Formation of Hyperprogression of Immunotherapy from Perspective of "Yang Deficiency and Toxin Knot" and Role of "Five Views on Differentiation and Treatment" Intervention / 中国实验方剂学杂志

Immune checkpoint inhibitors （ICIs） have shown good efficacy in tumor treatment and have changed the landscape of tumor treatment. However， some patients treated with ICIs have not only failed to achieve the desired therapeutic effect， but also developed an atypical response pattern of abnormally accelerated tumor growth， namely hyperprogressive disease （HPD）. The pathogenesis of HPD is still unclear and it is difficult to diagnose， which poses a challenge for clinical identification and treatment decisions. Exploring the underlying mechanism of HPD is important to improve the effect of immunotherapy. Based on the theory of "Yang deficiency and toxic knot"， this paper discussed the mechanism of HPD in immunotherapy from the perspective of "spleen and kidney Yang deficiency and hefty toxic pathogens". It was concluded that the inactivation of p53 oncogene and immunosuppressive microenvironment were the manifestations of the deficiency of healthy qi in the body and declined yang in the spleen and kidney， serving as an important basis for the occurrence of HPD. Adverse reactions caused by ICIs belong to the category of "drug toxicity". The occurrence and development of murine double minute 2 （MDM2）/murine double minute 4 （MDM4） activation， epidermal growth factor receptor （EGFR） mutation， and tumor inflammatory microenvironment are the manifestations of the hyperactivity of pathogenic Qi， conflict of cancer toxicity and drug toxicity， and being hefty by virtue of deficiency， which can promote the abnormal proliferation of tumor cells， and they are the core pathogenic elements of HPD and are closely related to disease prognosis. In terms of treatment， under the guidance of the theory of "five views on differentiation and treatment" （time-space view， core view， symptom view， precision view， and disease-before-onset view）， which was summarized according to the clinical practice of this research team， this paper， taking the prevention and treatment of HPD as the entry point， formulated traditional Chinese medicine （TCM） compounds to reinforce healthy Qi and warm Yang and realize the dynamic management of the whole spatiotemporal cycle， and removed toxins and resisted cancer to realize the all-round systemic intervention of the specimen. Additionally， targets were enriched in the macro-clinical manifestations and microscopic pathological changes of HPD to improve the targeting of drug selection and the precision of prevention and treatment， giving full play to the unique therapeutic advantages of TCM， and providing new ideas for the clinical application of TCM in the prevention and treatment of HPD.

Latent period and incubation period with associated factors of COVID-19 caused by Omicron variant / 中华预防医学杂志

Objective: To estimate the latent period and incubation period of Omicron variant infections and analyze associated factors. Methods: From January 1 to June 30, 2022, 467 infections and 335 symptomatic infections in five local Omicron variant outbreaks in China were selected as the study subjects. The latent period and incubation period were estimated by using log-normal distribution and gamma distribution models, and the associated factors were analyzed by using the accelerated failure time model (AFT). Results: The median (Q1, Q3) age of 467 Omicron infections including 253 males (54.18%) was 26 (20, 39) years old. There were 132 asymptomatic infections (28.27%) and 335 (71.73%) symptomatic infections. The mean latent period of 467 Omicron infections was 2.65 (95%CI: 2.53-2.78) days, and 98% of infections were positive for nucleic acid test within 6.37 (95%CI: 5.86-6.82) days after infection. The mean incubation period of 335 symptomatic infections was 3.40 (95%CI: 3.25-3.57) days, and 97% of them developed clinical symptoms within 6.80 (95%CI: 6.34-7.22) days after infection. The results of the AFT model analysis showed that compared with the group aged 18-49 years old, the latent period [exp(β)=1.36 (95%CI: 1.16-1.60), P<0.001] and incubation period [exp(β)=1.24 (95%CI: 1.07-1.45), P=0.006] of infections aged 0-17 years old were prolonged. The latent period [exp(β)=1.38 (95%CI: 1.17-1.63), P<0.001] and the incubation period [exp(β)=1.26 (95%CI: 1.06-1.48), P=0.007] of infections aged 50 years old and above were also prolonged. Conclusion: The latent period and incubation period of most Omicron infections are within 7 days, and age may be a influencing factor of the latent period and incubation period.

Long-term outcome of transcatheter repair of paravalvular leak post surgical mitral valve replacement / 中华心血管病杂志

