A decrease in integrin α5ß1/FAK is associated with increased apoptosis of aortic smooth muscle cells in acute type a aortic dissection.

BACKGROUND: Acute type A aortic dissection (AAAD) is a devastating disease. Human aortic smooth muscle cells (HASMCs) exhibit decreased proliferation and increased apoptosis, and integrin α5ß1 and FAK are important proangiogenic factors involved in regulating angiogenesis. The aim of this study was to investigate the role of integrin α5ß1 and FAK in patients with AAAD and the potential underlying mechanisms. METHODS: Aortic tissue samples were obtained from 8 patients with AAAD and 4 organ donors at Zhongshan Hospital of Fudan University. The level of apoptosis in the aortic tissues was assessed by immunohistochemical (IHC) staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays. The expression of integrin α5ß1 and FAK was determined. Integrin α5ß1 was found to be significantly expressed in HASMCs, and its interaction with FAK was assessed via coimmunoprecipitation (Co-IP) analysis. Proliferation and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assays and flow cytometry after integrin α5ß1 deficiency. RESULTS: The levels of integrin α5ß1 and FAK were both significantly decreased in patients with AAAD. Downregulating the expression of integrin α5ß1-FAK strongly increased apoptosis and decreased proliferation in HASMCs, indicating that integrin α5ß1-FAK might play an important role in the development of AAAD. CONCLUSIONS: Downregulation of integrin α5ß1-FAK is associated with increased apoptosis and decreased proliferation in aortic smooth muscle cells and may be a potential therapeutic strategy for AAAD.

PECSS: Pulmonary Embolism Comprehensive Screening Score to safely rule out pulmonary embolism among suspected patients presenting to emergency department.

BACKGROUND: Pulmonary embolism is a severe cardiovascular disease and can be life-threatening if left untreated. However, the detection rate of pulmonary embolism using existing pretest probability scores remained relatively low and clinical rule out often relied on excessive use of computed tomographic pulmonary angiography. METHODS: We retrospectively collected data from pulmonary embolism suspected patients in Zhongshan Hospital from July 2018 to October 2022. Pulmonary embolism diagnosis and severity grades were confirmed by computed tomographic pulmonary angiography. Patients were randomly divided into derivation and validation set. To construct the Pulmonary Embolism Comprehensive Screening Score (PECSS), we first screened for candidate clinical predictors using univariate logistic regression models. These predictors were then included in a searching algorithm with indicators of Wells score, where a series of points were assigned to each predictor. Optimal D-Dimer cutoff values were investigated and incorporated with PECSS to rule out pulmonary embolism. RESULTS: In addition to Wells score, PECSS identified seven clinical predictors (anhelation, abnormal blood pressure, in critical condition when admitted, age > 65 years and high levels of pro-BNP, CRP and UA,) strongly associated with pulmonary embolism. Patients can be safely ruled out of pulmonary embolism if PECSS ≤ 4, or if 4 < PECSS ≤ 6 and D-Dimer ≤ 2.5 mg/L. Comparing with Wells approach, PECSS achieved lower failure rates across all pulmonary embolism severity grades. These findings were validated in the held-out validation set. CONCLUSIONS: Compared to Wells score, PECSS approaches achieved lower failure rates and better compromise between sensitivity and specificity. Calculation of PECSS is easy and all predictors are readily available upon emergency department admission, making it widely applicable in clinical settings. TRAIL REGISTRATION: The study was retrospectively registered (No. CJ0647) and approved by Human Genetic Resources in China in April 2022. Ethical approval was received from the Medical Ethics Committee of Zhongshan Hospital (NO.B2021-839R).

Albumin alleviated esketamine-induced neuronal apoptosis of rat retina through downregulation of Zn2+-dependent matrix metalloproteinase 9 during the early development.

