Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Objective To investigate the mechanism of hsa_circRNA_000596 (circ-596) in promoting invasion and metastasis of cervical cancer cells. Methods The cervical squamous cell carcinoma (CSCC) tissue, normal cervical tissue adjacent to cancer and clinical data of 69 cases with CSCC were collected. RNA in situ hybridization (RISH) was used to detect the expression of circ-596 and analyze its association with clinical data of CSCC. The invasive ability of cervical cancer cells was detected by Transwell assay; the regulation of downstream target gene by circ-596 was detected by quantitative reverse transcriptase PCR (qRT-PCR). Dual luciferase reporting experiment was used to verify the regulation of miR-197-3p on the downstream target gene RNF146; the regulation of miR-197-3p/RNF146 by circ-596 and its effect on invasion ability were analyzed in rescue experiment. Results Circ-596 was mainly positively expressed in CSCC tissues, and the positive expression rate was 63.77%(44/69), which was higher than 17.39% (12/69) in adjacent normal tissues (χ²=8.254, P=0.004). Circ-596 positive expression was closely correlated with tumor differentiation and lymph node metastasis (P < 0.05). The results of Transwell experiment showed that compared with the control cells, the number of cervical cancer cells with overexpression of circ-596 increased, and the number of cells with knockdown expression of circ-596 decreased (P < 0.05). Bioinformatics prediction results showed that miR-197-3p was the downstream target gene of circ-596, and RNF146 was the downstream target gene of miR-197-3p. The results of qRT-PCR showed that overexpression of circ-596 could down-regulate the expression of miR-197-3p, and down-expression of circ-596 could up-regulate the expression of miR-197-3p (P < 0.05). The results of dual luciferase reporter gene experiments showed that miR-197-3p bound to the 3'UTR of RNF146 gene, thereby inhibiting the relative activity of luciferase. Rescue experiment results showed that circ-596 could inhibit the expression of miR-197-3p, and thereby promoting the expression of RNF146, and enhancing the invasion ability of cervical cancer cells. Conclusion Circ-596 is mainly positively expressed in CSCC tissues, and its positive expression is closely related to the degree of tumor differentiation and lymph node metastasis. Circ-596 promotes the expression of RNF146 by binding to miR-197-3p, thereby promoting the invasion and metastasis of cervical cancer cells.

Marine microorganisms, especially marine fungi, have historically proven their value as a prolific source for structurally novel and pharmacologically active secondary metabolites (Deshmukh et al., 2018; Carroll et al., 2022). The corals constitute a dominant part of reefs with the highest biodiversity, and harbor highly diverse and abundant microbial symbionts in their tissue, skeleton, and mucus layer, with species-specific core members that are spatially partitioned across coral microhabitats (Wang WQ et al., 2022). The coral-associated fungi were very recently found to be vital producers of structurally diverse compounds, terpenes, alkaloids, peptides, aromatics, lactones, and steroids. They demonstrate a wide range of bioactivity such as anticancer, antimicrobial, and antifouling activity (Chen et al., 2022). The genetically powerful genus Emericella (Ascomycota), which has marine and terrestrial sources, includes over 30 species and is distributed worldwide. It is considered a rich source of diverse secondary metabolites with antimicrobial activity or cytotoxicity (Alburae et al., 2020). Notably, Emericella nidulans, the sexual state of a classic biosynthetic strain Aspergillus nidulans, was recently reported as an important source of highly methylated polyketides (Li et al., 2019) and isoindolone-containing meroterpenoids (Zhou et al., 2016) with unusual skeletons.
