OBJECTIVE To analyze the research status， hotspots and trends in the research of intravenous thrombolytic drugs in the treatment of acute ischemic stroke. METHODS The original studies related to intravenous thrombolytic drugs for acute ischemic stroke were collected by searching the Web of Science core database； the authors， countries/regions， institutions and keywords of the literature were visualized and analyzed using CiteSpace 6.1.R6 software. RESULTS A total of 1 810 articles were included， and the number of articles published showed an increasing trend year by year， with the United States （556 articles） having the largest number of articles， and China ranking the second （339 articles， with centrality of 0）. The most published author was Ahmed of Sweden （32 articles）， and the most published institution was the University of Calgary in Canada （80 articles）. The current research status and hotspots were mainly the application and therapeutic exploration of new thrombolytic drugs， and the frontier and development trend were the adverse prognosis of neurological deterioration and hemorrhagic transformation accompanied by intravenous thrombolytic drug treatment. CONCLUSIONS The research hotspots and frontier about intravenous thrombolytic drugs for acute ischemic stroke are mainly the third generation of intravenous tissue plasminogen activator， and the exploration of new intravenous thrombolytic drugs and their safety and effectiveness will be the future research hotspots. Chinese scholars and research teams should strengthen cooperation and exchanges with other countries， which can be strengthened by carrying out multi-center clinical trials.

Objective To study the correlation between carotid bifurcation geometry and atherosclerotic plaque vulnerability using high-resolution magnetic resonance vessel wall imaging(HRMR-VWI),and to seek the potential predictor for vulnerable plaque for-mation.Methods The clinical information and imaging data of 104 patients with carotid bifurcation plaque detected by HRMR-VWI were analyzed retrospectively.Carotid bifurcation geometric parameters was measured to determine whether the carotid bifurcation plaque was vulnerable plaque,and they were divided into vulnerable plaque group(69 cases)and stable plaque group(35 cases).The difference of carotid bifurcation geometry of various groups was investigated,and the influence of common traditional risk factors to obtain independent risk factors was adjusted.Receiver operating characteristic(ROC)curve was drawn.Results Among 104 carotid artery,vulnerable plaque group had larger bifurcation angle(54.00 vs 48.80,P＜0.001),less luminal expansion(1.76 vs 1.94,P=0.002)and less outflow/inflow area ratio(0.79 vs 0.88,P＜0.001)compared with stable plaque group.After adjusting,binary logistic regres-sion indicated that bifurcation angle[odds ratio(OR)1.132 per 10° increase;95％confidence interval(CI)1.044-1.225],luminal expan-sion(OR 0.084 per 1 increase;95％CI 0.014-0.492)and outflow/inflow area ratio(OR 0.357 per 0.01 increase;95％CI 0.177-0.723)were independent risk factors of vulnerable plaque formation.Bringing them into the final model,the area under the curve(AUC)was 0.878 above the basic model(AUC=0.664).Conclusion Bifur-cation angle,luminal expansion and outflow/inflow area ratio are independently associated with vulnerable plaque formation.Carotid bifurcation geometry have the certain predictive efficiency of vulnerable plaque formation and have the incremental diagnostic value to traditional risk factors,which are expected to be effective imaging makers for the formation of vulnerable plaque.

