Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice.

BACKGROUND: Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown. METHODS: APOE (apolipoprotein E) or LDLR (low-density lipoprotein receptor) null mice treated with SHP099 were fed a Western diet for 8 weeks, while Shp2MKO:ApoE-/- or Shp2MKO:Ldlr-/- mice and exo-AAV8-SHP2E76K/ApoE-/- mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice. RESULTS: Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and LDLR null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and LDLR null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels. CONCLUSIONS: Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/LDLR null mice.

Amyloid-ß Oligomer-Induced Electrophysiological Mechanisms and Electrical Impedance Changes in Neurons.

Amyloid plays a critical role in the pathogenesis of Alzheimer's disease (AD) and can aggregate to form oligomers and fibrils in the brain. There is increasing evidence that highly toxic amyloid-ß oligomers (AßOs) lead to tau protein aggregation, hyperphosphorylation, neuroinflammation, neuronal loss, synaptic loss, and dysfunction. Although the effects of AßOs on neurons have been investigated using conventional biochemical experiments, there are no established criteria for electrical evaluation. To this end, we explored electrophysiological changes in mouse hippocampal neurons (HT22) following exposure to AßOs and/or naringenin (Nar, a flavonoid compound) using electrical impedance spectroscopy (EIS). AßO-induced HT22 showed a decreased impedance amplitude and increased phase angle, and the addition of Nar reversed these changes. The characteristic frequency was markedly increased with AßO exposure, which was also reversed by Nar. The AßOs decreased intranuclear and cytoplasmic resistance and increased nucleus resistance and extracellular capacitance. Overall, the innovative construction of the eight-element CPE-equivalent circuit model further reflects that the pseudo-capacitance of the cell membrane and cell nucleus was increased in the AßO-induced group. This study conclusively revealed that AßOs induce cytotoxic effects by disrupting the resistance characteristics of unit membranes. The results further support that EIS is an effective technique for evaluating AßO-induced neuronal damage and microscopic electrical distinctions in the sub-microscopic structure of reactive cells.

The effect of sodium bicarbonate on OHCA patients: A systematic review and meta-analysis of RCT and propensity score studies.

BACKGROUND: Evidence on the efficacy of sodium bicarbonate (SB) in out-of-hospital cardiac arrest (OHCA) is controversial and generally of low quality. A systematic review and meta-analysis was performed to evaluate the effect of SB in OHCA patients based on randomized controlled trial (RCT) and propensity score matching (PSM) cohort studies. METHODS: We searched the PubMed, Cochrane, and Embase databases for RCTs and PSM cohort studies from inception to July 15, 2023. We included studies involving adult (>16 years) no-trauma OHCA patients with clear comparisons between the Bicarbonate group and Control group. All studies reported our primary outcome of short-term survival rate included ROSC and survival to emergency department or hospital admission or secondary outcome of long-term survival rate included survival at hospital discharge and good neurologic survival at 1 month. Results were expressed as odds ratio (OR) with accompanying 95% confidence interval (CI). To reduce bias, we performed a subgroup analysis of RCTs and PSM cohort studies. Also, we performed sensitivity analysis to resolve the heterogeneity. RESULTS: Six studies (3 RCTs and 3 PSMs) comprising 21,402 patients were included. The primary outcome of this meta-analysis showed that short-term survival rate between the two groups was no difference (OR = 1.04; 95% CI, 0.98 to 1.12; P = 0.21; χ2 = 6.68; I2 = 25%). Secondary outcome demonstrated that long -term survival rate between the two groups was no difference (OR = 0.82; 95% CI, 0.50 to 1.34; P = 0.43; χ2 = 14.96; I2 = 80%). A sensitive analysis was performed by removing one study showed long-term survival rate of the Bicarbonate group was lower than that of the Control group. CONCLUSIONS: In patients with OHCA, sodium bicarbonate administration was associated neither with short-term survival rate nor with long-term survival rate, it may even worsen the long-term survival.