Animals ; Aspergillus nidulans ; Polyketides/chemistry* ; Anthozoa/microbiology* ; Anti-Infective Agents/pharmacology* ; Alkaloids

Objective To investigate the intervention effect of GDC-0449, a hedgehog signaling pathway inhibitor, on rats with liver fibrosis induced by carbon tetrachloride (CCl 4 ) combined with 2-acetylaminofluorene (2-AAF). Methods A total of 18 female Fisher344 rats were randomly divided into normal group, CCl 4 /2-AAF group, and GDC-0449 group, with 6 rats in each group. The rats in the CCl 4 /2-AAF group and the GDC-0449 group were given subcutaneously injected 30% CCl 4 -olive oil solution at a dose of 2 mL/kg twice a week for 6 weeks to induce liver fibrosis; since week 7, in addition to the injection of CCl 4 -olive oil solution, the rats in these two groups were given 2-AAF (100 mg/kg/d) by gavage, and the rats in the GDC-0449 group were given GDC-0449 (25 mg/kg/d) by gavage, while those in the normal group were given an equal volume of olive oil solution by injection and normal saline by gavage. All rats were sacrificed at the end of week 9, and related samples were collected. HE staining and sirius red (SR) staining were used to observe the changes in liver histopathology and collagen deposition, and the semi-quantitative analysis of SR-positive area and Ishak score were used to evaluate fibrosis degree; the alkaline hydrolysis method was used to measure the level of hydroxyproline (Hyp) in liver tissue; immunohistochemistry, Western blot, and qRT-PCR were used to measure the expression of α-smooth muscle actin (α-SMA), type Ⅰ collagen (Col-Ⅰ), type Ⅳ collagen (Col-Ⅳ), cytokeratin 19 (CK19), cytokeratin 7 (CK7), the epithelial cell adhesion molecule Epcam, and the hedgehog signaling pathway in liver tissue; double immunofluorescence staining was used to observe the colocalization of CK19 and the oval cell marker OV6. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results Compared with the normal group, the CCl 4 /2-AAF group had marked inflammatory cell aggregation and collagen deposition in liver tissue, with the formation of a pseudolobular structure, as well as significant increases in Hyp level and collagen positive area ratio in liver tissue ( P < 0.05), Ishak score ( P < 0.05), and the expression of α-SMA, Col-Ⅰ, Col-Ⅳ, Epcam, CK19, CK7, the transmembrane transporter Smoothened (Smo), Hedgehog ligand Desert Hedgehog (Dhh), the Indian Hedgehog membrane-binding receptor Patched (Ptch2), and glioma-related oncogenes Gli1, Gli2, and Gli3 (all P < 0.05); double immunofluorescence staining showed that CK19-positive cells also expressed OV6 in the liver tissue of rats in the CCl 4 /2-AAF group, with a significant increase compared with the normal group. Compared with the CCl 4 /2-AAF group, the GDC-0449 group had significant reductions in inflammatory cell aggregation and collagen deposition in liver tissue, Hyp level and collagen positive area ratio in liver tissue ( P < 0.05), Ishak score ( P < 0.05), and the expression of α-SMA, Epcam, CK19, CK7, Smo, Ptch2, Gli1, Gli2, and Gli3 (all P < 0.05); double immunofluorescence staining showed a significant reduction in the number of cells with co-expression of OV6 and CK19 in liver tissue. Conclusion The Hedgehog signaling pathway inhibitor GDC-0449 can significantly inhibit the progression of liver fibrosis induced by CCl 4 /2-AAF in rats, possibly by inhibiting hepatic stellate cell activation, collagen deposition, activation and proliferation of hepatic progenitor cells, and differentiation of hepatic progenitor cells into biliary epithelial cells.

Purpose: Recently, totally laparoscopic gastrectomy has been gradually accepted by surgeons worldwide for gastric cancer treatment. Complete dissection of the lymph nodes and the establishment of the surgical margin are the most important considerations for curative gastric cancer surgery. Previous studies have demonstrated that indocyanine green (ICG)-traced laparoscopic gastrectomy significantly improves the completeness of lymph node dissection. However, it remains difficult to identify the tumor location intraoperatively for gastric cancers that are staged ≤T3. Here, we investigated the feasibility of ICG fluorescence for lymph node mapping and tumor localization during totally laparoscopic distal gastrectomy. Materials and Methods: Preoperative and perioperative data from consecutive patients with gastric cancer who underwent a totally laparoscopic distal gastrectomy were collected and analyzed. The patients were categorized into the ICG (n=61) or the non-ICG (n=75) group based on whether preoperative endoscopic mucosal ICG injection was performed. Results: The ICG group had a shorter operation time and less intraoperative blood loss.Moreover, significantly more lymph nodes were harvested in the ICG group than the non-ICG group. No pathologically positive margin was found and there was no significant difference in either the proximal or distal surgical margins between the 2 groups. Conclusions Near-infrared fluorescence imaging with ICG can be successfully used in totally laparoscopic distal gastrectomy, and it contributes to both the completeness of D2 lymph node dissection and confirmation of the gastric transection line. Well-designed prospective randomized studies are needed in the future to fully validate our findings.

