Background::Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.Methods::This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied.Results::At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs. placebo, 95% CI 31%–69%) and 45% (low vs. placebo, 95% CI 26%–64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator’s Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. Conclusion::CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.Trial Registration::ClinicalTrials.gov, NCT04805411.

ObjectiveTo construct a quantitative prediction model of three indicators（moisture absorption rate， film thickness and coating weight gain） during the coating process of Vitamin C Yinqiao tablets（VCYT） by near-infrared spectroscopy（NIRS）， and to realize the endpoint judgment. MethodReal-time NIRS data of 4 batches of VCYT during the coating process were collected by diffuse reflection method. The coating method employed was the rolling coating method， and the samples were obtained at the spray stage from the coater's sampling port every 10 minutes， and 57 batches of samples（about 1 800 tablets） were collected at various coating times， the tablets were embedded in molten paraffin， cut longitudinally， and observed by stereomicroscope. The film thickness， with a target value of 38 μm， was then measured using Motic Images Advanced 3.2 software. Furthermore， the mositure absorption rate of samples， aiming for a target value of 3%， was determined in accordance with guiding principles for drug hygroscopicity testing in the 2020 edition of Chinese Pharmacopoeia， and 3 samples were randomly selected from each batch（10 tablets per batch）， and the coating weight gain was calculated（target value of 4%）. Partial least squares regression（PLSR） was used to construct a quantitative model of the 3 coating indicators， and the predicted values of the coating indicators were smoothed using the moving average method and used to determine the coating endpoints. ResultThe prediction determination coefficients（R_p²） for moisture absorption rate， film thickness and coating weight gain were 0.933 4， 0.932 6 and 0.965 9， the root mean square errors of prediction（RMSEP） were 0.163 5%， 1.870 9 μm and 0.240 3%， the relative percent deviations（RPD） were 3.711 0， 2.760 7 and 5.415 8， respectively. The results of the external validation set demonstrated that the real-time predicted values obtained by the models exhibited the same trend as the measured values， and the coating endpoint could be accurately predicted（with a prediction error of less than 7.32 min and a relative error of less than 5.63%）. ConclusionThe established NIRS model exhibits excellent predictive performance and can be used for quality control of VCYT during the coating process.

Objective To observe the improved effect of propofol on vascular hyporeactivity in septic rats and its underlying mechanism.Methods A total of 96 SD rats(12 weeks old,both genders,weighing 200～220 g)were randomly divided into sham group(n=16),sepsis group(n=16,cecal ligation and puncture),propofol group(n=16),propofol+ROCK inhibitor Y-27632 group(n=16),propofol+PKCαinhibitor GO6976 group(n=16),propofol+IP3 inhibitor 2-APB group(n=8)and propofol+gap junction inhibitor metoclopramide sodium(Movens)group(n=8).In vitro vascular ring reactivity and vascular calcium sensitivity were measured to observe the improved effects of propofol on vascular hyporeactivity in septic rats and its relationships with RhoA/ROCK,PKCα,IP3 and cell gap junction.Results Determination of in vitro vascular ring and calcium sensitivity showed that the contractile reactivity to norepinephrine(NE)and to calcium sensitivity were significantly decreased in the arterial rings isolated from the septic rats compared with those from the sham group,with the dose-response curve shifting to the right,and most significant decrease by 51.42％in the superior mesenteric artery(SMA,P＜0.05).Propofol treatment significantly improved the hyporeactivity and calcium sensitivity of the vessels isolated from the septic rats,especially those of the femoral artery with a recovery rate of 89.57％(P＜0.05).In comparison with the propofol group,the dose-response curves of the propofol+Y-27632 group and the propofol+GO6976 group were shifting to right,indicating that Y-27632 and GO6976 could significantly inhibit the amelioration of propofol on calcium sensitivity of SMA in severely septic rats with an inhibitory rate of 146.95％and 88.63％(P＜0.05),respectively.Isolated vascular reactivity measurement demonstrated that Y-27632 and Movens treatment significantly antagonized the ameliorated role of propofol on hyporeactivity of blood vessels from the septic rats with an inhibitory rate of 40.79％and 169.90％(P＜0.05),separately,while no such effect was observed in the propofol+GO6976 and propofol+2-APB groups.Conclusion Propofol treatment can significantly improve vascular hyporeactivity of septic rats,which may attribute to the increase of vascular calcium sensitivity through RhoA/ROCK pathway.