Value of variation of end-tidal carbon dioxide for predicting fluid responsiveness during the passive leg raising test in patients with mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: The ability of end-tidal carbon dioxide (ΔEtCO2) for predicting fluid responsiveness has been extensively studied with conflicting results. This meta-analysis aimed to explore the value of ΔEtCO2 for predicting fluid responsiveness during the passive leg raising (PLR) test in patients with mechanical ventilation. METHODS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched up to November 2021. The diagnostic odds ratio (DOR), sensitivity, and specificity were calculated. The summary receiver operating characteristic curve was estimated, and the area under the curve (AUROC) was calculated. Q test and I2 statistics were used for study heterogeneity and publication bias was assessed by Deeks' funnel plot asymmetry test. We performed meta-regression analysis for heterogeneity exploration and sensitivity analysis for the publication bias. RESULTS: Overall, six studies including 298 patients were included in this review, of whom 149 (50%) were fluid responsive. The cutoff values of ΔEtCO2 in four studies was 5%, one was 5.8% and the other one was an absolute increase 2 mmHg. Heterogeneity between studies was assessed with an overall Q = 4.098, I2 = 51%, and P = 0.064. The pooled sensitivity and specificity for the overall population were 0.79 (95% CI 0.72-0.85) and 0.90 (95% CI 0.77-0.96), respectively. The DOR was 35 (95% CI 12-107). The pooled AUROC was 0.81 (95% CI 0.77-0.84). On meta-regression analysis, the number of patients was sources of heterogeneity. The sensitivity analysis showed that the pooled DOR ranged from 21 to 140 and the pooled AUC ranged from 0.92 to 0.96 when one study was omitted. CONCLUSIONS: Though the limited number of studies included and study heterogeneity, our meta-analysis confirmed that the ΔEtCO2 performed moderately in predicting fluid responsiveness during the PLR test in patients with mechanical ventilation.

The effect of early vasopressin use on patients with septic shock: A systematic review and meta-analysis.

BACKGROUND: The effect of early vasopressin initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early start of vasopressin support within 6 h after the diagnosis on clinical outcomes in septic shock patients. METHODS: We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of February 2021. We included studies involving adult patients (> 16 years)with septic shock. All authors reported our primary outcome of short-term mortality and in the experimental group patients in the studies receiving vasopressin infusion within 6 h after diagnosis of septic shock and in the control group patients in the studies receiving no vasopressin infusion or vasopressin infusion 6 h after diagnosis of septic shock, clearly comparing with clinically relevant secondary outcomes(use of renal replacement therapy(RRT),new onset arrhythmias, ICU length of stay and length of hospitalization). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI). RESULTS: Five studies including 788 patients were included. The primary outcome of this meta-analysis showed that short-term mortality between the two groups was no difference (odds ratio [OR] = 1.09; 95% CI, 0.8 to 1.48; P = 0.6; χ2 = 0.83; I2 = 0%). Secondary outcomes demonstrated that the use of RRT was less in the experimental group than that of the control group (OR = 0.63; 95% CI, 0.44 to 0.88; P = 0.007; χ2 = 3.15; I2 = 36%).The new onset arrhythmias between the two groups was no statistically significant difference (OR = 0.59; 95% CI, 0.31 to 1.1; P = 0.10; χ2 = 4.7; I2 = 36%). There was no statistically significant difference in the ICU length of stay(mean difference = 0.16; 95% CI, - 0.91 to 1.22; P = 0.77; χ2 = 6.08; I2 = 34%) and length of hospitalization (mean difference = -2.41; 95% CI, -6.61 to 1.78; P = 0.26; χ2 = 8.57; I2 = 53%) between the two groups. CONCLUSIONS: Early initiation of vasopressin in patients within 6 h of septic shock onset was not associated with decreased short-term mortality, new onset arrhythmias, shorter ICU length of stay and length of hospitalization, but can reduce the use of RRT. Further large-scale RCTs are still needed to evaluate the benefit of starting vasopressin in the early phase of septic shock.

Galectin-3 in Predicting Mortality of Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: In recent years, galectin-3, an inflammatory marker, has been demonstrated to be closely related to cardiac fibrosis and heart failure. The purpose of this systematic review and meta-analysis is to define galectin-3 in predicting mortality of heart failure. METHODS: PubMed, Embase, and the Cochrane Library were searched. A total of 1540 studies were identified, and of these studies, 19 involving 9217 patients were included in our meta-analysis. RESULTS: The diagnostic hazard ratios of galectin-3 in predicting mortality in chronic heart failure patients was 1.13 (95% CI,:1.07-1.21 ) and 2.17 (95% CI:1.27-3.08) in acute heart failure (HF) patients. CONCLUSIONS: Our meta-analysis shows that elevated levels of galectin-3 are associated with higher mortality in both acute and chronic heart failure patients.

AFDN deficiency promotes liver tropism of metastatic colorectal cancer.

