Association Between Atherogenic Index of Plasma and Risk of Incident Major Adverse Cardiovascular Events.

It is unclear whether the atherogenic index of plasma (AIP) is associated with major adverse cardiovascular events (MACEs) in the general population. A total of 361,644 participants (aged 56.19 ± 8.09 years; 44.79% male) free of a history of MACEs at baseline from the UK Biobank data were included in the analysis. The AIP was calculated using log (triglyceride/high-density lipoprotein-cholesterol). Over a mean follow-up of 12.19 ± 1.60 years, 16,683 participants developed MACEs. After adjustment for traditional risk factors, each 1 unit increase in AIP was associated with a 45.3% higher risk of incident MACEs (hazard ratio (HR), 1.453 [95% confidence interval (CI) 1.371-1.540], P < 0.001). Results were similar when individuals were categorized by the AIP quartiles (HR, 1.283 [95% CI 1.217-1.351]; comparing extreme quartiles). The subgroup analyses showed that the association between AIP and risk of incident MACEs was more obvious in female participants who are < 60 years old and free of hypertension or diabetes. Sensitivity analysis included participants without any lipid-lowering medication or excluded incident MACEs in the first 2 years of follow-up confirming the robustness of the findings. Elevated AIP is a risk factor of incident MACEs in the general population, independent of traditional risk factors.Dynamic monitoring of the AIP may help select the population at high risk of cardiovascular events and guide primary prevention.

Diagnostic and prognostic value of autophagy-related key genes in sepsis and potential correlation with immune cell signatures.

Background: Autophagy is involved in the pathophysiological process of sepsis. This study was designed to identify autophagy-related key genes in sepsis, analyze their correlation with immune cell signatures, and search for new diagnostic and prognostic biomarkers. Methods: Whole blood RNA datasets GSE65682, GSE134347, and GSE134358 were downloaded and processed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify autophagy-related key genes in sepsis. Then, key genes were analyzed by functional enrichment, protein-protein interaction (PPI), transcription factor (TF)-gene and competing endogenous RNA (ceRNA) network analysis. Subsequently, key genes with diagnostic efficiency and prognostic value were identified by receiver operating characteristic (ROC) curves and survival analysis respectively. The signatures of immune cells were estimated using CIBERSORT algorithm. The correlation between significantly different immune cell signatures and key genes was assessed by correlation analysis. Finally, key genes with both diagnostic and prognostic value were verified by RT-qPCR. Results: 14 autophagy-related key genes were identified and their TF-gene and ceRNA regulatory networks were constructed. Among the key genes, 11 genes (ATIC, BCL2, EEF2, EIF2AK3, HSPA8, IKBKB, NLRC4, PARP1, PRKCQ, SH3GLB1, and WIPI1) had diagnostic efficiency (AUC > 0.90) and 5 genes (CAPN2, IKBKB, PRKCQ, SH3GLB1 and WIPI1) were associated with survival prognosis (p-value < 0.05). IKBKB, PRKCQ, SH3GLB1 and WIPI1 had both diagnostic and prognostic value, and their expression were verified by RT-qPCR. Analysis of immune cell signatures showed that the abundance of neutrophil, monocyte, M0 macrophage, gamma delta T cell, activated mast cell and M1 macrophage subtypes increased in the sepsis group, while the abundance of resting NK cell, resting memory CD4+ T cell, CD8+ T cell, naive B cell and resting dendritic cell subtypes decreased. Most of the key genes correlated with the predicted frequencies of CD8+ T cells, resting memory CD4+ T cells, M1 macrophages and naive B cells. Conclusion: We identified autophagy-related key genes with diagnostic and prognostic value in sepsis and discovered associations between key genes and immune cell signatures. This work may provide new directions for the discovery of promising biomarkers for sepsis.

The effects of external diaphragmatic pacing on diaphragm function and weaning outcomes of critically ill patients with mechanical ventilation: a prospective randomized study.

