OBJECTIVE To establish a multi-dimensional value assessment framework for new antidiabetic drugs based on multi-criteria decision analysis theory， thus providing a theoretical framework and methodology for evidence-informed medical insurance decision-making. METHODS Firstly， multi-dimensional evidence was searched and obtained to provide reliable data for the establishment of the framework. Secondly， in terms of the obtained evidence， the value assessment framework was preliminarily constructed. Its structure， main core criteria， and contextual criteria were determined through focus group discussion. Finally， the criteria and sub-criteria of the framework and their weights were further determined， reasons for inclusion of sub-criteria and the reasonableness of rating scores were evaluated， and methods of assessment were optimized through expert consultation. RESULTS The multi-dimensional value assessment framework for new antidiabetic drugs was composed of core criteria and contextualized criteria， which could be used for quantitative and qualitative value assessment of new drugs， respectively. The core criteria consisted of five dimensions， with affordability （6.31） having the highest weighting score， followed by comparative effectiveness （6.20）， comparative safety （6.01）， cost-effectiveness （5.89）， and quality of evidence （5.46）. After the normalization of weight within sub-criteria， the budget impact on medical insurance had the highest standardized weight， followed by the control of glycated hemoglobin and patient affordability. The contextual criteria included two dimensions， i. e.， innovation and equity. CONCLUSIONS The assessment framework integrates evidence， stakeholders’ values， and decision contexts to enable a multi- dimensional and evidence-based assessment of the value of new antidiabetic drugs.

Objective To investigate the role of hydrogen therapy in reducing radiation-induced lung injury and the specific mechanism. Methods Forty C57BL/6 mice were randomly divided into four groups: normal control group, model group, hydrogen therapy group I, and hydrogen therapy group II. A mouse model of radiation-induced lung injury was established. The pathological changes in the lung tissue of the mice were examined with HE staining. Immunofluorescence staining was used to detect the expression of surface markers of M1 and M2 macrophages to observe macrophage polarization. The expression of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-10 in the lung tissue was measured by immunohistochemistry. The expression of nuclear factor-kappa B (NF-κB) p65 and phosphorylated NF-κB (P-NF-κB) p65 was measured by Western blot. Results HE staining showed that compared with the control group, the model group exhibited alveolar septal swelling and thickening, vascular dilatation and congestion, and inflammatory cell infiltration in the lung tissue; the hydrogen groups had significantly reduced pathological damage and inflammatory response than the model group, with more improvements in hydrogen group II than in hydrogen group I. Immunohistochemical results showed that compared with those in the control group, the levels of the inflammatory cytokines IL-6 and TNF-α were significantly increased in the model group; the hydrogen groups showed significantly decreased IL-6 and TNF-α levels and a significantly increased level of the anti-inflammatory factor IL-10 than the model group, which were more marked in hydrogen group II than in hydrogen group I. Immunofluorescence results showed that compared with the control group, the expression of the surface marker of M1 macrophages in the model group was significantly upregulated; the hydrogen groups showed significantly downregulated M1 marker and significantly upregulated M2 marker, and hydrogen group II showed significantly increased M2 marker compared with hydrogen group I. Western blot results showed that compared with that in the control group, the ratio of P-NF-κB p65/NF-κB p65 in the model group was significantly increased; the P-NF-κB p65/NF-κB p65 ratio was significantly reduced in the hydrogen groups than in the model group, and was significantly lower in hydrogen group II than in hydrogen group I. Conclusion Hydrogen inhalation therapy may reduce the inflammatory response of radiation-induced lung injury by inhibiting the NF-κB signaling pathway to promote the polarization of the macrophage M1 subtype to the M2 subtype.