AIMS: Esketamine upregulates Zn2+-dependent matrix metalloproteinase 9 (MMP9) and increases the neuronal apoptosis in retinal ganglion cell layer during the early development. We aimed to test whether albumin can alleviate esketamine-induced apoptosis through downregulating Zn2+-dependent MMP9. METHODS: We investigate the role of Zn2+ in esketamine-induced neuronal apoptosis by immunofluorescence. MMP9 protein expression and enzyme activity were investigated by zymography in situ., western blot and immunofluorescence. Whole-mount retinas from P7 Sprague-Dawley rats were used. RESULTS: We demonstrated that esketamine exposure increased Zn2+ in the retinal GCL during the early development. Zn2+-dependent MMP9 expression and enzyme activity up-regulated, which eventually aggravated apoptosis. Albumin effectively down-regulated MMP9 expression and activity via binding of free zinc, ultimately protected neurons from apoptosis. Meanwhile albumin treatment promoted activated microglia into multi-nucleated macrophagocytes and decreased the inflammation. CONCLUSION: Albumin alleviates esketamine-induced neuronal apoptosis through decreasing Zn2+ accumulation in GCL and downregulating Zn2+-dependent MMP9.

The pathogens of secondary infection in septic patients share a similar genotype to those that predominate in the gut.

BACKGROUND: Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection. METHODS: In this prospective, observational case-control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks. RESULTS: The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice. CONCLUSION: Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.

Role of CD8+ T cell exhaustion in the progression and prognosis of acute respiratory distress syndrome induced by sepsis: a prospective observational study.

BACKGROUND: CD8+ T cells are important for protective immunity against intracellular pathogens. Excessive amounts of antigen and/or inflammatory signals often lead to the gradual deterioration of CD8+ T cell function, a state called "exhaustion". However, the association between CD8+ T cell exhaustion and acute respiratory distress syndrome (ARDS) has not been studied. This study was conducted to elucidate how CD8+ T cells and inhibitory receptors were related to the clinical prognosis of ARDS. METHODS: A prospective observational study in an emergency department enrolled patients who were diagnosed with sepsis-associated ARDS according to the sepsis-3 criteria and Berlin definition. Peripheral blood samples were collected within 24 h post recruitment. CD8+ T cell count, proliferation ratio, cytokine secretion, and the expression of coinhibitory receptors were assayed. RESULTS: Sixty-two patients with ARDS met the inclusion criteria. CD8+ T cell counts and proliferation rates were dramatically decreased in non-surviving ARDS patients. Increasing programmed cell death 1 (PD-1) expression on the CD8+ T cell surface was seen in patients with worse organ function, while an increasing level of T cell immunoglobulin mucin-3 (Tim-3) was associated with a longer duration of the shock. Kaplan-Meier analysis showed that low CD8+ T cell percentages and increased inhibitory molecule expression were significantly associated with a worse survival rate. CONCLUSIONS: CD8+ T cells and coinhibitory receptors are promising independent prognostic markers of sepsis-induced ARDS, and increased CD8+ T cell exhaustion is significantly correlated with poor prognosis.

Causes, Risk Factors and Outcomes of Patients Readmitted to the Intensive Care Unit After Esophageal Cancer Surgery: A Retrospective Cohort Study.

BACKGROUND: Readmission to intensive care unit (ICU) after esophageal cancer surgery is a major concern and can be associated with increased adverse outcomes. This study aims to explore causes, risk factors and early outcomes. METHODS: We performed a monocentric retrospective analysis in 1140 patients who received esophageal cancer surgery in a higher volume surgeon group between January 2016 and December 2019, at Shanghai Chest Hospital. Univariate and multivariate analysis were performed to identify risk factors, and 1:4 propensity score matching (PSM) analysis was conducted to compare early outcomes. RESULTS: The incidence of ICU readmission was about 3.8% (43 of 1140). The most common cause was respiratory failure, found in 30 patients (70%). ICU readmission mainly occurred within 3 days after surgery, accounting for 46.5% (20 of 43), with the median length of stay was 3 days. Multivariate analysis identified heavy smoking (odds ratio[OR] = 2.445, 95% CI = 1.128 to 5.301, P = 0.024), intraoperative hypoxemia (OR = 2.461, 95% CI = 1.078 to 5.621, P = 0.033), mechanical ventilation during initial ICU stay (OR = 16.036, 95% CI = 7.332 to 35.074, P < 0.001), postoperative anemia (OR = 3.993, 95% CI = 1.893 to 8.420, P < 0.001) and unplanned reoperation (OR = 45.378, 95% CI = 13.023 to 158.122, P < 0.001) as independent risk factors for ICU readmission. Compared with no-readmitted patients, patients readmitted to ICU were associated with increased postoperative pulmonary complications (44.2% vs 97.7%, P < 0.001), prolonged median length of hospital stay (9[7-11] vs 19[13-30], P < 0.001) and ICU stay (1[1-3] vs 7[4-11], P < 0.001), higher hospitalization expenses (14,916 ± 3483 vs 19,850 ± 7595 dollars, P < 0.001) and 30-day readmission rates (1.8% vs 9.3%, P = 0.011). After 1:4 PSM, the baseline characteristics were comparable and the matched results were similar. CONCLUSIONS: This study identified five independent risk factors for ICU readmission, which were associated with adverse early outcomes. Preemptive attention given to pulmonary complications within three days after surgery may be important to prevent patients from ICU readmission.

