Prediction of ventilator weaning failure in postoperative cardiac surgery patients using vasoactive-ventilation-renal score and nomogram analysis.

Objective: This study evaluated the predictive value of the vasoactive-ventilation-renal (VVR) score in identifying the risk of weaning failure after cardiac surgery and developing a nomogram model to help physicians improve the success rate of weaning from mechanical ventilation in adult patients undergoing postoperative cardiac surgery. Methods: Clinical data were retrospectively collected from adult patients who underwent extracorporeal circulation cardiac surgery at the First Affiliated Hospital of Nanjing Medical University between August 2022 and April 2023 and who were subsequently transferred to the Intensive Care Unit (ICU) and treated with vasoactive drugs. Patients were divided into successful and unsuccessful weaning groups based on first-attempt weaning success. Variable selection was regularized using univariate logistic regression and Least absolute shrinkage and selection operator (LASSO) regularization. Multivariate logistic regression was performed to identify predictors and a nomogram was created to predict the risk of weaning failure. Results: A total of 519 patients were included in the study. After selecting multiple stepwise variables, the VVR score before weaning, the modified Sequential Organ Failure Assessment (mSOFA) score on weaning day, and mechanical ventilation duration before weaning were determined as predictive indicators of weaning failure in adult patients after cardiac surgery. The optimal cut-off values for these indicators were 18.46 points, 4.33 points, and 20.50 h, respectively. The predictive model constructed using these three factors demonstrated good predictive performance. Conclusions: The VVR score before weaning accurately predicts the probability of weaning failure in adult patients after cardiac surgery. The weaning risk-predictive nomogram model, established based on the VVR score, mSOFA score, and mechanical ventilation duration before weaning, demonstrated robust predictive ability.

[Construction and verification of a nomogram of factors influencing the risk of death in patient with sepsis-associated thrombocytopenia].

OBJECTIVE: To construct a nomogram prediction model for predicting the risk of death in patients with sepsis-associated thrombocytopenia (SAT) in intensive care unit (ICU) for early indentification and active intervention. METHODS: Clinical data of SAT patients admitted to ICU of the First Affiliated Hospital of Nanjing Medical University from December 2019 to August 2021 were retrospectively collected, including demographic data, laboratory indicators, etc. According to the prognosis at 28 days, the patients were divided into the death group and the survival group, and the differences of clinical variables between the two groups were compared. Multivariate Logistic regression analysis was performed to analyze the independent risk factors influencing mortality of patients within 28 days, then a nomogram predictive model was constructed and its performance was verified with internal data. Receiver operator characteristic curve (ROC curve) was used to evaluate the diagnostic effectiveness of the nomogram model, and the clinical applicability of this model was evaluated by clinical decision curve analysis (DCA). RESULTS: A total of 275 patients were included, with 95 deaths at 28 days and a 28-day mortality of 34.5%. Compared with the survival group, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), lactic acid (Lac), platelet distribution width (PDW) on day 5 of ICU admission, blood urea nitrogen (BUN), total bilirubin (TBIL), aspartate aminotransferase (AST), C-reactive protein (CRP) of patients in the death group were higher, activated partial thromboplastin time (APTT) and prothrombin time (PT) were longer, platelet count (PLT) on day 3 and day 5 of ICU admission, direct bilirubin (DBIL), fibrinogen (FIB) were lower, the history of chronic lung disease, mixed site infection, lung infection, bloodstream infection, Gram-negative bacterial infection and fungal infection accounted for a higher proportion, the history of diabetes mellitus, urinary tract infection and no pathogenic microorganisms cultured accounted for a lower proportion, and the proportion of the use of vasoactive drugs, mechanical ventilation (MV), continuous renal replacement therapy (CRRT), bleeding events and platelet transfusion were higher. Multivariate Logistic regression analysis showed that APACHE II score at the day of ICU admission [odds ratio (OR) = 1.417, 95% confidence interval (95%CI) was 1.153-1.743, P = 0.001], chronic lung disease (OR = 72.271, 95%CI was 4.475-1 167.126, P = 0.003), PLT on day 5 of ICU admission (OR = 0.954, 95%CI was 0.922-0.987, P = 0.007), vasoactive drug (OR = 622.943, 95%CI was 10.060-38 575.340, P = 0.002), MV (OR = 91.818, 95%CI was 3.973-2 121.966, P = 0.005) were independent risk factors of mortality in SAT patients. The above independent risk factors were used to build a nomogram prediction model, and the area under the curve (AUC), sensitivity and specificity were 0.979, 94.7% and 91.7%, respectively, suggesting that the model had good discrimination. The Hosmer-Lemeshow goodness of fit test showed a good calibration with P > 0.05. At the same time, DCA showed that the nomogram model had good clinical applicability. CONCLUSIONS: Patients with SAT has a higher risk of death. The nomogram model based on APACHE II score at the day of ICU admission, chronic lung disease, PLT on day 5 of ICU admission, the use of vasoactive drug and MV has good clinical significance for the prediction of 28-day mortality, and the discrimination and calibration are good, however, further verification is needed.

CircCDYL Contributes to Apoptosis, Ferroptosis, and Oxidative Stress of Ang II-Induced Vascular Smooth Muscle Cells in Thoracic Aortic Aneurysm.