BACKGROUND:The traditional view is that proximal fibular fractures do not require fixation.Others and our research suggest that the proximal fibular structure plays an important role in the stability of the posterolateral structure of the knee joint,and its mechanism of action is worth studying. OBJECTIVE:To investigate the biomechanical effects of proximal fibular fractures on various structures of the knee joint in an extended state. METHODS:Finite element method was used to conduct simulated biomechanical experiments.A healthy young male volunteer was selected to establish a finite element model of the knee joint in an extended state using MRI and CT image data,and four proximal fibular shapes were simulated(Model A:intact,Model B:1 cm fracture below the fibular head,Model C:1 cm tip defect fracture from the proximal end of the fibula to the distal end,and Model D:2 cm bone defect from the proximal end of the fibula).A longitudinal concentrated load of 1 500 N was applied to the femoral shaft to compare and analyze the distribution and changing trend of the maximum equivalent stress and maximum first principal stress of each structure of the knee joint in an extended state under four working conditions. RESULTS AND CONCLUSION:(1)In Model A,the maximum equivalent stress in the tibial cartilage and lateral compartment of the meniscus was greater than that in the medial compartment,while the maximum first principal stress in the tibial plateau and medial compartment of the meniscus was greater than that in the lateral compartment.The maximum equivalent stress of the medial condyle of the femoral cartilage was greater than that of the lateral condyle,and the maximum first principal stress of the medial condyle of the femoral cartilage was greater than that of the medial condyle.(2)Compared to Model A,there was no significant difference in the magnitude and distribution of the maximum equivalent stress and maximum first principal stress in the cartilage and meniscus of Model C.(3)Compared to Model A,the maximum equivalent stress increase amplitude of Model B was in the order of medial tibial cartilage(14.9％),medial condyle of femoral cartilage(13.6％),and medial meniscus(6.6％).The maximum first principal stress increase amplitude was the medial meniscus(11.06％),the medial tibial cartilage(8.65％),and the medial condyle of the femoral cartilage(7.46％).The maximum equivalent stress increase amplitude of the ligament was as follows:popliteal arch ligament(33.2％)>anterior cruciate ligament(21.3％)>fibular collateral ligament(17％)>posterior cruciate ligament(14.3％)>anterior lateral collateral ligament(13.2％)>medial collateral ligament(10.1％).(4)Compared to Model A,the maximum equivalent stress increasing trend of Model D followed the medial tibial cartilage(19.5％),femoral cartilage medial condyle(17.9％),and medial meniscus(9.9％).The maximum first principal stress in sequence was the medial meniscus(14.04％),the medial tibial cartilage(13.03％),and the medial condyle of the femoral cartilage(11.37％).The increasing trend of maximum equivalent stress in ligaments was as follows:anterior cruciate ligament(25.2％)>posterior cruciate ligament(18.9％)>medial collateral ligament(18.5％)>anterior lateral collateral ligament(12.7％).(5)It is suggested that when the knee joint is extended,a 1 cm fracture below the fibular head and a 2 cm fibular tip bone defect have a significant impact on the structure of the medial ventricular cartilage,anterior cruciate ligament,and posterior lateral ligament complex.

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 pathogenesis of flunarizine-induced parkinsonism from gut-brain axis perspective.Methods:Thirty male C57BL/6 mice were randomly divided into control group and flunarizine group ( n=15). Mice in the control group were given 0.1 mL 50% polyethylene glycol 400+50% saline by gavage once/d for 2 weeks, while mice in the flunarizine group were given 6 mg/mL flunarizine+50% polyethylene glycol 400+50% saline by gavage at a daily dose of 30 mg/kg for 2 weeks. Body mass was recorded 1, 3, 5, 7, 10 and 14 d after drug administration, and motor function was assessed by rotarod test 14 d after drug administration; 16s RNA sequencing was performed in the feces to observe the intestinal flora; intestinal transit function was detected by Evans blue by gavage; and