ObjectiveTo investigate the mechanism by which Feixin decoction treats hypoxic pulmonary hypertension （HPH） by regulating the peroxisome proliferator-activated receptor gamma （PPARγ）/nuclear factor-kappa B （NF-κB）/NOD-like receptor pyrin domain containing 3 （NLRP3） signaling pathway. MethodsForty-eight male SD rats were randomly allocated into normal， hypoxia， and low-， medium- and high-dose （5.85， 11.7， 23.4 g·kg^-1， respectively） Feixin decoction groups， with 8 rats in each group. Except the normal group， the remaining five groups were placed in a hypoxia chamber with an oxygen concentration of （10.0±0.5）% for 8 h per day， 28 days， and administrated with corresponding drugs during the modeling process. After 4 weeks of treatment， echocardiographic parameters ［pulmonary artery acceleration time （PAT）， pulmonary artery ejection time （PET）， right ventricular anterior wall thickness （RVAWd）， and tricuspid annular plane systolic excursion （TAPSE）］ were measured for each group. The right ventricular systolic pressure （RVSP） was measured by the right heart catheterization method， and the right ventricular hypertrophy index （RVHI） was calculated by weighing the heart. The pathological changes in pulmonary arterioles were observed by hematoxylin-eosin staining. The co-localization of α-smooth muscle actin （α-SMA） with NLRP3， N-terminal gasdermin D （N-GSDMD）， and cysteinyl aspartate-specific proteinase-1 （Caspase-1） in pulmonary arteries was detected by immunofluorescence. The protein levels of PPARγ， NF-κB， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， N-GSDMD， interleukin-1β （IL-1β）， interleukin-18（IL-18）， and cleaved Caspase-1 in the lung tissue was determined by Western blot. The ultrastructural changes in pulmonary artery smooth muscle cells （PASMCs） were observed by transmission electron microscopy. ResultsCompared with the normal group， the hypoxia group showed increased RVSP and RVHI （P<0.01）， decreased right heart function （P<0.01）， increased pulmonary vascular remodeling （P<0.01）， increased co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 in pulmonary arterioles （P<0.01）， up-regulated protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， a down-regulated protein level of PPARγ （P<0.05， P<0.01）， and pyroptosis in PASMCs. Compared with the hypoxia group， Feixin decoction reduced RVSP and RVHI， improved the right heart function and ameliorated pulmonary vascular remodeling （P<0.05， P<0.01）， decreased the co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 （P<0.05， P<0.01）， down-regulated the protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， up-regulated the protein level of PPARγ （P<0.05， P<0.01）， and alleviated pyroptosis in PASMCs. ConclusionFeixin decoction can ameliorate pulmonary vascular remodeling and right heart dysfunction in chronically induced HPH rats by regulating pyroptosis in PASMCs through the PPARγ/NF-κB/NLRP3 pathway.

Objective:To investigate the mechanism of improving liver injury by enhancing the abundance of Akkermansia mu-ciniphila(AKK bacteria)with hepatocyte-specific Yap1 knockout during PD-1 monoclonal antibody treatment.Methods:Hepatocyte-specific Yap1 knockout mice(genotype Yap1Flox/Flox;albumin-Cre,labeled as Yap1LKO)and control mice(genotype Yap1Flox/Flox,labeled Yap1Flox),aristolocholic acidⅠ(AAⅠ)and CCl4 were used to induce liver injury,Yap1LKO mice and Yap1Flox mice were randomly di-vided into control group and PD-1 monoclonal antibody group.After the intervention,real-time PCR detected changes in the abun-dance of AKK bacteria in the fecal microbial DNA of mice,16S rRNA gene sequencing further analyzes intestinal flora changes,the livers of mice were made into wax blocks for HE staining to observe the histopathological changes of the liver.Results:Yap1Flox mice exhibited balloon-like edema degeneration of hepatocytes and infiltration of inflammatory factors in the manifold area,compared with Yap1Flox mice,Yap1LKO mice had reduced the abundance of AKK bacteria in the intestine,fibrosis of the liver,and the degree of dam-age was more serious;PD-1 monoclonal antibody treatment alone did not increase the abundance of AKK bacteria in the intestines of mice,and fibrosis appeared in the liver;however,the abundance of intestinal AKK bacteria in Yap1LKO mice treated with PD-1 mono-clonal antibody increased,the ratio(F/B value)of Firmicutes to Bacteroides at the phylum level decreased,and the morphology of he-patocytes returned to normal and the degree of liver damage decreased.Conclusion:In AAⅠ and CCl4 induced liver injury mice,he-patocyte-specific Yap1 knockout reduced the abundance of AKK bacteria in the intestine,and the degree of liver injury was more se-vere than that in Yap1Flox mice.When treated with PD-1 monoclonal antibody,hepatocyte-specific Yap1 knockout could increase the abundance of AKK bacteria in the intestine,change the composition of intestinal flora,maintain intestinal homeostasis and ameliorate liver injury.