The Prevalence and Impact of Undiagnosed Mild Cognitive Impairment in Elderly Patients Undergoing Thoracic Surgery: A Prospective Cohort Study.

OBJECTIVES: The objective of this study was to explore the prevalence of undiagnosed mild cognitive impairment (MCI) and its association with adverse outcomes in elderly patients undergoing thoracic surgery. DESIGN: A prospective cohort study. SETTING: Large tertiary medical center. PARTICIPANTS: The authors enrolled 170 patients aged 65 years or older who were scheduled for thoracic surgery between November 7, 2018, and April 1, 2019, at the Shanghai Chest Hospital. Patients with a history of schizophrenia or dementia disease, uncorrected vision or hearing impairment, and refusal to participate were excluded. INTERVENTIONS: A total of 154 elderly patients completed the Chinese version of the Montreal Cognitive Assessment (MoCA) test preoperatively and were included in the final analysis. They were categorized into a normal group (MoCA ≥ 26 scores, group N) and an abnormal group (MoCA < 26 scores, group AN) based on test results. Delirium was assessed with the Confusion Assessment Method twice daily during the first 3 postoperative days. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of postoperative delirium (POD). Secondary outcomes included the incidence of postoperative pulmonary complications (PPCs), cardiovascular complications, other complications, intensive care unit (ICU) stay, and the hospital length of stay (LOS). The incidence of MCI before thoracic surgery in elderly patients was 49.4% (76 of 154). Compared with group N, MCI could increase the incidence of POD (14.1% v 30.3%, p = 0.016) and median LOS (4 d v 5 d, p = 0.016). However, the differences in pulmonary complications, cardiovascular and other complications, and ICU stay were not significant. Multivariable logistic regression analysis showed preoperative MCI (OR = 2.573, 95% CI =1.092 to 6.060, p = 0.031) as an independent risk factor of POD. Compared with the elderly patients without POD, POD could increase the risk of PPCs (17.5% v 35.3%, p = 0.026) and median LOS (4 d v 5 d, p < 0.001). CONCLUSIONS: The incidence of MCI before thoracic surgery in elderly patients was higher and associated with a higher rate of adverse postoperative outcomes. The findings may be important for preoperative patient counseling, operative planning, and eventually reducing potential risk exposure and related outcomes.

Clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis: a retrospective observational study.

BACKGROUND: Secondary infection has a higher incidence in septic patients and affects clinical outcomes. This study aims to investigate the clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis. METHODS: A four-year retrospective study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between January, 2014 and January, 2018. Clinical data were acquired from medical records. CD14+ monocyte human leukocyte antigen-D related (HLA-DR) expression and serum cytokines levels were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: A total of 297 septic patients were enrolled, 92 of whom developed 150 cases of secondary infections. Respiratory tract was the most common site of secondary infection (n = 84, 56%) and Acinetobacter baumanii the most commonly isolated pathogen (n = 40, 31%). Urinary and deep venous catheterization increased the risk of secondary infection. Lower HLA-DR expression and elevated IL-10 level were found in secondary infection group. The expected prolonged in-hospital stay owing to secondary infection was 4.63 ± 1.87 days. Secondary infection was also associated with higher in-hospital, 30-day and 90-day mortality. Kaplan-Meier survival analysis and Log-rank test revealed that secondary infection group had worse survival between day 15 and day 90. CONCLUSIONS: Urinary and deep venous catheterization increased the risk of secondary infection, in which underlying immunosuppression might also play a role. Secondary infection affected the prognosis of septic patients and prolonged in-hospital length of stay.

hsa-miR-320d and hsa-miR-582, miRNA Biomarkers of Aortic Dissection, Regulate Apoptosis of Vascular Smooth Muscle Cells.

