Background: Given the traditional acceptance of higher central venous pressure (CVP) levels, clinicians ignore the incidence of acute kidney injury (AKI). The objective of this study was to assess whether elevated CVP is associated with increased AKI in critically ill patients with multiple comorbidities.Methods: This was a retrospective observational cohort study using data collected from the Medical Information Mart for Intensive Care (MIMIC)-III open-source clinical database (version 1.4). Critically ill adult patients with CVP and serum creatinine measurement records were included. Linear and multivariable logistic regression were performed to determine the association between elevated CVP and AKI.Results: A total of 11,135 patients were enrolled in our study. Critically ill patients in higher quartiles of mean CVP presented greater KDIGO AKI severity stages at 2 and 7 days. Linear regression showed that the CVP quartile was positively correlated with the incidence of AKI within 2 (R² = 0.991,P = 0.004) and 7 days (R² = 0.990,P = 0.005). Furthermore, patients in the highest quartile of mean CVP exhibited an increased risk of AKI at 7 days than those in the lowest quartile of mean CVP with an odds ratio of 2.80 (95% confidence interval: 2.32–3.37) after adjusting for demographics, treatments and comorbidities. The adjusted odds of AKI were 1.10 (95% confidence interval: 1.08–1.12) per 1 mmHg increase in mean CVP.Conclusions: Elevated CVP is associated with an increased risk of AKI in critically ill patients with multiple comorbidities. The optimal CVP should be personalized and maintained at a low level to avoid AKI in critical care settings.

BACKGROUND: The development of aortic dissection (AD) is closely associated with inflammation. The Trem2 (triggering receptor expressed on myeloid cells 2)/Tyrobp (TYRO protein tyrosine kinase-binding protein) signaling pathway critically regulates innate immunity and has emerged as an important target in cardiovascular diseases; however, its role in AD remains unclear. METHODS: Transcriptome data from human and mouse ADs were used to perform differentially expressed gene–based protein-protein interaction network analyses. Tyrobp knockout (Tyrobp ^−/− ), myeloid cell–specific Tyrobp ^−/− (Tyrobp ^fl/fl Lyz2 ^cre ), and Trem2 knockout (Trem2 ^−/− ) mice were given β-aminopropionitrile monofumarate in drinking water to induce AD. To dissect the role of macrophages in Tyrobp deficiency–mediated AD progression, macrophages were depleted using clodronate liposomes. Bulk and single-cell RNA sequencing, immunofluorescence staining, and quantitative real-time polymerase chain reaction were performed to assess inflammation and the underlying mechanisms of Tyrobp in AD. RESULTS: Network analysis identified Tyrobp as a hub gene of AD, with elevated levels observed in both human and mouse ADs. Global deletion and myeloid cell–specific deficiency of Tyrobp in mice significantly increased AD incidence and exacerbated extracellular matrix degradation and macrophage infiltration within the aortic wall. Macrophage depletion mitigated the adverse effects of Tyrobp deficiency on AD progression. Additionally, Tyrobp deficiency enhanced TLR (Toll-like receptor)-4 signaling and macrophage activation, which were abrogated by TLR4 inhibitors. Furthermore, deletion of the Tyrobp-associated receptor Trem2 significantly aggravated mouse AD development, whereas Trem2 agonist treatment conferred protection against AD. CONCLUSIONS: Our findings suggest a novel role for the Trem2/Tyrobp axis in AD development in mice. Enhancement of Trem2/Tyrobp signaling may represent a promising strategy for the prevention and treatment of AD. Future studies to clarify the role of Trem2/Tyrobp in human AD are warranted.

Background. Neurodegenerative diseases, such as Alzheimer’s disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. Methods. SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. Results. We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN‐induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. Conclusions. Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation.