Circular RNAs (circRNAs) have important regulation in thoracic aortic aneurysm (TAA). The function and mechanism of circCDYL (circ_0008285) was explored in TAA here. Angiotensin II (Ang II) was used to construct a TAA model. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed for the detection of circCDYL, miR-1270, and a disintegrin and metalloproteinase 10 (ADAM10). Cell viability was examined via cell counting kit-8 (CCK-8) assay and proliferation was analyzed using Ethynyl-2'-deoxyuridine (EdU) assay. Apoptosis rate was assessed via flow cytometry. Western blot was used for protein detection. Oxidative stress was evaluated by commercial kits. CircCDYL was upregulated in TAA tissues and Ang II-induced circCDYL upregulation in vascular smooth muscle cells (VSMCs). Knockdown of circCDYL weakened Ang II-aroused inhibition of viability, proliferation, and promotion of apoptosis, ferroptosis, and oxidative stress in VSMCs. CircCDYL served as a miR-1270 sponge. The mitigated regulation of circCDYL knockdown for Ang II-induced injury was restored after miR-1270 downregulation. CircCDYL positively regulated ADAM10 through interacting with miR-1270. Overexpression of miR-1270 abated Ang II-induced injury by downregulating ADAM10. In conclusion, circCDYL was involved in the Ang II-induced VSMC injury in TAA via the miR-1270/ADAM10 axis.

Investigating the impact of human blood metabolites on the Sepsis development and progression: a study utilizing two-sample Mendelian randomization.

Background: Existing data suggests a potential link between human blood metabolites and sepsis, yet the precise cause-and-effect relationship remains elusive. By using a two-sample Mendelian randomization (MR) analysis, this study aims to establish a causal link between human blood metabolites and sepsis. Methods: A two-sample MR analysis was employed to investigate the relationship between blood metabolites and sepsis. To assess the causal connection between sepsis and human blood metabolites, five different MR methods were employed, A variety of sensitivity analyses were conducted, including Cochrane's Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out (LOO) analysis. In order to ensure the robustness of the causal association between exposure and outcome, the Bonferroni adjustment was employed. Additionally, we conducted analyses of the metabolic pathways of the identified metabolites using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Small Molecule Pathway Database (SMPDB) database. Results: The MR analysis revealed a total of 27 metabolites (16 known and 11 unknown) causally linked to the development and progression of sepsis. After applying the Bonferroni correction, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) remained significant in relation to 28-day all-cause mortality in sepsis. By pathway enrichment analysis, we identified four significant metabolic pathways. Notably, the Alpha Linolenic Acid and Linoleic Acid metabolism pathway emerged as a pivotal contributor to the occurrence and progression of sepsis. Conclusion: This study provides preliminary evidence of causal associations between human blood metabolites and sepsis, as ascertained by MR analysis. The findings offer valuable insights into the pathogenesis of sepsis and may provide insight into preventive and therapeutic approaches.

[Discussion on the zero-calibration and the zero line in the measurement of central venous pressure and invasive arterial blood pressure].

OBJECTIVE: To figure out the timing of zeroing and the location of the zero line in the central venous pressure (CVP) monitoring and invasive arterial blood pressure (IBP) monitoring, and to provide scientific and accurate data for patients management. METHODS: The liquid vessel models were used to simulate the pressure measurement process of the continuous pressure monitoring system. Based on the theory of fluid mechanics and the knowledge of blood pressure physiology and cardiovascular anatomy, the composition and influencing factors of the pressure in the fluid-filled catheter system during the zeroing and placing the transducer in the zero line of CVP and IBP, were analyzed. RESULTS: The pressure in the liquid-filled catheter system was composed of atmospheric pressure, the pressure of pumping bag, the gravity of the water column (the vertical distance between the liquid level of Murphy's dropper and pressure transducer, ΔH), and the resistance of tube wall. This pressure value is set as a pressure of 0 mmHg (1 mmHg ≈ 0.133 kPa). In the process of pressure measurement, when the pressure transducer was placed at a horizontal position of 10 cm below the highest liquid level of the vessel, the pressure measured at different catheter tip positions was all 10 cmH2O (1 cmH2O ≈ 0.098 kPa); When the pressure transducer was placed at the horizontal position of the highest liquid level of the vessel, the measured pressure is 0 mmHg. CONCLUSIONS: Zeroing should repeatedly be performed only when one or more conditions (atmospheric pressure, pressure of pumping bag, gravity of ΔH water column and resistance of tube wall) are changed. In the measurement process, the pressure transducer should be placed at the zero line position at any time to eliminate the influence of hydrostatic pressure and to ensure the objective and accurate value.

[Role of inflammation and apoptosis in right ventricular dysfunction induced by injurious mechanical ventilation in rats].

