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.

Effect of continuous blood purification on immunity and endothelial cell function in patients with sepsis / 中华危重病急救医学

Objective:To explore the effect of continuous blood purification (CBP) on the immunity and endothelial cell function of patients with sepsis.Methods:A prospective study was conducted. The patients aged ≥18 years old and meeting the diagnostic criteria of sepsis admitted to the department of critical care medicine of Binzhou Medical University Hospital from March 2019 to October 2020 were selected as the research subjects, and the patients were divided into standard treatment group and CBP treatment group according to random number table method. Both groups were given standard treatment including initial fluid resuscitation, infection source control and antibiotics according to the 2016 international guidelines for the management of sepsis and septic shock. CBP treatment group was additionally given continuous veno-venous hemofiltration (CVVH) at a dose of 25-30 mL·kg -1·h -1 and blood flow rate of 150-200 mL/min for more than 20 hours a day for 3 days. The clinical data of patients including blood lactic acid (Lac), procalcitonin (PCT), lymphocyte count (LYM), acute physiology and chronic health evaluationⅡ(APACHEⅡ) score, sequential organ failure assessment (SOFA) score were recorded before treatment and 1 day and 3 days after treatment. At the same time, the venous blood was collected, and the immune function related indexes [interleukins (IL-4, IL-7), programmed death receptor-1 (PD-1), programmed death ligand-1 (PD-L1), interferon-γ (IFN-γ)] and endothelial cell injury related markers [soluble thrombomodulin (sTM), angiopoietin-2 (Ang-2), von Willebrand factor (vWF), heparan sulfate (HS), syndecan-1 (SDC-1)] levels in serum were determined by enzyme-linked immunosorbent assay (ELISA). The length of intensive care unit (ICU) stay of patients in the two groups was recorded, and the outcomes of patients in the two groups were followed up for 28 days. Results:Finally, 20 patients were enrolled in the standard treatment group, and 19 patients were enrolled in the CBP treatment group. There were no significant differences in gender, age and infection site between the two groups. The length of ICU stay in the standard treatment group was (10±5) days, and 5 patients died and 15 patients survived after 28 days. The length of ICU stay in the CBP treatment group was (9±4) days, and 8 patients died and 11 patients survived after 28 days. There were no significant differences in the length of ICU stay and number of patients who died within 28 days between the two groups (both P > 0.05). There were no significant differences in the Lac, PCT, LYM, APACHEⅡ score, SOFA score and immune function and endothelial cell injury related indexes before treatment and 1 day after treatment between the two groups. After 3 days of treatment, the Lac, PCT, APACHEⅡ score and SOFA score of the CBP treatment group were significantly lower than those before treatment, and pro-inflammatory and anti-inflammatory cytokines such as IFN-γ and IL-4, apoptosis-related indicators such as PD-1 and IL-7, and endothelial injury related factors such as sTM, SDC-1 and HS were significantly improved compared with the pre-treatment, the improvement degree of the above indicators was more obvious than that of the standard treatment group, and LYM was significantly higher than that of the standard treatment group (×10 9/L: 1.3±0.3 vs. 0.9±0.4, P < 0.05), IL-4, IFN-γ, IFN-γ/IL-4 ratio, IL-7, PD-1, sTM, SDC-1, HS, and Ang-2 were significantly lower than those of the standard treatment group [IL-4 (ng/L): 2.8 (1.5, 3.2) vs. 3.3 (2.7, 5.2), IFN-γ (ng/L): 6.3 (5.4, 106.5) vs. 217.9 (71.4, 517.1), IFN-γ/IL-4 ratio: 3.7 (1.8, 70.3) vs. 59.1 (18.3, 124.9), IL-7 (ng/L): 4.6 (3.2, 5.1) vs. 6.3 (5.2, 8.0), PD-1 (μg/L): 0.04 (0.03, 0.06) vs. 0.08 (0.05, 0.12), sTM (μg/L): 4.9 (4.3, 7.4) vs. 8.7 (6.0, 10.8), SDC-1 (μg/L): 0.6 (0.3, 1.1) vs. 0.9 (0.8, 2.5), HS (ng/L): 434.8 (256.2, 805.0) vs. 887.9 (620.1, 957.3), Ang-2 (ng/L): 934.0 (673.3, 1 502.1) vs. 2 233.9 (1 472.5, 3 808.4)], the differences were statistically significant (all P < 0.05). Conclusion:CBP treatment can eliminate the patient's immunosuppressive state, reduce a variety of endothelial injury markers and the degradation of glycocalyx, but cannot decrease the 28-day death risk or shorten the length of ICU stay.

Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulants and Their Use in Special Populations / 中山大学学报(医学科学版)

In the past few decades， heparin and warfarin have been the main anticoagulants used to treat and prevent venous thromboembolism. Recent studies at home and abroad have shown that non-vitamin K antagonist oral anticoagulants （NOACs） have similar or better efficacy and safety in the prevention and treatment of venous thromboembolism and non-valvular atrial fibrillation. NOACs do not require routine coagulation monitoring when used at a fixed dose. However， in special populations or specific scenarios such as emergency surgery， etc.， an overdose or underdose and abnormal metabolism of NOACs may reduce the drug efficacy and safety， so monitoring and evaluating the anticoagulant effect of NOACs is more conducive to the prognosis of patients.This paper briefly reviewed the common laboratory monitoring methods of NOACs and their use in special populations， aiming to explain different monitoring methods for different NOACs and the applicability of NOACs in special populations， and hoping to provide reference for clinical standard monitoring and use of NOACS.