Abnormal expression of microRNAs (miRNAs) has been associated with aortic dissection (AD). Next-generation sequencing was performed to identify the differentially expressed miRNAs in aortic tissue samples between AD and nondiseased individuals. Selected miRNAs, which showed significant variation between the 2 groups, were then transfected into human aortic vascular smooth muscle cells, and assessed for effects on cell migration and induced apoptosis. The changes in gene expression pattern in human aortic vascular smooth muscle cells transfected with the miRNAs were also investigated. Among the 314 miRNAs detected in the aortic tissues from both AD and normal subjects, 46 showed significantly different expression patterns. Only 7 of these differentially expressed miRNAs were found to be enriched in AD, whereas the majority had diminished. hsa-miR-320d and hsa-miR-582 were 2 representative miRNAs that exhibited a decrease of greater than 10-fold. Transfection of hsa-miR-320d and hsa-miR-582 did not affect the migration capability of the vascular smooth muscle cells, but remarkably enhanced the staurosporine and tumor necrosis factor-α-induced apoptosis by 15% and 29%, respectively. Furthermore, the transfection of both miRNAs affected the expression of a vast multitude of genes, most of which were related to apoptotic pathways. The fluorescence reporter assays demonstrated that hsa-miR-320d and hsa-miR-582 bind the 3' UTR region of TRIAP1 and NET1 genes, respectively. These results suggest that hsa-miR-320d and hsa-miR-582 may serve as putative biomarkers for AD research.

Clinical characteristics and prognosis of serous body cavity effusions in patients with sepsis: a retrospective observational study.

BACKGROUND: Cavity effusion is common in patients with infectious diseases. However, the incidence rate and characteristics of serous cavity effusions (SCE) in septic patients are not clear to date. The objective of this study was to investigate the incidence and characteristics of SCE in septic patients and to explore the correlations between the bloody effusions and the illness severity/prognosis in septic patients. METHODS: From January 2010 to January 2015, a total of 214 patients with severe sepsis and septic shock were enrolled in this retrospective observational study. Thoracentesis or abdominal paracentesis was performed in 45 septic patients because of massive pleural effusions or ascites. The serum concentrations of VEGF, VEGFR, Ang, sICAM-1, sVCAM-1, E-selectin, Serpine1 and VE-cadherin in 45 septic patients underwent paracentesis were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of the 214 septic patients, 155 (72.4%) had SCE according to imaging or ultrasound manifestations. 45 subjects with SCE underwent therapeutic thoracentesis or abdominal paracentesis. Effusion laboratory analysis showed that exudates were predominant when compared with transudates (95.6% vs. 4.4%), and 16 (35.6%) patients suffered bloody effusions. Compared with patients with non-bloody effusions, those with bloody effusions showed higher critical illness scores (13 vs. 17 for APACHE II; 7 vs. 9 for SOFA), and higher mortality (6.9% vs. 62.5%). Moreover, patients with bloody effusions had delayed TT and APTT, increased D-dimer concentration, and higher serum levels of CRP and PCT (P < 0.05). In addition, the serum levels of Ang2, sVCAM-1 and E-selectin were significantly higher in patients with bloody effusions than in those with non-bloody effusions (P < 0.05). However, the serum level of VEGFR2 was lower in patients with bloody fluids (P = 0.025). CONCLUSIONS: The incidence of serous cavity effusion is high in patients with sepsis. The septic patients with bloody effusions suffer a more inflammatory burden and a worse prognosis compared to septic patients with non-bloody effusions.

Diagnostic and prognostic utility of tissue factor for severe sepsis and sepsis-induced acute lung injury.