ObjectiveTo establish a rat model of diabetic wound by feeding on a high-fat and high-sugar diet combined with intraperitoneal injection of streptozotocin （STZ） and surgical preparation of full-thickness skin defects， observe the effect of cinnamaldehyde on the wound healing of diabetes rats， and explore the therapeutic mechanism of cinnamaldehyde in improving wound healing of diabetes rats based on the PTEN-induced putative kinase （PINK1）/Parkin pathway-mediated mitochondrial autophagy. MethodForty-eight male SD rats were randomly divided into blank group （n=12） and diabetes group （n=36）. The diabetes group was further randomly divided into model group， cinnamaldehyde group， and Beifuxin group， with 12 rats in each group. The blank group and the model group received routine disinfection with physiological saline after creating the wounds， while the cinnamaldehyde group received topical application of polyethylene glycol 400 （PEG 400） gel containing 4 μmol·L^-1 cinnamaldehyde， and the Beifuxin group received topical application of Beifuxin gel. Dressings were changed once daily. The wound healing rate of each group was observed. On the 7th and 14th days after intervention， the wound tissues of the rats were collected. Hematoxylin and eosin （HE） staining was performed to observe the pathological changes in the local tissues. Immunohistochemistry （IHC） was used to detect the expression of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， vascular endothelial growth factor （VEGF）， and collagen fibers. Immunofluorescence （IF） and Real-time polymerase chain reaction （Real-time PCR） were used to detect the protein， and mRNA expression of PINK1， Parkin， microtubule-associated protein 1 light chain 3 Ⅱ （LC3 Ⅱ）. ResultAfter intraperitoneal injection of STZ， compared with the blank group， the random blood glucose values of rats in the diabetic group increased significantly （P<0.01）， all higher than 16.7 mmol·L^-1， and persistently hyperglycemic for some time after modeling. Compared with the blank group， the model group showed poor growth and healing of granulation tissue in the wounds， and the wound healing rate decreased （P<0.01）. On the 7^th day after intervention， the blank group had squamous epithelial coverage on the wounds. Compared with the blank group， the model group only had a small amount of scab at the wound edges， with a large number of infiltrating inflammatory cells in the wounds. The protein expression levels of IL-6 and TNF-α in the tissues increased （P<0.01）， and the protein and mRNA levels of PINK1， Parkin， and LC3Ⅱ decreased （P<0.01）. On the 14^th day after the intervention， the granulation tissue in the wounds of the blank group was mature and well-healed. Compared with the blank group， the model group still had infiltrating inflammatory cells and red blood cell exudation. The protein expression levels of VEGF and collagen fibers in the tissues decreased （P<0.01）， and the protein and mRNA expression levels of PINK1， Parkin， and LC3Ⅱ increased （P<0.01）. Compared with the model group， the cinnamaldehyde group and the Beifuxin group showed better wound healing， with increased wound healing rates （P<0.01）. On the 7th day after intervention， the protein expression levels of IL-6 and TNF-α in the tissues decreased （P<0.01）， and the protein and mRNA expression levels of PINK1， Parkin， and LC3Ⅱ increased （P<0.01）. On the 14th day after intervention， the protein expression levels of VEGF and collagen fibers in the tissues increased （P<0.01）， and the protein and mRNA expression levels of PINK1， Parkin， and LC3Ⅱ decreased （P<0.01）. ConclusionCinnamaldehyde can promote the wound healing of diabetes rats by increasing the wound healing rate， reducing the levels of inflammatory factors IL-6 and TNF-α， and increasing the levels of VEGF and collagen fibers. Its mechanism may be related to the regulation of the PINK1/Parkin signaling pathway， activation of mitochondrial autophagy， inhibition of inflammatory responses， and promotion of angiogenesis and collagen synthesis， thereby promoting the wound healing of diabetes rats.