Objective:To observe the alteration of clinical features of intrahepatic lymphocyte subsets in C57BL/6N-TG (1.28HBV)/Vst hepatitis B virus (HBV) transgenic mice composite carbon tetrachloride (CCl 4) with intraperitoneal injection under the background of hepatitis B to induce liver fibrosis mice model, and analyze their correlation with serum HBV DNA and liver tissue hydroxyproline (Hyp) content. Methods:HBV-Tg mice were intraperitoneally injected with 10% CCl 4 to induce the rapid formation of hepatic fibrosis. Serum HBV DNA, HBsAg, HBeAg levels and liver tissue HBsAg expressional conditions were used to evaluate the virological characteristics of mice model. The degree of hepatic inflammation and fibrosis in mice were observed by HE, Sirius Red staining and liver tissue hydroxyproline (Hyp) content. Intrahepatic T lymphocyte, B lymphocyte, CD4+T lymphocyte, CD8+T lymphocyte, natural killer (NK) cell and natural killer T (NKT) cells distribution were observed by flow cytometry. One-way analysis of variance was used for intergroup data comparison, and LSD was used for pairwise comparison. Pearson’s correlation analysis was used to analyze the correlation between the above lymphocyte subsets and serum HBV DNA and liver tissue Hyp content. Results:Serum HBsAg, HBeAg and liver tissue HBsAg had equal positive expression in the HBV-Tg composite CCl 4 mice model group, and the serum HBV DNA load was > 1 × 10 6 IU / ml. Compared with the wild-type control group, liver tissue Hyp content of the composite model group was significantly higher [(196.39 ± 38.14) μg /g and (347.67 ± 59.53) μ g/g, P < 0.01). The degree of inflammation and fibrosis in liver tissues was aggravated, and the proportion of all intrahepatic CD4+T, NK and NKT cells was significantly reduced ( P < 0.01), while the proportion of CD8+T lymphocytes (30.58% ± 2.89% vs. 46.50% ± 2.24%, P < 0.01) and B lymphocytes (28.82% ± 2.24% vs. 37.10% ± 8.59%, P < 0.05) was significantly increased. Serum HBV DNA level was positively correlated with the proportion of intrahepatic T lymphocytes ( r = 0.413, P < 0.05), and negatively correlated with the proportion of NK cells ( r = -0.419, P < 0.05). Liver tissue Hyp content was negatively correlated with the proportion of all CD4+T lymphocytes ( r = -0.871), NK cells ( r = -0.716), and NKT cells ( r = -0.876) (all P < 0.01), and positively correlated with the proportion of all CD8 + T lymphocytes ( r = 0.852), and B lymphocytes ( r = 0.593) (all P < 0.01). Conclusion:HBV-Tg composite CCl4 mice model can induce positive HBV virological indicators, liver inflammation and fibrosis in mice model of hepatitis B coexisting with fibrosis. This model has the features of immune disorder of liver lymphocyte similar to human disease, and the immune disorder of intrahepatic lymphocytes is correlated with HBV viral load and liver fibrosis degree.