Liver metastasis is a major cause of morbidity and mortality in patients with colorectal cancer. A better understanding of the biological mechanisms underlying liver tropism and metastasis in colorectal cancer could help to identify improved prevention and treatment strategies. In this study, we performed genome-side CRISPR loss-of-function screening in a mouse colorectal cancer model and identified deficiency of AFDN, a protein involved in establishing and maintaining cell-cell contacts, as a driver of liver metastasis. Elevated AFDN expression was correlated with prolonged survival in patients with colorectal cancer. AFDN-deficient colorectal cancer cells preferentially metastasized to the liver but not in the lungs. AFDN loss in colorectal cancer cells at the primary site promoted cancer cell migration and invasion by disrupting tight intercellular junctions. Additionally, CXCR4 expression was increased in AFDN-deficient colorectal cancer cells via the JAK-STAT signaling pathway, which reduced the motility of AFDN-deficient colorectal cancer cells and facilitated their colonization of the liver. Collectively, these data shed light on the mechanism by which AFDN deficiency promotes liver tropism in metastatic colorectal cancer.

Predictive value of extubation failure by decrease in central venous oxygen saturation: A systematic review and meta-analysis.

Background: The predictive power of extubation failure diagnosed by decrease in central venous oxygen saturation (ΔScvO2) varies by studies. Here we summarized the diagnostic value of extubation failure tested by ΔScvO2. Methods: A comprehensive online search was performed to select potentially eligible studies that evaluated the predictive power of extubation failure tested by ΔScvO2. A manual search was also performed to identify additional studies. Data were extracted to calculate the pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) to evaluate the predictive power of extubation failure. Results: Overall, five studies including 353 patients were included in this review, of whom 105 (30%) were extubation failure. The cutoff values of ΔScvO2 varied across studies, ranging from 3.8% to 5.4%. Heterogeneity between studies was assessed with an overall Q = 0.007, I2 = 0%, and P = 0.498. The pooled sensitivity and specificity for the overall population were 0.83 (95% CI: 0.74-0.90) and 0.88 (95% CI: 0.83-0.92), respectively. The pooled positive LR and negative LR were 7.2 (95%CI: 4.6-11.2) and 0.19 (95%CI: 0.12-0.31), respectively. The DOR was 38 (95% CI: 17-86). Overall, the pooled AUROC was 0.92 (95% CI: 0.90-0.94). Conclusions: The ΔScvO2 performed well in predicting extubation failure in adult mechanical ventilation patients. Further studies with a larger data set and well-designed models are required to confirm the diagnostic accuracy and utility of ScvO2 in predicting extubation outcomes in mechanical ventilation patients.

Bayesian network meta-analysis comparing hot balloon, laser balloon and cryoballoon ablation as initial therapies for atrial fibrillation.

Background: Balloon-based catheter ablation (CA) technologies, including hot balloon ablation (HBA), laser balloon ablation (LBA) and cryoballoon ablation (CBA) have been introduced in recent years as alternatives to conventional radiofrequency ablation therapy for atrial fibrillation (AF). However, the results remain controversial concerning the optimal approach. Thus, we conducted a network meta-analysis (NMA) to comprehensively evaluate the efficacy and safety of HBA, LBA and CBA. Methods: Clinical trials comparing the efficacy and safety of HBA, LBA and CBA were identified through a systematic search up to October 2022. The primary outcomes of interest were the recurrence of AF and procedure-related complications. Results: Twenty clinical trials with a total of 1,995 patients were included in the meta-analysis. The NMA results demonstrated that HBA, LBA and CBA had comparable AF recurrence rates (HBA vs. CBA: odds ratio OR = 0.88, 95% credible interval CrI: 0.56-1.4; LBA vs. CBA: OR = 1.1, 95% CrI: 0.75-1.5; LBA vs. HBA: OR = 1.2, 95% CrI: 0.70-2.0) and procedure-related complications (HBA vs. CBA: OR = 0.93, 95% CrI: 0.46-2.3; LBA vs. CBA: OR = 1.1, 95% CrI: 0.63-2.1; LBA vs. HBA: OR = 1.2, 95% CrI: 0.44-2.8). The surface under the cumulative ranking curve (SUCRA) suggested that HBA may be the optimal approach concerning the primary outcomes (SUCRA = 74.4%; 61.1%, respectively). However, HBA (40.1%) had a significantly higher incidence of touch-up ablation (TUA) than LBA (8.5%, OR = 2.8, 95% CrI: 1.1-7.1) and CBA (11.9%, OR = 3.7, 95% CrI: 1.9-7.5). LBA required more procedure time than CBA [mean difference (MD = 32.0 min, 95% CrI: 19.0-45.0 min)] and HBA (MD = 26.0 min, 95% CrI: 5.6-45.0 min), but less fluoroscopy time than HBA (MD = -9.4 min, 95% CrI: -17.0--2.4 min). Conclusions: HBA, LBA and CBA had comparable efficacy and safety as initial treatments for AF. HBA ranked highest in the primary outcomes, but at the cost of a higher incidence of TUA and longer fluoroscopy time. Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022381954, identifier: CRD42022381954.