Predictive Effects of Different Insulin Resistance Indexes on Diabetes Risk in Hypertensive Population / 中国医学科学院学报

Objective To explore the roles of different insulin resistance indexes[triglyceride-glucose (TyG),triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C),and metabolic score for insulin resistance (METS-IR)]and combinations of two indexes in predicting diabetes risk in hypertensive population. Methods The survey of hypertension was conducted for the residents in Wuyuan county,Jiangxi province from March to August in 2018.The basic information of hypertensive residents was collected by interview.Blood was drawn on an empty stomach in the morning and physical measurements were carried out.Logistic regression model was employed to analyze the relationship between different insulin resistance indexes and diabetes,and the area under the receiver operating characteristic curve was used for evaluating the predictive effects of each index on diabetes risk. Results A total of 14 222 hypertensive patients with an average age of (63.8±9.4) years old were included in this study,including 2616 diabetic patients.The diabetic hypertensive population had higher TyG (t=50.323,P<0.001),TG/HDL-C (Z=17.325,P<0.001),and METS-IR (t=28.839,P<0.001) than the non-diabetic hypertensive population.Multivariate analysis showed that each insulin resistance index was positively correlated with diabetes risk.The area under curve of each insulin index was in a descending order of TyG (0.770)> METS-IR (0.673)> TG/HDL-C (0.620).The difference in the area under curve between two indexes was statistically significant[TyG vs.TG/HDL-C (Z=42.325,P<0.001);TyG vs.METS-IR(Z=17.517,P<0.001);METS-IR vs.TG/HDL-C (Z=10.502,P<0.001)]. Conclusions Elevated insulin resistance indexes can increase the risk of diabetes.TyG and the combination of indexes outperform TG/HDL-C and METS-IR in the prediction of diabetes.

c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

Mechanism of high mobility group protein B1 in lipopolysaccharide-induced acute lung injury/acute respiratory distress syndrome / 中华危重病急救医学

Objective:To investigate the role and possible pathogenesis of high mobility group protein B1 (HMGB1) in lipopolysaccharide (LPS)-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS).Methods:① In vivo, 24 SPFC57BL/6 male mice were randomly divided into normal control group, ALI/ARDS model group, ethyl pyruvate (EP) treatment group and EP control group, with 6 mice in each group. The ALI/ARDS model was established by intraperitoneal injection of 20 mg/kg LPS. Mice in normal control group and EP control group were intraperitoneally injected with the same amount of sterile normal saline. Then, mice in the EP treatment group and EP control group were intraperitoneally injected with 40 mg/kg HMGB1 inhibitor EP. After 6 hours, the mice were sacrificed and lung tissues were collected. The expressions of heparan sulfate (HS), syndecans-1 (SDC-1), heparanase (HPA) and matrix metalloproteinases-9 (MMP-9) in lung tissues were detected by immunofluorescence technique. Orbital blood of mice was collected and serum was extracted to detect the content of HMGB1 by enzyme linked immunosorbent assay (ELISA). ② In vitro, human umbilical vein endothelial cells (HUVECs) were randomly divided into 6 groups: normal control group, HUVECs damage group (treated with 1 mg/L LPS for 6 hours), HMGB1 group (treated with 1 μmol/L recombinant HMGB1 for 6 hours), HMGB1+EP group (treated with recombinant HMGB1 for 1 hour and then added 1 μmol/L EP for 6 hours), LPS+EP group (treated with LPS for 1 hour and then added 1 μmol/L EP for 6 hours), EP group (treated with 1 μmol/L EP for 6 hours). The expressions of HS, SDC-1, HPA and MMP-9 in endothelial cells were detected by immunofluorescence technique. Results:① In vivo, light microscopy showed that the alveolar space was thickened after LPS stimulation, and there were a large number of inflammatory cells infiltrating in the alveolar space. Compared with ALI/ARDS model group, the expressions of HS and SDC-1 in lung tissue of EP treatment group were significantly increased [HS (fluorescence intensity): 0.80±0.20 vs. 0.53±0.02, SDC-1 (fluorescence intensity): 0.72±0.02 vs. 0.51±0.01, both P < 0.05], and the expressions of HPA and MMP-9 were significantly decreased [HPA (fluorescence intensity): 2.36±0.05 vs. 3.00±0.04, MMP-9 (fluorescence intensity): 2.55±0.13 vs. 3.26±0.05, both P < 0.05]; there were no significant changes of the above indexes in EP control group. Compared with ALI/ARDS model group, the content of serum HMGB1 in EP treatment group decreased significantly (μg/L: 131.88±16.67 vs. 341.13±22.47, P < 0.05); there was no significant change in the EP control group. ② In vitro, compared with HMGB1 group, the expressions of HS and SDC-1 in HMGB1+EP group were significantly higher [HS (fluorescence intensity): 0.83±0.07 vs. 0.56±0.03, SDC-1 (fluorescence intensity): 0.80±0.01 vs. 0.61±0.01, both P < 0.05], and the expressions of HPA and MMP-9 were significantly lower [HPA (fluorescence intensity): 1.30±0.02 vs. 2.29±0.05, MMP-9 (fluorescence intensity): 1.55±0.04 vs. 2.50±0.06, both P < 0.05]; the expression of HS, SDC-1, HPA and MMP-9 had no significant changes in EP group. Conclusion:HMGB1 participates in LPS-induced injury of endothelial cell glycocalyx, leading to increased lung permeability, and inhibition of HMGB1 can alleviate lung injury.