BACKGROUND: Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) play a central role in the endothelial permeability regulation and dysfunction, which is associated with the development of sepsis and acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The aim of this study is to assess the diagnostic and prognostic values of TF and TFPI in patients with sepsis and sepsis-induced ARDS. METHODS: A total of 62 patients with sepsis, 167 patients with severe sepsis and 32 healthy volunteers were enrolled in this prospective observational study. TF and TFPI levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with sepsis-induced ARDS showed significantly higher median levels of TF compared with patients without ARDS (1425.5 (1019.9 to 2595.2) pg/ml vs 916.2 (724.1 to 1618.2) pg/ml, P < 0.001), and compared with sepsis patients (943.5 (786.4 to 992.4) pg/ml, P < 0.001) on the day of admission. However, there was no significant difference between sepsis patients and healthy subjects, or between septic shock and non-septic shock patients (P > 0.05). The AUC of TF for the diagnosis of sepsis-induced ARDS was 0.749 (95% confidence interval (CI) 0.675-0.822). Plasma TF levels in the non-survivors of severe sepsis were significantly higher than those of survivors (1618.6 (1017.1 to 2900.8) pg/ml vs. 979.9 (757.2 to 1645.5) pg/ml, P < 0.001), and multivariate logistic regression showed the plasma value of TF was the independent predictor for 30-day mortality in patients with severe sepsis (P = 0.0022, odds ratio (OR) = 1.41, 95% CI 1.24-1.69). The AUC of TF for predicting 30-day mortality in severe sepsis patients was 0.718 (95% CI 0.641-0.794). However, there was no significant difference in the plasma TFPI values among the healthy control, sepsis and severe sepsis groups (P > 0.05). CONCLUSIONS: Our data showed that tissue factor is a valuable diagnostic biomarker for the diagnosis of sepsis-induced ARDS. Moreover, tissue factor is a strong prognostic marker for short-term mortality in severe sepsis and sepsis-induced ARDS patients.

Genetic variation in the tissue factor gene is associated with clinical outcome in severe sepsis patients.

INTRODUCTION: Activation of inflammation and coagulation was closely related and mutually interdependent in sepsis. Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI) was the main regulators of the initiation of coagulation process. Altered plasma levels of TF and TFPI have been related to worse outcome in sepsis. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the TF and TFPI genes were associated with risk and outcome for patients with severe sepsis. METHODS: Seventeen SNPs in TF and TFPI were genotyped in samples of sepsis (n =577) and severe sepsis patients (n =476), and tested for association in this case-control collection. We then investigated correlation between the associated SNPs and the mRNA expression, and protein level of the corresponding gene. The mRNA levels of TF were determined using real-time quantitative reverse transcription-polymerase chain reaction and the soluble plasma levels of TF were measured using enzyme linked immunosorbent assay (ELISA) method. RESULTS: Association analysis revealed that three TF SNPs in perfect linkage disequilibrium, rs1361600, rs3917615 and rs958587, were significantly associated with outcome of severe sepsis. G allele frequency of rs1361600 in survivor patients was significantly higher than that in nonsurvivor severe sepsis patients (P =4.91 × 10(-5), odds ratio (OR) =0.48, 95% confidence interval (CI) 0.33 to 0.69). The association remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. Lipopolysaccharide-induced TF-mRNA expression levels in peripheral blood mononuclear cells from subjects carrying rs1361600 AG and GG genotypes, were significantly lower than those subjects carrying AA genotype (P =0.0012). Moreover, severe sepsis patients of GG and GA genotypes showed lower serum levels of TF than patients with AA genotype (P adj =0.02). The plasma levels of TF were also associated with outcome of severe sepsis patients (P adj =0.01). However, genotype and allele analyses did not show any significant difference between sepsis and severe sepsis patients. CONCLUSIONS: Our findings indicate that common genetic variation in TF was significantly associated with outcome of severe sepsis in Chinese Han population.

Heat shock protein 90α reduces CD8+ T cell exhaustion in acute lung injury induced by lipopolysaccharide.