Objectives:To summarize the characteristics of Fabry′s disease with cardiac involvement.Methods:This was a single-center, cross-sectional, retrospective study. Patients with Fabry disease who were admitted to Zhongda Hospital Affiliated to Southeast University from January 2022 to March 2023 were included. Clinical data, laboratory results, electrocardiogram, echocardiography and cardiac magnetic resonance findings of enrolled patients were collected. Clinical presentations and imaging features of patients with Fabry′s disease with cardiac involvement were summarized and analyzed.Results:A total of 17 patients from 8 families were included, with 9 males and diagnosis age of (44.35±13.72) years. Cardiac involvement and other organ involvement were presented in all patients and the heart was the most vulnerable organ (17/17). 24 h electrocardiogram showed frequent sinus arrhythmia in 3 patients. Echocardiography showed reduced left ventricular ejection fraction in 1 patient, myocardial hypertrophy in 13 patients, and left ventricular wall thickness ≥13 mm in 10 patients. Mitral regurgitation was observed in 11 patients and tricuspid regurgitation in 12 patients. Two patients underwent two-dimensional speckle tracking echocardiography, both revealing reduced regional longitudinal strain of the left ventricle, primarily in the basal segments. Cardiac magnetic resonance showed reduced left ventricular ejection fraction in 2 patients, myocardial hypertrophy in 16 patients, and left ventricular wall thickness≥13 mm in 14 patients. T1 value was reduced in 16 patients, with late gadolinium enhancement observed in 9 patients and “pseudo-normalization” of T1 values in 1 patient. The most susceptible target organ besides the heart was the kidneys (14/17), followed by the central nervous system (9/17). Additional findings inclucling cutaneous angiokeratoma in 4 patients, peripheral neuropathy with burning pain and hypohidrosis or hyperhidrosis in 6 patients, and corneal vortex opacities in 2 patients.Conclusion:The main manifestations of cardiac involvement in Fabry′s disease are decreased cardiac function, left ventricular hypertrophy and myocardial fibrosis. Advanced imaging techniques such as two-dimensional speckle tracking, T1 Mapping, and late gadolinium enhancement are useful in detecting myocardial pathological changes of Fabry′s disease.

Objectives:To investigate the prognostic difference of different revascularization strategies in AMI patients with multi-vessel disease and diabetes.Methods:AMI patients with multi-vessel disease and diabetes admitted to the Department of Cardiology of the First Hospital of Lanzhou University from January 2022 to June 2024 were retrospectively included.Patients were divided into non complete revascularization(NCR)group(n=166),staged complete revascularization(SCR)group(n=152)and immediate complete revascularization(ICR)group(n=120).Baseline clinical characteristics,coronary angiography data and postoperative medication were compared among the groups.Primary endpoint was the major adverse cardiovascular and cerebrovascular events(MACCE)during follow-up.MACCE includes all-cause mortality,cardiogenic mortality,non-fatal myocardial infarction,unplanned revascularization and stroke.The log-rank test was used to analyze the significance of the differences in the cumulative incidence of MACCE among the three groups.Cox regression was used to explore the influencing factors of poor prognosis in patients.Results:There were statistically significant differences among NCR group,SCR group and ICR group in terms of the history of previous percutaneous coronary intervention,the use of intraoperative coronary intravascular ultrasound(IVUS)and the dosage of contrast agent(all P<0.05).During a median follow-up of 21(11,25)months,MACCE events occurred in 59 cases(35.5%)in the NCR group,26 cases(17.1%)in the SCR group,and 30 cases(25.0%)in the ICR group.The Kaplan-Meier curve showed that the differences in the cumulative incidence of MACCE among the three groups were statistically significant(log-rank P<0.001).Using the Bonferroni correction(adjusted α′=0.05/3≈0.0167),pairwise comparisons revealed statistically significant differences between the NCR and SCR groups(log-rank P<0.001)and between the NCR and ICR groups(log-rank P=0.011).However,no statistically significant difference was observed between the SCR and ICR groups(log-rank P=0.228).Cox multivariate regression analysis demonstrated that history of hypertension was an independent risk factor for MACCE in AMI patients with multivessel coronary artery disease and diabetes(HR=1.71,95%CI:1.10-2.64,P<0.05).The difference in the incidence of MACCE between the SCR group and the NCR group was statistically significant(HR=0.45,95%CI:0.28-0.73,P=0.001).Conclusions:Staged complete revascularization serves as the preferred revascularization strategy for AMI patients with multivessel coronary disease and diabetes mellitus.Additionally,for patients with concomitant hypertension,blood pressure management should be intensified to reduce the risk of MACCE.

