Dynamic Nomogram for Subsyndromal Delirium in Adult Intensive Care Unit: A Prospective Cohort Study.

Purpose: To develop a dynamic nomogram of subsyndromal delirium (SSD) in intensive care unit (ICU) patients and internally validate its efficacy in predicting SSD. Patients and Methods: Patients who met the inclusion and exclusion criteria in the ICU of a tertiary hospital in Zhejiang from September 2021 to June 2022 were selected as the research objects. The patient data were randomly divided into the training set and validation set according to the ratio of 7:3. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to screen the predictors of SSD, and R software was used to construct a dynamic nomogram. Receiver operating characteristic (ROC) curve, calibration band and decision curve were used to evaluate the discrimination, calibration and clinical effectiveness of the model. Results: A total of 1000 eligible patients were included, including 700 in the training set and 300 in the validation set. Age, drinking history, C reactive protein level, APACHE II, indwelling urinary catheter, mechanical ventilation, cerebrovascular disease, respiratory failure, constraint, dexmedetomidine, and propofol were predictors of SSD in ICU patients. The ROC curve values of the training set was 0.902 (95% confidence interval: 0.879-0.925), the best cutoff value was 0.264, the specificity was 78.4%, and the sensitivity was 88.0%. The ROC curve values of the validation set was 0.888 (95% confidence interval: 0.850-0.930), the best cutoff value was 0.543, the specificity was 94.9%, and the sensitivity was 70.9%. The calibration band showed good calibration in the training and validation set. Decision curve analysis showed that the net benefit in the model was significantly high. Conclusion: The dynamic nomogram has good predictive performance, so it is a precise and effective tool for medical staff to predict and manage SSD in the early stage.

An Autophagy-Associated MITF-GAS5-miR-23 Loop Attenuates Vascular Oxidative and Inflammatory Damage in Sepsis.

BACKGROUND: Sepsis induces GAS5 expression in the vascular endothelium, but the molecular mechanism is unclear, as is the role of GAS5 in sepsis. METHODS AND RESULTS: We observed that GAS5 expression in the endothelium was significantly upregulated in a sepsis mouse model. ChIP-PCR and EMSA confirmed that the oxidative stress (OS)-activated MiT-TFE transcription factor (MITF, TFE3, and TFEB)-mediated GAS5 transcription. In vitro, GAS5 overexpression attenuated OS and inflammation in endothelial cells (ECs) while maintaining the structural and functional integrity of mitochondria. In vivo, GAS5 reduced tissue ROS levels, maintained vascular barrier function to reduce leakage, and ultimately attenuated sepsis-induced lung injury. Luciferase reporter assays revealed that GAS5 protected MITF from degradation by sponging miR-23, thereby forming a positive feedback loop consisting of MITF, GAS5, and miR-23. Despite the fact that the OS-activated MITF-GAS5-miR-23 loop boosted MITF-mediated p62 transcription, ECs do not need to increase mitophagy to exert mitochondrial quality control since MITF-mediated Nrf2 transcription exists. Compared to mitophagy, MITF-transcribed p62 prefers to facilitate the autophagic degradation of Keap1 through a direct interaction, thereby relieving the inhibition of Nrf2 by Keap1, indicating that MITF can upregulate Nrf2 at both the transcriptional and posttranscriptional levels. Following this, ChIP-PCR demonstrated that Nrf2 can also transcribe MITF, revealing that there is a reciprocal positive regulatory association between MITF and Nrf2. CONCLUSION: In sepsis, the ROS-activated MITF-GAS5-miR-23 loop integrated the antioxidant and autophagy systems through MITF-mediated transcription of Nrf2 and p62, which dynamically regulate the level and type of autophagy, as well as exert antioxidant and anti-inflammatory effects.

Is catheter-based foam sclerotherapy more effective than direct foam sclerotherapy when combined with high ligation for the treatment of primary great saphenous vein incompetence?