AIM: To investigate the relationship between vascular smooth muscle cell (VSMC) injury, organelle stress response and autophagic cell death (autophagy) and ferroptosis induced by the chemical hypoxia inducer cobalt chloride (CoCl2) through the bioinformatics analysis and in vitro cell experimentation. METHODS: The dataset GSE119226 of VSMC treated with cobalt chloride was acquired from the gene expression database (GEO). The R language was used to investigate the relationship between CoCl2 treatment and organelle stress response (Golgi stress, endoplasmic reticulum stress) and two forms of cell death (ferroptosis and autophagic cell death). With primary cultured rat VSMC (rVSMC) and CoCl2-induced anoxia model, the changes in cell viability were detected by CCK-8 method, and reactive oxygen species (ROS) levels were measured using DCFH-DA method. The expression levels of HIF-1α (a key molecule in hypoxia), Golgi stress markers GM130 and p115, endoplasmic reticulum stress markers GRP78 and CHOP, autophagy markers LC3-II / LC3-I and Beclin1, and ferroptosis markers GPx4 and xCT were detected by Western blot. The effect of inducing or inhibiting organelle stress and cell death on the CoCl2-induced cell damage was also observed. RESULTS: Differentially expressed genes analysis of GSE119226 dataset showed that CoCl2 treatment of VSMCs had significant effects on organelle function and stress response, autophagy and ferroptosis-related genes, in which endoplasmic reticulum stress, protein processing in endoplasmic reticulum, regulation of Golgi to plasma membrane protein transport, autophagy / autophagic cell death, and ferroptosis pathways were remarkably enriched. The results of in vitro experiment showed that compared with normal rVSMC, cell viability was significantly decreased after CoCl2 treatment, as well as HIF-1α protein expression and ROS levels in rVSMCs were increased. In rVSMC treated with Co-Cl2, the expression levels of Golgi structural proteins GM130 and p115 (reflecting the occurrence of Golgi stress) were decreased, while the markers GRP78 and CHOP (reflecting the occurrence of endoplasmic reticulum stress) were increased. At the same time, CoCl2 treatment also reduced the expression of autophagy markers LC3-II/LC3-I and Beclin1 (indicating the decrease levels of autophagy), while the expression of ferroptosis markers GPx4 and xCT were decreased (indicating the occurrence of ferroptosis). Compared with CoCl2 treatment group, induced Golgi stress, endoplasmic reticulum stress, or ferroptosis could further reduce cell viability, while inhibition of these processes could improve cell viability. On the other hand, increasing the level of autophagy can improve the cell viability. CONCLUSION: Hypoxia induced by cobalt chloride can lead to VSMC injury. Golgi stress, endoplasmic reticulum stress, ferroptosis, and the reduction of autophagy level play an important role in it. Inhibition of organelle stress response and ferroptosis, or increase of autophagy level can improve VSMC injury caused by cobalt chloride.