Second-generation cryoballoon versus contact force radiofrequency ablation for atrial fibrillation: an updated meta-analysis of evidence from randomized controlled trials.

Catheter ablation has been recommended for patients with symptomatic atrial fibrillation (AF), with pulmonary vein isolation being the cornerstone of the ablation procedure. Newly developed technologies, such as cryoballoon ablation with a second-generation cryoballoon (CB2) and the contact force radiofrequency (CF-RF) ablation, have been introduced in recent years to overcome the shortcomings of the widely used RF ablation approach. However, high-quality results comparing CB2 and CF-RF remain controversial. Thus, we conducted this meta-analysis to assess the efficacy and safety between CB2 and CF-RF using evidence from randomized controlled trials (RCTs). Databases including Embase, PubMed, the Cochrane Library, and ClinicalTrials.gov were systematically searched from their date of inception to January 2021. Only RCTs that met the inclusion criteria were included for analysis. The primary outcome of interest was freedom from atrial tachyarrhythmia (AT) during follow-up. Secondary outcomes included procedure-related complications, procedure time and fluoroscopy time. Six RCTs with a total of 987 patients were finally enrolled. No significant differences were found between CB2 and CF-RF in terms of freedom from AT (relative risk [RR] = 1.03, 95% confidence interval [CI] 0.92-1.14, p = 0.616) or total procedural-related complications (RR = 1.25, 95% CI 0.69-2.27, p = 0.457). CB2 treatment was associated with a significantly higher risk of phrenic nerve palsy (PNP) than CF-RF (RR = 4.93, 95% CI 1.12-21.73, p = 0.035). The occurrences of pericardial effusion/tamponade and vascular complications were comparable between the CB2 and CF-RF treatments (RR = 0.41, p = 0.398; RR = 0.82, p = 0.632). In addition, CB2 treatment had a significantly shorter procedure time than CF-RF (weighted mean difference [WMD] = - 20.75 min, 95% CI - 25.44 ~ - 16.05 min, P < 0.001), whereas no difference was found in terms of fluoroscopy time (WMD = 4.63 min, p = 0.179). CB2 and CF-RF treatment are comparable for AF patients regarding freedom from AT and procedure-related complications. Compared to CF-RF, CB2 treatment was associated with a shorter procedure time but a higher incidence of PNP. Further large-scale studies are warranted to compare these two techniques and provide an up-to-date recommendation.

Tanyu Tongzhi Formula Delays Atherosclerotic Plaque Progression by Promoting Alternative Macrophage Activation via PPARγ and AKT/ERK Signal Pathway in ApoE Knock-Out Mice.

We previously demonstrated that the Tanyu Tongzhi Formula (TTF) significantly alleviated the clinical symptoms of patients with coronary heart disease and lowered serum lipid and inflammatory factor levels in patients with coronary heart disease and atherosclerosis model rats. However, the mechanism underlying TTF remains unknown. In this study, we examined the effect of TTF on atherosclerotic plaques in ApoE-/- mice and underlying mechanisms involved in macrophage polarization. Sixty male ApoE-/- mice were randomly divided into four groups. Mice in the control group were fed a regular diet, whereas experimental mice were fed a high-fat diet and received either saline (HFD group) or TTF at concentrations of 0.60 (TTF-L group) or 2.25 g/ml (TTF-H group) by daily oral gavage for 16 weeks. In the TTF-L and TTF-H groups, the levels of serum cholesterol, triglyceride, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were decreased, lipid content was significantly decreased, and percentage area of collagen/lipid increased in atherosclerotic plaque compared to in the HFD group. Moreover, we found TTF promoted the expression of alternative macrophage markers (Fizz1, Arg1, and Mrc) and suppressed the expression of M1 macrophage markers (TNF-α, IL-1ß, and IL-6) by regulating peroxisome proliferator-activated receptor γ (PPARγ) expression and AKT/extracellular signal-regulated kinase (ERK) activation. We further investigated whether alternative macrophage was reduced when PPARγ was inhibited or the AKT/ERK signaling pathway was activated. TTF delayed atherosclerotic plaque progression by promoting alternative macrophage activation through increasing PPARγ expression and inhibiting AKT/ERK phosphorylation, providing a theoretical basis for its clinical application.