BACKGROUND: To retrospectively analyze the short-term outcomes of catheter-based versus direct foam sclerotherapy when combined with high ligation (HL) for the treatment of great saphenous vein (GSV) incompetence. METHODS: From July 2018 to October 2019, a total of 82 lower limbs of 70 patients with GSV incompetence received HL combined with catheter-based foam sclerotherapy (CFS group) or direct foam sclerotherapy (DFS group) for GSV proximal trunk. Among them, 40 limbs of 36 patients were treated with CFS, and 42 limbs of 34 patients were treated with DFS. The occlusion of GSV proximal trunk was evaluated with venous duplex ultrasound examinations; Venous Clinical Severity Scores (VCSS) was used to assess clinical improvement; Aberdeen Varicose Veins Questionnaire (AVVQ) was used to assess quality-of-life scores; and Complications was used for the safety evaluation. RESULTS: At day 7 post-operatively, complete occlusion of proximal trunk of the GSV was achieved in 92.5% legs of the CFS group and 71.4% of the DFS group (p = 0.014). Additionally, anterograde flow was found in 7.5% legs of the CFS group and 26.2% of the DFS group (p = 0.025). No significant differences in the occurrence of complications were observed between the two groups. The median follow-up was 285.5 days in the DFS group and 318 days in the CFS group (p = 0.140). VCSS and AVVQ reduction were significant in both CFS group and DFS group (5.3 ± 2.5, 5.5 ± 2.4, p < 0.001 for VCSS; 15.9 ± 8.0, 16.3 ± 8.6, p < 0.001 for AVVQ), but no significant difference were observed between two groups (p = 0.655 for VCSS, p = 0.934 for AVVQ). CONCLUSIONS: Although the occlusion of great saphenous vein proximal trunk were different, two modalities result in similar clinical and quality-of-life improvements. DFS is a feasible alternative to CFS when combined with HL.

Family members' perceptions of surrogate decision-making in the intensive care unit: A systematic review.

BACKGROUND: A better understanding of the perceptions of family members in making surrogate decisions for loved ones during intensive care is needed to inform the development of targeted supportive interventions. OBJECTIVE: To examine and synthesize qualitative data on family members' perceptions of surrogate decision-making in the intensive care unit. DESIGN: We conducted a systematic review and qualitative data synthesis. Eligible studies contained family members' quotes about surrogate decision-making experiences and perceptions in adult intensive care units, published in English or Chinese, in a peer-reviewed journal up to February 2022. Data sources included Embase, PubMed, ISI Web of Science, PsychINFO, CINAHL, Biomedical Literature Service System, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Journal. METHODS: The searches yielded 5974 identified articles, of which 23 studies were included. At least two different reviewers independently assessed the study quality and extracted data into a Microsoft Excel spreadsheet. A thematic synthesis was performed by classifying all text units into one of the broad themes and subsequently analyzed to inductively develop the first-, second-, and third-order themes. Six family members with experience in intensive care unit surrogate decision-making contributed to the analysis. RESULTS: The qualitative data synthesis resulted in five major themes. The following key new insights into family members' perceptions of surrogate decision-making in the intensive care unit were obtained: in individual systems, family members suffered from emotional distress and psychological stress; different cognitive styles emerged; some family members reshaped a new order of life in the disruption; in family systems, the family as a whole was closely connected with each other; and in medical systems families perceived asymmetry in relationships with clinicians, many factors influencing trust, the necessity for role-specific mediators and issues with operations and environments not being sufficiently humanized. CONCLUSION: This qualitative synthesis showed that individuals' emotions and cognition underwent complex processes during surrogate decision-making. The family as a whole, with disparate functional states, also faced different processes and outcomes under the crisis situation. At a broader level, the decision-making process reflected society's perceptions of the medical system. Future studies should use these insights to further explore and optimize the many aspects of surrogate decision support measures for families of critically ill patients and include the measurement of outcomes after interventions at multiple layers of the individual, family, and medical systems. REGISTRATION NUMBER: The protocol was prospectively published on International Prospective Register of Systematic Reviews (PROSPERO)-CRD42022316687. TWEETABLE ABSTRACT: Families of critically ill patients undergo a complex interactional process within the individual, family, and medical systems during surrogate decision-making.

PDGFRß modulates aerobic glycolysis in osteosarcoma HOS cells via the PI3K/AKT/mTOR/c-Myc pathway.