The joint effect of cardiovascular-kidney-metabolic (CKM) health and genetic susceptibility on dementia remains unclear. This prospective cohort study utilized data from the UK Biobank. CKM syndrome was characterized by the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease. We employed Cox proportional hazards models to examine the association between CKM syndrome and dementia incidence, while also investigating the influence of genetic risk via polygenic risk score (PRS) and apolipoprotein E (APOE) ε4 status. We also examined the association between CKM syndrome and cognitive function via linear regression model. Among 331,731 participants (mean ± SD age, 56.53 ± 8.1 years; 156,762 [47.26 %] male), 4413 (1.33 %) developed dementia during a mean follow-up of 12.8 years. Advanced CKM syndrome correlated with higher risk of dementia; compared to stage 0, HRs for dementia were 1.19 (95 % CI 1.01-1.39, P = 0.036), 1.26 (95 % CI 1.09-1.45, P = 0.002), and 2.06 (95 % CI 1.77-2.39, P < 0.001) for stages 1, 2, and 3-4, respectively. Genetic susceptibility further strengthened this association, and the synergistic effect of CKM syndrome, dementia PRS, and APOE ε4 status surpasses the individual contributions of any single factor. These findings remained robust in a series of subgroups and sensitivity analyses. Individuals in the later stages of CKM syndrome demonstrated poorer performance on cognitive function tests. Poor CKM health was independently associated with cognitive impairment and an increased risk of dementia. The association between CKM syndrome and risk of dementia could be further strengthened by genetic susceptibility.

Background: Aortic dissection (AD) is a fatal cardiovascular disease for which the key involved genes are largely unknown. Here, we aimed to identify promising AD biomarkers from high-throughput RNA expressing data. Methods: In the GSE98770 dataset, differentially expressed mRNAs (DE-mRNAs) and microRNAs (DE-microRNAs) were identified through differentially expressed gene analysis and gene set enrichment analysis. The regulatory network between DE-mRNAs and DE-microRNAs was established, and hub genes were identified with Cytoscape. Relationships between hub genes and AD were confirmed in the Comparative Toxicogenomics Database (CTD). Potential key transcription factors were discovered with Cytoscape. Hub gene verification was performed by qPCR and immunofluorescence analyses of human specimens. Results: DE-mRNAs and DE-microRNAs were identified. Four mRNAs and microRNA-1321 (miR-1321) were found to have the most connections with other genes. CBL was connected to the most genes and interacted with miR-1321, which was also connected to the most genes among the DE-microRNAs. In addition, CBL was associated with AD in the CTD. Among the top five transcription factors potentially regulating CBL transcription, only HOXB13 was a DE-mRNA. The findings were further successfully verified in human specimens. Conclusion: CBL, which may be transcriptionally regulated by HOXB13 and post-transcriptionally regulated by miR-1321, was identified as the most promising potential biomarker for AD.

Non-invasive detection of unstable angina (UA) patients with different severity of coronary lesions remains challenging. This study aimed to identify plasma lipoproteins (LPs) that can be used as potential biomarkers for assessing the severity of coronary lesions, determined by the Gensini score (GS), in UA patients. We collected blood plasma from 67 inpatients with angiographically normal coronary arteries (NCA) and 230 UA patients, 155 of them with lowGS (GS ≤ 25.4) and 75 with highGS (GS > 25.4), and analyzed it using proton nuclear magnetic resonance spectroscopy to quantify 112 lipoprotein variables. In a logistic regression model adjusted for four well-known risk factors (age, sex, body mass index and use of lipid-lowering drugs), we tested the association between each lipoprotein and the risk of UA. Combined with the result of LASSO and PLS-DA models, ten of them were identified as important LPs. The discrimination with the addition of selected LPs was evaluated. Compared with the basic logistic model that includes four risk factors, the addition of these ten LPs concentrations did not significantly improve UA versus NCA discrimination. However, thirty-two selected LPs showed notable discrimination power in logistic regression modeling distinguishing highGS UA patients from NCA with a 14.9% increase of the area under the receiver operating characteristics curve. Among these LPs, plasma from highGS patients was enriched with LDL and VLDL subfractions, but lacked HDL subfractions. In summary, we conclude that blood plasma lipoproteins can be used as biomarkers to distinguish UA patients with severe coronary lesions from NCA patients.