Objective:To assess the clinical application of voriconazole therapeutic drug monitoring in the individualized dosing of liver transplant recipients, aiming to optimize its therapeutic efficacy and safety.Methods:This is a single-center, case-control study that collected data from 55 liver transplant recipients at Renji Hospital, Shanghai Jiao Tong University School of Medicine, between August 2, 2019, and May 28, 2023. Among the participants, 33 were male and 22 were female, with an average age of (41.94±22.12) years. All patients received voriconazole, with a total of 235 drug concentration tests conducted. The concentrations of voriconazole were measured by liquid chromatography-tandem mass spectrometry. The study analyzed the correlation between different drug concentration levels and efficacy outcomes (negative fungal culturing result) and hepatoxicity (ALT, AST, and ALP exceeding three times the upper limit of normal). Factors influencing voriconazole concen tration levels were assessed using multiple linear regression analysis.Results:The coefficient of variation ( CV) for inter-individuals and intra-individuals voriconazole blood concentration was 94% and 58%, respectively. The difference in globulin levels among three groups with different drug concentrations (<1 μg/ml, 1-5.5 μg/ml,>5.5 μg/ml) was statistically significant ( H=8.65, P=0.013). Receiver operating characteristic curve analysis indicated that the risk of treatment failure increased when the trough concentration was<1.0 μg/ml, with an area under the curve (AUC) of 0.75; the risk of hepatotoxicity increased when the drug concentration was>4.4 μg/ml (AUC=0.62). Multiple linear regression analysis showed that the combined use of proton pump inhibitors (| t|=8.07, P<0.001) and other antifungal agents (| t|=3.82, P<0.001) was significantly positively correlated with voriconazole concentration, while the use of glucocorticoids (| t|=5.60, P<0.001) and antiviral drugs (| t|=3.59, P<0.001) was significantly negatively correlated with voriconazole concentration. Conclusion:There is significant inter-individual variability in voriconazole blood concentrations among liver transplant recipients, influenced by the mode of administration and types of concomitant medications. Maintaining blood concentrations within the range of 1.0-4.4 μg/ml can optimize therapeutic efficacy while reducing the occurrence of adverse effects.

Objectives:To investigate the prognostic difference of different revascularization strategies in AMI patients with multi-vessel disease and diabetes.Methods:AMI patients with multi-vessel disease and diabetes admitted to the Department of Cardiology of the First Hospital of Lanzhou University from January 2022 to June 2024 were retrospectively included.Patients were divided into non complete revascularization(NCR)group(n=166),staged complete revascularization(SCR)group(n=152)and immediate complete revascularization(ICR)group(n=120).Baseline clinical characteristics,coronary angiography data and postoperative medication were compared among the groups.Primary endpoint was the major adverse cardiovascular and cerebrovascular events(MACCE)during follow-up.MACCE includes all-cause mortality,cardiogenic mortality,non-fatal myocardial infarction,unplanned revascularization and stroke.The log-rank test was used to analyze the significance of the differences in the cumulative incidence of MACCE among the three groups.Cox regression was used to explore the influencing factors of poor prognosis in patients.Results:There were statistically significant differences among NCR group,SCR group and ICR group in terms of the history of previous percutaneous coronary intervention,the use of intraoperative coronary intravascular ultrasound(IVUS)and the dosage of contrast agent(all P<0.05).During a median follow-up of 21(11,25)months,MACCE events occurred in 59 cases(35.5%)in the NCR group,26 cases(17.1%)in the SCR group,and 30 cases(25.0%)in the ICR group.The Kaplan-Meier curve showed that the differences in the cumulative incidence of MACCE among the three groups were statistically significant(log-rank P<0.001).Using the Bonferroni correction(adjusted α′=0.05/3≈0.0167),pairwise comparisons revealed statistically significant differences between the NCR and SCR groups(log-rank P<0.001)and between the NCR and ICR groups(log-rank P=0.011).However,no statistically significant difference was observed between the SCR and ICR groups(log-rank P=0.228).Cox multivariate regression analysis demonstrated that history of hypertension was an independent risk factor for MACCE in AMI patients with multivessel coronary artery disease and diabetes(HR=1.71,95%CI:1.10-2.64,P<0.05).The difference in the incidence of MACCE between the SCR group and the NCR group was statistically significant(HR=0.45,95%CI:0.28-0.73,P=0.001).Conclusions:Staged complete revascularization serves as the preferred revascularization strategy for AMI patients with multivessel coronary disease and diabetes mellitus.Additionally,for patients with concomitant hypertension,blood pressure management should be intensified to reduce the risk of MACCE.