Osteosarcoma is a malignant tumor abundant in vascular tissue, and its rich blood supply may have a significant impact on its metabolic characteristics. PDGFRß is a membrane receptor highly expressed in osteosarcoma cells and vascular wall cells, and its effect on osteosarcoma metabolism needs to be further studied. In this study, we discussed the effect and mechanism of action of PDGFRß on glucose metabolism in human osteosarcoma (HOS) cells. GSEA, Pearson's correlation test, and PPI correlation analysis indicated positive regulation of PDGFRß on aerobic glycolysis in osteosarcoma. The results of qPCR and western blot further confirmed the prediction of bioinformatics. Glucose metabolism experiments proved that PDGF/PDGFRß could effectively promote aerobic glycolysis in osteosarcoma cells. In addition, the mitochondrial membrane potential (ΔΨm) experiment proved that the metabolic change triggered by PDGFRß was not caused by mitochondrial damage. The PI3K pathway inhibitor LY294002, MEK pathway inhibitor U0126, or Warburg effect inhibitor DCA was used to perform western blot and glucose metabolism experiments, and the results showed that PDGFBB/PDGFRß mainly activated the PI3K/AKT/mTOR/c-Myc pathway to promote aerobic glycolysis in osteosarcoma HOS cells. The newly elucidated role of PDGFRß provides a novel metabolic therapeutic target for osteosarcoma.

Adventitial Progenitor Cells of Human Great Saphenous Vein Enhance the Resolution of Venous Thrombosis via Neovascularization.

BACKGROUND: Vascular adventitia contains progenitor cells and is shown to participate in vascular remolding. Progenitor cells are recruited into the venous thrombi in mice to promote neovascularization. We hypothesized that the adventitial progenitor cells of human great saphenous vein (HGSV-AdPC) enhance the resolution of venous thrombosis via neovascularization. METHODS: Human great saphenous vein (HGSV) was harvested from the patients with great saphenous vein varicose and sectioned for immunohistochemistry, or minced for progenitor cell primary culture, or placed in sodium dodecyl sulfate solution for decellularization. Human venous thrombi were collected from patients with great saphenous vein varicose and superficial thrombophlebitis. Infrarenal abdominal aorta of New Zealand white rabbits was replaced with interposing decellularized vessel, and the patency of the grafts was confirmed by ultrasonic examination. Animal venous thrombi in the left infrarenal vena cava of mice were produced with Prolene suture ligation and ophthalmic force clipping of this portion. After HGSVs were digested by collagenase, the CD34+CD117+ HGSV-AdPC were isolated on FACS system, labelled with CM-Dil, and transplanted into the adventitia of infrarenal vena cava of nude mice. The percentage of thrombus organization area to the thrombus area was calculated as the organization rate. The thrombus cell, endothelial cells, and macrophages in the thrombi were counted in sections. Cell smears and frozen sections of human saphenous veins and venous thrombi were labeled with Sca1, CD34, CD117, Flk1, CD31, and F4/80 antibodies. The CD34+CD117+ HGSV-AdPC were cultured in endothelial growth medium with vascular endothelial growth factor (VEGF) to induce endothelial cell differentiation and analyzed with real time-PCR, Western blotting, and tube formation assays. RESULTS: Immunohistochemical staining showed that the CD34+CD117+ cells were located within the adventitia of HGSVs, and many CD34+ and CD117+ cells have emerged in the human venous thrombi. The number of progenitor cells within the marginal area of 7 days mice thrombi was shown to be Sca1+ ≈21%, CD34+ ≈12%, CD117+ ≈9%, and Flk1+ ≈5%. Many CD34+adventitial progenitor cells have migrated into the decellularized vessels. FACS showed that the number of CD34+CD117+ HGSV-AdPC in primary cultured cells as 1.2 ± 0.07%. After CD34+CD117+HGSV-AdPC were transplanted into the adventitia of nude mice vena cava with venous thrombi, the organization rate, nucleate cell count, endothelial cells, and macrophage cells of thrombi were shown to be significantly increased. The transplanted CD34+CD117+ HGSV-AdPC at the adventitia have crossed the vein wall, entered the venous thrombi, and differentiated into endothelial cells. The CD34+CD117+ HGSV-AdPC in the culture medium in the presence of VEGF-promoted gene and protein expression of endothelial cell markers in vitro and induced tube formation. CONCLUSIONS: HGSV-AdPC could cross the vein wall and migrate from the adventitia into the venous thrombi. Increased HGSV-AdPC in the adventitia has enhanced the resolution of venous thrombi via differentiating into endothelial cells of neovascularization.