OBJECTIVE: To investigate whether myocardial inflammation and apoptosis are involved in right ventricular dysfunction (RVD) induced by injurious mechanical ventilation with high tidal volume (VT) in rats. METHODS: Total 30 adult male SD rats were randomly divided into the control group (CON group), the low VT ventilation group (LVT group) and the injurious mechanical ventilation group (HVT group), with 10 rats in each group. The CON group was maintained spontaneous breathing, the LVT group and HVT group were ventilated with different VT 6 mL/kg and 20 mL/kg for 4 hours, respectively. The right jugular vein and the left carotid artery were catheterized and connected with the PowerLab biological signal acquisition and analysis system to record heart rate (HR), mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), the maximum rate of rising of right ventricular pressure (+dp/dt max). Echocardiography was performed to measure left ventricular end-diastolic diameter (LVEDd), right ventricular end-diastolic diameter (RVEDd), tricuspid annulus plane systolic migration (TAPSE) and myocardial performance index (MPI). The rats were sacrified by cervical dislocation. Specimens of right ventricle tissues were taken for hematoxylin-eosin (HE) staining, and morphological changes of right ventricle tissues were observed under light microscope. Real time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the mRNA and protein expressions of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), caspase-3, apoptosis-related proteins Bax and Bcl-2. RESULTS: HR, MAP, +dp/dt max gradually decreased, while RVSP gradually increased in different group with the increase of VT ventilation. There was no significant difference between the CON group and LVT group. However, there was a statistically significant difference with respect to these index in HVT group as compared to CON group and LVT group [HR (bpm): 397.6±5.7 vs. 433.0±4.8, 441.6±7.8; MAP (mmHg, 1 mmHg ≈ 0.133 kPa): 102.0±2.4 vs. 108.5±2.2, 110.6±2.1; +dp/dt max (mmHg/s): 2 357.65±62.80 vs. 2 661.27±55.62, 2 679.43±75.13; RVSP (mmHg): 28.8±1.0 vs. 22.6±10.8, 21.9±0.4; all P < 0.05]. Echocardiography findings showed that RVEDd/LVEDd and MPI gradually increased, TAPSE gradually decreased in different group with the increase of VT ventilation. There was no significant difference between the LVT group and CON group. However, there was a statistically significant difference with respect to these indexes in HVT group as compared to the CON group and LVT group [RVEDd/LVEDd: 0.36±0.02 vs. 0.26±0.01, 0.23±0.02; MPI: 1.23±0.03 vs. 0.84±0.04, 0.86±0.03; TAPSE (mm): 1.65±0.03 vs. 1.88±0.02, 1.91±0.04; all P < 0.05]. Histopathological observation of the right ventricle tissue showed that myocardial cells of the rats in the CON group were orderly arranged and uniformed in size. In the LVT group, there was a small amount of inflammatory cell infiltration in the myocardial interstitium, while in the HVT group, the myocardial cell arrangement was obviously disordered, the structure was obviously damaged, and more inflammatory cell infiltration was found. RT-PCR and Western blotting analysis showed that the mRNA and protein expressions of IL-6, TNF-α, caspase-3 and Bax in HVT group were significantly higher than those in the LVT group and CON group [mRNA expression (2-ΔΔCt): IL-6 were 1.97±0.07 vs. 1.09±0.02, 1.02±0.03, TNF-α were 1.69±0.10 vs. 1.10±0.03, 1.05±0.04, caspase-3 were 1.82±0.09 vs. 1.08±0.02, 1.06±0.03, Bax were 2.19±0.14 vs. 1.07±0.03, 1.04±0.03; protein expression (gray value): IL-6 were 0.64±0.02 vs. 0.38±0.03, 0.31±0.04, TNF-α were 0.50±0.04 vs. 0.16±0.01, 0.15±0.01, caspase-3 were 0.58±0.02 vs. 0.29±0.01, 0.25±0.02, Bax were 0.50±0.03 vs. 0.21±0.01, 0.26±0.02; all P < 0.05], and the mRNA and protein expressions of Bcl-2 in the HVT group were lower than those in the LVT group and CON group [mRNA expression (2-ΔΔCt): 1.23±0.05 vs. 1.43±0.05, 1.50±0.08; protein expression (gray value): 0.42±0.02 vs. 0.62±0.03, 0.65±0.03, all P < 0.05]. CONCLUSION: Myocardial inflammation and apoptosis may be involved in RVD induced by injurious mechanical ventilation.

Hsa_circ_0000527 Downregulation Suppresses the Development of Retinoblastoma by Modulating the miR-27a-3p/HDAC9 Pathway.

BACKGROUND: Accumulating evidence indicates that the progression of retinoblastoma (RB) may involve circRNA dysfunction. We aimed to disclose the role of hsa_circ_0000527 and its potential functional mechanism in RB. METHODS: The expression of hsa_circ_0000527, miR-27a-3p and histone deacetylase 9 (HDAC9) mRNA was monitored using quantitative real-time polymerase chain reaction (qPCR). Functional assays, including cell proliferation and apoptosis, were investigated using cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay. The expression of apoptosis-associated proteins and HDAC9 protein was detected by western blot. The targeting relationship between miR-27a-3p and hsa_circ_0000527 or HDAC9 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Besides, Xenograft models were constructed to confirm the effect of hsa_circ_0000527 in vivo. RESULTS: Hsa_circ_0000527 and HDAC9 were upregulated, while miR-27a-3p was downregulated in RB tissues and cells. Hsa_circ_0000527 downregulation repressed RB cell proliferation and induced RB cell apoptosis. MiR-27a-3p was a target of hsa_circ_0000527, and hsa_circ_0000527 suppressed the expression of miR-27a-3p. MiR-27a-3p inhibition reversed the role of hsa_circ_0000527 downregulation. In addition, HDAC9 was a target of miR-27a-3p, and hsa_circ_0000527 indirectly regulated HDAC9 expression by targeting miR-27a-3p. MiR-27a-3p restoration inhibited RB cell proliferation and promoted apoptosis, which was reversed by HDAC9 overexpression. Hsa_circ_0000527 downregulation could inactivate the PI3K/AKT pathway. Moreover, hsa_circ_0000527 downregulation blocked tumor growth rate in vivo. CONCLUSION: hsa_circ_0000527 downregulation blocked the progression of RB by regulating the miR-27a-3p/HDAC9 pathway, which might be associated with the inactivation of the PI3K/AKT pathway.