Objective:To analyze the value of peritumoral vascular invasion (PVI) on the prognosis of patients with osteosarcoma.Methods:A total of 232 patients with primary osteosarcoma from 2007 to 2016 were retrospectively analyzed, including 142 males and 90 females. The average age was 17.9±8.2 years (range, 3-39 years). There were 22 positive and 210 negative cases of PVI, 94 deaths and 138 survivals. Univariate survival analysis (Log-rank test and univariate Cox regression) was used to evaluate the effects of age, gender, PVI status, tumor location, surgical method, sensitivity to chemotherapy, and chemotherapy regimen on the prognosis of osteosarcoma. The indicators with statistically significant differences were included in the multivariate Cox regression model to finally determine the risk factors affecting the prognosis of osteosarcoma. The relationship between PVI status and 5-year survival and the incidence of recurrence or metastasis was evaluated using the Kaplan-Meier method.Results:All patients were followed up for 7.6±4.5 years (range, 0.1-15 years). The differences in sensitivity to chemotherapy (χ 2=9.52, P=0.002), choice of chemotherapy regimen (χ 2=8.87, P=0.012), choice of surgical modality (χ 2=13.50, P<0.001), tumor metastasis rate (χ 2=8.51, P=0.004) and mortality rate (χ 2=5.39, P= 0.020) of PVI positive group and PVI negative group had statistically significant differences. Univariate survival analysis was performed on 232 patients with osteosarcoma (gender, age, PVI status, site of tumor development, surgical modality, sensitivity to chemotherapy, and chemotherapy regimen). Indicators with statistically significant differences were included in a multifactorial Cox regression model. The results showed PVI positive [5-year survival rate: HR=2.02, 95% CI (1.61, 2.79), P=0.010; 5-year recurrence or metastasis rate: HR=2.25, 95% CI (1.55, 3.14), P<0.001], surgical procedure as amputation [5-year survival rate: HR=1.22, 95% CI (0.94, 1.78), P=0.037; 5-year recurrence or metastasis rate: HR=1.58, 95% CI (1.11, 2.23), P=0.026] and poor sensitivity to chemotherapy [5-year survival rate: HR=2.71, 95% CI (1.84, 3.98), P=0.001; 5-year recurrence or metastasis rate: HR=2.52, 95% CI (1.88, 3.45), P<0.001] was associated with poor prognosis. Kaplan-Meier curve showed that the 5-year survival rate of PVI positive group was 34%, which was lower than 68% of PVI negative group. The 5-year recurrence or metastasis rate was 72% in the PVI negative group, which was significantly higher than 38% in the PVI negative group ( P<0.05). Conclusion:The 5-year survival rate of PVI positive group was lower than that of PVI negative group, and the 5-year recurrence or metastasis rate was higher than that of PVI negative group. The presence of microvascular angiosarcoma plugs infiltrating the peritumoral tissue in surgical specimens of osteosarcoma after neoadjuvant chemotherapy is a useful indicator to assess the prognosis of patients with osteosarcoma.

Objective:To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) for early hypopharyngeal carcinoma and precancerous lesions.Methods:Clinical data of 41 patients who received ESD for early hypopharyngeal carcinoma and precancerous lesions from August 2013 to August 2019 in the Department of Endoscopy of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively analyzed. Main outcome measurements included operation completion rate, operation time, en bloc resection rate, R0 resection rate, complication rate and recurrence.Results:ESD was successfully completed in all 41 cases, with a success rate of 100.0% and a mean time of 49.1 min (ranged 10-110 min). Fifty-four lesions underwent en bloc resection, with an en bloc resection rate of 98.2% (54/55), of which 41 had negative horizontal and vertical margins, and the R0 resection rate was 74.5% (41/55). During the operation of 55 lesions, there was a small amount of blood oozing on the wound surface, and electrocoagulation with thermal biopsy forceps could successfully stop the bleeding. No perforation occurred, and 2 cases (4.3%) had delayed bleeding after ESD, and hemostasis was successful under emergency endoscopy. Postoperative endoscopy showed that 1 case (2.2%) had esophageal entrance stenosis, and the obstruction was relieved after repeated water balloon dilatation. The follow-up period ranged from 3 to 72 months, and the median time was 18 months. One case was found to have mucosal lesions in the same part of the hypopharynx and received ESD treatment again. Follow-up to October 2020, no residual lesions and recurrence were found.Conclusion:ESD is a safe and effective option for the treatment of early hypopharyngeal carcinoma and precancerous lesions, which is worthy of clinical application.