Prognostic value of PCSK9 and blood lipid in patients with sepsis / 中华危重病急救医学

Objective:To investigate the prognostic value of proprotein convertase subtilisin/kexin type 9 (PCSK9) and blood lipid indexes in patients with sepsis.Methods:Patients with sepsis or septic shock who were ≥ 18 years old and met the Sepsis-3.0 diagnostic criteria admitted to the department of critical care medicine of Binzhou Medical University Hospital from January to October 2021 were enrolled. Healthy adults at the same period were selected as healthy control group. Baseline characteristics, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) and sequential organ failure assessment (SOFA) score were recorded. Venous blood samples were collected within 24 hours after diagnosis, and serum PCSK9 was determined by enzyme-linked immunosorbent assay (ELISA) at 1, 3 days and 5 days. Meanwhile, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG) and lipoprotein A were detected. The differences of each index between sepsis group (28-day death group and survival group) and healthy control group were compared. Meanwhile, the indexes of patients with different severity and 28-day prognosis in sepsis group were compared. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of PCSK9 and blood lipid for the prognosis of sepsis. Multivariate Logistic regression was used to analyze the influencing factors for the prognosis of sepsis, and the Kaplan-Meier survival curve at 28th day was drawn.Results:There were 50 patients in sepsis group (including 19 patients with sepsis, 31 patients with septic shock) and 27 patients in healthy control group. In the sepsis group, 19 patients died and 31 patients survived within 28 days. The serum PCSK9 in the sepsis group was significantly higher than that in the healthy control group [μg/L: 223.09 (198.47, 250.82) vs. 188.00 (165.27, 214.90), P < 0.01], and HDL-C, LDL-C, TC and lipoprotein A were significantly lower than those in the healthy control group [HDL-C (mmol/L): 0.82±0.35 vs. 1.45±0.24, LDL-C (mmol/L): 1.53 (1.14, 2.47) vs. 2.89 (2.55, 3.19), TC (mmol/L): 2.03 (1.39, 2.84) vs. 4.24 (3.90, 4.71), lipoprotein A (g/L): 8.80 (5.66, 17.56) vs. 27.03 (14.79, 27.03), all P < 0.01]. PCSK9 in the sepsis death group was higher than that in the survival group [μg/L: 249.58 (214.90, 315.77) vs. 207.01 (181.50, 244.95), P < 0.01], and the HDL-C, LDL-C and TC were lower than those in the survival group [HDL-C (mmol/L): 0.64±0.35 vs. 0.93±0.30, LDL-C (mmol/L): 1.32±0.64 vs. 2.08±0.94, TC (mmol/L): 1.39 (1.01, 2.23) vs. 2.69 (1.72, 3.81), all P < 0.01]. With the progression of the disease, the PCSK9 in the sepsis death group and the survival group was significantly lower than that within 1 day of diagnosis (all P < 0.05). ROC curve analysis showed that PCSK9 had higher predictive value of 28-day death than HDL-C, LDL-C, TC [area under ROC curve (AUC) and 95% confidence interval (95% CI): 0.748 (0.611-0.885) vs. 0.710 (0.552-0.868), 0.721 (0.575-0.867), 0.702 (0.550-0.854)]. Multivariate Logistic regression analysis showed that PCSK9 was an independent risk factor affecting the 28-day prognosis of sepsis (β value was 1.014, P = 0.020). Kaplan-Meier survival curve analysis showed that when PCSK9 ≥ 208.97 μg/L, with the increase of PCSK9, the 28-day survival rate of sepsis patients decreased significantly. Conclusions:PCSK9, HDL-C, LDL-C and TC can all predict the 28-day prognosis of patients with sepsis. The prognostic value of PCSK9 is the highest. PCSK9 is an independent risk factor affecting the prognosis of sepsis. In the early stage of the disease, PCSK9 may have a good predictive value for the prognosis of sepsis. When PCSK9 ≥ 208.97 μg/L, the 28-day survival rate decreased significantly.