OBJECTIVE: To investigate the risk factors of postoperative pulmonary infection (PPI) in patients over 60 years of age with gastric cancer after radical gastrectomy. METHODS: Clinicopathological data of 373 patients over 60 years of age who underwent radical gastrectomy at Department IV of Gastrointestinal Cancer Center, Peking University Cancer Hospital, from April 2009 to December 2016 were retrospectively collected in this case-control study. The clinicopathological characteristics of patients with postoperative pulmonary infection (including postoperative atelectasis) and those without pulmonary infection were compared. A Student t-test (reported as Mean±SD if data matching normal distribution) or Mann-Whitney U test [reported as median (quartile) if data did not conform to normal distribution] was used to analyze continuous variables. A χ² test or Fisher exact tests (reported as number and percentage) was used for categorical variables. Multivariable logistic regression was used to analyze the risk factors for pulmonary infection after operation of gastric cancer.PPI was defined as postoperative patients with elevated body temperature (>38.0 degrees centigrade) for more than 24 hours; cough and expectoration; positive sputum bacteria culture;recent infiltration, consolidation or atelectasis confirmed by chest imaging examination. RESULTS: Among 373 patients, 50 cases had PPI(13.4%, PPI group), 323 cases had no PPI(86.6%, non-PPI group). There were 39 (78.0%) and 178(55.1%) patients with comorbidities (including hypertension, diabetes and cardiopulmonary disease) preoperatively in PPI and non-PPI group, respectively. The difference between two groups was statistically significant (χ²=9.325,P=0.002). The incidence of preoperative hypoalbuminemia in PPI group was also significantly higher than that in non-PPI group [10.0%(5/50) vs. 3.1% (10/323),χ²=4.098, P=0.048]. Compared to non-PPI group, the rate of total gastrectomy [54.0%(27/50) vs. 34.4% (111/323), χ²=12.501, P=0.002], postoperative wound pain [34.0%(17/50) vs. 11.8% (38/323),χ²=16.928, P<0.001], secondary operation [6.0%(3/50) vs. 0.6% (2/323), χ²=6.032, P=0.014] and the rate of gastric tube removal later than 7 days postoperatively [96.0%(48/50) vs. 84.5%(273/323),χ²=4.811, P=0.028] were significantly higher in PPI group, respectively. The postoperative hospital stay was also prolonged in PPI group [16.0(9.5) days vs. 12.0(5.0) days, U=4 275.0, P<0.001]. Multivariate logistic regression analysis showed that preoperative comorbidities (OR=4.008, 95%CI:1.768-9.086, P=0.001), abdominal infection (OR=3.164, 95%CI:1.075-9.313, P=0.037), and wound pain (OR=3.428, 95%CI:1.557-7.548, P=0.002) were independent risk factors for PPI in patients over 60 years of age with gastric cancer. Furthermore, 50 patients with pulmonary infection were classified according to the length of latency and the type of infection. The patients with PPI latency ≤ 3 days were classified as early onset (34 cases, 68.0%), and those with latency ≥ 4 days as delayed onset (16 cases, 32.0%); PPI combined with surgical infection (including anastomotic leakage, abdominal infection, duodenal stump leakage, wound infection, etc.) was classified into mixed infection group (13 cases, 26.0%), with non-surgical infection as simple infection group (37 cases, 74.0%). The results showed that the pulmonary infection occurred 0 to 12 days (median 3 days) before surgical infection in mix infection group. The incidence of previous chronic obstructive pulmonary disease (COPD) in patients with early onset was significantly higher than that in patients with delayed onset [17.6%(6/34) vs. 0, χ²=5.005, P=0.025], and the incidence of mixed infection in patients with delayed onset was significantly higher than that in patients with early onset [50%(8/16) vs. 14.7%(5/34), χ²=6.730, P=0.009],but there was no significant difference in postoperative hospital stay between the two groups[17.0(9.8) days vs. 14.0(9.5) days, U=224.0, P=0.317]. CONCLUSIONS Postoperative pulmonary infection is common in gastric cancer patients over 60 years of age. Preoperative comorbidities, abdominal infection and wound pain are independent risk factors for postoperative pulmonary infection. Pulmonary infection within 3 days after operation is associated with preoperative COPD. For patients suffering from PPI after the 4th day,attentions should be paid to abdominal infection and anastomotic leakage.