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

Objective:To explore sex and rural-urban differences in the associations of different blood pressure levels with the risk of prediabetes.Methods:We used a multi-stage stratified cluster random sampling method to investigate 21 637 residents aged ≥18 years from 10 survey areas in Hubei province in 2020. The data on questionnaire, physical measurements, and laboratory indicators of the participants were collected. The associations of different blood pressure levels with risk of prediabetes by sex and regions were analyzed using multivariate logistic regressions after complex weighting.Results:A total of 16 111 subjects were included. The prevalence (95% CI) of prediabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG complicated with IGT were 25.1% (14.4%-35.9%), 12.7% (3.2%-22.1%), 8.1% (6.3%-9.8%), and 4.4% (2.3%-6.5%), respectively. After multivariate adjustment, the risk of prediabetes, IFG, IGT, and IFG complicated with IGT increased with the increment of blood pressure (both P for trend <0.05). The positive dose-response relationships between blood pressure levels and risk of prediabetes were also significant among male, urban, and rural residents (both P for trend <0.05), and the interactions between sex and blood pressure showed significant associations for risk of prediabetes and IGT (both P for interaction <0.05). Conclusions:Higher blood pressure levels were associated with an increased risk of prediabetes. The association with prediabetes was stronger in males, but no significant difference was found between urban and rural residents. More distinctive and effective prevention and control strategies should be developed for different populations.

Objective:To explore the effect of three-dimensional(3D) design and printing in the reoperation of asymmetric deformity after orthognathic surgery.Methods:Patients of facial asymmetry after orthognathic surgery were included in the Department of Stomatology, Shenzhen University General Hospital and Department of Oral & Maxillofacial Surgery, Shenzhen Stomatology Hospital Affiliated to Shenzhen University from January 2016 to August 2020. Surgical plans and guide plates (positioning guide plate, bone cutting guide plate, reset guide plate) were made by 3D design and printing. During the operations, guide plates were used to guide osteotomy. The facial shape satisfaction of clinicians/patients/third-party were recorded and analyzed at preoperation and 6-12 months postoperation. These patients’ CT scan data was imported to the digital surgery software. Then the distance of chin-midpoint to mid-sagittal plane and the difference of bilateral protuberant point of mandible body to mid-sagittal plane were measured at preoperation and 6-12 months postoperation to determine whether the asymmetry were corrected and postoperative distance were the same as the preoperative design. Data analysis was conducted using SPSS 17.0 statistical software, and measurement data were expressed as Mean±SD. The preoperative and postoperative satisfaction of patients/clinicians/third-party, digital data of preoperation/postoperation and digital data of design-operations/postoperation were analyzed by paired t-test. Analysis of variance and dunnett- t test were used to compare the satisfaction of the surgeon, the third party and patients before and after operation. Results:There were 16 cases of facial asymmetry after orthognathic surgery, including 3 males and 13 females, aged from 18 to 35 years. In 9 cases, genioplasty were used to correct chin deviation. In the other 4 cases, unilateral buccal cortical bone resection were used to correct mandibular body deviation. In the last 3 cases, genioplasty and unilateral buccal cortical bone resection were both applied. All 16 patients successfully received the operation according to the preoperative digital designed plate. Postoperative follow-up ranged 6 months to 1 year. In the 12 cases of genioplasty, the distance of chin-midpoint to mid-sagittal plane reduced from(4.99±0.83) mm preoperatively to (1.63±0.80) mm postoperatively and the difference significant ( t=9.09, P<0.001). There was no significant difference between the distance of preoperative design [(1.50±0.43) mm] and the postoperative one ( t=-0.83, P=0.423). In the 7 cases of unilateral buccal cortical bone resection, the difference of bilateral protuberant point of mandible body to mid-sagitta plane reduced from (7.26±1.20) mm preoperatively to (2.44±0.56) mm postoperatively and the difference was statistically significant ( t=10.26, P<0.001). There was no significant difference was observed between the distance of preoperative design [(2.39±0.16) mm] and the postoperative one ( t=-0.29, P=0.779). The preoperative satisfaction of patients, clinicians and third-party were 65.94±8.21, 79.69±5.91, 79.38±7.50. The postoperative satisfaction of patients, clinicians and third-party were 90.00±5.48, 90.63±2.50, 90.00±4.08. The postoperative satisfaction of patients, chief surgeon and third party was higher than that preoperative satisfaction and the difference was statistically significant( t=-9.15, P<0.001; t=-7.50, P<0.001; t=-6.04, P<0.001). The difference of preoperation satisfaction was statistically significant( F=18.66, P<0.001). The difference of satisfaction of the clinicians and the patients was statistically significant ( P<0.001). The difference of satisfaction of the third-party and the patients was statistically significant ( P<0.001). The difference of postoperation satisfaction was not statistically significant( F=0.12, P=0.889). Conclusions:3D design and printing can 3D analyze comprehensively, simulate surgery accurately, visualize proposed result and guide 3D printing digital guiding plate to perform surgery accurately. In addition, it can improve postoperative satisfaction. So 3D design and printing had obvious advantages in the secondary surgery of asymmetric deformity correction after orthognathic surgery.