Prognostic Association Between Perioperative Red Blood Cell Transfusion and Postoperative Cardiac Surgery Outcomes.

Objective: To investigate the correlation between red blood cell transfusion and clinical outcome in patients after cardiac surgery. Methods: Demographic, clinical characteristics, treatment with/without transfusion, and outcomes of patients after cardiac surgery from the Medical Information Mart for Intensive Care-III database were collected. Patients were divided into two groups according to perioperative transfusion. A multivariable logistic regression analysis was utilized to adjust for the effect of red blood cell transfusion on outcomes for baseline and covariates and to determine its association with outcomes. Results: In total, 6,752 patients who underwent cardiac surgery were enrolled for the analysis. Among them, 2,760 (40.9%) patients received a perioperative transfusion. Compared with patients without red blood cell transfusion, transfused patients demonstrated worse outcomes in inhospital mortality, 1-year mortality, and all-cause mortality. Adjusting odds ratios (ORs) for the significant characteristic, patients with perioperative transfusion remained significantly associated with an increased risk of inhospital mortality [OR = 2.8, 95% confidence interval (CI) 1.5-5.1, P = 0.001], 1-year mortality (OR = 2.0, 95% CI 1.4-2.7, P < 0.001), and long-term mortality (OR = 2.2, 95% CI 1.8-2.8, P < 0.001). Conclusion: Perioperative red blood cell transfusion is associated with a worse prognosis of cardiac surgery patients. Optimal perioperative management and restricted transfusion strategy might be considered in selected patients.

Ceftazidime-Avibactam-Based Versus Tigecycline-Based Regimen for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae-Induced Pneumonia in Critically Ill Patients.

INTRODUCTION: The aim of the present study was to assess the safety profile and outcomes of a ceftazidime-avibactam (CAZ-AVI)-based regimen and compare them with those of a tigecycline (TGC)-based regimen in intensive care unit (ICU) for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP), which is classified into hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). METHODS: Clinical and microbiological cure rates, 28-day survival rates, and safety evaluation findings were compared between patients treated with CAZ-AVI-based regimen and those treated with TGC-based regimen in this retrospective study. Conventional multivariate logistic regression analysis and regression adjustment analysis with propensity score (PS) were performed to control for confounding variables. RESULTS: A total of 105 cases of critically ill ICU patients with CRKP-induced HAP or VAP were included in the present study from July 2019 to September 2020; 62 patients (59%) received TGC-based regimen and 43 patients (41%) received CAZ-AVI-based regimen. The most common concomitant agent in the CAZ-AVI group and TGC group was carbapenem (44.2% versus 62.9%, P = 0.058), while only a small proportion of the study population received CAZ-AVI and TGC monotherapy (20.9% versus 6.5%, P = 0.027). The clinical and microbiological cure rates of the CAZ-AVI group were superior to those of the TGC group [51.2% versus 29.0% (P = 0.022) and 74.4% versus 33.9% (P < 0.001), respectively]. No significant differences in the 28-day survival rates were identified between the two groups (69.8% versus 66.1%, P = 0.695). Conventional multivariate logistic regression and PS analyses showed that patients who had used CAZ-AVI were more likely to have achieved a clinical cure [4.767 (95%CI 1.694-13.414), P=0.003;3.405 (95%CI 1.304-8.889), P=0.012] and microbiological success [6.664 (95%CI 2.626-16.915), P<0.001;7.778 (95%CI 2.717-22.265), P<0.001] than patients who used TGC. However, the difference in the 28-day survival rates between the two groups was not significant. According to the safety evaluation findings, the CAZ-AVI group exhibited a generally lower incidence of adverse reactions compared with that in the TGC group. CONCLUSIONS: CAZ-AVI may be a suitable alternative for TGC in the treatment of critically ill patients with CRKP-induced HAP or VAP. These observations require further confirmation in larger randomized prospective clinical trials.

[Monocyte/lymphocyte ratio as a predictor of 30-day mortality and adverse events in critically ill patients: analysis of the MIMIC-III database].