Objective:To investigate the mechanism of improving liver injury by enhancing the abundance of Akkermansia mu-ciniphila(AKK bacteria)with hepatocyte-specific Yap1 knockout during PD-1 monoclonal antibody treatment.Methods:Hepatocyte-specific Yap1 knockout mice(genotype Yap1Flox/Flox;albumin-Cre,labeled as Yap1LKO)and control mice(genotype Yap1Flox/Flox,labeled Yap1Flox),aristolocholic acidⅠ(AAⅠ)and CCl4 were used to induce liver injury,Yap1LKO mice and Yap1Flox mice were randomly di-vided into control group and PD-1 monoclonal antibody group.After the intervention,real-time PCR detected changes in the abun-dance of AKK bacteria in the fecal microbial DNA of mice,16S rRNA gene sequencing further analyzes intestinal flora changes,the livers of mice were made into wax blocks for HE staining to observe the histopathological changes of the liver.Results:Yap1Flox mice exhibited balloon-like edema degeneration of hepatocytes and infiltration of inflammatory factors in the manifold area,compared with Yap1Flox mice,Yap1LKO mice had reduced the abundance of AKK bacteria in the intestine,fibrosis of the liver,and the degree of dam-age was more serious;PD-1 monoclonal antibody treatment alone did not increase the abundance of AKK bacteria in the intestines of mice,and fibrosis appeared in the liver;however,the abundance of intestinal AKK bacteria in Yap1LKO mice treated with PD-1 mono-clonal antibody increased,the ratio(F/B value)of Firmicutes to Bacteroides at the phylum level decreased,and the morphology of he-patocytes returned to normal and the degree of liver damage decreased.Conclusion:In AAⅠ and CCl4 induced liver injury mice,he-patocyte-specific Yap1 knockout reduced the abundance of AKK bacteria in the intestine,and the degree of liver injury was more se-vere than that in Yap1Flox mice.When treated with PD-1 monoclonal antibody,hepatocyte-specific Yap1 knockout could increase the abundance of AKK bacteria in the intestine,change the composition of intestinal flora,maintain intestinal homeostasis and ameliorate liver injury.

Objective:To assess the clinical application of voriconazole therapeutic drug monitoring in the individualized dosing of liver transplant recipients, aiming to optimize its therapeutic efficacy and safety.Methods:This is a single-center, case-control study that collected data from 55 liver transplant recipients at Renji Hospital, Shanghai Jiao Tong University School of Medicine, between August 2, 2019, and May 28, 2023. Among the participants, 33 were male and 22 were female, with an average age of (41.94±22.12) years. All patients received voriconazole, with a total of 235 drug concentration tests conducted. The concentrations of voriconazole were measured by liquid chromatography-tandem mass spectrometry. The study analyzed the correlation between different drug concentration levels and efficacy outcomes (negative fungal culturing result) and hepatoxicity (ALT, AST, and ALP exceeding three times the upper limit of normal). Factors influencing voriconazole concen tration levels were assessed using multiple linear regression analysis.Results:The coefficient of variation ( CV) for inter-individuals and intra-individuals voriconazole blood concentration was 94% and 58%, respectively. The difference in globulin levels among three groups with different drug concentrations (<1 μg/ml, 1-5.5 μg/ml,>5.5 μg/ml) was statistically significant ( H=8.65, P=0.013). Receiver operating characteristic curve analysis indicated that the risk of treatment failure increased when the trough concentration was<1.0 μg/ml, with an area under the curve (AUC) of 0.75; the risk of hepatotoxicity increased when the drug concentration was>4.4 μg/ml (AUC=0.62). Multiple linear regression analysis showed that the combined use of proton pump inhibitors (| t|=8.07, P<0.001) and other antifungal agents (| t|=3.82, P<0.001) was significantly positively correlated with voriconazole concentration, while the use of glucocorticoids (| t|=5.60, P<0.001) and antiviral drugs (| t|=3.59, P<0.001) was significantly negatively correlated with voriconazole concentration. Conclusion:There is significant inter-individual variability in voriconazole blood concentrations among liver transplant recipients, influenced by the mode of administration and types of concomitant medications. Maintaining blood concentrations within the range of 1.0-4.4 μg/ml can optimize therapeutic efficacy while reducing the occurrence of adverse effects.

