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 establish a nucleic acid detection and genotyping method for Mycoplasma pneumoniae ( Mp) based on nucleic acid in clinical samples. Methods:Through genomic comparison, the specific target sequences of Genotype 1 and Genotype 2 Mp strains were selected to design synthetic primers and probes, and a PCR detection and classification method for Mp dual fluorescent probe was established, and the specificity, accuracy, detection limit and repeatability of the method were evaluated. The established fluorescence PCR method was used to detect the nucleic acid of clinical specimens and compared with the reported fluorescent PCR methods. Results:The nucleic acid of 18 pathogens, including other species of Mycoplasma and common respiratory bacteria and viruses, which were closely related to the Mp species, were detected, and the results showed that there was no cross-reactivity. The accuracy of detection and typing of 90 Mp nucleic acid was 100%. The detection limits of Genotype 1 and Genotype 2 Mp samples were 1.0 copy/μl, and the experimental coefficient of variation of repeatability within groups and between groups was less than 2.5%. In the detection of 88 nucleic acid of clinical specimens, the Kappa value was 0.675 and the P value was 0.267 compared with the reported real-time PCR method, showing a high degree of agreement. Conclusions:The method for detecting and genotyping Mp in this study has high sensitivity, specificity, and accuracy, which can be applied to the monitoring and prevention and control of Mp in the disease control system of provinces and cities at all levels in China. This method promotes the improvement of the Mp prevention and control system in China, strengthens the surveillance ability, and is of great significance for the early warning and prediction of Mp.

Humans ; Arthroplasty, Replacement, Knee/adverse effects* ; Arthroplasty, Replacement, Hip/adverse effects* ; Reoperation ; Prosthesis-Related Infections ; Retrospective Studies

Objective:To investigate the correlation of peripheral blood 25-hydroxyvitamin D3 [25 (OH) D3] level with T cell subsets in multiple myeloma (MM).Methods:The clinical data of 11 newly diagnosed MM patients hospitalized in Heze Municipal Hospital and the First People's Hospital of Jining from June 2019 to June 2021 were retrospectively analyzed, and 8 healthy people were selected as the healthy control group. The patients achieved disease remission after 4 courses of BD (bortezomib + dexamethasone) regimen. High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to measure the peripheral blood 25-(OH) D3 level in MM patients at initial diagnosis and after 4 courses of treatment, as well as people in the healthy control group. The proportion of peripheral blood helper T cell (Th) 1, Th2, Th17, and regulatory T cells (Treg cells) in CD3 + CD8 + T cells was measured by using flow cytometry. IgA, IgG, IgM, lactic dehydrogenase (LDH), β 2-microglobulin (β 2-MG) levels were analyzed by using fully automatic biochemical analyser. Cytoanalyze was used to detect the hemoglobin level in the peripheral blood. The differences of all indicators in MM patients at initial diagnosis, remission after treatment and the healthy control group were compared. Pearson method was used to analyze the correlation of the peripheral blood 25-(OH) D3 level with T cell subsets and other biochemical indicators in MM patients at initial diagnosis and remission after treatment. Results:Compared with the healthy control group, the peripheral blood 25-(OH) D3 level, Th1-to-Th2 ratio (Th1/Th2), the proportion of Treg cells were all decreased (all P < 0.01), and Th17-to-Treg cells ratio (Th17/Treg) was increased ( P = 0.002). The proportion of Th17 and Th17/Treg in MM patients achieving remission after treatment was higher than that in the healthy control group (all P < 0.05); the proportion of Treg cells in MM patients achieving remission after treatment was lower than that in the healthy control group ( P = 0.010); 25-(OH) D3 level in MM patients achieving remission after treatment was lower than that in the healthy control group, while the difference was not statistically significant ( P = 0.060). The peripheral blood IgM in MM patients at initial diagnosis and those achieving remission after treatment was lower than that in the healthy control group (all P < 0.01); the levels of LDH and β 2-MG in MM patients at initial diagnosis and those achieving remission after treatment was higher than that in the healthy control group (all P < 0.05). The peripheral blood 25-(OH) D3 level in MM patients at initial diagnosis was positively correlated with the proportion of Th1, Th1/Th2 ( r values 0.89, 0.60, all P < 0.05), and negatively correlated with the proportion of Th17 and Th17/Treg ( r values -0.61, -0.75, all P < 0.05). After treatment, there was no correlation of the proportion of Th1, Th2, Th17, Treg, Th1/Th2, Th17/Treg with peripheral blood 25- (OH) D3 level for patients achieving remission ( r values were -0.36, -0.45, -0.10, 0.10, 0.19, 0.03, all P > 0.05). IgM, LDH, β 2-MG was negatively correlated with 25- (OH) D3 level in the peripheral blood of MM patients at initial diagnosis ( r values were -0.76, -0.71, -0.62, all P < 0.05); while there was no correlation of 25-(OH) D3 level with IgA, IgG, IgM, LDH, β 2-MG, hemoglobin for patients achieving remission after treatment ( r values were -0.36, 0.19, -0.09, 0.47, 0.47, -0.11, all P > 0.05). Conclusions:MM patients show the decreased peripheral blood 25-(OH) D3 level, the increased Th17 and the decreased Treg cells; 25-(OH) D3 level is related to the imbalance of Th1/Th2/Th17/Treg, which suggests that 25-(OH) D3 may be related to the development, progression, prognosis and abnormal immune responses in the body of MM.