CD8+ T-cell exhaustion is a promising prognostic indicator of sepsis-induced acute respiratory distress syndrome (ARDS). Patients with sepsis-related ARDS had reduced levels of HSP90AA1. However, whether the changes in CD8+ T cells were related to HSP90α, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90α and its impact on CD8+ T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8+ T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8+ T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90α and STAT1 decreased significantly. The in vitro studies showed that HSP90α stimulation or inhibition affected the CD8+ T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90α and impaired its regulation of CD8+ T cells. The Co-Immunoprecipitation results indicated that HSP90α can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90α inhibited CD8+ T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90α was required.

Machine learning prediction model of major adverse outcomes after pediatric congenital heart surgery: a retrospective cohort study.

BACKGROUND: Major adverse postoperative outcomes (APOs) can greatly affect mortality, hospital stay, care management and planning, and quality of life. This study aimed to evaluate the performance of five machine learning (ML) algorithms for predicting four major APOs after pediatric congenital heart surgery and their clinically meaningful model interpretations. METHODS: Between August 2014 and December 2021, 23 000 consecutive pediatric patients receiving congenital heart surgery were enrolled. Based on the split date of 1 January 2019, the authors selected 13 927 participants for the training cohort, and 9073 participants for the testing cohort. Four predefined major APOs including low cardiac output syndrome (LCOS), pneumonia, renal failure, and deep venous thrombosis (DVT) were investigated. Thirty-nine clinical and laboratory features were inputted in five ML models: light gradient boosting machine (LightGBM), logistic regression (LR), support vector machine, random forest, and CatBoost. The performance and interpretations of ML models were evaluated using the area under the receiver operating characteristic curve (AUC) and Shapley Additive Explanations (SHAP). RESULTS: In the training cohort, CatBoost algorithms outperformed others with the mean AUCs of 0.908 for LCOS and 0.957 for renal failure, while LightGBM and LR achieved the best mean AUCs of 0.886 for pneumonia and 0.942 for DVT, respectively. In the testing cohort, the best-performing ML model for each major APOs with the following mean AUCs: LCOS (LightGBM), 0.893 (95% CI: 0.884-0.895); pneumonia (LR), 0.929 (95% CI: 0.926-0.931); renal failure (LightGBM), 0.963 (95% CI: 0.947-0.979), and DVT (LightGBM), 0.970 (95% CI: 0.953-0.982). The performance of ML models using only clinical variables was slightly lower than those using combined data, with the mean AUCs of 0.873 for LCOS, 0.894 for pneumonia, 0.953 for renal failure, and 0.933 for DVT. The SHAP showed that mechanical ventilation time was the most important contributor of four major APOs. CONCLUSIONS: In pediatric congenital heart surgery, the established ML model can accurately predict the risk of four major APOs, providing reliable interpretations for high-risk contributor identification and informed clinical decisions-making.

Development and external validation of a novel model for predicting new clinically important atrial fibrillation after thoracoscopic anatomical lung cancer surgery: a multicenter retrospective cohort study.

BACKGROUND: New clinically important postoperative atrial fibrillation (POAF) is the most common arrhythmia after thoracoscopic anatomical lung cancer surgery and is associated with increased morbidity and mortality. The full spectrum of predictors remains unclear, and effective assessment tools are lacking. This study aimed to develop and externally validate a novel model for predicting new clinically important POAF. METHODS: This retrospective study included 14 074 consecutive patients who received thoracoscopic anatomical lung cancer surgery from January 2016 to December 2018 in Shanghai Chest Hospital. Based on the split date of 1 January 2018, we selected 8717 participants for the training cohort and 5357 participants for the testing cohort. For external validation, we pooled 2941 consecutive patients who received this surgical treatment from July 2016 to July 2021 in Shanghai Ruijin Hospital. Independent predictors were used to develop a model and internally validated using a bootstrap-resampling approach. The area under the receiver operating characteristic curves (AUROCs) and Brier score were performed to assess the model discrimination and calibration. The decision curve analysis (DCA) was used to evaluate clinical validity and net benefit. New clinically important POAF was defined as a new-onset of POAF that causes symptoms or requires treatment. RESULTS: Multivariate analysis suggested that age, hypertension, preoperative treatment, clinical tumor stage, intraoperative arrhythmia and transfusion, and operative time were independent predictors of new clinically important POAF. These seven candidate predictors were used to develop a nomogram, which showed a concordance statistic (C-statistic) value of 0.740 and good calibration (Brier score; 0.025). Internal validation revealed similarly good discrimination (C-statistic, 0.736; 95% CI: 0.705-0.768) and calibration. The decision curve analysis showed positive net benefits with the threshold risk range of 0-100%. C-statistic value and Brier score were 0.717 and 0.028 in the testing cohort, and 0.768 and 0.012 in the external validation cohort, respectively. CONCLUSIONS: This study identified seven predictors of new clinically important POAF, among which preoperative treatment, intraoperative arrhythmia, and operative time were rarely reported. The established and externally validated model has good performance and clinical usefulness, which may promote the application of prevention and treatment in high-risk patients, and reduce the development and related adverse outcomes of this event.

