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To assess the outcomes and risk factors for adult patients with acute fulminant myocarditis (AFM) supported with venoarterial extracorporeal membrane oxygenation (VA ECMO) in China mainland.Data were extracted from Chinese Society of ExtraCorporeal Life Support (CSECLS) Registry database. Data from adult patients who were diagnosed with AFM and needed VA ECMO in the database were retrospectively analyzed. The primary outcome was 90-day mortality after ECMO initiation in patients with AFM supported with VA ECMO. Cox proportional hazard regression model was used to examine the risk factors associated with 90-day mortality.Among 221 patients enrolled and followed up to 90 days, 186 (84.2%) patients weaned from ECMO and 159 (71.9%) patients survived and discharged home. The median age was 38 years (IQR 29-49) and males (n = 115) represented 52.0% of the total accounted patients. The median ECMO duration was 134 h (IQR 96-177 h). The main adverse event during ECMO course was bleeding (16.3%), followed by infection (15.4%). In the multivariate Cox model analysis, cardiac arrest prior to ECMO initiation (adjusted HR 2.529; 95%CI: 1.341-4.767, p = 0.004), lower pH value (adjusted HR 0.016; 95%CI: 0.010-0.059, p 0.001) and higher lactate concentration at 24 h after ECMO initiation (adjusted HR 1.146; 95%CI: 1.075-1.221, p 0.001) were associated with 90-day mortality.71.9% patients with AFM (clinical diagnosed) supported with VA ECMO survived. Cardiac arrest prior to ECMO, lower pH and higher lactate concentration at 24 h after ECMO initiation were correlated with 90-day mortality of AFM patients supported with VA ECMO.

The course of depression is variable; however, few studies examined the relationship between long-term cumulative depressive symptoms and adverse health outcomes in the elderly.In this cohort study, we used data from the Health and Retirement Study (HRS) over 24 years and the English Longitudinal Study of Ageing (ELSA) over 16 years. Cumulative depressive symptoms were estimated by calculating the areas under the curve based on the Center for Epidemiological Research Depression scale assessed at four examinations. Outcomes include cognitive decline, incident dementia, cardiovascular disease (CVD), cancer, and all-cause mortality.A total of 8284 American (mean age: 60.1 years; male: 35.4 %) and 4314 British (60.1 years; 42.4 %) were included in the analysis. The median follow-up was 16.1 years in the HRS and 9.9 years in the ELSA. Similar results were observed in two cohorts. Comparing with the first tertile of cumulative depressive symptoms, the third tertile experienced faster cognitive decline (p = 0.013 in the ELSA and p 0.001 in the HRS), increased risk of dementia (both p 0.001), CVD (both p 0.001) and all-cause mortality (p = 0.002 in the HRS). Strong dose-response relationships were observed. We did not found clearly association between cumulative depressive symptoms and incident cancer.This study suggests that long-term cumulative depressive symptoms were associated with subsequent faster cognitive decline and greater risks for dementia, CVD and all-cause mortality, but not cancer. These findings provide insights on potential effective strategy that may improve health in the elderly, future clinical trials are needed to determine causality.

Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) caused by the aberrant attack of the immune system on its own joint tissues. Genetic and environmental factors are the main reasons of immune system impairment and high incidence of RA. Although there are medications on the market that lessen disease activity, there is no known cure for RA, and patients are at risk in varying degrees of systemic immunosuppression. By transporting (encapsulating or surface binding) RA-related self-antigens, nucleic acids, immunomodulators, or cytokines, tolerogenic nanoparticles-also known as immunomodulatory nano-preparations-have the potential to gently regulate local immune responses and ultimately induce antigen-specific immune tolerance. We review the recent advances in immunomodulatory nano-preparations for delivering self-antigen or self-antigen plus immunomodulator, simulating apoptotic cell avatars