Objective: To explore the long-term clinical efficacy of transcatheter repair of mitral paravalvular leak (PVL) post surgical mitral valve replacement. Methods: This study is a retrospective study. Patients who completed transcatheter repair of paravalvular leak after surgical mitral valve replacement at Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine from March 2010 to December 2018 were included. Technical success was defined as the occluder being stably implanted in the paravalvular leak site without affecting the function of the mitral valve and surrounding tissues; and there were no intervention-related complications, such as new hemolysis or aggravated hemolysis, and echocardiography confirmed mitral paravalvular regurgitation reduced by more than 1 grade. Patients were followed up at 30 days, 1, and 3 years after the intervention. The main endpoints were all-cause death and re-surgery due to interventional failure or serious complications. The occurrence of occluder-mediated hemolysis and chronic renal insufficiency was recorded, and patients were monitored with echocardiography during follow up. Results: A total of 75 patients were included, aged (54.3±22.9) years old, and 38 patients were males. All patients had decreased cardiac function and/or hemolysis before intervention. Procedural success was achieved in 54 patients (72.0%). Incidence of device-mediated hemolysis was 18.7% (14/75). During the follow-up period, all-cause death occurred in 7 patients (9.3%), and 3 were cardiac deaths.The 3-year event-free survival rate was 81.3% (61/75). The need for cardiac surgery was 9.3% (7/75): 3 cases due to severe device-mediated hemolysis, 2 cases due to prosthetic valve failure and 2 cases due to moderate to severe residual regurgitation. The echocardiography follow-up results showed that the position of the occluder was stable, there was no impact on the artificial valve function and surrounding structures, and the residual regurgitation was stable without progressive increase in event-free patients. Compared with pre-intervention, the left ventricular end systolic diameter ((33.9±7.4)mm vs. (38.3±8.9) mm, P=0.036), end diastolic diameter ((53.7±8.3) mm vs. (58.4±9.1) mm, P=0.045) and left atrial diameter (59.3 (44.5, 90.7) mm vs. 64.3 (44.8, 96.6) mm, P=0.049) were significantly reduced, pulmonary artery systolic pressure was also significantly decreased ((36.5±15.8) mmHg vs. (46.3±14.9) mmHg, P=0.022, 1 mmHg=0.133 kPa). There was no significant difference between 3 years and 1 year after transcatheter repair of mitral paravalvular leak post surgical mitral valve replacement (all P>0.05). Conclusion: Transcatheter repair of mitral paravalvular leak post surgical mitral valve replacement is an effective treatment option in selective patients.

Prevalence and distribution of ossification of ligamentum flavum at the adjacent segment of the apex in patients with degenerative kyphosis / 中华骨科杂志

Objective:To evaluate the prevalence and distribution of ossification of ligamentum flavum (OLF) at the segments adjacent to the apex in patients with degenerative kyphosis.Methods:All of 74 patients with degenerative kyphosis from January 2018 to December 2021 were retrospective reviewed. All patients were taken anteroposterior and lateral radiographs, CT scan and magnetic resonance imaging (MRI) of the entire spine. Global kyphosis, the morphology of kyphosis and the occurrence of OLF at three segments adjacent to the kyphosis apex were recorded.Results:Of the 74 patients, 54 patients (73%) developed OLF in three segments adjacent to the kyphotic apex. The mean age of the 54 patients was 61.4±6.8 years, and the mean global kyphosis was 49.5°±21.2°. Among other 20 patients without OLF, the mean age was 56.1±7.5 years, and the mean kyphosis angle was 52.1°±19.1°. There was a statistically significant difference in ages ( t=2.92, P=0.005), but no statistically significant difference was observed regarding global kyphosis ( t=0.48, P=0.634). In these 74 patients, 9 patients had angular kyphosis, of which 8 (89%) developed OLF; of the 65 patients without angular kyphosis, 46 patients (71%) developed OLF. There was no significant difference between them (χ 2=1.32, P=0.251). Among the 54 patients diagnosed with OLF, 5 patients (9%) suffered ossification of the posterior longitudinal ligament (OPLL) and 20 patients (37%) suffered dural ossification; 43 patients (80%) developed OLF at proximal segments of apex, 6 patient (11%) developed OLF at distal segments of apex, and 5 patients (9%) developed OLF both at proximal and distal segments of apex. Thirty-two patients (59%) developed OLF at the first segment adjacent to the kyphotic apex, 27 patients (50%) developed OLF at the second segment, and 15 patients (28%) developed OLF at the third segment. Conclusion:Among patients with degenerative kyphosis, about 73% may development OLF within three segments adjacent to the kyphotic apex, and it mostly occurred within two segments adjacent to the apex proximally.

The late-onset spine deformity in patients underwent myelomeningocele repair: radiologic characteristic and surgical strategy / 中华骨科杂志

Objective:To investigate the imaging features and surgical strategies of late-onset spinal deformity after myelomeningocele (MMC) repair.Methods:A total of 23 patients with late-onset spinal deformity after MMC repair from January 2006 to December 2019 were retrospectively analyzed, including 16 males and 7 females, aged 15.4±5.9 years (range, 6-28 years). All patients underwent MMC resection and repair in infancy (0-4 years). The complications of MMC, imaging characteristics of spinal deformity (Cobb angle of scoliosis, coronal balance, regional kyphosis), surgical methods, clinical outcomes and incidence of complications were analyzed. The Scoliosis Research Society-22 (SRS-22) score and Oswestry disability index (ODI) were used to evaluate the quality of life.Results:All patients were followed up for 2.4±0.8 years (range, 1-4 years). Among 23 patients, MMC occurred in the upper thoracic segment in 3 cases, thoracic segment in 1 case, thoracolumbar segment in 13 cases, and lumbosacral segment in 6 cases. 16 patients had scoliosis or kyphosis with the apex of the spine in the same segment as the MMC lesion. Among 13 patients with MMC located in thoracolumbar segment, 12 patients had scoliosis and 9 patients had kyphosis. Among 6 patients with MMC located in lumbosacral segment, 3 patients had pelvic tilt. Vertebral deformities included widening of pedicle space in 21 cases, enlargement of spinal canal in 19 cases, absence of spinous process in 17 cases, malsegmentation in 17 cases, and hemivertebra deformity in 9 cases. Intramedullary lesions included split cord in 6 cases and tethered cord in 9 cases. The overall implant density was 57.2%±17% (range, 16.6%-100%). At the last follow-up, the Cobb angle of scoliosis was 40.9°±19.1°, which was significantly smaller than 71.5°±28.2° before operation ( P<0.001). The local kyphosis angle was 26.7°±12.9°, which was significantly lower than that before operation (40.4°±21.5°), the difference was statistically significant ( P<0.001).The coronal balance was 16.1±13.6 mm, which was smaller than that before operation 28.5± 23.7 mm, the difference was statistically significant ( P<0.001). The total score of SRS-22 was 18.7±0.7, which was higher than that before operation 17.7±0.9, and the difference was statistically significant ( t=-9.74, P<0.001); ODI was 25.5%±6.2% after operation, which was significantly lower than that before operation (44.8%±10.1%), the difference was statistically significant ( t=13.66, P<0.001). Dural rupture occurred in 4 patients, including postoperative cerebrospinal fluid leakage in 2 cases; postoperative pleural effusion in 1 patient; and screw malposition in 2 patients. Three patients had broken rods and one had deep infection at final follow-up. Conclusion:About 70% of MMC patients who underwent resection and repair in early childhood developed late-onset spinal deformity in adulthood with the lesion at the parietal vertebrae. Posterior correction can obtain satisfactory clinical results. If the posterior element of the apical vertebral body is hypoplastic, the implant density can be increased by anterior vertebral screw, lamina hook fixation, and S 2 sacroiliac screw.

