous mutation rate and 37.70% heterozygous mutation rate.In neonatal hyperbilirubinemia group, there were ten cases of homozygous mutation(A/A), 28 cases of heterozygous mutation(A/G) and 22 cases of wild type(G/G), with 16.67% homozygous mutation rate and 46.67% heterozygous mutation rate.In the control group, there were nine cases of homozygous mutation (A/A), 28 cases of heterozygous mutation(A/G) and 25 cases of wild type(G/G), among which the homozygous mutation rate was 14.52% and the heterozygous mutation rate was 45.16%.The genotype frequency( χ2=4.14, P=0.38)and allele frequency( χ2=2.47, P=0.29)of G71R in severe neonatal hyperbilirubinemia group, neonatal hyperbilirubinemia group and control group were not statistically significant. Conclusion:The G71R polymorphism of the UGT1A1 gene may not be significantly correlated with the prevalence of neonatal hyperbilirubinemia.

Objective:To investigate the prevalence of depression symptoms in residents, and to analyze the demographic characteristics, training status and psychological influencing factors in order to provide the evidence for the mental health management and intervention of residents in China at current stage.Methods:A total of 1 050 participants from eight different training centers in Shenyang, Dalian, Jinzhou and Fushun of Liaoning Province were investigated by Pittsburgh sleep quality index, International physical activity questionnaire, Survey of perceived organizational support, Psychological capital questionnaire and Minnesota satisfaction questionnaire, which covered questions including social demographic information, training information, sleep status, physical activity, organization support, psychological capital, job satisfaction and depressive symptoms of residents. SPSS 22.0 were used to carry out statistical analysis such as logistic regression.Results:A total of 962 valid questionnaires were collected and the results showed that 44.59% (429/962) of residents had depressive symptoms. High training grade ( ORPGY-3=1.775, P=0.006) and poor quality of sleep ( OR=1.662, P<0.001) were risk factors of depressive symptoms, whereas psychological capital ( OR=0.962, P<0.001) and job satisfaction ( OR=0.972, P=0.001) were protective factors of depressive symptoms. Conclusion:The prevalence of depressive symptoms is high in residents. Training grade, sleep quality, psychological capital and job satisfaction are closely associated with the high prevalence of depressive symptoms, which should be paid more attention to.

Objective:To explore the feasibility of sirolimus as an alternative graft versus host disease (GVHD) prophylaxis in patients with kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Retrospective case series study. Medical records of 11 patients in Peking University People′s Hospital from 1 August 2008 to 31 October 2022, who received sirolimus instead of cyclosporine to prevent GVHD, due to renal insufficiency after allo-HSCT, were analyzed retrospectively. Incidence of GVHD, infection, and transplant-associated thrombotic microangiopathy (TA-TMA), as well as renal function, were evaluated.Results:Among the 11 patients who received sirolimus, 6 were treated with haploidentical donor HSCT, and 5 were treated using matched sibling donor HSCT. The median (range) time of sirolimus administration was 30 (7-167) days after allo-HSCT, and the median (range) sirolimus course duration was 52 (9-120) days. During sirolimus treatment, 1 case did not undergo combined treatment with other prophylactic drugs, 3 cases received combined mycophenolate mofetil (MMF), and 1 case underwent combined CD25 monoclonal antibody treatment, while 6 cases had combined therapy with both MMF and CD25 monoclonal antibody. Of the 11 patients, 2 developed Grade Ⅲ acute GVHD, 1 developed severe pneumonia and died, and 1 developed TA-TMA, while nine patients had normal or improved renal function. Median (range) follow-up time was 130 (54-819) days. Non-relapse mortality was observed in 1 patient. Relapse mortality was also observed in 1 patient.Conclusion:Sirolimus-based alternative GVHD prophylaxis is a potentially viable option for patients undergoing allo-HSCT who cannot tolerate cyclosporine, but its efficacy and safety require further optimization and verification in prospective studies.

OBJECTIVE To investigate the mechanism of Fuke duanhongyin capsule in improving dysfunctional uterine bleeding （DUB） in rats. METHODS Pregnant SD rats were randomly divided into blank control group （distilled water）， model control group （distilled water） and Fuke duanghongyin capsule group （1.296 g/kg）， with 6 rats in each group. Except for blank control group， DUB model was established in other groups. After modeling， they were given relevant medicine/distilled water 10 mL/kg intragastrically， once a day， for consecutive 14 d. After medication， uterine index， ovary index and hemorheology indexes （whole blood high shear relative index， whole blood low shear relative index， erythrocyte aggregation index， Carson viscosity） of rats were all determined. The pathological changes of uterus and ovary tissues were observed； mRNA relative expression levels of epidermal growth factor （EGF）， hypoxia-inducible factor 1α （HIF-1α）， epidermal growth factor receptor （EGFR） and serine/ threonine-protein kinase 1（AKT1）， and protein relative expression levels of EGF and EGFR in uterine tissue were all measured. RESULTS Compared with model control group， the uterine index， ovary index， erythrocyte aggregation index were all decreased significantly in Fuke duanghongyin capsule group （P＜0.05 or P＜0.01）； whole blood high shear relative indexes， mRNA relative expression levels of EGF， HIF-1α and EGFR and protein relative expression levels of EGF and EGFR in uterine tissue were all increased significantly （P＜0.05 or P＜0.01）. The pathological changes of ovary and uterus were improved. CONCLUSIONS Fuke duanhongyin capsule can improve DUB in rat， the mechanism of which may be related to the activation of EGF-EGFR signaling pathway.