Objective:To explore the effect of three-dimensional(3D) design and printing in the reoperation of asymmetric deformity after orthognathic surgery.Methods:Patients of facial asymmetry after orthognathic surgery were included in the Department of Stomatology, Shenzhen University General Hospital and Department of Oral & Maxillofacial Surgery, Shenzhen Stomatology Hospital Affiliated to Shenzhen University from January 2016 to August 2020. Surgical plans and guide plates (positioning guide plate, bone cutting guide plate, reset guide plate) were made by 3D design and printing. During the operations, guide plates were used to guide osteotomy. The facial shape satisfaction of clinicians/patients/third-party were recorded and analyzed at preoperation and 6-12 months postoperation. These patients’ CT scan data was imported to the digital surgery software. Then the distance of chin-midpoint to mid-sagittal plane and the difference of bilateral protuberant point of mandible body to mid-sagittal plane were measured at preoperation and 6-12 months postoperation to determine whether the asymmetry were corrected and postoperative distance were the same as the preoperative design. Data analysis was conducted using SPSS 17.0 statistical software, and measurement data were expressed as Mean±SD. The preoperative and postoperative satisfaction of patients/clinicians/third-party, digital data of preoperation/postoperation and digital data of design-operations/postoperation were analyzed by paired t-test. Analysis of variance and dunnett- t test were used to compare the satisfaction of the surgeon, the third party and patients before and after operation. Results:There were 16 cases of facial asymmetry after orthognathic surgery, including 3 males and 13 females, aged from 18 to 35 years. In 9 cases, genioplasty were used to correct chin deviation. In the other 4 cases, unilateral buccal cortical bone resection were used to correct mandibular body deviation. In the last 3 cases, genioplasty and unilateral buccal cortical bone resection were both applied. All 16 patients successfully received the operation according to the preoperative digital designed plate. Postoperative follow-up ranged 6 months to 1 year. In the 12 cases of genioplasty, the distance of chin-midpoint to mid-sagittal plane reduced from(4.99±0.83) mm preoperatively to (1.63±0.80) mm postoperatively and the difference significant ( t=9.09, P<0.001). There was no significant difference between the distance of preoperative design [(1.50±0.43) mm] and the postoperative one ( t=-0.83, P=0.423). In the 7 cases of unilateral buccal cortical bone resection, the difference of bilateral protuberant point of mandible body to mid-sagitta plane reduced from (7.26±1.20) mm preoperatively to (2.44±0.56) mm postoperatively and the difference was statistically significant ( t=10.26, P<0.001). There was no significant difference was observed between the distance of preoperative design [(2.39±0.16) mm] and the postoperative one ( t=-0.29, P=0.779). The preoperative satisfaction of patients, clinicians and third-party were 65.94±8.21, 79.69±5.91, 79.38±7.50. The postoperative satisfaction of patients, clinicians and third-party were 90.00±5.48, 90.63±2.50, 90.00±4.08. The postoperative satisfaction of patients, chief surgeon and third party was higher than that preoperative satisfaction and the difference was statistically significant( t=-9.15, P<0.001; t=-7.50, P<0.001; t=-6.04, P<0.001). The difference of preoperation satisfaction was statistically significant( F=18.66, P<0.001). The difference of satisfaction of the clinicians and the patients was statistically significant ( P<0.001). The difference of satisfaction of the third-party and the patients was statistically significant ( P<0.001). The difference of postoperation satisfaction was not statistically significant( F=0.12, P=0.889). Conclusions:3D design and printing can 3D analyze comprehensively, simulate surgery accurately, visualize proposed result and guide 3D printing digital guiding plate to perform surgery accurately. In addition, it can improve postoperative satisfaction. So 3D design and printing had obvious advantages in the secondary surgery of asymmetric deformity correction after orthognathic surgery.