Risk of post-thrombotic syndrome after deep vein thrombosis treated with rivaroxaban versus vitamin-K antagonists: A systematic review and meta-analysis.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a burdensome long-term complication of deep vein thrombosis (DVT). Recent studies have suggested that rivaroxaban may reduce PTS events compared to vitamin-K antagonists (VKAs). We, therefore, systematically reviewed available literature that compared rivaroxaban versus VKAs on the risk of PTS. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis using PubMed, EMBASE and Cochrane Library for all related studies from inception until March 2020. Two reviewers independently screened studies, extracted data, and appraised the quality of included studies. The primary outcome was overall risk of PTS. The secondary outcomes were risks of each PTS category (mild, moderate, severe) and venous ulcer. RESULTS: Seven comparative studies, comprising 2364 participants, qualified for this meta-analysis. The use of rivaroxaban for DVT treatment was associated with a lower risk of PTS compared with conventional VKAs [pooled unadjusted odds ratio (OR): 0.53, 95%CI: 0.43-0.65, P < 0.00001]. This effect was maintained after adjustment of potential confounders (pooled adjusted OR: 0.44, 95%CI: 0.35-0.56, P < 0.00001). Furthermore, rivaroxaban therapy was found to be associated with reduced risk of mild PTS (OR: 0.64, 95%CI: 0.50-0.82, P = 0.0005), moderate PTS (OR: 0.64, 95%CI: 0.45-0.91, P = 0.01), and severe PTS (OR: 0.52, 95%CI: 0.33-0.82, P = 0.005). There was also a similar trend towards reduced risk for venous ulcer, albeit not statistically significant (OR: 0.41, 95%CI: 0.15-1.08, P = 0.07). CONCLUSION: In comparison to VKAs, the use of rivaroxaban for DVT treatment has the potential to reduce PTS events. However, well-designed studies with larger sample sizes are needed to corroborate these findings.

Knockdown MTMR14 promotes cell apoptosis and inhibits migration in liver cancer cells.

Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family and plays a key role in cardiomyopathy and autophagy. However, its potential implication in human cancer is unclear. In this study, we have investigated the expression profile of MTMR14 and its functional impact in liver cancer for the first time. Expression analysis by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry demonstrated that MTMR14 expression is obviously overexpressed in liver cancer, and positively correlated with clinical stage. A loss-of-function study showed that knockdown of MTMR14 promotes cell apoptosis and inhibits cell migration. MTMR14 knockdown also inhibits tumor migration in vivo in liver cancer peritoneal implantation nude mouse model. A molecular mechanistic study by western blot showed that Knockdown MTMR14 causes downregulation of N-cadherin and E-cadherin, and promotes the cleavage and activation of caspase12, caspase9 and caspase3, but excluding caspase8. These results suggest that MTMR14 affects cell migration through N-cadherin and E-cadherin. Additionally, MTMR14 affects cell apoptosis through mitochondrial pathway but not the death receptor pathway. Herein, our results indicate MTMR14 could have an oncogenic role in human liver cancer and thus demonstrates its potential as a target for the diagnosis and/or treatment of liver cancer.

LncRNA NCK1-AS1 promotes proliferation and induces cell cycle progression by crosstalk NCK1-AS1/miR-6857/CDK1 pathway.

The purpose of this study was to develop an lncRNA signature to improve the prediction of the prognosis of cervical cancer through integration bioinformatics and analysis of TCGA RNA sequencing data. In this study, we established a set of four lncRNA signatures that was significantly associated with recurrence-free survival using the Cox regression model. Functionally, we screened the CC-associated lncRNA NCK1-AS1 as a new candidate lncRNA and regulator which promotes development and progression in CC. qRT-PCR and RNA in situ hybridization (RISH) results showed that NCK1-AS1 was significantly up-regulated in 77.4% (24/31) of the CC tissue group compared with the normal group (P < 0.01). Interestingly, we demonstrated that transcription factor SP1 directly binds to the promoter to activate NCK1-AS1 expression in SiHa cells. In vitro and in vivo assays of silencing NCK1-AS1 significantly inhibited cell proliferation and invasion, with induction of cell arrest in S phase of the cell cycle. Furthermore, Human Transcriptome Array 2.0 analysis after NCK1-AS1 silencing highlighted alterations in cell proliferation and cell cycle pathways. NCK1-AS1 functioned as a molecular sponge for miR-6857, antagonizing its ability to repress CDK1/6 protein translation. In conclusion, these findings suggest that NCK1-AS1/miR-6857/CDK1 crosstalk serve as a critical effector in cervical cancer progression and may serve as a potential target in cervical cancer.