OBJECTIVE: To investigate the correlation of monocyte/lymphocyte ratio (MLR) with the prognosis and adverse event in critically ill patients. METHODS: Basic information of patients were extracted from Medical Information Mart for Intensive Care-III (MIMIC-III), including demographics, blood routine, biochemical indexes, systemic inflammatory response syndrome score (SIRS), sequential organ failure assessment (SOFA) score, and outcome, etc. MLR on the first day of intensive care unit (ICU) admission was calculated. The receiver operating characteristic curve (ROC curve) was applied to evaluate the prognostic value of MLR on the 30-day mortality and its cut-off value. According to the cut-off value, the patients were divided into two groups, and the differences between the groups were compared. Logistic regression model was used to analyze the relationship of MLR with 30-day mortality, continuous renal replacement therapy (CRRT), mechanical ventilation, the length of ICU stay, and total hospitalization time. RESULTS: (1) A total of 43 174 critically ill patients were included. ROC curve showed that area under ROC curve (AUC) of MLR in predicting 30-day mortality was 0.655 [95% confidence interval (95%CI) was 0.632-0.687]. The cut-off value of MLR calculated according to the maximum Yoden index was 0.5. There were 16 948 patients with MLR ≥ 0.5 (high MLR group) and 26 226 patients with MLR < 0.5 (low MLR group). (2) Compared with the low MLR group, the high MLR group had higher age, proportion of male, body mass index (BMI) [age (years old): 66.0 (51.7, 78.4) vs. 57.6 (27.1, 74.6), proportion of male: 57.2% vs. 52.5%, BMI (kg/m2): 26.5 (22.5, 31.1) vs. 24.7 (14.3, 29.7)]. The high MLR group also had higher incidence of complications (hypertension: 49.2% vs. 44.6%, chronic heart failure: 32.6% vs. 21.7%, diabetes mellitus: 27.0% vs. 23.4%, chronic obstructive pulmonary disease: 21.5% vs. 16.1%, renal insufficiency: 19.3% vs. 13.1%), and higher white blood cell count (WBC), blood glucose, lactate (Lac), serum creatinine (SCr), SIRS score and SOFA score [WBC (×109/L): 13.8 (9.6, 19.2) vs. 11.5 (8.4, 15.6), blood glucose (mmol/L): 8.66 (6.88, 11.49) vs. 8.27 (6.55, 10.88), Lac (mmol/L): 2.2 (1.5, 3.7) vs. 2.1 (1.4, 3.3), SCr (µmol/L): 106.1 (70.7, 176.8) vs. 88.4 (70.7, 132.6), SIRS score: 3 (2, 4) vs. 2 (2, 3), SOFA score: 4 (2, 7) vs. 3 (1, 5)]. The 30-day mortality, and the proportion of patients with length of ICU stay > 5 days, total hospitalization time > 14 days, CRRT and mechanical ventilation > 5 days were significantly higher in high MLR group (30-day mortality: 20.0% vs. 8.3%, length of ICU stay > 5 days: 33.2% vs. 20.4%, total hospitalization time > 14 days: 33.7% vs. 16.2%, CRRT: 3.6% vs. 0.7%, mechanical ventilation > 5 days: 18.4% vs. 5.7%), with statistically significant differences (all P < 0.05). (3) After adjusted with the related factors, multivariate Logistic regression analysis showed that elevated MLR was an independent risk factor for increased 30-day mortality [odd ratio (OR) = 1.54, 95%CI was 1.37-1.72, P < 0.001]. Moreover, the increased MLR was independently associated with the increased risk of usage of CRRT (OR = 2.77, 95%CI was 2.18-3.51), mechanical ventilation > 5 days (OR = 2.45, 95%CI was 2.21-2.72), the length of ICU stay > 5 days (OR = 2.29, 95%CI was 2.10-2.49), and total hospitalization time > 14 days (OR = 2.28, 95%CI was 2.08-2.49), all P < 0.001. CONCLUSIONS: Retrospective analysis of large sample shows that MLR elevation is an independent risk factor for 30-day mortality, usage of CRRT, prolonged mechanical ventilation time, prolonged hospitalization, prolonged length of ICU stay. MLR can be used for risk stratification of severe patients.

Prognostic Association of TERC, TERT Gene Polymorphism, and Leukocyte Telomere Length in Acute Heart Failure: A Prospective Study.

Background: Telomere length and telomerase are associated in development of cardiovascular diseases. Study aims to investigate the associations of TERC and TERT gene polymorphism and leukocyte telomere length (LTL) in the prognosis of acute heart failure (AHF). Methods: Total 322 patients with AHF were enrolled and divided into death and survival group according to all-cause mortality within 18 months. Seven single nucleotide polymorphisms (SNPs) of TERC and TERT were selected. Baseline characteristics, genotype distribution and polymorphic allele frequency, and genetic model were initially analyzed. Genotypes and the LTL were determined for further analysis. Results: Compared to carrying homozygous wild genotype, the risk of death in patients with mutated alleles of four SNPs- rs12696304(G>C), rs10936599(T>C), rs1317082(G>A), and rs10936601(T>C) of TERC were significantly higher. The dominant models of above were independently associated with mortality. In recessive models, rs10936599 and rs1317082 of TERC, rs7726159 of TERT were independently associated with long-term mortality. Further analysis showed, in haplotype consisting with TERC - rs12696304, rs10936599, rs1317082, and rs10936601, mutant alleles CCAC and wild alleles GTGT were significant difference between groups (P<0.05). CCAC is a risk factor and GTGT is a protective factor for AHF patients. Relative LTL decreased over age, but showed no difference between groups and genotypes. Conclusions: The SNPs of TERC and TERT are associated with the prognosis of AHF, and are the independent risk factors for predicting 18-month mortality in AHF.

Inhibiting miR­1 attenuates pulmonary arterial hypertension in rats.