Bonding of brackets to dental fluorosis has always been a difficult problem for clinicians. At present, clinical research has adopted several methods to facilitate bracket bonding, including prolonging etching time, enamel microabrasion, enamel ground, using adhesion promoter and laser etching. Prolonging etching time is suitable for mild-to-moderate dental fluorosis with easy chair-side operation; however, over-etching may cause severe tooth damage. Microabrasion can be applied to mild dental fluorosis while removing pigment deposition simultaneously; however, rubber dam protection is needed. Enamel ground can improve the bond strength to all kinds of dental fluorosis at the price of removing a relatively large amount of superficial enamel. Adhesion promoters might improve the bond strength of moderate to severe dental fluorosis; however, the current results conflict with one another. This needs further verification using larger-sample clinical trials. Laser etching has no effect on improving bond strength; however, it can remove pigment without destroying tooth enamel, which is worth further modification and enhancement.

Objective:To compare the effects of two different surgical methods (endovascular embolization and microsurgical craniotomy) on hemodynamics and quality of life in patients with anterior circulation aneurysms.Methods:From January 2014 to December 2018, 63 patients with anterior circulation aneurysms in Linfen Central Hospital were divided into group A (micro craniotomy) 30 cases and group B (intravascular embolization) 33 cases according to the different operation method.The changes of heart rate, systolic blood pressure, diastolic blood pressure, cardiac output, cardiac output per stroke and cardiac output index were compared between the two groups before operation (T0), during operation (T1), after operation (T2) and 24 hours after operation (T3). The quality of life of the patients was evaluated by the MOS 36-item short-form health status survey (SF-36) at the time of discharge from hospital, and the prognosis of the patients at three months after operation was evaluated by Glasgow outcome score (GOS). The quality of life and complications were evaluated by the ability of daily living and the modified Barthel index.Results:Compared with group A, group B showed a significant increase in cardiac output index[(2.86±0.63)L·min -1·(m 2) -1 vs.(3.39±0.83)L·min -1·(m 2) -1], a significant decrease in heart rate[(90±15)times/min vs.(79±9)times/min], systolic blood pressure[(132±18)mmHg vs.(123±9)mmHg], diastolic blood pressure[(96±13)mmHg vs.(89±12)mmHg] and cardiac output per stroke[(88.64±18.53)mL vs.(78.54±13.35)mL] at T1 ( t=2.50, 3.61, 2.89, 2.63, 3.02, all P< 0.05). Compared with group A, group B showed a significant decrease in heart rate[(86±12)times/min vs.(75±11)times/min], systolic blood pressure[(134±20)mmHg vs.(122±11)mmHg] and diastolic blood pressure[(93±11)mmHg vs.(77±14)mmHg] at T2, and a significant decrease in systolic blood pressure[(128±13)mmHg vs.(113±14)mmHg] and diastolic blood pressure[(85±9)mmHg vs.(78±13)mmHg] at T3 ( t=2.68, 3.14, 3.95, 4.15, 3.05, all P<0.05). The scores of energy[(55.07±8.76)points], physiological function[(53.65±8.62)points], physiological function[(62.25±9.53)points], mental health[(72.26±13.95)points], emotional function[(61.89±12.25)points] and overall health[(47.63±8.61)points] in SF-36 scale in group B were significantly higher than those in group A[(45.86±7.62)points, (49.21±9.76)points, (43.58±8.75)points, (50.14±10.33)points, (44.76±9.42)points, (35.86±7.60)points]( t=4.43, 2.35, 8.07, 7.09, 6.18, 5.73, all P< 0.05). There was no statistically significant difference in GOS score at three months after operation between the two groups ( P>0.05). After 2 years of follow-up, the scores of activities of daily living[(86.89±4.54)points] and modified Barthel index[(1.34±0.42)points] in group B were significantly lower than those in group A[(92.48±6.09)points, (2.79±0.61)points]( t=4.15, 11.07, all P<0.01). There was no statistically significant difference in the incidence of complications between the two groups ( P>0.05). Conclusion:For the patients with anterior circulation aneurysms, the therapeutic effect of microsurgical craniotomy and endovascular embolization is the same, but the latter can stabilize the hemodynamic state of the patients during the operation, and the short-term prognosis is better at discharge, but the long-term prognosis may be worse than that of microsurgical craniotomy.