then, the mice were sacrificed and homogenate or frozen sections (brain and intestinal tissues) were prepared; dopamine-ergic neuron expression was detected by Western blotting; RT-qPCR was applied to detect the expressions of inflammatory factors in the substantia nigra, and immunofluorescent staining was used to detect the expressions of ZO-1 and Claudin-5 in the intestinal epithelial tissues. Results:Compared with the control group, the flunarizine group had lower body mass ratio 1, 3, 5, 7, 10 and 14 d after drug administration (ratio to body mass before drug administration). Compared with the control group, the flunarizine group had significantly shortened residence time in rod rotating and lower rotational speed when falling ( P<0.05). Compared with the control group, the flunarizine group had decreased tyrosine hydroxylase protein in the substantia nigra without significant difference ( P>0.05). Compared with the control group, the flunarizine group had significantly increased interleukin-6 and tumor necrosis factor-α in the substantia nigra (1.00±0.00 vs. 2.79±0.83; 1.00±0.00 vs. 3.39±1.37), significantly lower intestinal Evans blue propulsion rate (80.67%±4.51% vs. 50.67%±6.03%), and statistically decreased ZO-1 and Claudin-5 expressions in the colonic epithelial tissues (27.01±1.41 vs. 16.32±2.83; 37.00±2.80 vs. 24.52±2.12, P<0.05). Totally, 576 microorganisms were noted in both control group and flunarizine group, 744 in the control group alone, and 634 in the flunarizine group alone. The intestinal flora β diversity indices in the 2 groups were significantly different based on weighted Unifrac-principle coordinates analysis (PCoA, PCoA1: 39.88%; PCoA2: 30.69%). Compared with the control group, the microbial colony structure of mice in flunarizine group was dominated by phylum thick-walled bacteria and phylum warty microbacteria, and by families Muribaculaceae, Lachnospiraceae and Akkermansiaceae. Compared with the control group, the flunarizine group had significantly decreased relative abundance of Ackermannia spp. and Lactobacillus spp. in the intestinal flora ( P<0.05). Conclusion:Flunarizine may contribute to the pathogenesis of DIP by causing structural disturbances in the intestinal flora and inducing neuroinflammation based on the gut-brain axis.

Objective:To evaluate the clinical significance of neoadjuvant immunotherapy combined with chemotherapy in the treatment of larynx preservation in locally advanced hypopharyngeal squamous cell carcinoma. Methods:Patients with locally advanced HPSCC（cT3-T4aN0-N3M0） were eligible. All received 2 cycles of pembrolizumab combined with docetaxel and platinum neoadjuvant induction therapy. After two cycles, the efficacy was evaluated, followed by radical chemoradiotherapy or surgery and adjuvant chemoradiotherapy according to the efficacy. The primary endpoints were objective response rate（ORR） ，larynx-preservation（LP） rate at 3 months post-treatment and the adverse reactions during neoadjuvant therapy. Results:From December 2021 to December 2022, 10 patients with locally advanced HPSCC（cT3-T4aN0-N3M0） were enrolled. After 2 cycles of the neoadjuvant therapy, 2 patients achieved complete response（CR）, 7 patients achieved partial response（PR）, 1 patient was stable disease（SD）, objective response rate（ORR） was 90%, and disease control rate（DCR） was 100%. 5 patients received radical chemoradiotherapy, 5 patients received surgery and adjuvant chemoradiotherapy, four of them received partial laryngectomy and partial hypopharyngeal resection surgery, and one of them received total laryngectomy and partial hypopharyngeal resection surgery. All patients were able to withstand adverse reactions of neoadjuvant therapy and successfully completed the whole treatment of HPSCC without grade 3-4 treatment-related adverse reactions. There was no recurrence or metastasis during 3-18 months of follow-up. 1 patient died of severe pneumonia 3 months after the completion of radical chemoradiotherapy. At 3 months after treatment, the larynx-preservation rate was 80%. Conclusion:Neoadjuvant immunotherapy combined with chemotherapy has good short-term efficacy and the adverse reactions were tolerable. It can improve the larynx-preservation rate of patients with locally advanced HPSCC, thus improving the prognosis and quality of life of patients.