Objective:To observe the effect of peripheral 5-hydroxytryptophan (5-HT)-induced neutrophil extracellular trap (NET) on lung injury in septic mice.Methods:Wild-type (WT type) and Tph1 knockout (KO) C57 mice (6-8 weeks) were selected and divided into WT mice sham group, WT mice sepsis group, Tph1 KO mice sham group and Tph1 KO mice sepsis group according to the random number table method. Mice in the sham group received sham surgery (only open the abdominal cavity to flip the cecum without ligation and puncture, and then close the abdominal cavity); the mice in the sepsis group received cecal ligation and puncture (CLP) to establish sepsis model. The mice were sacrificed 12 hours after the operation, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in bronchialalveolar lavage fluid (BALF) were detected by enzyme linked immunoadsordent assay (ELISA); at the same time, the lung tissues were collected, and the pathological changes of lung tissues were observed under light microscope, and the production of NET in lung tissues was observed by immunofluorescence microscope. Results:The pathological results suggested that the lung tissue structure in sham groups was intact without exudation, while the alveolar structures of mice in the sepsis groups were damaged, with obvious exudation in the alveolar cavity and thickened alveolar walls accompanied by a large number of inflammatory cell infiltration, and the degree of lung injury in the sepsis group of WT mice was more severe than that of the sepsis group of Tph1 KO mice. ELISA results showed that there was no statistically significant difference in the contents of TNF-α and IL-6 in mice BALF from different strains of the sham group; while the contents of TNF-α and IL-6 in BALF of septic mice group were significantly higher than those in sham group [WT mice: TNF-α (μg/L) was 158.20±28.46 vs. 14.00±3.28, IL-6 (μg/L) was 304.98±21.78 vs. 57.70±12.30; Tph1 KO mice: TNF-α (μg/L) was 85.88±20.13 vs. 14.95±1.53, IL-6 (μg/L) was 169.50±45.61 vs. 55.05±12.68, all P < 0.01], and the above index levels in the sepsis group of WT mice were significantly higher than the sepsis group of Tph1 KO mice [TNF-α (μg/L): 158.20±28.46 vs. 85.88±20.13, IL-6 (μg/L): 304.98±21.78 vs. 169.50±45.61, both P < 0.01]. Immunofluorescence staining showed that a very small amount of NET formation was detected in the mice lungs from the sham group; a large amount of NET formation was detected in the lung tissues in the sepsis group, which were significantly higher than those in sham group [WT mice: (34.75±7.27)% vs. (1.75±0.96)%, Tph1 KO mice: (14.25±5.74)% vs. (2.50±1.29)%, both P < 0.01], and the amount of NET produced in the lung tissues of the WT mice sepsis group was significantly higher than that of the Tph1 KO mice sepsis group [(34.75±7.27)% vs. (14.25±5.74)%, P < 0.01]. Conclusions:In sepsis, the increased production of inflammatory factors in the mice lung tissues induces to lung injury. The mechanism may relate to the increased production of NET in the lung tissues mediated by peripheral 5-HT synthesized by enterochromaffin cells and released into the blood; inhibiting the production of 5-HT in the peripheral blood can effectively reduce the production of NET in the lung tissues, thereby reducing lung injury.