BACKGROUND: SureFil SDR as a lining material has better adaptability and unique automatic leveling characteristics as compared with other flowing resins, but its application in preventive resin filling has not been reported. OBJECTIVE: To compare the roughness and bacterial adhesion among pit and fissure sealant, Z350 XT fluid resin and SureFil SDR resin, and to explore the feasibility of preventive resin filling with SureFil SDR resin. METHODS: Pit and fissure sealant, Z350 XT fluid resin and SureFil SDR resin were prepared into 8 mm× 2 mm× 2 mm cuboid specimens respectively. The surface roughness of the three specimens was measured by MarSurf roughness meter. Pit and fissure sealant, Z350 XT fluid resin and SureFil SDR resin were prepared into 8 mm× 8 mm× 2 mm cylinder specimens respectively. The specimens were cultured in Streptococcus mutans suspension for 48 hours to detect the bacterial adhesion on the material surface. RESULTS AND CONCLUSION: The roughness of the three materials was ranked as follows: SureFil SDR resin < Z350 XT fluid resin < pit and fissure sealant, and there were significant differences between groups (P < 0.05). The bacterial adhesion on the surface of the three materials was ranked as follows: SureFil SDR resin < Z350 XT fluid resin < pit and fissure sealant, and there were significant difference between groups (P < 0.05). The correlation between roughness and bacterial adhesion was analyzed, and there was a high positive correlation between roughness and bacterial adhesion, indicating, with the decrease of material roughness, bacterial adhesion decreased (r=0.962, P=0.017 6). The results show that SureFil SDR is an ideal preventive resin filling and sealing material relative to pit and fissure sealant and Z350 XT fluid resin.

Objective To investigate the target organs function damage in elderly patients with H type hypertension and its association with blood pressure variability.Methods Ninety-two patients with H type hypertension in the Affiliated Hospital of Inner Mongolia Medical University from January 2014 to January 2016 were collected as the observation group and contemporaneous 135 elderly patients with non-H type hypertension were collected as the control group.The main observation indicators included 24 h systolic/diastolic blood pressure variability,24 h average systolic/diastolic blood pressure,glomerular filtration rate(GFR),serum creatinine,24 h urinary microalbumin,carotid intima-media thickness and left ventricular mass index.Results Compared with the control group,24 h systolic blood pressure variability,24 h diastolic blood pressure variability,creatinine,24 h urinary microalbumin,carotid intima-media thickness and left ventricular mass index in the observation group were significantly increased(P＜0.05);GFR was significantly decreased (P＜0.05).The multiple linear regression analysis showed that 24 h systolic blood pressure variability was the factors affecting GFR (P＜0.05);24 h systolic blood pressure variability was the factor affecting~the creatinine level (P＜0.05);24 h systolic blood pressure,24 h systolic blood pressure variability and 24 h diastolic blood pressure variability were the influence factors of carotid intima-media thickness (P＜0.05);24 h systolic blood pressure variability was the influence factor of left ventricular mass index (P＜0.05).Conclusion The target organs function damage in the patients with H type hypertension is serious,and the blood pressurevariability enlargement is the influencing factor of target organs function damage.

Objective To analyze the 10-year survival outcome and failure patterns for patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT),aiming to provide reference for optimized treatment for NPC.Methods Clinical data of 866 patients with NPC receiving IMRT from January 2001 to December 2008 were retrospectively analyzed.Survival analysis was performed using the Kaplan-Meier estimator.Univariate analysis was carried out by log-rank test and multivariate analysis was performed using Cox proportional hazards model.Results The median follow-up time was 132 months.The 10-year local recurrence-free survival (LRFS),distant metastasis-free survival (DMFS),progression-free survival (PFS) and disease specific survival (DSS) were 92.0％,83.4％,75.7％ and 78.6％,respectively.A total of 210 patients died including 124 patients (59.0％) from distant metastasis,which was the primary cause of death,and 47 (22.3％) from local regional recurrence.Independent negative factors of DSS included age＞50 years (P=0.00),LDH ≥ 245 IU/L (P=0.00),Hb＜ 120 g/L (P=0.01),T2-T4 staging (P=0.00),N1-N3 staging (P=0.00) and GTV-nx＞20 cm3(P=0.00).The 10-year LRFS,DMFS and DSS of stage Ⅱ NPC patients did not significantly differ after IMRT alone and chemoradiotherapy (P=0.83,0.22,0.23).For patients with stage Ⅲ NPC,the 10-year LRFS and DSS in the chemoradiotherapy arm were significantly higher than those in the IMRT alone (P=0.01,0.01),whereas no statistical significance was observed in the DMFS between two groups (P=0.14).The overall survival of stage Ⅳa+Ⅳb NPC patients is relatively poor.Conclusions IMRT can improve the long-term survival of NPC patients.Distant metastasis is the primary failure pattern.Patients with stage Ⅰ-Ⅱ NPC can obtain satisfactory survival outcomes after IMRT alone.The addition of chemotherapy can further enhance the LRFS and DSS of stage Ⅲ NPC patients.However,the optimal therapeutic strategy remains to be urgently investigated for stage a+ Ⅳb NPC patients.