Humans ; Squamous Cell Carcinoma of Head and Neck/etiology* ; Neoadjuvant Therapy ; Quality of Life ; Cisplatin ; Treatment Outcome ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Larynx ; Head and Neck Neoplasms ; Immunotherapy

Objective:To investigate the diversity and clinical effect of supraclavicular island flap in repairing the defect after head and neck tumor surgery. Methods:A retrospective analysis was performed on 30 patients who received the repair of head and neck defects with supraclavicular island flaps at Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Chongqing Medical University from January 2017 to March 2023. The sites and types of defects, intraoperative blood loss, time of flaps preparation, areas of flaps, survival of the flaps and other complications were recorded. Results:A total of 30 patients were enrolled, including 26 males and 4 females, aged 36-82 years. Among them, 22 patients with hypopharyngeal partial defect were repaired （19 patients with ipsilateral defect and 3 patients with contralateral defect）. In addition, 2 patients were repaired with contralateral pectoralis major musculocutaneous flap around the hypopharynx, the neck skin defect was repaired in 2 patients, the parotid skin defect was repaired in 2 patients, the temporal bone skin defect was repaired in 1 patient, and the cervical esophageal defect was repaired in 1 patient. The average blood loss during the operation was 8 ml, and the average time was 32 min. The flap areas ranged from 5.0 cm×4.0 cm to 20.0 cm×8.0 cm. 27 of 30 flaps survived（90.0%）, and pharyngeal fistula occurred in 6 patients after operation（4 flaps survived after local dressing）. One patient was complicated with venous thrombosis（the flap necrosis after local dressing）. Shoulder and neck functions（lift, internal rotation and abduction） were not significantly affected in 29 patients, and the function of 1 patient with shoulder infection was not affected after treatment. Conclusion:Supraclavicular island flap is a highly vascularized axial fascial flap. It is easy to make, thin, and soft in texture, and can be used to repair different sites and types of postoperative head and neck tumor defects with a low donor site complication rate. Good results in post-operative repair of head and neck tumors are worth promoting.
Male ; Female ; Humans ; Plastic Surgery Procedures ; Retrospective Studies ; Skin Transplantation ; Soft Tissue Injuries/surgery* ; Treatment Outcome ; Surgical Flaps ; Head and Neck Neoplasms/surgery*

Objective:To observe the clinical effect of four-point fixation in patients with posterior chamber intraocular lens dislocation.Methods:A retrospective case series study was adopted.Sixteen patients (16 eyes) with posterior chamber intraocular lens dislocation who underwent suture suspension techniques with four-point fixation in Changzhou No.2 people's Hospital from January 2015 to January 2018 were enrolled.Postoperative effects were observed during follow-up, ranging from 6 to 13 months.The preoperative and 6-month postoperative uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), corneal endothelium cell count and astigmatism were measured and the differences were compared, and the relationships between total astigmatism and corneal astigmatism or intraocular lens induced astigmatism were analyzed, and the postoperative position of intraocular lens and complications were observed.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of Changzhou No.2 People's Hospital (No.2015-C-012-01).Written informed consent was obtained from each patient before surgery.Results:The mean preoperative UCVA (LogMAR) and BCVA (LogMAR) were 1.09±0.24 and 0.48±0.20, respectively, which were significantly improved to 0.30±0.12 and 0.26±0.13 at 6 months after operation, respectively.And the differences were statistically significant ( t=11.782, 3.795; both at P<0.01).The preoperative and 6-month postoperative corneal endothelium cell count were (2 270±360)/mm 2 and (2 032±327)/mm 2, respectively, and the difference was not significant ( t=1.921, P=0.074).The 6-month postoperative mean total astigmatism, corneal astigmatism and intraocular lens induced astigmatism were (-1.47±0.82)D, (-1.34±0.61)D and (-0.22±0.35)D, respectively.There was a highly positive correlation between total astigmatism and corneal astigmatism ( r=0.885, P<0.05), but there was no significant correlation between total astigmatism and intraocular lens induced astigmatism ( r=-0.432, P=0.095).No dislocation, deviation or torsion of intraocular lens were observed during the follow-up.Varying degree of symptoms of iridocyclitis were observed during early stage after operation, which disappeared after treatment.There were two cases of high intraocular pressure, which were normal after treatment.No retinal detachment, choroidal detachment, expulsive suprachoroidal hemorrhage, endophthalmitis, corneal endothelial decompensation or other complications occurred during and after operation. Conclusions:There is a stable position of intraocular lens, good visual acuity and few complications after four-point fixation with suture and suspension, which is a feasible method to treat dislocated intraocular lens.