Objectives:To summarize the characteristics of Fabry′s disease with cardiac involvement.Methods:This was a single-center, cross-sectional, retrospective study. Patients with Fabry disease who were admitted to Zhongda Hospital Affiliated to Southeast University from January 2022 to March 2023 were included. Clinical data, laboratory results, electrocardiogram, echocardiography and cardiac magnetic resonance findings of enrolled patients were collected. Clinical presentations and imaging features of patients with Fabry′s disease with cardiac involvement were summarized and analyzed.Results:A total of 17 patients from 8 families were included, with 9 males and diagnosis age of (44.35±13.72) years. Cardiac involvement and other organ involvement were presented in all patients and the heart was the most vulnerable organ (17/17). 24 h electrocardiogram showed frequent sinus arrhythmia in 3 patients. Echocardiography showed reduced left ventricular ejection fraction in 1 patient, myocardial hypertrophy in 13 patients, and left ventricular wall thickness ≥13 mm in 10 patients. Mitral regurgitation was observed in 11 patients and tricuspid regurgitation in 12 patients. Two patients underwent two-dimensional speckle tracking echocardiography, both revealing reduced regional longitudinal strain of the left ventricle, primarily in the basal segments. Cardiac magnetic resonance showed reduced left ventricular ejection fraction in 2 patients, myocardial hypertrophy in 16 patients, and left ventricular wall thickness≥13 mm in 14 patients. T1 value was reduced in 16 patients, with late gadolinium enhancement observed in 9 patients and “pseudo-normalization” of T1 values in 1 patient. The most susceptible target organ besides the heart was the kidneys (14/17), followed by the central nervous system (9/17). Additional findings inclucling cutaneous angiokeratoma in 4 patients, peripheral neuropathy with burning pain and hypohidrosis or hyperhidrosis in 6 patients, and corneal vortex opacities in 2 patients.Conclusion:The main manifestations of cardiac involvement in Fabry′s disease are decreased cardiac function, left ventricular hypertrophy and myocardial fibrosis. Advanced imaging techniques such as two-dimensional speckle tracking, T1 Mapping, and late gadolinium enhancement are useful in detecting myocardial pathological changes of Fabry′s disease.

Objective To monitor heart-related parameters of hypoxic pulmonary hypertension(PH)mouse models induced by hypoxia alone and hypoxia combined with vascular endothelial growth factor receptor inhibitor SU5416 using echocardiography,and to construct the prediction equation of right ventricular systolic pressure(RVSP).Twenty-four C57BL/6J male mice were randomly divided into simple hypoxia group(group A),hypoxia combined with SU5416 group(group B),control group(group C),each group 8 mice.Hypoxic PH models were constructed with hypoxia alone and hypoxia combined with SU5416 in group A and group B,respectively.Echocardiography was performed before and during modeling(2,3,4 weeks after interventions),and the relevant parameters were obtained.RVSP was measured using right heart catheterization after the last echocardiography.The changes of ultrasonic parameters were observed,the correlations of ultrasonic parameters 4 weeks after intervention with RVSP were observed,and linear equations for predicting RVSP were established.Results With time going,during modeling,pulmonary artery diameter(PAD),PAD/aorta diameter(AOD)and right ventricle anterior wall thickness(RVAWT)increased,while heart rate,pulmonary artery acceleration time(PAAT),PAAT/pulmonary artery ejection time(PAET)and tricuspid annular plane systolic excursion(TAPSE)decreased in group A and B(all P＜0.05).Three and 4 weeks after interventions,PAET,PAAT/PAET and TAPSE in group B decreased compared with those in group A(all P＜0.05).Four weeks after interventions,RVSP in group A and B were highly correlated with PAD/AOD,RVAWT,PAAT,PAAT/PAET and TAPSE(all P＜0.05).The linear regression equations of PAAT/PAET and TAPSE for predicting RVSP in simple hypoxic PH mice models included RVSP=-161.7 ×(PAAT/PAET)+63.85,as well as RVSP=-36.53 ×TAPSE+71.55,while of predicting RVSP in hypoxia combined with VEGFR-2 inhibitor PH mouse models were as follows:RVSP=-266.4 ×(PAAT/PAET)+91.59,RVSP=-69.14 × TAPSE+116.5.Conclusion Four weeks after inerventions,the phenotypes of hypoxic PH mouse models induced by hypoxia alone and hypoxia combined with SU5416 became obvious.Prediction equations of RVSP established based on PAAT/PAET and TAPSE obtained with echocardiography could provide references for relevant research.