Objective:To discuss the effect of fluid resuscitation on the occurrence of ferroptosis in vascular tissue and the structure of vascular cells in the rats with blast injury complicated with hemorrhagic shock,and to clarify its mechanism.Methods:A total of 54 healthy adult SD rats were randomly divided into normal group,blast injury complicated with hemorrhagic shock(model)group,and the fluid resuscitation(treatment)group,and there were 18 rats in each group.Among them,10 rats were randomly selected to observe the surival status and another 8 rats were selected to detect the other indexes.The average survival time(ST),24 h and 72 h survival rates of the rats in various groups were observed;the blood pressure(BP),heart rate(HR),and respiratory rate(RR)of the rats in various groups were observed;the levels of serum creatinine(Scr),blood urea nitrogen(BUN),lactate(LAC),glucose(GLU),iron ions,glutathione(GSH),and malondialdehyde(MDA)and the activities of aspartate aminotransferase(AST),alanine aminotransferase(ALT)and lactate dehydrogenase(LDH)in serum of the rats in various groups were detected;Western blotting method was used to detect the expression levels of ferroptosis marker proteins glutathione peroxidase 4(GPX4),solute carrier family 7 member 11(SLC7A11),and heme oxygenase 1(HO-1)proteins in superior mesenteric artery tissue of the rats in various groups;the pathomorphology of the superior mesenteric artery of the rats in various groups was observed.Results:All the rats in normal group survived for 72 h,while the longest ST of the rats in model group did not exceed 9 h.Compared with model group,the ST and 24 h survival rate(SR)of the rats in treatment group were significantly increased(P＜0.05).Compared with normal group,the BP,HR,and RR of the rats in model group were significantly decreased(P＜0.01).Compared with model group,the BP,HR,and RR of the rats in treatment group were significantly increased after fluid resuscitation(P＜0.05).Compared with normal group,the activities of AST and ALT,and the levels of Scr and BUN in serum of the rats in model group were significantly increased(P＜0.01).Compared with model group,the serum levels of LAC and GLU of the rats in treatment group were significantly decreased(P＜0.01).Compared with normal group,the concentration of iron ion,GSH level,MDA level,LDH activity in serum of the rats in model group were significantly increased(P＜0.05);compared with model group,the concentration of iron ion and LDH activity in serum of the rats in treatment group was significantly decreased(P＜0.01).Compared with normal group,the expression levels of GPX4 and SLC7A11 in superior mesenteric artery tissue of the rats in model group were significantly decreased(P＜0.05);compared with model group,the expression levels of GPX4 and SLC7A11 in superior mesenteric artery tissue of the rats in treatment group were significantly increased(P＜0.05).Compared with normal group,the expression level of HO-1 protein in superior mesenteric artery tissue of the rats in model group was increased(P＜0.01);compared with model group,the expression level of HO-1 protein in superior mesenteric artery tissue of the rats in treatment group was increased(P＜0.01).The microscopic pathology results showed that the cell arrangement in the layers of the superior mesenteric artery tissue of the rats in model group was disordered,the swelling was significant and the thickness was increased;the pathological changes in superior mesenteric artery tissue of the rats in treatment group was alleviated.The ultramicroscopic pathology results showed that the endothelial cell structure of blood vessels of the rats in normal group was intact,and there was no swelling in the subendothelial matrix;the vascular endothelial cell membrane of the rats in model group was damaged,there were cytoplasmic dissolution and fragmentation,and the swelling of the subendothelial matrix was significant;the swelling of the vascular endothelial cells in treatment group was alleviated.Conclusion:Ferroptosis occurs in vascular tissue of the rats with blast injury complicated with hemorrhagic shock,and fluid resuscitation can alleviate the structural damage of the vascular cells by inhibiting the vascular tissue ferroptosis.

Objective:To explore the module of the construction and application of medical first-aid at the door of the space capsule and the air evacuation.Methods:According to the purpose, principle, and method set by the module, it was divided into two sub-modules: medical first-aid at the door of the space capsule and the air evacuation. During the comprehensive first-aid training, independent training and combined training were carried out respectively according to different mission stages of launch and recovery and different recovery terrain. Meanwhile, research was performed to ensure that medical carrying equipment was lightweight, modular, and portable, and the efficiency of modularization construction was tested in the comprehensive training.Results:The module of medical first-aid at the door of the space capsule and the air evacuation obviously shortened the rescuing time during the comprehensive training, the saving effect was remarkable, and the overall saving efficiency was significantly improved.Conclusions:The module of medical first-aid at the door of the space capsule and the air evacuation meet the requirements that the emergency support system of aerospace medicine should function on an immediate basis, ensuring accurate treatment and air evacuation without any delay, so that to achieve the aim of aerospace medicare.