Objective:To analyze the metabolites of isoacteoside in rat's urine after oral administration by UHPLC-LTQ-Orbitrap and then summarize its metabolic pathways.Methods:The rats were randomly divided into treatment and control groups. Isoacteoside dissolved in saline was orally administered to the rats in the treatment group witht a single dose of 100 mg/kg. At the same time, saline was orally administered to the control group with the same volume. The urine samples were collected for 12 h and then purified. Sample analyses were performed on a Thermo Scientific BOS Hypersil C18 column (2.1 mm × 150 mm, 2.4 μm), the mobile phase consisted of water containing 0.1% formic acid-acetonitrile in a gradient program, the flow rate was set at 0.3 ml/min and the column was maintained at 30 ℃. The urine samples of the treatment group and control groups were detected with negative ion mode.Results:The metabolites were identified according to their protonated molecular ions and fragment ions and by comparing the mass data with that of reference standards and the published data. In total, 8 metabolites of isoacteoside were detected and identified in the urine samples of treatment group and the major metabolic pathway of isoacteoside included glucuronide conjugation, dehydroxylation, hydrolyzation, methyl conjugation and sulphate conjugation.Conclusions:UHPLC-LTQ-Orbitrap could be used to analyze the main metabolites and metabolic pathways of isophylloside in rats, which can provide references for further studies on pharmacodynamics and pharmacological mechanisms.

Objective: To investigate the characteristics of neuropsychological factors in patients with persistent postural-perceptual dizziness(PPPD) and provide the basis for the psychosomatic comprehensive treatment. Methods: Cartel Personality Test (16PF), Symptom Checklist 90 (SCL-90), HAMA, HDMD, SAS and SDS were used to evaluate personality and mental state in patients with PPPD(PPPD group, n=65) and control group(n=63). Dizziness handicap inventory(DHI) was used to evaluate the degree of vertigo.The correlation analysis was carried out between the DHI scores and 16-PF, SCL-90 factor scores. Results: (1)16PF factor scores: the factor scores of assertiveness(8.50±1.84), excitability (6.59±1.73), boldness (7.46±1.78), sensitivity (7.25±1.79), doubtfulness (6.55±1.74), fantasy(6.20±1.60), anxiety(7.67±1.61) and tension(6.81±1.67)in PPPD group were higher than those in the control group, and the differences were statistically significant (all P<0.05). The gregariousness (4.38±1.65), intelligence (4.51±1.67), stability (3.51±1.75), independence (4.39±1.56) and self-discipline (4.70±1.82) factor scores in PPPD group were lower than those in the control group, and the differences were statistically significant (all P<0.05). (2)SCL-90 factor scores: the factor scores of somatization(1.62±0.40), anxiety (1.64±0.56), interpersonal sensitivity (1.79±0.42), terrifying(1.71±0.53), total points(150.77±21.60), total average score (1.62±0.51) in PPPD group were higher than those in control group (all P<0.05). There were no differences in obsessive-compulsive (1.50±0.55), depression (1.45±0.44), hostility (1.69±0.60), paranoia (1.76±0.53), somatization (1.42±0.49) and psychotic (1.29±0.35) between PPPD group and the control group (all P>0.05). (3)The factor scores of HAMA(9.08±1.77) and SAS(37.88±2.96)in patients with PPPD were higher than that in the control group, and the differences were statistically significant (all P<0.05). There was no significant difference in HAMD (6.19±2.82) and SDS (36.36±4.71) scores between PPPD group and control group (all P>0.05). (4)The DHI scores were positively correlated with assertiveness, sensitivity, tension and doubtfulness factors of 16PF.The DHI scores were positively correlated with somatization, interpersonal sensitivity, anxiety and terrifying factors of SCL-90. Conclusion Patients with persistent postural-perceptual dizziness suffer from personality changes, mental disorders and anxiety disorder.