Value of the imaging features of extrapancreatic nerve plexus in predicting the early postoperative recurrence of ductal adenocarcinoma of pancreatic head / 中华肝胆外科杂志

Objective:To study the value of imaging features of extrapancreatic nerve plexus in predicting early postoperative recurrence of ductal adenocarcinoma of pancreatic head.Methods:The clinical, imaging and pathological data of patients with ductal adenocarcinoma of pancreatic head undergoing pancreati-coduodenectomy at the Hepatobiliary Pancreatic Center of Beijing Tsinghua Changgung Hospital, Tsinghua University from January 2014 to April 2022 were retrospectively analyzed. A total of 73 patients were included, including 51 males and 22 females, aged (66.1±9.0) years old. The patients were followed up by telephone or outpatient review, who were divided into two groups according to the recurrence within 6 months after surgery: the recurrence group ( n=26) and the non-recurrence group ( n=47). Streaks or soft-tissue densities in the distribution area of extrapancreatic nerve plexus, difference in CT values between the portal and arterial phases of the distribution area of extrapancreatic nerve plexus, maximum tumor diameter, and regional lymph node enlargement were compared between the two groups. Results:The incidences of streaks or soft-tissue densities showing in the distribution area of extrapancreatic nerve plexus were 80.8%(21/26) in the recurrence group and 51.1%(24/47) in the non-recurrence group, respectively. A CT value difference ≥15 HU between the portal and arterial phases of the distribution area of extrapancreatic nerve plexus occurred in 50.0%(13/26) patients of the recurrence group and 25.5%(27/47) of the non-recurrence group, respectively. Maximum tumor diameter ≥25 mm were found in 80.8% (21/26) patients of the recurrence group and 57.4% (27/47) of the non-recurrence group, respectively. ≥3 reginal lymph node enlargement showed in 65.4% (17/26) patients of the recurrence group and 31.9% (15/47) of the non-recurrence group, respectively (all P<0.05). The risk of early postoperative recurrence increased in patients with a CT value difference ≥15 HU between the portal and arterial phases of the distribution area of extrapancreatic nerve plexus ( OR=3.609, 95% CI: 1.099-11.855), and regional lymph node enlargement ≥ 3 ( OR=4.665, 95% CI: 1.400-15.545) (all P<0.05). And these two independent risk factors were combined to predict early postoperative recurrence of ductal adenocarcinoma of pancreatic head with an area under receiver operating characteristic curve of 0.748, sensitivity of 92.3%, and specificity of 48.9% ( P<0.001). Conclusion:≥ 15 HU CT value difference between the portal and arterial phases of the distribution area of extrapancreatic nerve plexus and ≥ 3 regional lymph node enlargement are independent risk factors for the early postoperative recurrence of pancreatic head ductal adenocarcinoma, which could provide more predictive information preoperatively.

Analysis of 17 cases of Vaterian system adenomyomatous hyperplasia / 中华肝胆外科杂志

Objective:To study the features of adenomyomatous hyperplasia (AH) of the Vaterian system (common bile duct and ampulla of Vater) to help in the diagnosis and management of this disease.Methods:A retrospective analysis on the data of 17 patients who had a postoperative pathological diagnosis of AH of the Vaterian system treated from January 2005 to December 2021 at the First Medical Center of the PLA General Hospital was carried out with 12 males and 5 females, aged (58.4±11.3) years. The clinical presentations, treatment and postoperative pathology of these patients were analyzed. Patients with dysplasia of the tubular mucosal epithelium in the non-cancerous area around the AH under microscopy were included in the AH with dysplasia group ( n=8), and those without dysplasia were included in the control group ( n=9). The clinical characteristics of the two groups were compared. Results:The main clinical symptoms were abdominal pain in 8 patients, jaundice in 7 patients and fever in 2 patients. Preoperative imaging showed 10 cases of occupying lesions and 6 cases of abnormally dilated intrahepatic and extrahepatic bile ducts without obvious lesions or stones or biliary tract injury stenosis. Sixteen patients underwent radical pancreaticoduodenectomy, and 1 patient underwent extrahepatic biliary resection combined with choledochojejunostomy for bile duct obstruction due to biliary stones, 3 patients had combined malignant tumors, 1 patient had a carcinoma of AH origin at the ampulla of Vater, and the other 2 patients had neoplastic lesions in the mucosal epithelium adjacent to the AH (cholangiocarcinoma and ampullary carcinoma, respectively). There were no significant differences in age, gender, bile duct stones, cholangitis, combined carcinoma and liver function indexes between the two groups of patients with AH of the Vaterian system (all P>0.05). Conclusion:Adenomyomatous hyperplasia of the Vaterian system was difficult to distinguish preoperatively from malignant tumors basing on its clinical presentations or imaging findings. Such patients are recommended to be treated surgically.