Bioinformatics Analysis Reveals Diagnostic Markers and Vital Pathways Involved in Acute Coronary Syndrome.

BACKGROUND: Acute coronary syndrome (ACS) has a high incidence and mortality rate. Early detection and intervention would provide clinical benefits. This study aimed to reveal hub genes, transcription factors (TFs), and microRNAs (miRNAs) that affect plaque stability and provide the possibility for the early diagnosis and treatment of ACS. METHODS: We obtained gene expression matrix GSE19339 for ACS patients and healthy subjects from public database. The differentially expressed genes (DEGs) were screened using Limma package in R software. The biological functions of DEGs were shown by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Protein-protein interaction (PPI) network was mapped in Cytoscape, followed by screening of hub genes based on the Molecular Complex Detection (MCODE) plug-in. Functional Enrichment analysis tool (FunRich) and Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to predict miRNAs and TFs, respectively. Finally, GSE60993 expression matrix was chosen to plot receiver operating characteristic (ROC) curves with the aim of further assessing the reliability of our findings. RESULTS: We obtained 176 DEGs and further identified 16 hub genes by MCODE. The results of functional enrichment analysis showed that DEGs mediated inflammatory response and immune-related pathways. Among the predicted miRNAs, hsa-miR-4770, hsa-miR-5195, and hsa-miR-6088 all possessed two target genes, which might be closely related to the development of ACS. Moreover, we identified 11 TFs regulating hub gene transcriptional processes. Finally, ROC curves confirmed three genes with high confidence (area under the curve > 0.9), including VEGFA, SPP1, and VCAM1. CONCLUSION: This study suggests that three genes (VEGFA, SPP1, and VCAM1) were involved in the molecular mechanisms of ACS pathogenesis and could serve as biomarkers of disease progression.

Watch-n-Patch: Unsupervised Learning of Actions and Relations.

There is a large variation in the activities that humans perform in their everyday lives. We consider modeling these composite human activities which comprises multiple basic level actions in a completely unsupervised setting. Our model learns high-level co-occurrence and temporal relations between the actions. We consider the video as a sequence of short-term action clips, which contains human-words and object-words. An activity is about a set of action-topics and object-topics indicating which actions are present and which objects are interacting with. We then propose a new probabilistic model relating the words and the topics. It allows us to model long-range action relations that commonly exist in the composite activities, which is challenging in previous works. We apply our model to the unsupervised action segmentation and clustering, and to a novel application that detects forgotten actions, which we call action patching. For evaluation, we contribute a new challenging RGB-D activity video dataset recorded by the new Kinect v2, which contains several human daily activities as compositions of multiple actions interacting with different objects. Moreover, we develop a robotic system that watches and reminds people using our action patching algorithm. Our robotic setup can be easily deployed on any assistive robots.

Treelets Binary Feature Retrieval for Fast Keypoint Recognition.

Fast keypoint recognition is essential to many vision tasks. In contrast to the classification-based approaches, we directly formulate the keypoint recognition as an image patch retrieval problem, which enjoys the merit of finding the matched keypoint and its pose simultaneously. To effectively extract the binary features from each patch surrounding the keypoint, we make use of treelets transform that can group the highly correlated data together and reduce the noise through the local analysis. Treelets is a multiresolution analysis tool, which provides an orthogonal basis to reflect the geometry of the noise-free data. To facilitate the real-world applications, we have proposed two novel approaches. One is the convolutional treelets that capture the image patch information locally and globally while reducing the computational cost. The other is the higher-order treelets that reflect the relationship between the rows and columns within image patch. An efficient sub-signature-based locality sensitive hashing scheme is employed for fast approximate nearest neighbor search in patch retrieval. Experimental evaluations on both synthetic data and the real-world Oxford dataset have shown that our proposed treelets binary feature retrieval methods outperform the state-of-the-art feature descriptors and classification-based approaches.