Age Factors ; Anastomotic Leak ; etiology ; Case-Control Studies ; Gastrectomy ; adverse effects ; methods ; Humans ; Intraabdominal Infections ; etiology ; Middle Aged ; Pneumonia ; etiology ; Pulmonary Atelectasis ; etiology ; Pulmonary Disease, Chronic Obstructive ; complications ; Retrospective Studies ; Risk Factors ; Stomach Neoplasms ; complications ; surgery

Objective: To observe the therapeutic effect of terlipressin on refractory ascites (RA) in cirrhosis, and its role and impact on acute kidney injury (AKI). Methods: A non-randomized controlled clinical trial data of 111 hospitalized cases of liver cirrhosis accompanied with RA was collected from Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Zhongshan Hospital of Hubei Province, The First Affiliated Hospital of Zhengzhou University, The First Affiliated Hospital of Medical School of Zhejiang University, and People's Hospital of Pudong New Area of Shanghai between March 2015 and March 2017. 26 cases of conventional treatment group (control group) were divided into two subgroups: RA without AKI (RA-NAKI) and RA with AKI (RA-AKI), and each subgroup consisted 13 cases. Patients with bacterial infection were treated with diuretics, albumin supplementation and antibiotics. 85 cases were presented in terlipressin combined treatment group, of which 27 cases were of RA-NAKI and 58 cases were of RA-AKI. Control group was injected terlipressin 1mg of intravenous drip or static push (once q6 h ~ 12 h) for more than 5 days. The treatment duration lasted for 2 weeks with 4 weeks of follow-up. Body weight, 24-hour urine volume, abdominal circumference, mean arterial pressure (MAP), liver and kidney function, anterior hepatic ascites, deepest point of ascites, and ultrasonographic detection of ascites in supine position before treatment, one and two weeks after treatment and 4 weeks after follow-up were compared. Count data were tested by χ ². Samples of four groups at baseline were compared. One-way analysis of variance was used for normal distribution data and Kruskal-Wallis H test for non-normal distribution data. Repeated measures analysis of variance was used to compare the difference in efficacy between different time points before and after treatment in the group. The LSD method of one-way ANOVA was used to compare the two groups. A t-test of independent samples was used to compare the efficacy of different time series between the two groups. Mann-Whitney rank- sum test was used to compare the data of non-normal distribution between the two groups. Results: (1) Baseline data were compared among 4 subgroups of terlipressin RA-NAKI and control RA-AKI. Control group age was higher than that of terlipressin group, and the serum creatinine (SCr) of the RA-AKI group was higher than RA-NAKI group, and there was no significant difference in the rest of the baseline data and the combined medication (P > 0.05). (2) An intra-group comparison between control and trelipressin before and after treatment showed that all patients had lower body mass, abdominal circumference and deepest ascites, and higher serum albumin (P < 0.05). 24-hour urine volume and MAP was significantly increased in the terlipressin group, while the pre-ascites, SCr and child Turcotte Pugh (CTP) scores were decreased. Body weight, abdominal circumference, pre-ascites, and deepest ascites of the terlipressin group were decreased, while MAP was increased during the treatment and follow-up periods. The differences were statistically significant when compared with the control group at the same time (P < 0.05). There was a statistically significant difference in the increase of 24-h urine volume in the terlipressin group compared with the control group (P < 0.05). The decrease in SCr and CTP in the terlipressin group after 2 weeks of treatment and 4 weeks of follow-up was statistically significant compared with the control group (P < 0.05). (3) Among the two subgroups of RA-AKI and RA-NAKI in the terlipressin group, the baseline SCr value of the former was higher than that of the latter. After treatment, the body weight, abdominal circumference, pre-ascites, deepest ascites and CTP scores were decreased. In the RA-AKI group, 24-hour urine volume, MAP, SCr and serum albumin concentration were significantly increased. The difference between the two subgroups before and after treatment was compared, and the body weight of RA-AKI group at 1, 2 weeks of treatment and 4 weeks of follow-up was significantly lower than RA-NAKI group, which were (- 2.3 ± 0.2 vs. - 1.5 ± 0.2) kg, (- 4.1 ± 0.2 vs. - 2.6 ± 0.2) kg, (- 4.2 ± 0.3 vs. - 2.4 ± 0.3) kg, respectively. RA-NAKI group urine volume was significantly increased at 2 weeks of treatment and 4 weeks of follow-up, which was (468 ± 42 vs. 110 ± 131) ml, (272 ± 34 ml vs. 11 ± 112) ml, respectively. SCr reduction (18.3 ± 4.7 vs. 0.9 ± 2.4) µmol/l at 4 weeks of follow-up was apparent in RA-NAKI group, and the difference was statistically significant (P < 0.05). Conclusion Addition of terlipressin to conventional treatment may significantly increase MAP, 24-h urine volume, improve renal function and promote ascites resolution in patients with refractory cirrhotic ascites. Moreover, its combination effect is more obvious in AKI patients, and adverse reactions are mild.