Treatment of patients with sentinel bleeding after hepatobiliary and pancreatic surgery / 中华肝胆外科杂志

Objective:To compare the results of operative versus interventional treatments in patients presenting with sentinel hemorrhage after hepatobiliary and pancreatic surgery.Methods:The clinical data of patients presenting with sentinel hemorrhage after hepatobiliary and pancreatic surgery at the Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University from August 2017 to July 2022 were retrospectively analyzed. Of 82 patients who were enrolled in this study, there were 50 males and 32 females, aged (59.0±7.7) years. The patients were divided into the interventional group ( n=42) and the surgical group ( n=40) based on the treatment they received for sentinel hemorrhage. The vascular injury rate, the first operation time for sentinel bleeding, the rate of successful hemostasis in a single operation, the number of deaths and other indicators were compared between groups. Results:In both the two groups of patients who underwent percutaneous transhepatic cholangial drainage, hepatectomy, endoscopic retrograde cholangiopancreatography, hilar cholangiocarcinoma resection and cholecystectomy were mainly performed hepatic artery injury, pancreaticoduodenectomy with gastroduodenal artery injury, and splenectomy with splenic artery injury. In the intervention group, 36 patients (85.7%) were successfully hemostasis after single treatment, and 32 patients (80.0%) in the operation group, and there was no significant difference between the two groups (χ 2=0.47, P=0.492). The first operation time for the intervention group was (40.5±8.5) min and the mortality rate was 2.4% (1/42), which were significantly better than that of the operation group (90.6±20.8) min and 15.0% (6/40) (all P<0.05). Conclusion:Interventional therapy can be used as the first-line diagnosis and treatment for sentinel bleeding after hepatobiliary and pancreatic surgery. It has the advantages of a lower mortality rate in treating these patients.

Dosimetric analysis of the optimization algorithm for intracavitary/interstitial brachytherapy of cervical cancer / 中华放射医学与防护杂志

Objective:To provide a basis for selecting the optimization method for intracavitary/interstitial brachytherapy (IC/ISBT) of cervical cancer by comparing graphical optimization (GO), inverse planning simulated annealing (IPSA), and hybrid inverse planning optimization (HIPO) using dosimetric and radiobiological models.Methods:This study selected 65 patients with cervical cancer who were treated with image-guided IC/ISBT. The afterloading therapy plans for these patients were optimized using GO, IPSA, and HIPO individually, with a prescription dose high-risk clinical target volume (HRCTV) D90 of 6 Gy. The non-parametric Friedman test and the non-parametric Wilcoxon rank test were employed to analyze the differences in duration, dose-volume parameters, and radiobiology between the three types of optimized plans. Results:Inverse planning optimization (IPSA: 46.53 s; HIPO: 98.36 s) took less time than GO (135.03 s). In terms of gross target volume (GTV) dose, the high-dose irradiation V150% (53.66%) was slightly higher in the HIPO-optimized plans, while the V200% (30.29%) was higher in the GO-optimized plans. The GO-optimized plans had a higher conformity index (CI; 0.91) than other plans, showing statistically significant differences. Compared with other plans, the HIPO-optimized plans showed the lowest doses of D1 cm 3 and D2 cm 3 at bladders and rectums and non-statistically significant doses at small intestines ( P > 0.05). In terms of the equivalent uniform biologically effective dose (EUBED) for HRCTV, the HIPO-optimized plans showed a higher value (12.35 Gy) than the GO-optimized plans (12.23 Gy) and the IPSA-optimized plans (12.13 Gy). Moreover, the EUBED at bladders was the lowest (2.38 Gy) in the GO-optimized plans, the EUBED at rectums was the lowest (3.74 Gy) in the HIPO-optimized plans, and the EUBED at small intestines was non-significantly different among the three types of optimized plans ( P = 0.055). There was no significant difference in the tumor control probability (TCP) predicted using the three types of optimized plans ( P > 0.05). The normal tissue complication probabilities (NTCPs) of bladders and rectums predicted using the HIPO-optimized plans were lower than those predicted using the GO- and IPSA-optimized plans( χ2 = 12.95-38.43, P < 0.01), and the NTCP of small intestines did not show significant differences ( P > 0.05). Conclusions:Among the three types of optimization algorithms, inverse optimization takes less time than GO. GO-optimized plans are more conformal than IPSA- and HIPO-optimized plans. HIPO-optimized plans can increase the biological coverage dose of the target volume and reduce the maximum physical/biological exposure and NTCP at bladders and rectums. Therefore, HIPO is recommended preferentially as an optimization algorithm for IC/ISBT for cervical cancer.