MicroRNAs (miRs) are reported to serve key roles in pulmonary arterial hypertension (PAH). miR­1 has been found in cardiovascular diseases. The present study aimed to determine whether the knockdown of miR­1 could inhibit right ventricle (RV) remodeling and thereby control PAH in model rats. PAH model rats were established by exposing rats to hypoxia, while cardiac fibroblasts (CFs) obtained from PAH model rats were treated with hypoxia to establish an in vitro model, and RV remodeling was evaluated by Masson staining and the levels of collagen I, collagen III, α­smooth muscle actin (α­SMA) and connective tissue growth factor (CTGF) evaluated by western blotting or reverse transcription­quantitative PCR. The results revealed that the expression levels of miR­1 were upregulated in the RV of PAH model rats induced with hypoxia and in the CFs treated with hypoxia. The mean pulmonary arterial pressure, RV systolic pressure, RV/(left ventricle + interventricular septum) and RV/tibia length were increased in PAH rats; however, the increases in all parameters were subsequently reversed by transfection with a miR­1 antagomiR in PAH model rats. The transfection with the miR­1 antagomiR inhibited the development of RV fibrosis and downregulated the mRNA expression levels of collagen I, collagen III, α­SMA and CTGF in the RV tissue of PAH model rats. The upregulation of collagen I, collagen III, α­SMA and CTGF expression levels in hypoxia­treated CFs was also subsequently reversed by miR­1 antagomiR transfection. The expression levels of collagen I, collagen III, α­SMA and CTGF were also upregulated in the CFs obtained from PAH model rats, and these increases were attenuated by miR­1 antagomiR transfection. The expression levels of phosphorylated (p)­PI3K and p­AKT were also upregulated in hypoxia­treated CFs, and these increases were also inhibited by transfection with miR­1 antagomiR. In conclusion, these results indicated that inhibiting miR­1 may attenuate RV hypertrophy and fibrosis in PAH model rats, a mechanism that may involve the PI3K/AKT signaling pathway.

[Effects of mechanical ventilation with different tidal volumes on right ventricular hemodynamics in acute respiratory distress syndrome rats].

OBJECTIVE: To explore the effect of different tidal volumes (VT) on the hemodynamics of right heart in acute respiratory distress syndrome (ARDS) rats induced by oleic acid (OA). METHODS: Sixty adult male Sprague-Dawley (SD) rats were divided into control group (n = 20), ARDS model group (n = 20), low VT (LVT) group (n = 10) and high VT (HVT) group (n = 10) by random number table. ARDS model was reproduced by injecting OA 0.15 mL/kg through a jugular vein. The control group was given the same amount of normal saline. The success of modeling was judged by the oxygenation index (PaO2/FiO2) 2 hours after modeling, at the same time, the lung tissues were collected, the wet/dry weight (W/D) ratio was determined, and the lung histopathological changes were measured by lung injury score. The rats in the LVT group and HVT group were given mechanical ventilation with VT of 6 mL/kg or 20 mL/kg for 4 hours, respectively at 2 hours after modeling. The rats in the control group and the ARDS model group maintained spontaneous breathing. After mechanical ventilation for 4 hours, the heart rate (HR), right ventricular systolic pressure (RVSP), the maximum rate of rising of right ventricular pressure (dp/dt max), and the blood pressure (BP) were measured. Meanwhile, arterial blood samples were collected for blood gas analysis, including pH value, arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2) and PaO2/FiO2. RESULTS: The rats in the ARDS model group showed symptoms of respiratory distress 1 hour after modeling, and the lung tissue samples showed obvious patchy bleeding 2 hours after modeling, while the control group showed no such changes. The PaO2/FiO2 in the ARDS model group was significantly lower than that in the control group [mmHg (1 mmHg = 0.133 kPa): 294.3±5.9 vs. 459.0±4.4, P < 0.01], and the lung W/D ratio and lung injury score were significantly higher (lung W/D ratio: 8.24±0.25 vs. 4.48±0.13, lung injury score: 0.60±0.03 vs. 0.12±0.02, both P < 0.01). It indicated that ARDS model was successfully reproduced. The arterial blood gas analysis and hemodynamic parameters of the ARDS model group were significantly worse than those of the control group. After 4-hour mechanical ventilation, the blood gas parameters of the LVT group were better than those of the ARDS model group and the HVT group [pH value: 7.36±0.02 vs. 7.24±0.02, 7.13±0.01; PaO2 (mmHg): 92.4±2.1 vs. 61.8±2.3, 76.6±2.2; PaCO2 (mmHg): 49.6±1.7 vs. 61.8±1.8, 33.6±1.3; PaO2/FiO2 (mmHg): 440.0±10.2 vs. 274.3±21.4, 364.7±10.5; all P < 0.05]. HR, BP and dp/dt max in the LVT group were significantly higher than those in the ARDS model group and the HVT group [HR (bpm): 346.9±5.4 vs. 302.3±10.1, 265.5±12.2; BP (mmHg): 125.4±2.2 vs. 110.0±2.5, 89.2±2.8; dp/dt max (mmHg/s): 1 393.3±30.3 vs. 1 236.4±20.5, 896.1±19.5; all P < 0.05], and RVSP was significantly lower than that in the ARDS model group and the HVT group (mmHg: 31.3±0.4 vs. 34.0±1.0, 38.8±0.9, both P < 0.05). CONCLUSIONS: Mechanical ventilation with low VT can improve the hemodynamic parameters of the right ventricle and protect the function of the right heart in ARDS rats.

miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3.