A novel nomogram for predicting the decision to delayed extubation after thoracoscopic lung cancer surgery.

OBJECTIVE: Delayed extubation was commonly associated with increased adverse outcomes. This study aimed to explore the incidence and predictors and to construct a nomogram for delayed extubation after thoracoscopic lung cancer surgery. METHODS: We reviewed medical records of 8716 consecutive patients undergoing this surgical treatment from January 2016 to December 2017. Using potential predictors to develop a nomogram and using a bootstrap-resampling approach to conduct internal validation. For external validation, we additionally pooled 3676 consecutive patients who underwent this procedure between January 2018 and June 2018. Extubation performed outside the operating room was defined as delayed extubation. RESULTS: The rate of delayed extubation was 1.60%. Multivariate analysis identified age, BMI, FEV1/FVC, lymph nodes calcification, thoracic paravertebral blockade (TPVB) usage, intraoperative transfusion, operative time and operation later than 6 p.m. as independent predictors for delayed extubation. Using these eight candidates to develop a nomogram, with a concordance statistic (C-statistic) value of 0.798 and good calibration. After internal validation, similarly good calibration and discrimination (C-statistic, 0.789; 95%CI, 0.748 to 0.830) were observed. The decision curve analysis (DCA) indicated the positive net benefit with the threshold risk range of 0 to 30%. Goodness-of-fit test and discrimination in the external validation were 0.113 and 0.785, respectively. CONCLUSION: The proposed nomogram can reliably identify patients at high risk for the decision to delayed extubation after thoracoscopic lung cancer surgery. Optimizing four modifiable factors including BMI, FEV1/FVC, TPVB usage, and operation later than 6 p.m. may reduce the risk of delayed extubation.Key Messages:This study identified eight independent predictors for delayed extubation, among which lymph node calcification and anaesthesia type were not commonly reported.Using these eight candidates to develop a nomogram, we could reliably identify high-risk patients for the decision to delayed extubation.Optimizing four modifiable factors, including BMI, FEV1/FVC, TPVB usage, and operation later than 6 p.m. may reduce the risk of delayed extubation.

Progesterone alleviates esketamine-induced hypomyelination via PI3K/Akt signaling pathway in the developing rat brain.

The neurodevelopmental toxicity of anesthetics has been confirmed repeatedly, and esketamine is now widely used in pediatric surgeries. Oligodendrocyte precursor cells (OPCs) evolved into mature oligodendrocytes (OLs) and formed myeline sheath during the early brain development. In this study, we investigated whether esketamine exposure interrupted development of OPCs and induced hypomyelination in rats. Further we explored the roles of PI3K/Akt phosphorylation in OPCs development and myelination. Sprague Dawley rats with different ages (postnatal day (P) 1, 3, 7 and 12) were exposed to 40mg/kg esketamine. Progesterone treatment was given (16 mg/kg per day for 3 days) 24 h after esketamine exposure via the intraperitoneal route. Corpus callosum tissues were collected at P8 or P14 for western blot and immunofluorescence analyses. Esketamine exposure at P7 and P12 significantly reduced myelin basic protein (MBP) expression and CC1+ OLs number in corpus callosum. Esketamine exposure at P7 not only aggravated the mature OLs apoptosis, also decreased the OPCs proliferation and differentiation, which was related with dephosphorylation of PI3K/Akt. Progesterone was able to promote OPCs differentiation and ameliorate esketamine-induced hypomyelination by enhancing PI3K/Akt phosphorylation. Stage-dependent abnormality of OPCs/OLs after esketamine leads to the esketamine-induced hypomyelination. Esketamine interrupted OPCs evolution via PI3K/Akt signaling pathway, which can be ameliorated by progesterone.