Simulation calculation of relative biological effectiveness based on DNA double strand break clusters / 中华放射医学与防护杂志

Objective:To obtain the relative biological effectiveness (RBE) of DNA double strand breaks (DSB) clusters by tracing the mechanism of radiated DNA damage, and explore the relationship among the biological effectiveness of DNA damage, chromosomal aberrations and germ cell death.Methods:Taking low-energy electrons, protons, and α particles as the research objects, this study simulated the process that cell nuclei were exposed to particle radiation using a radiation-related physicochemical model. On the ground of the DSB density-based spatial clustering of applications with noise (DBSCAN) algorithm, the DSB cluster classification method was improved to weaken the connection between the DSBs and the random distribution assumptions of energy depositions during the simulation. In this manner, the DSB clusters can be much closer to a non-random distribution. Furthermore, this study obtained the yields of DSB clusters and proposed a method to calculate the RBE values of DSB clusters.Results:The calculated RBE value (12.29) of DSB clusters of 2 MeV α particles was similar to the experimental RBE values of chromosomal fragments (15.3±5.9) and cell survival (14.7±5.1).Conclusions:After high-LET ionizing radiation, unlike the single DSB, the RBE of DSB clusters was similar to that of chromosomal aberration and cell survival.

Medicated effect of CDKN1B on promoting proliferation of islet β cells in diabetes mellitus / 中国综合临床

The serious decrease in the number of functional β cells is one of the main features in the pathogenesis of diabetes mellitus. CDKN1B is a new kind of regulatory protein, which can bind and inactivate cyclin and cyclin-dependent kinase complex to control the process of cell cycle. It was suggested that down-regulation or deletion of CDKN1B in islet β cells could accelerate the proliferation of islet β cells, thus increasing the number of islet β cells, which is of great significance for treatments of diabetes.

Predictive value of atherogenic index of plasma in the assessment of acute pancreatitis / 中国医师杂志

Objective:To investigate the predictive value of atherogenic index of plasma (AIP) in the assessment of acute pancreatitis (AP).Methods:598 patients diagnosed with AP admitted to the Affiliated Hospital of Yangzhou University between January 2016 and December 2020 were recruited and divided into severe acute pancreatitis group (SAP group, n=57) and non-severe acute pancreatitis group (non SAP group, n=541) according to the Atlanta Classification (2012 revision). General clinical data and related biochemical indicators of all enrolled patients were collected, and Bedside Index of Acute Pancreatitis Severity (BISAP) score, Ranson score and CT Severity Index (CTSI) score were performed. The risk factors of SAP were analyzed by logistic regression. Receiver operating characteristic (ROC) curve was used to analyze the evaluation value of AIP and various scoring systems on the severity of pancreatitis. Results:The AIP, white blood cell (WBC), neutrophil count (NEUT), fasting blood glucose (FBG), serum total cholesterol (TC) level, proportion of hyperlipidemia, proportion of diabetes, Ranson score, BISAP score, CTSI score of patients in SAP group were higher than those in non SAP group, and the difference was statistically significant (all P<0.05). Multivariate logistic regression analysis showed that AIP was an independent risk factor for SAP ( P<0.05). ROC curve showed that the are under the curve (AUC) of SAP predicted by AIP was 0.706(95% CI: 0.631-0.782, P<0.001). Conclusions:AIP is an independent risk factor for SAP, which helps to assess the severity of AP.

Effect of proprotein convertase subtilisin/kexin type 9 on platelet activation associated with sepsis / 中华危重病急救医学

Objective:To investigate the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on platelet activation in sepsis.Methods:① Clinical trial: a prospective study was conducted. Patients with sepsis and septic shock aged ≥ 18 years old who met the diagnostic criteria of Sepsis-3 admitted to the department of intensive care medicine of the Affiliated Hospital of Binzhou Medical College from January to October in 2021 were selected as subjects. Healthy subjects in the same period were taken as healthy control group. Platelet count (PLT) in the first routine blood test after admission was recorded. Venous blood was taken 1 day after diagnosis, and serum PCSK9 level was determined by enzyme-linked immunosorbent assay (ELISA). The differences of PCSK9 level and PLT between the two groups were compared, and subgroup analysis was conducted based on PLT for patients with sepsis. The correlation between PCSK9 level and PLT in septic patients was analyzed by Pearson correlation method. ② Animal experiment: 80 male C57BL/6 mice were randomly divided into control group, sepsis model group [lipopolysaccharide (LPS) group], PCSK9 inhibitor pretreatment group (PCSK9 inhibitor+LPS group) and PCSK9 inhibitor control group (PCSK9 inhibitor group), with 20 mice in each group. The mouse model of sepsis was reproduced by intraperitoneal injection of LPS 12 mg/kg, and the control group and PCSK9 inhibitor group were intraperitoneally injected with the same amount of sterile normal saline. PCSK9 inhibitor+LPS group and PCSK9 inhibitor group were pretreated with PCSK9 inhibitor 5 mg/kg intraperitoneal injection for 7 days before injection of LPS or normal saline, respectively, and the control group and LPS group were injected with an equal amount of sterile normal saline. The lung tissues were taken for pathological and immunohistochemical observation 24 hours after modeling. Blood was taken from the heart for determining PLT. Platelet activation was detected by flow cytometry. The expression level of platelet-activation marker CD40L was detected by Western blotting.Results:① Clinical trial: there were 57 cases in the sepsis group and 27 cases in the healthy control group. Serum PCSK9 level in the sepsis group was significantly higher than that in the healthy control group (μg/L: 232.25±72.21 vs. 191.72±54.92, P < 0.05), and PLT was significantly lower than that in the healthy control group [×10 9/L: 146.00 (75.50, 204.50) vs. 224.00 (194.00, 247.00), P < 0.01]. Subgroup analysis showed that the serum PCSK9 level in the thrombocytopenia patients ( n = 20) was significantly higher than that in the non-thrombocytopenia patients ( n = 37; μg/L: 264.04±60.40 vs. 215.06±72.95, P < 0.01). Correlation analysis showed a significant negative correlation between serum PCSK9 levels and PLT in septic patients ( r = -0.340, P = 0.010). ② Animal experiment: there were no significant pathological changes in lung tissue in the control group and PCSK9 inhibitor group under light microscope, and no significant differences in PLT, platelet activation and plasma CD40L protein expression was found between the two groups. In the LPS group, a large number of inflammatory cells were infiltrated in the pulmonary interstitium, the alveolar structure was damaged obviously, the alveolar septum was widened, the alveolar cavity was extensively bleeding, the capillary dilatation with bleeding and platelet aggregation were found, the PLT was significantly decreased, the platelet activation and the expression level of CD40L protein in plasma were significantly increased. The infiltration of inflammatory cells in lung tissue of mice in the PCSK9 inhibitor+LPS group was reduced to a certain extent, the thickening of alveolar septa was reduced, the platelet aggregation in lung tissue was decreased as compared with the LPS group, the PLT was significantly increased (×10 9/L: 515.83±46.60 vs. 324.83±46.31, P < 0.05), the platelet activation and the expression level of CD40L protein in plasma were significantly decreased [positive expression rate of platelet activation dependent granule surface facial mask protein CD62P: (12.15±1.39)% vs. (18.33±2.74)%, CD40L protein (CD40L/β-actin): 0.77±0.08 vs. 1.18±0.10, both P < 0.05]. Conclusion:PCSK9 level has a certain effect on promoting platelet activation in sepsis, and inhibition of PCSK9 level may have potential research value in improving adverse outcomes caused by sepsis thrombocytopenia.