Characteristics of obstructive sleep apnea in children with allergic rhinitis / 中国小儿急救医学

Objective:To analyze the characteristics of sleep disordered breathing (SDB) in children with allergic rhinitis (AR), and improve the diagnosis and treatment at AR combined with obstructive sleep apnea (OSA).Methods:The clinical data of 120 patients with AR and OSA (AR and OSA group) admitted to the respiratory department at Shenzhen Children′s Hospital from May 2019 to December 2020 were retrospectively analyzed.A total of 120 children diagnosed with OSA and excluded AR during the same period were selected as control group.The SDB day and night symptoms, sleep structure characteristics and sleep breathing events were compared between two groups.Results:The average course of disease in children with AR and OSA was significantly longer than that in control group ( P=0.030). The main manifestations of children in AR and OSA group were mouth breathing (100.0%), snoring (99.2%), nasal obstruction (88.5%), and restless sleep (68.0%). There was no significant difference in sleep structure between two groups ( P>0.05), but the sleep efficiency of AR and OSA group was significantly lower than that of control group ( P=0.028). The respiratory events apnea hypopnea index, obstructive apnea index, obstructive apnea hypopnea index, hypopnea index and oxygen desaturation index of each sleep period in AR and OSA group were significantly higher than those in control group ( P<0.05). Among the children in AR and OSA group, moderate and severe OSA were the main manifestations, and the difference between two groups was statistically significant ( P<0.001). Conclusion:The combination of AR delayed the course of OSA in children.The main characteristics of sleep disordered breathing in children with AR are mouth opening, restless sleep, snoring and nasal obstruction.The sleep efficiency is decreased.Obstructive hypopnea and apnea are the most common respiratory events, and oxygen deficiency often occurs in rapid eye movement phase.Children with AR are more likely to have moderate or severe obstructive sleep apnea.

IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia / 医学前沿

The morbidity and mortality of myeloproliferative neoplasms (MPNs) are primarily caused by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. However, identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge. We have previously shown that interferon regulatory factor-8 (IRF8) and IRF4 serve as tumor suppressors in myeloid cells. In this study, we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs. Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis (MF) and secondary AML (sAML) transformed from MPNs versus essential thrombocythemia (ET). Negative correlations between the JAK2V617F allele burden and the expression of IRF8 (P < 0.05) and IRF4 (P < 0.001) and between white blood cell (WBC) count and IRF4 expression (P < 0.05) were found in ET patients. IRF8 expression was negatively correlated with the JAK2V617F allele burden (P < 0.05) in polycythemia vera patients. Complete response (CR), partial response (PR), and no response (NR) were observed in 67.5%,10%, and 22.5% of ET patients treated with hydroxyurea (HU), respectively, in 12 months. At 3 months, patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups. In the 12-month therapy period, low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count. Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype, which may serve as biomarkers for the response to HU in ET.

Efficacy and safety study of Chinese botulinum toxin A 100U in patients with overactive bladder: a prospective, multicenter, double-blind and randomized controlled trial / 中华泌尿外科杂志