Objective To evaluate the effect of virtual reality(VR)on alleviation of fatigue in patients undergoing chemotherapy for non-small cell cancer so as to enhance the quality of life of the patients.Methods This study was conducted with a quasi-randomised controlled trial.Sixty patients with non-small cell cancer treated under initial chemotherapy in a general hospital in Shanghai were enrolled in the study between January 2020 and January 2021.The patients in Ward-Ⅰ were assigned as the control group and those in Ward-Ⅱ as the trial group,with 30 patients per group.The patients in control group was treated with routine nursing strategy and those in the trial group with VR intervention in addition to routine nursing.An interactive immersion with six 3-D switching relaxation-oriented scenes was introduced in the VR intervention including travel,starry sky,four seasons,globe,parks and ocean world.Patients received a 20-minute VR intervention before chemotherapy at two times per week during the intermittent periods of chemotherapy.The revised piper fatigue scale in Chinese version(RPFS-CV)was used to assess the patients on admission and early,middle and late phases referring the third,fifth and seventh courses of the chemotherapy,respectively.Scores of the assessments were compared between the groups.Results All of the 60 patients had smoothly completed the 7 courses of chemotherapy.With repeated measures analysis of variance,the differences were found to be statistically significant in the scores of RPFS-CV,time,and interaction across different time points(all P<0.001).The scores of RPFS-CV taken at the fifth and seventh courses of chemotherapy in the trial group were significantly lower than that of the control group(P<0.001).There were no significant differences in the scores of RPFS-CV within the control group at the fifth and seventh courses of chemotherapy,but the differences were statistically significant in the other courses of chemotherapy(P<0.008 or P<0.001),showing a trend that the later the treatment course,the higher the score of RPFS-CV would be,and ultimately it went steady.In the trial group,there was no significant difference between the third course of chemotherapy and the fifth and seventh courses,as well as between the fifth and seventh courses(P>0.05);but the score taken before the chemotherapy was significantly lower as compared to those taken at the third,fifth and seventh courses(all P<0.001).Conclusion VR intervention with deep relaxation immersive interactive experience could inhibit fatigue by activating the hypothalamic-pituitary-adrenal axis and facilitating the secretion of cortisol via enhancing visual stimulation,thus alleviating cancer fatigue in patients undergoing chemotherapy for non-small cell cancer.