Epidemiological investigation of adult thyroid diseases in urban and rural areas of Hebei Province / 中华地方病学杂志

Objective:To study the prevalence and distribution of adult thyroid diseases in urban and rural areas of Hebei Province.Methods:A multi-stage stratified cluster sampling method was used to select Renqiu City and Licun Town, Luquan City of Hebei Province as the urban and rural survey sites, respectively. Questionnaire survey, physical examination and thyroid B ultrasound examination were conducted on local permanent residents (≥ 5 years of residencies) over 18 years old. The fasting venous blood sample was collected to determine the serum thyroid function indicaters.Results:A total of 2 650 adults were surveyed, including 1 393 urban residents and 1 257 rural residents (1 357 males and 1 293 females). A total of 435 patients with thyroid diseases were diagnosed, the detection rate was 16.42%. There were seven thyroid diseases, including subclinical hypothyroidism (60.92%, 265/435), Hashimoto's thyroiditis (34.02%, 148/435), hypothyroidism (4.83%, 21/435), simple goiter (3.22%, 14/435), hyperthyroidism (2.53%, 11/435), subclinical hyperthyroidism (2.53%, 11/435), and thyroid cancer (1.84%, 8/435). The detection rates of thyroid diseases in urban and rural areas were 21.18% (295/1 393) and 11.14% (140/1 257), respectively. The detection rates of thyroid diseases in males and females were 11.42% (155/1 357) and 21.66% (280/1 293), respectively. The detection rates of thyroid diseases in 18-< 30, 30-< 40, 40-< 50, 50-< 60 and ≥60 years old were 13.46% (91/676), 14.81% (81/547), 15.42% (89/577), 20.94% (85/406) and 20.05% (89/444), respectively. There were statistically significant differences between different areas, gender and age groups (χ 2 = 48.54, 50.53, 14.68, P < 0.05). Conclusions:The detection rate of subclinical hypothyroidism in adults in urban and rural areas of Hebei Province is relatively high, followed by Hashimoto's thyroiditis. Attention should be paid to the screening, evaluation, and intervention of thyroid function among urban female populations.

Comprehensive and deep profiling of the plasma proteome with protein corona on zeolite NaY / 药物分析学报

Proteomic characterization of plasma is critical for the development of novel pharmacodynamic bio-markers.However,the vast dynamic range renders the profiling of proteomes extremely challenging.Here,we synthesized zeolite NaY and developed a simple and rapid method to achieve comprehensive and deep profiling of the plasma proteome using the plasma protein corona formed on zeolite NaY.Specifically,zeolite NaY and plasma were co-incubated to form plasma protein corona on zeolite NaY(NaY-PPC),followed by conventional protein identification using liquid chromatography-tandem mass spectrometry.NaY was able to significantly enhance the detection of low-abundance plasma proteins,minimizing the"masking"effect caused by high-abundance proteins.The relative abundance of middle-and low-abundance proteins increased substantially from 2.54％to 54.41％,and the top 20 high-abundance proteins decreased from 83.63％to 25.77％.Notably,our method can quantify approxi-mately 4000 plasma proteins with sensitivity up to pg/mL,compared to only about 600 proteins iden-tified from untreated plasma samples.A pilot study based on plasma samples from 30 lung adenocarcinoma patients and 15 healthy subjects demonstrated that our method could successfully distinguish between healthy and disease states.In summary,this work provides an advantageous tool for the exploration of plasma proteomics and its translational applications.

Screening of natural drug molecules against Fusarium oxysporum of ginseng root rot based on machine learning / 药学学报

italic>Fusarium oxysporum widely exists in farmland soil and is one of the main pathogenic fungi of root rot, which seriously affects the growth and development of plants and often causes serious losses of cash crops. In order to screen out natural compounds that inhibit the activity of Fusarium oxysporum more economically and efficiently, random forest, support vector machine and artificial neural network based on machine learning algorithms were constructed using the information of known inhibitory compounds in ChEMBL database in this study. And the antibacterial activity of the screened drugs was verified thereafter. The results showed that the prediction accuracy of the three models reached 77.58%, 83.03% and 81.21%, respectively. Based on the inhibition experiment, the best inhibition effect (MIC = 0.312 5 mg·mL-1) of ononin was verified. The virtual screening method proposed in this study provides ideas for the development and creation of new pesticides derived from natural products, and the screened ononin is expected to be a potential lead compound for the development of novel inhibitors of Fusarium oxysporum.