Objective:To evaluate the role of α7 nicotinic acetylcholine receptor (α7nAChR) in penehyclidine hydrochloride-induced reduction of endotoxin-induced acute lung injury (ALI) in mice.Methods:Forty SPF healthy male C57BL/6 mice, aged 6-8 weeks, weighing 18-25 g, were divided into 4 groups ( n=10 each) using a random number table method: control group (group C), ALI group, penehyclidine hydrochloride group (PHC group), and α7nAChR inhibitor MLA group (MLA group). ALI was induced by intraperitoneal injection of lipopolysaccharide 15 mg/kg in anesthetized animals, while normal saline was given instead in group C. In PHC group, penehyclidine hydrochloride 2 mg/kg was intraperitoneally injected at 30 min before developing the model. MLA 10 mg/kg was intraperitoneally injected at 10 min before administration of penehyclidine hydrochloride in MLA group. Mice were sacrificed at 6 h after lipopolysaccharide administration, and lung tissues were collected for microscopic examination of the pathological changes (by HE staining) and for determination of the wet/dry weight ratio (W/D ratio), content of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-10 (by enzyme-linked immunosorbent assay) and expression of α7nAChR (by Western blot). Results:Compared with C group, the W/D ratio and contents of TNF-α and IL-1β were significantly increased, the content of IL-10 was decreased, and the expression of α7nAChR was up-regulated in ALI, PHC and MLA groups ( P<0.05). Compared with ALI group, the W/D ratio and contents of TNF-α and IL-1β were significantly decreased, the content of IL-10 was increased, and the expression of α7nAChR was up-regulated in PHC group ( P<0.05). Compared with PHC group, the W/D ratio and contents of TNF-α and IL-1β were significantly increased, the content of IL-10 was decreased, and the expression of α7nAChR was down-regulated in MLA group ( P<0.05). Compared with ALI group, the pathological changes of lung tissues were significantly mitigated in PHC group, while this effect of PHC was partially reversed by α7nAChR inhibitor MLA. Conclusions:α7nAChR is involved in penehyclidine hydrochloride-induced reduction of endotoxin-induced ALI in mice.

Objective:To evaluate the role of Toll-like receptor 4 (TLR4) in the mechanism by penehyclidine hydrochloride alleviating lipopolysaccharide (LPS)-induced acute lung injury(ALI)in rats.Methods:Twenty-four healthy male Sprague-Dawley rats, aged 10 weeks, weighing 220-250 g, were divided into 4 groups ( n=6 each) according to the random number table method: normal saline group (NS group), endotoxin-induced ALI group (ALI group), penehyclidine hydrochloride + normal saline group (PHC+ NS group) and penehyclidine hydrochloride + endotoxin-induced ALI group (PHC+ ALI group). ALI was induced by intratracheal instillation of LPS 5 mg/kg in anesthetized animals. In group PHC+ ALI, penehyclidine hydrochloride 2 mg/kg was intraperitoneally injected immediately after intratracheal instillation of LPS. The equal volume of normal saline was injected into the airway in group NS, and penehyclidine hydrochloride 2 mg/kg was intraperitoneally injected immediately after intratracheal instillation of normal saline in group PHC+ NS. The rats were sacrificed at 6 h after intratracheal instillation of LPS or normal saline, and lungs were removed. The lung was lavaged and broncho-alveolar lavage fluid (BALF) was collected for determination of concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) by enzyme-linked immunosorbent assay. Lung tissues were obtained for microscopic examination of the pathological changes (with a light microscope) and for determination of wet to dry lung weight ratio (W/D ratio) and TLR4 protein and mRNA expression (by immuno-histochemistry or real-time polymerase chain reaction). Results:Compared with group NS and group PHC+ NS, the W/D ratio and concentrations of TNF-α and IL-1β in BALF were significantly increased, the expression of TLR4 protein and mRNA in lung tissues was up-regulated ( P<0.01), and the pathological changes of lung tissues were aggravated in group ALI . Compared with group ALI, the W/D ratio and concentrations of TNF-α and IL-1β in BALF were significantly decreased, the expression of TLR4 protein and mRNA in lung tissues was down-regulated ( P<0.01), and the pathological changes of lung tissues were significantly mitigated in group PHC+ ALI. Conclusions:The mechanism by which penehyclidine hydrochloride reduces endotoxin-induced lung injury may be related to reduction of TLR4 activity and thus inhibition of pulmonary inflammatory responses in rats.