Continuous Relationship of Operative Duration with Risk of Adverse Perioperative Outcomes and Early Discharge Undergoing Thoracoscopic Lung Cancer Surgery.

Background: For thoracoscopic lung cancer surgery, the continuous relationship and the trigger point of operative duration with a risk of adverse perioperative outcomes (APOs) and early discharge remain unknown. Methods: This study enrolled 12,392 patients who underwent this surgical treatment. Five groups were stratified by operative duration: <60 min, 60−120 min, 120−180 min, 180−240 min, and ≥240 min. APOs included intraoperative hypoxemia, delayed extubation, postoperative pulmonary complications (PPCs), prolonged air leakage (PAL), postoperative atrial fibrillation (POAF), and transfusion. A restricted cubic spline (RCS) plot was used to characterize the continuous relationship of operative duration with the risk of APOs and early discharge. Results: The risks of the aforementioned APOs increased with each additional hour after the first hour. A J-shaped association with APOs was observed, with a higher risk in those with prolonged operative duration compared with those with shorter values. However, the probability of early discharge decreased from 0.465 to 0.350, 0.217, and 0.227 for each additional hour of operative duration compared with counterparts (<60 min), showing an inverse J-shaped association. The 90 min procedure appears to be a tipping point for a sharp increase in APOs and a significant reduction in early discharge. Conclusions: Our findings have important and meaningful implications for risk predictions and clinical interventions, and early rehabilitation, for APOs.

Derivation of a HEAR Pathway for Emergency Department Chest Pain Patients to Safely Avoid a Second Troponin Test.

The study aims to develop a decision pathway based on HEAR score and 0 h high-sensitivity cardiac troponin T (hs-cTnT) to safely avoid a second troponin test for suspected non-ST elevation myocardial infarction (NSTEMI) in emergency departments. A HEAR score consists of history, electrocardiogram, age, and risk factors. A HEAR pathway is established using a Bayesian approach based on a predefined safety threshold of NSTEMI prevalence in the rule-out group. In total, 7131 patients were retrospectively enrolled, 582 (8.2%) with index visit NSTEMI and 940 (13.2%) with 180-day major adverse cardiovascular events (MACE). For patients with a low-risk HEAR score (0 to 2) and low 0 h hs-cTnT (<14 ng/L), the HEAR pathway recommends early discharge without further testing. After the HEAR pathway had been applied to rule out NSTEMI, the negative predictive value of index visit NSTEMI was 100.0% (95% CI, 99.8% to 100.0%) and false-negative rate of 180-day MACE was 0.40% (95% CI, 0.18% to 0.87%). Compared with the 0 h hs-cTnT < limit of detection (LoD) strategy (<5 ng/L), the HEAR pathway could correctly reclassify 1298 patients without MACE as low risk and lead to a 18.2% decrease (95% CI, 17.4-19.1%) in the need for a second troponin test. The HEAR pathway may lead to a substantial and safe reduction in repeated troponin test for emergency department patients with suspected NSTEMI.

Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury.

BACKGROUND: Recent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population. METHODS: Fourteen tag single nucleotide polymorphisms (tagSNPs) in MyD88, IRAK1, IRAK4 and TRAF6 were genotyped in samples of sepsis-induced ALI (n = 272) and sepsis alone patients (n = 276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS) ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The association analysis revealed that rs4755453, an intronic SNP of TRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P = 0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37-0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. TRAF6 mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P = 0.012 and P = 0.003, respectively) as well as after LPS stimulation (P = 0.009 and P = 0.005). Moreover, the concentrations of TNF-α and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases. CONCLUSIONS: Our findings indicated that common genetic variants in TRAF6 were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role for TRAF6 in ALI.