Renal ischemia-reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI). So far, there have been many studies on renal IRI, although an effective treatment method has not been developed. In recent years, growing evidence has shown that small noncoding RNAs play an important regulatory role in renal IRI. This article aims to explore whether microRNA-25-3p (miR-25-3p) plays a role in the molecular mechanism of renal IRI. The results showed that the expression level of miR-25-3p was significantly downregulated in a rat renal IRI model, and this result was confirmed with in vitro experiments. After the hypoxia-reoxygenation treatment, the apoptosis level of NRK-52E cells transfected with miR-25-3p mimics decreased significantly, and this antiapoptotic effect was antagonized by miR-25-3p inhibitors. In addition, we confirmed that DKK3 is a target of miR-25-3p. miR-25-3p exerts its protective effect against apoptosis on NRK-52E cells by inhibiting the expression of DKK3, and downregulating the expression level of miR-25-3p could disrupt this protective effect. In addition, we reconfirmed the role of miR-25-3p in rats. Therefore, we confirmed that miR-25-3p may target DKK3 to reduce renal cell damage caused by hypoxia and that miR-25-3p may be a new potential treatment for renal IRI.

The etiological role of endoplasmic reticulum stress in acute lung injury-related right ventricular dysfunction in a rat model.

This study aimed to ascertain whether endoplasmic reticulum (ER) stress participates in acute lung injury (ALI) and related right ventricular dysfunction (RVD) as well as to explore the underlying mechanisms of these conditions. A single intratracheal instillation of lipopolysaccharide (LPS) (10 mg/kg) was used to establish the RVD model. The ER stress inhibitor, 4-PBA (500 mg/kg), was administered using a gavage 2 hours before and after the LPS treatment for prevention and treatment, respectively. At 12 hours post-LPS exposure, mRNA and protein expressions of ER stress-specific biomarkers, glucose regulating protein 78 (GRP78) and CCAAT/enhancer binding protein homology (CHOP), were significantly upregulated. This effect was inhibited by both 4-PBA prevention and treatment. In addition, echocardiography showed that 4-PBA improved the LPS-induced abnormality in the tricuspid annular plane systolic excursion (TAPSE) and the right ventricular end-diastolic diameter (RVEDD), however not in the pulmonary artery acceleration time (PAAT). Furthermore, hematoxylin and eosin staining (HE) and terminal transferase dUTP nick end labeling (TUNEL) assays revealed that the proportion of proapoptotic cells was higher in RVD rats. This was prominently ameliorated by 4-PBA treatment. Moreover, 4-PBA had a similar reverse effect on the LPS-induced increase in the Bax/Bcl-2 ratio, caspase-12, and caspase-3 expressions as revealed by western blotting. Furthermore, 4-PBA improved LPS-induced right ventricle (RV) myeloperoxidase (MPO)-positive neutrophil infiltration percentage, inhibited nuclear factor kappa B (NF-κB) activity, and reduced the expressions of inflammatory cytokines, TNF-α, IL-1ß, and IL-6, in serum and RV. Taken together, our results indicated that ER stress-mediated apoptosis and inflammation might contribute to the development of ALI-related RVD induced by intratracheal LPS instillation. Gavage-administered 4-PBA could improve right ventricle (RV) systolic dysfunction and dilation, plausibly by blocking ER stress.

Curcumin attenuates inflammation and cell apoptosis through regulating NF-κB and JAK2/STAT3 signaling pathway against acute kidney injury.

Curcumin alleviates septic acute kidney injury (SAKI); however, the underlying mechanism remained unclear. To explore this, SAKI cell model and mice model were conducted by using LPS and cecal ligation and puncture (CLP), respectively. Cell counting kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA) assays indicated that LPS reduced the viability, but upregulated the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6, whereas Curcumin pretreatment had no effect on viability, but reduced the levels of TNF-α and IL-6. Further assays showed that Curcumin partly attenuated the LPS-induced injury as the viability was enhanced, TNF-α and IL-6 expressions and cell apoptosis rates were reduced. Western blot analysis indicated that Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, p-65-NF-κB and cell apoptosis pathways were activated by LPS but suppressed by Curcumin. Mice SAKI model further indicated that the serum Cystatin C (Cys-C), creatinine (Cr) and blood urea nitrogen (BUN) were increased within 24 h of model construction while those indicators were decreased at 48 h. Pretreated with Curcumin, NF-κB inhibitor (PDTC) or JAK2 inhibitor (AG-490) could weaken the renal histological injury and the increased serum Cys-C, Cr and BUN, IL-6 and TNF-α induced by CLP. Moreover, PDTC, AG-490 and Curcumin all significantly reversed the previously increased expressions of p-JAK2/STAT3, p-p65 and proapoptotic proteins in the mice with AKI. The present study revealed that Curcumin attenuated SAKI through inhibiting NF-κB and JAK2/STAT3 signaling pathways, and proposed that Curcumin could be a potential therapeutic agent for treating SAKI.

Pulmonary fibrosis and cytokine release syndrome after hyperactivation with sintilimab.

WHAT IS KNOWN AND OBJECTIVE: Immunotherapy-related adverse events (irAEs) are common immunotherapy-associated diseases. Severe pulmonary fibrosis with hypercytokinaemia has not been reported with programmed cell death 1 (PD-1) inhibitors. We describe a case of sintilimab-induced pulmonary fibrosis with cytokine storm induced in a 50-year-old patient with colon cancer refractory to second-line systemic chemotherapy. CASE SUMMARY: Our patient developed hypercytokinaemia with elevated levels of interleukin (IL)-6 and IL-10 and pulmonary fibrosis, which differed from other irAEs. The patient benefited from a back-titrated regimen of methylprednisolone with the initial dosage of 2 mg/kg and anti-fibrotic effect of nintedanib and was successfully weaned from the ventilator. WHAT IS NEW AND CONCLUSION: This is the first report that a PD-1 inhibitor may have caused pulmonary fibrosis and a cytokine storm. This case indicates that the addition of nintedanib and glucocorticoid might possibly have potentially therapeutic effects of PD-1 induced pulmonary fibrosis and hypercytokinaemia.