Objective:To assess the efficacy and safety of 100 units of botulinum toxin A (BTX-A) intradetrusor injection in patients with overactive bladder.Methods:From April 2016 to December 2018, 17 tertiary hospitals were selected to participate in this prospective, multicenter, randomized, double-blind, placebo-controlled study. Two phases of study were conducted: the primary phase and the extended phase. This study enrolled patients aged 18 to 75 years who had been inadequately managed by anticholinergic therapy (insufficient efficacy or intolerable side effects) and had spontaneous voiding with overactive bladder. Exclusion criteria included patients with severe cardiac, renal and hepatic disorders, patients with previous botulinum toxin treatment for 6 months or allergic to BTX-A, patients with urinary tract infections, patients with urinary stones, urinary tract tumors, diabetes mellitus, and bleeding tendency. Eligible patients were randomly assigned to BTX-A group and placebo control group in a ratio of 2∶1. Two groups of patients received 20 intradetrusor injections of BTX-A 100U or placebo at the depth of the submucosal muscle layer respectively under cystoscope, including 5 injections at the base of the bladder, 3 injections to the bladder triangle, 5 injections each to the left and right walls and 2 injections to the top, sparing the bladder neck. As a placebo control group, patients received same volume of placebo containing no BTX-A and only adjuvant freeze-dried preparations for injection with the same method. A combination of gelatin, sucrose, and dextran served as adjuvants. Average micturition times per 24 hours, urinary incontinence (UI) episodes per day, average micturition volume per day, OAB symptom score(OABSS), and quality of life (QOL) score were recorded at baseline and the 2nd, 6th and 12th week after treatment. The primary efficacy endpoint was the change from baseline in the average micturition times per 24 hours at the 6th week after treatment. The secondary efficacy endpoints included the change from baseline in the average micturition times per 24 hours at 2nd and 12th week, as well as the change from baseline in the OABSS, QOL score, average frequency of urgency and UI episodes per day, urgency score, average micturition volume per day at 2nd, 6th and 12th week after treatment. Patients were followed for 12 weeks to assess adverse events (AEs). After assessed at week 12, if the micturition times has decreased less than 50% compared to baseline and the patient is willing to receive retreatment, then patients could enter the extended trial phase. In that phase, patients in both groups were injected with 100 units BTX-A from 12th week onwards and then followed up the same indicators for 12 weeks.Results:216 patients were enrolled in this trial (144 cases in the BTX-A group and 72 cases in the placebo control group). Baseline characteristics such as age (47.75±14.20 in the BTX-A group and 46.39±15.55 in the control group), sex (25 male/117 female in the BTX-A group and 10/61 in the control group), and disease duration (0.51 years in the BTX-A group and 0.60 years in the control group) were balanced between the two groups( P>0.05). A marked reduction from baseline in average micturition times per 24 hours was observed in all treatment groups at the 6th week and the reduction of the two groups was statistically different ( P<0.001 and P=0.008 respectively). Compared with the baseline, the average micturition times per 24 hours at the 6th week decreased from baseline by 2.40(0.70, 4.60)times for the BTX-A group and 0.70(-1.00, 3.30) times for the placebo control group respectively, and the difference between the two groups was considered to be statistically significant ( P=0.003). The change rates of average micturition times per 24 hours from baseline at the 6th week of the two groups were (16±22)% and (8±25)% respectively, and the difference between the two groups was statistically significant ( P=0.014). Compared with the baseline, the average micturition times per 24 hours at 2nd and 12th week decreased by 2.00(0.00, 4.00)and 3.30(0.60, 5.03)for the BTX-A group, 1.00(-1.00, 3.00)and 1.70(-1.45, 3.85)for the placebo control group respectively. The difference between two groups was considered to be statistically significant ( P=0.038 and P=0.012); the changes of average urgency times per day for the BTX-A group and the control group at the 2nd, 6th and 12th week were 2.00(0.00, 4.30)and 2.40(0.30, 5.00), 3.00(0.30, 5.70)and 0.70(-1.30, 2.70), 0.70(-1.30, 3.00) and 1.35(-1.15, 3.50), respectively. There were significant differences between two groups at the 2nd, 6th and 12th week, ( P=0.010, P=0.003 and P=0.025, respectively). The OABSS of the BTX-A group and the control group at the 6th week decreased by 1.00(0.00, 4.00)and 0.50(-1.00, 2.00) compared with the baseline, and the difference between the two groups was statistically significant ( P=0.003). 47 cases of BTX-A group and 34 cases of placebo control group entered the extended trial phase, and 40 and 28 cases completed the extended trial phase, respectively. The average micturition volume per 24 hours changed by -16.60(-41.60, -0.60)ml and -6.40(-22.40, 13.30)ml, (-35.67±54.41)ml and(-1.76±48.69)ml, (-36.14±41.51)ml and (-9.28±44.59)ml, (-35.85±43.35)ml and(-10.41±40.29)ml for two groups at the 12th, 14th, 18th and 24th week, and the difference between two groups was statistically significant at each follow-up time ( P=0.01, 0.006, 0.012 and 0.016, respectively). There was no significant difference in other parameters( P>0.05). However, adverse reactions after intradetrusor injection included increased residual urine volume (27 in the BTX-A group and 3 in the control group), dysuria (21 in the BTX-A group and 6 in the control group), urinary infection (19 in the BTX-A group and 6 in the control group), bladder neck obstruction (3 in the BTX-A group and 0 in the control group), hematuria (3 in the BTX-A group and 1 in the control group), elevated alanine aminotransferase (3 in the BTX-A group and 0 in the control group), etc. During the follow-up period, there was no significant difference in the other adverse events between two groups except the increase of residual urine volume( P<0.05). In the primary trial phase, among the 27 cases with increased residual urine volume in BTA group, only 1 case (3.70%) with PVR more than 300 ml; the PVR of 3 patients in the placebo group was less than 100 ml. The increase of residual urine volume caused by the injection could be improved or disappeared with the passage of time. Conclusions:Intradetrusor injection of Chinese BTX-A improved the average micturition times per 24 hours, the average daily urgent micturition times, OABSS, and average micturition volume per time, and reduced the adverse effects in patients with overactive bladder.Chinese BTX-A at dose of 100U demonstrated durable efficacy and safety in the management of overactive bladder.

Mental symptoms and its influencing factors of patients with malignant tumor undergoing chemotherapy in general hospital / 中华行为医学与脑科学杂志

Objective:To estimate the mental symptoms in malignant tumor patients undergoing chemotherapy using DSM-5 cross cutting symptom measure.Methods:A total of 314 patients who undergoing chemotherapy in oncology department of Zhongshan Hospital, Fudan University who met all standards were chosen. The DSM-5 cross cutting symptom measure Level 1 Scale was used to assess the mental symptoms of the patients. SPSS 25.0 software was used for χ 2 test, Pearson correlation analysis and multiple regression analysis. Results:The most common symptoms in the patients were depressive symptoms(85/314, 27.1%), somatic symptoms (79/314, 25.2%), manic symptoms (78/314, 24.5% ) and anxiety symptoms (76/314, 24.3%). The proportion of anxiety symptoms in malignant tumor patients who were taken care of by other personnel(26/64, 40.6%) was significantly higher than that in patients who were taken care of by immediate relatives(50/250, 20.0%)(χ 2=12.23, P<0.05). Patients with unstable working conditions were more likely to have depressive symptoms (χ 2=7.64, P<0.05). There was a significant negative correlation between the patients' understanding of the disease and their scores of depressive symptoms, somatic symptoms, manic symptoms, anxiety symptoms and the total score of mental symptoms( r= -0.26, -0.15, -0.12, -0.25, -0.22, all P<0.05). In addition, the total score of mental symptoms of malignant tumor patients was significantly positively correlated with family burden and family status( r=0.11, 0.11, both P<0.05), and negatively correlated with patients' education ( r=-0.13, P<0.05). Multiple regression analysis showed that the degree of understanding of the disease( β=-0.203) and family status( β=0.197) were the influencing factors of mental symptoms of inpatients malignant tumors undergoing chemotherapy in general hospital ( F=13.653, P<0.001). Conclusion:Malignant tumor patients undergoing chemotherapy may have a variety of mental symptoms. The high incidence mainly includes depressive symptoms, somatic symptoms, manic symptoms and anxiety symptoms. The understanding of the patients to the disease and family situation are the main influencing factors.