Objective:To study the distribution and antibiotics resistance of the main pathogens of neonatal purulent meningitis in different regions of China.Methods:A retrospective descriptive clinical epidemiological study was conducted in children with neonatal purulent meningitis which admitted to 18 tertiary hospitals in different regions of China between January 2015 to December 2019. The test results of blood and cerebrospinal fluid, and drug sensitivity test results of the main pathogens were collected. The distributions of pathogenic bacteria in children with neonatal purulent meningitis in preterm and term infants, early and late onset infants, in Zhejiang Province and other regions outside Zhejiang Province, and in Wenzhou region and other regions of Zhejiang Province were analyzed. The chi-square test was used for statistical analysis.Results:A total of 210 neonatal purulent meningitis cases were collected. The common pathogens were Escherichia coli ( E. coli)(41.4%(87/210)) and Streptococcus agalactiae ( S. agalactiae)(27.1%(57/210)). The proportion of Gram-negative bacteria in preterm infants (77.6%(45/58)) with neonatal purulent meningitis was higher than that in term infants (47.4%(72/152)), and the difference was statistically significant ( χ2=15.54, P=0.001). There were no significant differences in the constituent ratios of E. coli (36.5%(31/85) vs 44.8%(56/125)) and S. agalactiae (24.7%(21/85) vs 28.8%(36/125)) between early onset and late onset cases (both P>0.05). The most common pathogen was E. coli in different regions, with 46.7%(64/137) in Zhejiang Province and 31.5%(23/73) in other regions outside Zhejiang Province. In Zhejiang Province, S. agalactiae was detected in 49 out of 137 cases (35.8%), which was significantly higher than other regions outside Zhejiang Province (11.0%(8/73)). The proportions of Klebsiella pneumoniae, and coagulase-negative Staphylococcus in other regions outside Zhejiang Province (17.8%(13/73) and 16.4%(12/73)) were both higher than those in Zhejiang Province (2.9%(4/137) and 5.1%(7/137)). The differences were all statistically significant ( χ2=14.82, 12.26 and 7.43, respectively, all P<0.05). The proportion of Gram-positive bacteria in Wenzhou City (60.8%(31/51)) was higher than that in other regions in Zhejiang Province (38.4%(33/86)), and the difference was statistically significant ( χ2=6.46, P=0.011). E. coli was sensitive to meropenem (0/45), and 74.4%(32/43) of them were resistant to ampicillin. E. coli had different degrees of resistance to other common cephalosporins, among which, cefotaxime had the highest resistance rate of 41.8%(23/55), followed by ceftriaxone (32.4%(23/71)). S. agalactiae was sensitive to penicillin, vancomycin and linezolid. Conclusions:The composition ratios of pathogenic bacteria of neonatal purulent meningitis are different in different regions of China. The most common pathogen is E. coli, which is sensitive to meropenem, while it has different degrees of resistance to other common cephalosporins, especially to cefotaxime.

Objective:To explore the consistency of MRI fast field echo resembling a CT using restricted echo-spacing (FRACTURE) and CT in the evaluation of knee and ankle bone changes.Methods:From November 2020 to November 2021, seventeen patients who underwent CT and MRI FRACTURE examinations of knee joint or ankle joint in the First Affiliated Hospital of Dalian Medical University were retrospectively collected, including 14 patients with knee joint examinations and 3 patients with ankle joint examinations. According to the number of joint components, 80 components were included, including 14 for femur and patella, 17 for tibia and fibula, and 3 for talus, scaphoid, medial cuneiform, medial cuneiform, lateral cuneiform and calcaneus, respectively. The fracture, hyperosteogeny, and bone destruction of the joint bones were evaluated by two observers using CT and FRACTURE images, respectively. Kappa test was used to analyze the consistency of CT and FRACTURE images between observers in the evaluation of joint bone lesions.Results:The Kappa values (95%CI) of the consistency evaluation of fracture, hyperosteogeny, and bone destruction by CT and FRACTURE images were 0.925 (0.823-1.027), 0.905 (0.799-1.011) and 0.895(0.752-1.038) respectively for observer 1, and were 0.963 (0.892-1.034), 0.933 (0.843-1.023) and 0.886 (0.731-1.041) respectively for observer 2. The Kappa values (95%CI) of the consistency evaluation of fracture, hyperosteogeny, and bone destruction by observers 1 and 2 via CT images were 1.000 (1.000-1.000), 0.937(0.851-1.023) and 0.945 (0.839-1.051) respectively, and that by FRACTURE images were 0.962 (0.888-1.036), 0.966 (0.899-1.033) and 0.836 (0.656-1.016) respectively.Conclusion:For the evaluation of fracture, hyperosteogeny, and bone destruction of knee joint and ankle joint, MRI FRACTURE sequence is highly consistent with CT.