Clinical and Autoimmune Characteristics of Severe and Critical Cases of COVID-19.

In this study we report on the clinical and autoimmune characteristics of severe and critical novel coronavirus pneumonia caused by severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). The clinical, autoimmune, and laboratory characteristics of 21 patients who had laboratory-confirmed severe and critical cases of coronavirus disease 2019 (COVID-19) from the intensive care unit of the Huangshi Central Hospital, Hubei Province, China, were investigated. A total of 21 patients (13 men and 8 women), including 8 (38.1%) severe cases and 13 (61.9%) critical cases, were enrolled. Cough (90.5%) and fever (81.0%) were the dominant symptoms, and most patients (76.2%) had at least one coexisting disorder on admission. The most common characteristics on chest computed tomography were ground-glass opacity (100%) and bilateral patchy shadowing (76.2%). The most common findings on laboratory measurement were lymphocytopenia (85.7%) and elevated levels of C-reactive protein (94.7%) and interleukin-6 (89.5%). The prevalence of anti-52 kDa SSA/Ro antibody, anti-60 kDa SSA/Ro antibody, and antinuclear antibody was 20%, 25%, and 50%, respectively. We also retrospectively analyzed the clinical and laboratory data from 21 severe and critical cases of COVID-19. Autoimmune phenomena exist in COVID-19 subjects, and the present results provide the rationale for a strategy of preventing immune dysfunction and optimal immunosuppressive therapy.

[Protective effect of sodium 4-phenylbutyrate on rats with acute respiratory distress syndrome related right ventricular dysfunction by alleviating endoplasmic reticulum stress].

OBJECTIVE: To investigate the role of endoplasmic reticulum stress (ERS) in rats with acute respiratory distress syndrome (ARDS) related right ventricular dysfunction and the protective effect of sodium 4-phenylbutyrate (4-PBA) on right ventricle. METHODS: Sixty male Spragne-Dawley (SD) rats were randomly divided into control group (CON group), lipopolysaccharide (LPS) model group, 4-PBA prevention group and 4-PBA treatment group, with 15 rats in each group. ARDS rat model was established by intratracheal instillation of LPS 10 mg/kg after tracheotomy; CON group was given the same amount of saline. 4-PBA prevention group and 4-PBA treatment group were given 4-PBA 500 mg/kg intragastric administration 2 hours before and after LPS respectively. Echocardiography was performed 12 hours after treatment to evaluate the right ventricular function. Then, the rats were sacrificed by bloodletting, and the serum and right ventricular tissue were harvested. The histopathological changes of myocardial were observed by hematoxylin-eosin (HE) staining, the levels of tumor necrosis factor-α (TNF-α), interleukins (IL-1ß and IL-6) in serum and myocardial were detected by enzyme linked immunosorbent assay (ELISA), and Western Blot was used to detect the expression of the marker proteins of ERS in myocardial, including glucose regulatory protein 78 (GRP78), C/EBP cyclic adenosine phosphate reaction primitive binding transcription factor homologous protein (CHOP), caspase-12 and caspase-3. RESULTS: Compared with the CON group, the echocardiography showed pulmonary artery maximum pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE) in LPS model group were significantly decreased, and right ventricular end-diastolic excursion (RVDd) was significantly increased, and the levels of TNF-α, IL-1ß and IL-6 in serum and myocardial, as well as the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly increased. Compared with LPS model group, TAPSE of 4-PBA preventive and treatment groups were significantly increased (mm: 3.08±0.65, 2.96±0.61 vs. 2.48±0.45), RVDd were significantly decreased (mm: 3.67±0.58, 3.60±0.61 vs. 4.18±0.71), the levels of TNF-α, IL-1ß and IL-6 in serum and myocardial were significantly decreased [TNF-α (ng/L): 187.98±18.98, 176.08±17.98 vs. 332.00±19.90 in serum, 135.06±19.00, 132.78±17.00 vs. 155.00±20.00 in myocardial; IL-1ß(ng/L): 12.07±2.98, 11.05±2.41 vs. 24.06±4.01 in serum, 19.89±2.80, 21.06±2.80 vs. 26.00±2.60 in myocardial; IL-6 (ng/L): 42.98±7.90, 34.05±6.09 vs. 89.80±10.07 in serum, 129.45±25.00, 127.08±26.06 vs. 145.77±23.00 in myocardial]; the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly decreased (GRP78/GAPDH: 0.090±0.070, 0.103±0.060 vs. 0.167±0.090, CHOP/GAPDH: 0.109±0.090, 0.090±0.080 vs. 0.186±0.090, caspase-12/GAPDH: 0.769±0.230, 0.799±0.210 vs. 1.040±0.350, caspase-3/GAPDH: 0.391±0.060, 0.401±0.054 vs. 0.603±0.340), with statistically significant differences (all P < 0.05). There were no significant differences in each indexes between 4-PBA prevention group and 4-PBA treatment group (all P > 0.05). CONCLUSIONS: ERS is involved in ARDS-related right ventricular dysfunction. 4-PBA can protect the right ventricular function of ARDS rats by inhibiting ERS and alleviating inflammation, and the preventive and therapeutic effects of 4-PBA are similar.