Discovery of alkaloids from the leaves of Isatis indigotica Fortune with neuroprotective activity / 中国天然药物

Seven alkaloids including five undescribed ones (1a/1b, 2, 3 and 5) were obtained from the leaves of Isatis indigotica Fortune. Their structures were established by extensive spectroscopic analyses. The absolute configurations of compounds 1a, 1b, 3 and 5 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Subsequently, the neuroprotective effects of all the isolates against H

Assistant role of manifestations under tracheoscopy in the diagnosis of invasive pulmonary aspergillosis in severe patients / 中华危重病急救医学

Objective:To evaluate the assistant role of manifestations under tracheoscopy in the diagnosis of invasive pulmonary aspergillosis (IPA) in severe patients.Methods:A retrospective study was conducted. The patients with suspected IPA admitted to intensive care unit (ICU) of Affiliated Hospital of Binzhou Medical College from January 2015 to December 2019 were enrolled. The diagnosis, clinical diagnosis and suspected diagnosis were made according to the grading criteria of Guidelines for the diagnosis and treatment of invasive fungal infection in severe patients (2007). Those who met the criteria were enrolled in the IPA group, and those who did not meet the criteria or other pathogens were enrolled in the non-IPA group. The general data of the patients were collected, and the changes of tracheal and bronchial mucosa under tracheal microscope before and after treatment were recorded, as well as the results of galactomannan (GM) test and aetiology culture of bronchoalveolar lavage fluid (BALF). The baseline, bronchoscopy and pulmonary CT manifestations and their dynamic changes were compared in each group. Results:A total of 142 patients with suspected IPA were finally enrolled. Among them, 12 were pathologically proven IPA, 77 were probable IPA, 22 were possible IPA, and 31 were undefined IPA. Of the 142 patients, 60 had typical manifestations of mucosal injury under bronchoscopy, including 7 proven IPA patients (58.3%), 52 probable IPA patients (67.5%), and 1 possible IPA patient (4.5%), but none undefined IPA patient. The patients undergoing lung CT scan were 12 proven IPA patients (100%), 73 probable IPA patients (94.8%), and 21 possible IPA patients (95.5%), respectively. Most of the Chest CT showed patchy or strip density increasing and other non-specific manifestations. There were 3 proven IPA patients (25.0%), 7 probable IPA patients (9.0%), and 0 possible IPA patient (0%) who had typical IPA CT manifestations (halo sign and cavity or crescent sign). Among the patients of proven IPA and probable IPA (89 cases), there were a total of 35 cases with endoscopic airway mucosal injury and tracheoscopy reexamination ≥ 3 times. All the 35 patients received anti-aspergillus treatment, among which 16 survived and 19 died. Among the 16 patients who survived, the microscopic appearance of mucosal injury was gradually reduced and the clinical manifestations were gradually improved. Of the 19 patients who died, 16 had deteriorated endoscopic airway mucosal injury.Conclusions:The specific manifestations of severe patients with bronchial mucosal injury are of great significance in the diagnosis of IPA. In the case of severe patients who cannot receive pathological examination or chest CT in time, dynamic observation of the changes of airway mucosal injury is a simple auxiliary method to discover the changes of patients' condition in time, evaluate the effect of antifungal therapy and the prognosis of IPA.

Predictive value of combined detection of multiple inflammatory factors for premature rupture of membranes complicated with chorioamnionitis / 中国基层医药