Mechanism of Dendrobium huoshanense Polysaccharide Against Neuroinflammation in Parkinson's Disease Model： Based on NLRP3 Inflammasome / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Dendrobium huoshanense polysaccharide （DHP） against inflammatory damage of neurons in Parkinson's disease （PD） model. MethodSH-SY5Y cells were randomized into blank group， model group， and DHP group. The survival rate of cells was measured by thiazole blue（MTT） assay， and the levels of lactate dehydrogenase （LDH）， reactive oxygen species （ROS）， malondialdehyde （MDA）， and superoxide dismutase （SOD） were measured by colorimetric analysis. BV-2 microglia were classified into blank group， model group， DHP group， and MCC950 group （positive control group）， and enzyme-linked immunosorbent assay （ELISA） was applied to detect the levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18）. The expression of NOD-like receptor protein 3 （NLRP3）， adaptor protein apoptosis-associated dot protein （ASC）， cysteine aspartic protease-1 （Caspase-1）， and IL-1β was measured by Western blot. A total of 50 C57BL/6 mice were randomized into blank group， model group， DHP low-dose （100 mg·kg-1） group， DHP equivalent-dose （350 mg·kg-1） group， and MCC950 group （positive control group）， 10 mice in each group. The motor balance and coordination of C57BL/6 mice were observed by beam walking test， tail suspension test and rotarod test. The levels of Iba-1 and tyrosine hydroxylase （TH） were detected by immunofluorescence staining. The damage of dopaminergic neurons in the substantia nigra was detected by FJB staining. The levels of inflammatory factors such as IL-1β， IL-18， and TNF-α in mouse midbrain tissues were detected by ELISA and the protein levels of NLRP3， ASC， Caspase-1， and IL-1β protein were measured by Western blot. ResultCompared with the blank group， the SH-SY5Y model group showed decreased cell survival， increased levels of LDH， ROS， and MDA （P<0.05）， and decreased levels of SOD （P<0.05）. Compared with the model group， the DHP group demonstrated increased cell survival， decreased levels of LDH， ROS， and MDA （P<0.01）， and increased level of SOD （P<0.01）. Compared with the blank group， BV-2 model group had high levels of IL-1β， IL-18， and TNF-α （P<0.05） and high protein expression of NLRP3， Caspase-1， IL-1β， and ASC （P<0.05）. Compared with the model group， DHP and MCC950 groups demonstrated low levels of IL-1β， IL-18， and TNF-α （P<0.01） and low protein expression of NLRP3， Caspase-1， IL-1β， and ASC （P<0.01）. Compared with the blank group， the C57BL/6 model group displayed long time to pass the balance wood （P<0.05）， short time spent on the rod in the rotarod test （P<0.05）， high levels of IL-1β， IL-18， and TNF-α （P<0.05） and expression of Iba-1 in the midbrain substantia nigra （P<0.05）， low TH expression （P<0.05）， more positive neurons in the FJB staining （P<0.05）， and high expression of NLRP3， Caspase-1， ASC， and IL-1β proteins （P < 0.05）. Compared with the model group， the mice in the DHP and MCC950 groups had short time to pass the balance beam （P<0.01）， long time spent on the rod （P<0.01）， low levels of IL-1β， IL-18， and TNF-α （P<0.01）， low Iba-1 expression in midbrain substantia nigra （P<0.01）， high TH expression （P<0.01）， and small number of positive neurons in the midbrain substantia nigra （P<0.01）. The expression of NLRP3， ASC， and IL-1β proteins was lower in the MCC950 group （P<0.01）， and the expression of NLRP3， ASC， Caspase-1 and IL-1β proteins was lower in the DHP equivalent-dose group （P<0.01） than in the model group. ConclusionDHP has anti-oxidative stress effect. It regulates the expression of NLRP3 inflammasome and inhibits the overactivation of microglia， thereby alleviating the neuroinflammatory injury in PD and exerting the neuroprotective effect.

The pharmaceutical care of a multidrug-resistant bacterial infection patient with tigecycline-induced hypofibri-nogenemia / 中国药房

OBJECTIVE To provide reference for pharmaceutical care of multidrug-resistant bacterial infection patients with tigecycline-induced hypofibrinogenemia and the safe use of tigecycline. METHODS Clinical pharmacists participated in a case of hypofibrinogenemia caused by tigecycline with multidrug-resistant bacterial infection， to determine the correlation of hypofibrinogenemia and tigecycline， and to analyze the risk factors and possible mechanisms of the occurrence of hypofibrinogenemia caused by tigecycline in combination with relevant literature. Clinical pharmacists recommended that physicians discontinued tigecycline and provided human fibrinogen and plasma for correction. RESULTS & CONCLUSIONS Tigecycline was associated with hypofibrinogenemia of the patient. The physician followed the advice of clinical pharmacists and the patient’s fibrinogen level returned to normal. The risk factors of hypofibrinogenemia induced by tigecycline included high dose， long course of treatment， and complication with renal dysfunction. Clinical pharmacists should timely advise physicians to stop taking the drug， and give human fibrinogen and blood product infusion for correction when necessary， so as to avoid the occurrence of serious life- threatening coagulation disorders and ensure the safety of tigecycline use.