Background: Diaphragmatic pacing can improve diaphragm function, which is beneficial for the prognosis of patients treated with prolonged mechanical ventilation (MV). While most previous studies have focused on the role of implanted diaphragm pacing (IDP), our study is the first to examine the effects of external diaphragmatic pacing (EDP) in mechanically ventilated patients. Specifically, the effect of EDP on diaphragm function, the success rate of weaning, the duration of MV (DMV), and the intensive care unit (ICU) length of stay (ILOS) were assessed. Methods: From September 2019 to December 2020, a total of 51 mechanically ventilated patients in the ICU of the Sun Yat-sen Memorial Hospital, Sun Yat-sen University were enrolled and randomly divided into an EDP group of 27 patients and a control group of 24 patients. The control group received routine treatment, and the EDP group received EDP treatment in addition to routine treatment. The diaphragm excursion (DE), diaphragm thickening fraction (DTF), DMV, ILOS, and average survival time were recorded to evaluate efficacy. Results: Patients treated with EDP had increased DE [exp(B) =1.86, 95% CI: 1.39 to 2.50, P<0.001] and DTF [exp(B) =1.35, 95% CI: 1.05 to 1.76, P=0.022], shortened weaning time (P=0.026) and prolonged average survival time (P<0.001) compared to patients who did not receive EDP therapy. Especially in cases with difficult weaning, the improvement of DE and DTF in the EDP treatment group was more obvious than that in the control group (P=0.013 and P=0.032). Moreover, the DTF upon attempted spontaneous breathing trial (SBT) was negatively correlated with the fraction of inspired oxygen (FiO2) [r=-0.54; 95% confidence interval (CI): -0.77 to -0.19; P=0.004], the arterial partial pressure of oxygen (PaO2) (r=-0.58; 95% CI: -0.79 to -0.25; P=0.001), the PaO2/FiO2 ratio (r=-0.52; 95% CI: -0.75 to -0.16; P=0.006), and the serum lactate concentration (Lac) (r=-0.39; 95% CI: -0.68 to 0.003; P=0.046). Conclusions: EDP treatment can effectively reduce the DMV and prolong the average survival time of mechanically ventilated patients. Trial Registration: Chinese Clinical Trial Registry ChiCTR1900024096.

MicroRNA-338-5p alleviates neuronal apoptosis via directly targeting BCL2L11 in APP/PS1 mice.

MicroRNAs have become pivotal modulators in the pathogenesis of Alzheimer's disease. MiR-338-5p is associated with neuronal differentiation and neurogenesis, and expressed aberrantly in patients with cognitive dysfunction. However, its role and potential mechanism involved in Alzheimer's disease remain to be elucidated. Herein, we showed that the expression of miR-338-5p decreased in APP/PS1 mice, accompanied by the elevation in the expression level of amyloid ß, which indicated a reverse relationship between Alzheimer's disease progression and miR-338-5p. In addition, lentiviral overexpression of miR-338-5p through intrahippocampal injection mitigated the amyloid plaque deposition and cognitive dysfunction in APP/PS1 mice, suggesting a protecting role of miR-338-5p against the development of Alzheimer's disease. Moreover, miR-338-5p decelerated apoptotic loss of neurons in APP/PS1 mice. MiR-338-5p decreased neuronal apoptosis in vitro induced by amyloid ß accumulation, which was attributed to the negative regulation of BCL2L11 by miR-338-5p, since the restoration of BCL2L11 eliminated the protective role of miR-338-5p against neuronal apoptosis. Taken together, all of these results may indicate miR-338-5p as an innovative modulator in the pathogenesis of Alzheimer's disease, and also suggest that the protective effect of miR-338-5p on neuronal apoptosis may underlie its beneficial effect on APP/PS1 mice.

LncRNA DANCR upregulation induced by TUFT1 promotes malignant progression in triple negative breast cancer via miR-874-3p-SOX2 axis.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with poorest survival outcome and is prone to metastasis. TUFT1 and the long non-coding RNA (lncRNA), DANCR, play vital roles in metastasis and progression of various cancers. However, the correlation between TUFT1 and DANCR in TNBC and their downstream molecular mechanisms are still undetermined. We demonstrated that upregulation of TUFT1 in TNBC was related to a worse survival in TNBC patients. The TNBC cells invasiveness was augmented by TUFT1 in a dose-dependent manner, while inhibiting TUFT1 repressed the invasiveness. Particularly, the expression of TUFT1 was positively correlated with the expression of DANCR in TNBC tissues. In addition, TUFT1 increased DANCR expression, while silencing DANCR ameliorated the invasiveness of TNBC cells induced by TUFT1. As demonstrated, TUFT1 interacted with miR-874-3p. Subsequently, qRT-PCR together with luciferase reporter further demonstrated that DANCR acted as competing endogenous (ceRNA) for miR-874-3p, thereby regulating the de-repression of SOX2 and advancing epithelial-mesenchymal transition (EMT) in TNBC. The present research shows that TUFT1 promotes the malignant development in TNBC via enhancing the expression of DANCR. The upregulation of DANCR may contribute to the progression and tumor invasiveness of TNBC, considering that DANCR functions as a miR-874-3p sponge, thus modulating SOX2 positively. Collectively, the present study explored the molecular mechanism underlying TUFT1 in TNBC, raising a TUFT1-mediated therapy for the treatment of patients with TNBC.