Fusobacterium nucleatum (F. nucleatum) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum-infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum-infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection.
Humans ; Fusobacterium nucleatum/metabolism* ; NF-kappa B/metabolism* ; Periodontal Ligament/metabolism* ; Signal Transduction ; Fusobacterium Infections/pathology* ; Stem Cells/metabolism*

Objective:To compare and analyze rhizome and main root of Ginseng Radix et Rhizoma (GRR); To provide the basis of whether removing the rhizome of Ginseng (RG) when processing by checking whole consistency of chromatographic fingerprints from rhizome and main root of GRR.Methods:The chromatographic consistency of different parts of GRR samples was compared using high performance thin layer chromatography (HPTLC); HPLC was used to determine the fingerprint of different parts of GRR, and combining it with the reference substance for common peak identification and similarity analysis; differences were analyzed using principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA).Results:In the HPTLC spectrum, the characteristic spectra of rhizome and main root of GRR and whole GRR were similar, and there was a clear total of 7-9 spots. HPLC fingerprints of RRR presented 13 common peaks, and identified 6 peaks, including ginsenoside Rg1&Re (mixed), Rf, Rb1, Rc, Ro and Rd; the similarity of all samples ranged from 0.842 to 0.993; the differences in peak areas comprehensively contributed to the similarity differences between samples, with head being the main influence; ginsenoside Ro, Rb1 and other six components were differential markers, and the relative content in the head of GRR is significantly higher than that in the main root. Conlusions 　The analysis of differential profiling of chemical constituents showed that the chemical substances are almost the same between the head and the main root. The processing of GRR to remove head will result in the loss of ginsenosides, the overall effective component of GRR. Considering the human and resource costs, it was suggested that the whole root of GRR, instead of removing its rhizome, could be used in classical and traditional prescriptions.

Objective:To evaluate the effectiveness of Evidence-based Nursing Practice Guideline for Enteral Nutrition of Infants with Congenital Heart Disease application on improving the nutritional status of infants with congenital heart disease (CHD) in the target population, and to explore the effective strategies of evidence implementation in the process of dissemination, implementation and integration into clinical practice. Methods:This was an implementation study. Promoting Action on Research Implementation in Health Services Integrated Framework (i-PARIHS) was used as a theoretical model. Infants with CHD who received cardiac surgery from the heart ICU of Children ′s Hospital of Fudan University from January 2019 to February 2020 were selected as the study subjects. January to June 2019 and September to February 2020 were the pre and post implementation phase respectively. For medical staff, communication strategy, implementation process strategy, integration strategy and capacity-building strategy were used to advance the implementation process. According to the implementation strategy of children, the 26 best practice recommendations in the guide were translated into operable nursing processes and enteral nutrition programs, which were implemented in four stages: admission to the hospital, pre operation, post operation cardiac care room, post operation ward recovery, and pre discharge. Implementation Results Variable Assessment Form was used to evaluate effectiveness of the implementation strategies; hospitalization weight and upper arm circumference, serum albumin and pre-albumin before discharge were used to evaluate effectiveness of the interventions. Results:Scores of eight aspects of Implementation Results Variable Assessment reached more than 75% of the total score. Pre-albumin of post-implementation was (166.53 ± 42.57) g/L, which was statistically significantly higher than (148.41 ± 30.66) g/L before discharge ( t=-3.21, P<0.01); the weight loss of pre-implementation was 0.00 (0.41) kg, while the weight change of post-implementation was -0.10 (0.40) kg, the difference was statistically significant ( Z=-2.90, P<0.01). Conclusions:The strategies of diffusing, implementing, integrating the CHD enteral nutrition protocol based on guide could improve the implementation results and the nutrition status of infants with CHD.