Objective:To investigate the expression levels of matrix metalloproteinase-9 (MMP-9), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells (sTREM-1) and soluble cell differentiation 14 (sCD14) in pregnant women with premature rupture of membranes (PROM) and their predictive value for chorioamnionitis.Methods:A total of 132 pregnant women with PROM who received treatment in Tengzhou Central People's Hospital from January 2016 to June 2017 were included in the study group. These women were assigned to pre-term PROM group (gestational age < 37 weeks, n = 58) and full-term PROM group (gestational age > 37 weeks, n = 74). A total of 106 concurrent full-term healthy pregnant women were included in the control group. Pregnant women in the PROM group were also assigned into an infection group ( n = 51) and a non-infection group ( n = 81). Serum levels of MMP-9, PCT, sTREM-1 and sCD14 were compared between study and control groups, and their value in the diagnosis of PROM complicated with chorioamnionitis was analyzed. Results:The expression levels of MMP-9 [(271.42 ± 34.16) ng/L], PCT [(54.57 ± 8.16) pg/mL], sTREM-1 [(0.51 ± 0.11) ng/mL] and sCD14 [(60.23 ± 9.49) ng/mL] in the study group were significantly higher than those in the control group [(54.97 ± 10.08) ng/L, (26.04 ± 1.98) pg/mL, (0.19 ± 0.04) ng/mL, (42.04 ± 10.33) ng/mL, t = 27.064, 13.767, 14.831, -13.342, all P < 0.01). The expression levels of MMP-9 [(314.05 ± 45.37) ng/L], PCT [(0.61 ± 0.18) ng/mL], sTREM-1 [(63.12 ± 10.12) pg/mL] and sCD14 [(68.07 ± 11.05) ng/mL] in the pre-term PROM group were significantly higher than those in the full-term PROM group [(238.01 ± 40.45) ng/L, (47.87 ± 8.90) pg/mL, (0.43 ± 0.14) ng/mL, (54.09 ± 10.33) ng/mL, t = 9.103, 8.862, -10.538, 6.494, all P < 0.05). The expression levels of MMP-9 [(343.74 ± 43.74) ng/L], PCT [(69.88 ± 8.83) pg/mL], sTREM-1 [(0.67 ± 0.16) ng/mL], sCD14 [(70.41 ± 8.89) ng/mL] in the infection group were significantly higher than those in the non-infection group [(230.09 ± 49.82) ng/L, (45.82 ± 11.04) pg/mL, (0.42 ± 0.19) ng/mL and (54.41 ± 12.42) ng/mL, t = 23.655, 12.014, 9.382, 11.306, all P < 0.01]. The sensitivity (94.23%), specificity (93.75%), positive predictive value (92.45%) and negative predictive value (96.20%) of combined detection of these indexes in the diagnosis of PROM complicated by chorioamnionitis were significantly higher than those of other indexes detected alone (all P < 0.05). Conclusion:Combined detection of serum levels of MMP-9, PCT, sTREM-1 and sCD14 can be used as an effective auxiliary index for the diagnosis of early premature rupture of membranes complicated with chorioamnionitis.

Classification and reconstruction of complex defects after lateral facial tumor surgery / 中华耳鼻咽喉头颈外科杂志

Objective: To explore the classification and reconstruction strategy of defects in lateral face region after operation of malignant tumors. Methods: Eighteen cases with the reconstruction of complicated defects after resection of tumors in the region of lateral face from January 2015 to January 2018 in Hunan Cancer Hospital were retrospectively reviewed. There were 14 males and 4 females, aged from 32 to 68 years. According to the presence or absence of bony scaffold, complicated defects were divided into two main categories: soft tissue perforating defects and soft tissue defects combined with bony scaffold defects. All soft tissue perforating defects in 5 cases were repaired with free anterolateral femoral flaps. Among 13 cases with soft tissue plus bony scaffold defects, 3 were repaired with free fibular flaps, 6 with free fibular flaps combined with free anterolateral femoral flaps, and 4 with chimeric deep circumflex iliac artery perforator flaps combined with anterolateral femoral flaps. Results: All flaps survived well. Two patients complicated with fistula in floor of mouth, but the wound healed after dressing change. Transoral feeding was resumed within 2 weeks after surgery in all patients. One year follow-up evaluation showed that 14 cases had symmetrical face and 10 cases had mouth opening more than 3 transverse fingers. After 36-50 months of follow-up, 6 patients died, with an overall 3-year survival rate of 66.7%. Conclusion: The classification of defects with or without bony stent loss is conducive to the overall repair design, the recovery of facial contour stent, the effective fill of dead space and the maintain of residual occlusal relationship. Good reconstruction results require a multi flap combination of osteocutaneous and soft tissue flaps.

The efficacy of hemostatic powder for chronic rhinosinusitis in endoscopic sinus surgery: a prospective, randomised, controlled and single blinded clinical trial / 中华耳鼻咽喉头颈外科杂志

Objective: To study the efficacy and patient comfort of absorbable hemostatic powder after endoscopic sinus surgery (ESS). Methods: A total of 21 (17 males, 4 females) patients with an average age of 42(ranging from 18 to 65) underwent bilateral ESS for chronic rhinosinusitis(CRS) in Beijing Tongren Hospital, Capital Medical University between October 2015 and July 2019 were enrolled to compare the effect of absorbable hemostasis powder with Nasopore using an intrapatient control design. A randomized controlled trial was conducted in the left and right nasal cavities of the same patient. If hemostatic powder was applied in the experiment nasal cavity, the Nasopore was applied in the control nasal cavity. The mean preoperative sinus computed tomography (CT) score was 6.25. All patients competed for symptom diaries using a visual analog scale (VAS, score out of 10) at baseline, through 1, 7, 14 and 30 days. Outcomes including bleeding, facial pain, nasal obstruction, nasal discharges using VAS were recorded separately for both sides. Postoperative endoscopic scores were also investigated. SPSS 22 and Graphpad prism 8.0 statistical softwares were used for the analysis. Paired t-test or nonparametric test was used between the test side and the control side. The difference was statistically significant (P<0.05). Results: The bleeding score and total nasal symptom VAS scores at postoperative days (POD) 1, 7, 14 and 30 were not significantly different(t=1.341, 0.552, 0.631, 0.158, all P>0.05;t=0.944, 1.471, 1.612, 2.251, all P>0.05). There was no significant difference between absorbable hemostasis powder and Nasopore side on POD 1, 7, 14 and 30 in terms of each nasal symptom VAS scores(all P>0.05). On POD 1, 7 and 14, the packing material degeneration scores of the absorbable hemostasis powder side were significantly lower than those of the Nasopore side [(1.33±0.21)vs(2.00±0.00),(0.38±0.18) vs (1.95±0.22), 0 vs (1.80±0.13), all P<0.01]. There were significant differences between absorbable hemostasis powder and Nasopore side on POD 1, 7, 14 and 30 in terms of endoscopic scores (edema, crusting, discharges, scar, polyps and material degeneration, t=3.07, 7.00, 6.41, 2.69, all P<0.05). Conclusions: The absorbable hemostasis powder and Nasopore has similar postoperative hemostasis effect. The absorbable hemostasis powder is rapidly cleared and without negative effects on mucosal wound healing 14 days postoperatively.