Objective:To investigate the application value of endoscopic ultrasound (EUS) in tumor staging of adenocarcinoma of the esophagogastric junction (AEG) after neoadjuvant concurrent chemoradiotherapy.Methods:The clinical data of 40 patients diagnosed with stage Ⅲ AEG and treated with neoadjuvant concurrent chemoradiotherapy from January 2016 to December 2021 in the First Affiliated Hospital of Hebei North University were retrospectively analyzed. EUS was used to perform preoperative tumor staging after neoadjuvant concurrent chemoradiotherapy to evaluate the therapeutic effect, and the consistency between EUS and postoperative pathological staging was analyzed.Results:In 40 AEG patients after neoadjuvant chemoradiotherapy, the EUS staging was stage yp-uT 2 in 12 cases, stage yp-uT 3 in 18 cases, and stage yp-uT 4 in 10 cases. The postoperative pathological staging was stage pT 1 in 2 cases, stage pT 2 in 14 cases, stage pT 3 in 12 cases, and stage pT 4 in 12 cases. Taking postoperative pathological results as the gold standard, the accuracy of EUS for T staging after neoadjuvant chemoradiotherapy was 62.5%, and the accuracy, sensitivity and specificity for stage T 2 were 58.3%, 50.0% and 80.8%, respectively. The accuracy, sensitivity and specificity for stage T 3 were 61.1%, 91.7% and 75.0%, respectively. The accuracy, sensitivity and specificity for stage T 4 were 70.0%, 58.3% and 89.3%, respectively. The Kappa value of the consistency test between yp-uT staging and pT staging was 0.453. The EUS staging of lymph nodes was stage yp-uN 0 in 15 cases, stage yp-uN 1 in 10 cases, stage yp-uN 2 in 10 cases, and stage yp-uN 3 in 5 cases. The postoperative pathological staging was stage pN 0 in 18 cases, stage pN 1 in 7 cases, stage pN 2 in 7 cases, and stage pN 3 in 8 cases. Taking postoperative pathological results as the gold standard, the accuracy rate of EUS for N staging after neoadjuvant chemoradiotherapy was 57.5%, and the accuracy, sensitivity and specificity of EUS for stage N 0 were 73.3%, 61.1% and 81.8%, respectively. The accuracy, sensitivity and specificity for stage N 1 were 50.0%, 71.4% and 84.8%, respectively. The accuracy, sensitivity and specificity for stage N 2 were 40.0%, 57.1% and 81.8%, respectively. The accuracy, sensitivity and specificity for stage N 3 were 60.0%, 37.5% and 93.8%, respectively. The Kappa value of the consistency test between yp-uN staging and pN staging was 0.409. Conclusions:EUS is not accurate for T staging in patients with stage Ⅲ AEG after neoadjuvant therapy, but has high sensitivity for stage T 3 and high specificity for stage T 4. EUS has low sensitivity for N staging in patients with stage Ⅲ AEG after neoadjuvant therapy, but has high specificity for stage N 3.