Network Pharmacology and in vitro Experimental Verification on Intervention of Quercetin, Present in Chinese Medicine Yishen Qutong Granules, on Esophageal Cancer / 中国结合医学杂志

OBJECTIVE@#To explore the potential mechanism of Yishen Qutong Granules (YSQTG) for the treatment of esophageal cancer using network pharmacology and experimental research.@*METHODS@#The effective components and molecular mechanism of YSQTG in treating esophageal cancer were expounded based on network pharmacology and molecular docking. The key compound was identified by high-performance liquid chromatography and mass spectrometry (HPLC-MS) to verify the malignant phenotype of the key compounds in the treatment of esophageal cancer. Then, the interaction proteins of key compounds were screened by pull-down assay combined with mass spectrometry. RNA-seq was used to screen the differential genes in the treatment of esophageal cancer by key compounds, and the potential mechanism of key compounds on the main therapeutic targets was verified.@*RESULTS@#Totally 76 effective compounds of YSQTG were found, as well as 309 related targets, and 102 drug and disease interaction targets. The drug-compound-target network of YSQTG was constructed, suggesting that quercetin, luteolin, wogonin, kaempferol and baicalein may be the most important compounds, while quercetin had higher degree value and degree centrality, which might be the key compound in YSQTG. The HPLC-MS results also showed the stable presence of quercetin in YSQTG. By establishing a protein interaction network, the main therapeutic targets of YSQTG in treating esophageal cancer were Jun proto-oncogene, interleukin-6, tumor necrosis factor, and RELA proto-oncogene. The results of cell function experiments in vitro showed that quercetin could inhibit proliferation, invasion, and clonal formation of esophageal carcinoma cells. Quercetin mainly affected the biological processes of esophageal cancer cells, such as proliferation, cell cycle, and cell metastasis. A total of 357 quercetin interacting proteins were screened, and 531 genes were significantly changed. Further pathway enrichment analysis showed that quercetin mainly affects the metabolic pathway, MAPK signaling pathway, and nuclear factor kappa B (NF- κ B) signaling pathway, etc. Quercetin, the key compound of YSQTG, had stronger binding activity by molecular docking. Pull-down assay confirmed that NF- κ B was a quercetin-specific interaction protein, and quercetin could significantly reduce the protein level of NF- κ B, the main therapeutic target.@*CONCLUSION@#YSQTG can be multi-component, multi-target, multi-channel treatment of esophageal cancer, it is a potential drug for the treatment of esophageal cancer.

Clinical features and related risk factors of chronic hepatitis B patients with concomitant minimal hepatic steatosis / 临床肝胆病杂志

Objective To investigate the changes of clinical indices in chronic hepatitis B (CHB) patients with concomitant minimal hepatic steatosis and related factors for minimal hepatic steatosis. Methods A total of 179 CHB patients who underwent liver biopsy in Department of Infectious Diseases, Affiliated Drum Tower Hospital of Nanjing University Medical School, from July 2018 to March 2022 were enrolled, and according to the degree of steatosis, they were divided into non-steatosis group with 98 patients and minimal hepatic steatosis group with 81 patients. Demographic information, clinical data, and liver histopathology data were collected, and related observation indices were compared between the two groups. The independent samples t -test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between groups. A Spearman correlation analysis was performed, and a Logistic regression analysis was used to investigate the risk factors for minimal hepatic steatosis. Results Compared with the non-steatosis group, the minimal hepatic steatosis group had a significantly higher proportion of male patients (69.1% vs 52.0%, χ 2 =5.390, P < 0.05) and a significantly higher proportion of patients with significant liver fibrosis (43.2% vs 25.5%, χ 2 =6.234, P < 0.05). Compared with the non-steatosis group, the minimal hepatic steatosis group had significantly higher levels of body mass index (BMI) (23.61±2.95 kg/m 2 vs 22.13±2.67 kg/m 2 , t =-4.150, P < 0.05), uric acid (UA) [333.0(291.0-375.5) μmol/L vs 287.5(244.8-345.3) μmol/L, Z =-3.620, P < 0.05], triglyceride [0.92 (0.66-1.14) μmol/L vs 0.77 (0.62-1.02) μmol/L, Z =-2.224, P < 0.05], and controlled attenuation parameter (CAP) [234 (214-258) dB/m vs 218 (201-237) dB/m, Z =-2.867, P < 0.05]. In the group with normal body weight, the patients with minimal hepatic steatosis had significantly higher levels of UA (333.0±63.9 μmol/L vs 291.0±72.8 μmol/L, t =-2.395, P < 0.05) a nd HBV DNA [4.44 (3.51-6.79) log 10 IU/mL vs 3.42 (3.00-5.03) log 10 IU/mL, Z =-2.474, P < 0.05]. BMI (odds ratio [ OR ]=1.223, 95% confidence interval [ CI ] : 1.086-1.378, P =0.001) and UA ( OR =1.006, 95% CI : 1.002-1.010, P =0.008) were risk factors for minimal hepatic steatosis in CHB patients, and UA ( OR =1.007, 95% CI : 1.001-1.013, P =0.022) was a risk factors for minimal hepatic steatosis in CHB patients with normal body weight. Conclusion Compared with the non-steatosis CHB patients, the CHB patients with minimal hepatic steatosis have a significantly higher proportion of patients with significant liver fibrosis and a significantly higher level of CAP. BMI and UA are independent risk factors for minimal hepatic steatosis in CHB patients, and for the CHB patients with normal body weight, elevated UA is closely associated with the onset of minimal hepatic steatosis.