Gastric cancer (GC) is the fifth most common cancer worldwide and the third most fatal. Cancer-associated fibroblasts (CAFs) play an essential role in promoting the occurrence and development of gastric cancer in all stages. NFYB is highly expressed in multiple tumors and promotes tumor invasion, metastasis, and drug resistance, but its role in the occurrence and development of gastric cancer remains unclear. Hence, we used TCGA, TIMER, Kaplan-Meier Plot, and UALCAN databases to analyze the expression of NFYB in pan-cancers and assess its clinical prognostic value. We found that high expression of NFYB may be a promising prognostic biomarker in patients with gastric cancer. High expression of NFYB was associated with high T stage, high histological grade, diffuse gastric cancer, and early-onset GC. Moreover, High expression of NFYB was associated with CAFs infiltration in the GC microenvironment. The prognosis of GC patients with high expression of NFYB and high infiltration of CAFs was worse. Therefore, NFYB may serve as a potential prognostic biomarker in patients with GC.

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. This study aimed to uncover the underlying molecular features for different types of IPF. IPF microarray datasets were retrieved from GEO databases. Weighted gene co-expression analysis (WGCNA) was used and identified subgroup-specific WGCNA modules. Infiltration-level immune cells in different subgroups of microenvironments were analyzed with CIBERSORT algorithms. The result is we classified 173 IPF cases into two subgroups based on gene expression profiles, which were retrieved from the GEO databases. The SGRQ score and age were significantly higher in C2 than in C1. Using WGCNA, five subgroup-specific modules were identified. M4 was mainly enriched by MAPK signaling, which was mainly expressed in C2; M1, M2, and M3 were mainly enriched by metabolic pathways and Chemokine signaling, and the pathway of M5 was phagosome inflammation; M1, M2, M3, and M5 were mainly expressed in C1. Utilizing the CIBERSORT, we showed that the number of M1 macrophage cells, CD8 T cells, regulatory T cells (Tregs), and Plasma cells was significantly different between C1 and C2. We found the molecular subgroups of IPF revealed that cases from different subgroups may have their unique patterns and provide novel information to understand the mechanisms of IPF itself.

Postoperative cognitive dysfunction (POCD) is a severe postsurgical complication, but its underlying mechanisms remain unclear. Neuroinflammation mediated by microglial activation plays a major role in POCD pathophysiology. Upregulation of vascular cell adhesion molecule 1 (VCAM1) on brain endothelial cells is closely correlated with microglial activation in the mouse hippocampus. However, the role of VCAM1 upregulation in microglial activation remains unknown. Soluble VCAM1 (sVCAM1) activates the very late antigen-4 (VLA-4) receptor under inflammatory conditions. Therefore, we hypothesized that sVCAM1 which is shed from VCAM1 contributes to POCD by triggering hippocampal microglial activation through the VLA-4 receptor. We found that VCAM1 and sVCAM1 expression in the mouse hippocampus was upregulated after surgery, and the upregulation was accompanied by hippocampal microglial activation. sVCAM1 levels in mouse and human serum were increased after surgery. Anti-VCAM1 treatment inhibited microglial activation, proinflammatory cytokine production, VLA-4 expression and P38 mitogen-associated protein kinase (MAPK) pathway activation and attenuated hippocampal-dependent cognitive dysfunction. In vitro, recombinant sVCAM1 promoted M1 polarization in BV2 cells, increased VLA-4 expression and activated the P38 MAPK pathway. These effects were reversed by VLA-4 receptor blockade. Anti-VLA-4 treatment ameliorated hippocampal-dependent cognitive dysfunction after surgery by inhibiting microglial activation, proinflammatory cytokine production and P38 pathway activation. In conclusion, increased sVCAM1 in the hippocampus is involved in microglial activation and cognitive dysfunction induced by surgery. Inhibiting the sVCAM1-VLA-4 interaction in microglia may be a therapeutic strategy for POCD.