Objective:To compare efficacy and erectile function outcome of Non-transecting Urethroplasty (NTU)with excision and primary anastomotic urethroplasty(EPA) in the management of bulbar urethral stricture.Method:A retrospective analysis of the case data of 73 patients with bulbar urethral stricture admitted to Shanghai Sixth People's Hospital from January 2016 to December 2019. The patients are 18 to 60 years old, because of the stenosis of the bulbous urethra, the length of the stenosis is less than 2 cm, and there is no history of urethral surgery, no multiple urethral stricture, and no obvious ED before surgery. According to the operation method, the patients were divided into 25 cases in NTU group and 48 cases in EPA group. The ages of the NTU group and the EPA group were (39.2±9.4) years and (42.1±9.3) years, respectively. The course of the disease was 6.0(3.0-14.0) months and 6.5(3.0-11.0) months, respectively, and the body mass index was (23.7±3.2) kg/m 2 and (24.5±2.7) kg/m 2, the preoperative maximum urine flow rate (Q max) was (8.7±4.3) ml/s and (7.9±4.6) ml/s, respectively, and the length of the stenosis was respectively (1.7±0.4) cm and (1.8±0.2) cm, the preoperative International Erectile Function Questionnaire (IIEF-5) was (20.9±1.9) points and (21.3±2.1) points, respectively, the difference was not statistically significant ( P>0.05). The etiology of NTU group and EPA group were 8 cases (32.0%) and 31 cases (64.6%) of trauma, 11 cases (44.0%) and 9 cases (18.8%) of iatrogenic injury, and 6 cases (24.0%) and 8 cases (16.7%), the difference was statistically significant ( P=0.023). All operations were performed by the same team of doctors. The urethral scar was assessed during the operation. If the scar tissue can be completely removed without breaking the urethra, NTU is performed. The distal end of the urethra is cut at the dorsal side of the narrow segment of the urethra, and the urethral scar is removed in a transverse wedge shape. The urethra is sutured; otherwise, EPA is performed, the urethra is completely cut off, the stricture of the urethra and surrounding scar tissue is completely removed, and the urethra end-to-end anastomosis is performed. Record the operation time and intraoperative bleeding. Difficulty urinating after surgery, urethral microscopy and urethral angiography showed that the urethral stricture at the surgical site was defined as a failure of the operation. The urinary catheter was removed 3 weeks after surgery, urine flow rate was measured at 3 weeks, 6 months, and 12 months after surgery, erectile function was evaluated 12 months after surgery, and urethral angiography was performed 1 to 2 years after surgery. Result:All 73 operations in this study were successfully completed. The operation time of NTU group and EPA group were (67.6±11.3) min and (62.7±10.1) min, respectively, and the difference was not statistically significant ( P=0.063); intraoperative blood loss was (71.6±16.2) ml and (86.0±20.8) ml, the difference was statistically significant ( P=0.004). The postoperative median follow-up time was 18.0 months (13-38 months). The surgical success rates of the NTU group and EPA group were 92.0%(23/25) and 93.8%(45/48), respectively. The Q max of the NTU group and the EPA group were (26.7±3.6) ml/s and (28.1±8.7) ml/s, (25.2±3.5) ml/s and (26.7±8.1) ml/s, (25.0±4.3) ml/s and (26.2±7.2) ml/s; the IIEF-5 scores were (21.8±1.6) and (20.6±2.9) points respectively at 12 months after operation, the difference was both No statistical significance ( P>0.05). There was a statistically significant difference in IIEF-5 between NTU group and preoperative ( P=0.023). Conclusion:NTU can achieve the same outcomes as EPA in the management of bulbar urethral stricture. More importantly, the continuance of bulbar urethra is attained and avoiding rupture of bulbar cavernous artery, so as to protect the blood supply of penile and erectile function. NTU is a minimally invasive, feasible surgical method, which is advised for the patients with shorter stricture segment and fewer fibrosis.