Correlation between color and content of eight components of Gardeniae Fructus at different harvest time / 中国中药杂志

This research is to establish an HPLC method for determination of geniposidic acid, genipin-1-β-D-gentiobioside, geniposide, p-trans-coumaroylgenipin gentiobioside, chlorogenic acid, crocin-Ⅰ, crocin-Ⅱ and crocin-Ⅲ in Gardeniae Fructus at different harvest time. The detection wavelength was 238, 320 and 440 nm. Principal component analysis(PCA), correlation analysis, regression analysis and partial least squares(PLS) analysis were used to explore the relationship of color and content of eight components in Gardeniae Fructus. The result showed that the trend of the eight components in Gardeniae Fructus at harvest time in different three years was varied similarly. According to the variation of eight components at different harvest time, the mature and immaturate Gardeniae Fructus were discriminated. The content of crocin-Ⅰwas correlated positively with a~* of color significance. The redder color of Gardeniae Fructus showed the higher value of a~* and content of crocin-Ⅰ, indicating the better quality of Gardeniae Fructus. This method provided reference for justifying the color and quality of Gardeniae Fructus and scientific evidence for "assessing quality by distinguishing color".

Lung transplantation as therapeutic option in acute respiratory distress syndrome for coronavirus disease 2019-related pulmonary fibrosis / 中华医学杂志(英文版)

BACKGROUND@#Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients.@*METHODS@#From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores.@*RESULTS@#Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation.@*CONCLUSIONS@#LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.

Clinicopathologic features and prognosis of membranous nephropathy after renal allografting / 中华器官移植杂志

Objective:To explore the clinicopathologic features and renal prognosis of patients with post-transplant membranous nephropathy (MN).Methods:Patients with allograft biopsy-proven MN were reviewed retrospectively and divided into unknown etiology group (A, n=12) and recurrent membranous nephropathy (rMN) group (B, n=7). Their clinicopathological data and renal prognosis were assessed and compared.Results:No differences existed in the proportion of living-related donor or post-transplant allograft function. Group B had recurrence at 16.4 months after transplantation and it was significantly shorter than group A. Allograft impairment manifested as proteinuria, nephrotic syndrome and/or renal insufficiency in both groups. The positive rate of serum anti-PLA2R antibody and renal PLA2R staining was significantly higher in group B than that in group A. Similarly, the intensity of IgG4 subtype staining was also stronger in group B than that in group A. The 5-year cumulative renal survival rates from end-stage renal disease (ESRD) were 77.8% and 66.7% in groups A and B respectively. No significant inter-group difference existed in renal prognosis.Conclusions:Anti-PLA2R antibody plays an important role in the recurrence of rMN after renal allografting. PLA2R staining is useful for detecting primary disease and its sensitivity is higher than that of serum anti-PLA2R antibody. Rituximab is an effective treatment for post-transplant MN. Follow-up studies with a larger sample size are required for further verification.

Risk factors for mortality after laparotomy for hemorrhage in patients with bleeding after liver transplantation / 中华麻醉学杂志

Objective:To identify the risk factors for mortality after laparotomy for hemorrhage in the patients with bleeding after liver transplantation.Methods:The patients who underwent re-laparotomy for hemorrhage after liver transplantation, aged>18 yr, from June 2005 to June 2013, were selected.The preoperative clinical characteristics of patients, time of liver transplantation, mode of operation, intraoperative massive hemorrhage, intraoperative use of vasoactive drugs, atropine, lidocaine and immunosuppressive agents, and postoperative tracheotomy and renal failure were collected.Patients were divided into survival group (group S) and death group (group D) according to the survival outcome at 3 months after surgery.Factors of which P values were less than 0.05 would enter the multiple logistic regression analysis to stratify the risk factors for mortality of patients with bleeding after liver transplantation. Results:A total of 128 patients were included in this study , with 117 cases in group S and 11 cases in group D. Postoperative renal failure was the independent risk factor for mortality of patients with bleeding after liver transplantation, and OR value (95% confidence interval) was 11.307 (1.992-64.188) ( P<0.05). The area under the curve of postoperative renal failure (95% confidence interval) was 0.849 (0.712-0.986), and the sensitivity and specificity were 81.8% and 12.0%, respectively. Conclusion:Postoperative renal failure is an independent risk factor for mortality after laparotomy for hemorrhage in the patients with bleeding after liver transplantation.