Psoriasis is a chronic systemic inflammatory disease, and hyperuricemia is a common comorbidity in patients with psoriasis. However, there are limited reports on the relationship between serum uric acid levels and biological treatment efficacy. The purposes of this study were to compare the differences in serum uric acid levels between patients with psoriasis and healthy controls and analyze the risk of hyperuricemia.A total of 196 patients with psoriasis and 191 age- and sex-matched healthy controls were enrolled in this retrospective cohort study. One hundred and twenty-seven patients with severe psoriasis were treated with biologics. Sixty-eight patients received adalimumab, and 59 patients received secukinumab. Serum uric acid levels were measured at baseline, week 24, and week 48 of treatment.Patients with psoriasis had higher serum uric acid levels than healthy controls (6.4 ± 1.7 mg/dL vs. 5.7 ± 1.5 mg/dL, P 0.001). Hyperuricemia was found in 33.7% (66/196) of patients with psoriasis, which was significantly higher than that in healthy controls (13.1% [25/191], P 0.001). Serum uric acid levels and hyperuricemia were not related to the severity of psoriasis ( P 0.05). No significant changes in serum uric acid levels and hyperuricemia were observed following adalimumab treatment ( P 0.05). The serum uric acid level in patients treated with secukinumab was 6.7 ± 1.6 mg/dL at week 24, which was not statistically different from that at baseline (6.6 ± 1.4 mg/dL, P = 0.885). Serum uric acid levels were significantly decreased at week 48 (6.3 ± 1.5 mg/dL vs. 6.6 ± 1.4 mg/dL, P = 0.007) in patients treated with secukinumab. Secukinumab had no significant effect on hyperuricemia either ( P 0.05).The serum uric acid levels and prevalence of hyperuricemia in patients with psoriasis were significantly higher than those in healthy controls. Secukinumab treatment for 48 weeks successfully decreased serum uric acid levels in patients with psoriasis, whereas adalimumab had no significant effect on serum uric acid levels.

Bleeding is a severe complication of patients supported with extracorporeal membrane oxygenation (ECMO). This study aimed to analyze the occurrence, risk factors, and clinical outcomes of patients on ECMO with bleeding complications.ECMO cases reported to the multicenter ECMO registry database of the Chinese Society of Extracorporeal Life Support (CSECLS) from January 2017 to December 2020 were enrolled. General information, ECMO indications, application, complications, and patient outcomes were collected and analyzed.A total of 6541 ECMO patients from 112 centers were enrolled. Overall, 1185 patients (18.1%) presented with one of the following bleeding complications, including 82 cases (1.3%) with severe bleeding during ECMO catheterization, 462 cases (7.1%) with bleeding at the ECMO cannulation site, 200 cases (3.5%) with bleeding at the surgical site, 180 cases (2.8%) with cerebral hemorrhage, 99 cases (1.5%) with pulmonary hemorrhage, 200 cases (3.5%) with gastrointestinal hemorrhage, 82 cases (1.3%) with ECMO withdrawal, and 118 (1.8%) deaths due to severe bleeding. Extracorporeal cardiopulmonary resuscitation (ECPR) patients had the highest incidence of bleeding complications (22.4%), followed by those on circulatory support (18.7%) and respiratory support (15.4%) (p 0.001). Multivariate analysis showed that pediatric patients (odds ratio [OR] 1.509, p 0.001), patients receiving renal replacement therapy (OR 1.932, p 0.001), and patients receiving central ECMO cannulation (OR 3.023, p 0.001) were independent risk factors for all bleeding complications, while peripheral cannulation (OR 0.712, p 0.001) was an independent protective factor. Patients with any bleeding complication had significantly higher in-hospital mortality than patients without (61.9% vs. 46.3%, p 0.001).Up to 18.1% of ECMO patients in the CSECLS registry experienced bleeding complications, which was associated with higher in-hospital mortality, especially in patients who received ECPR, patients on circulatory support, and pediatric patients, which should arouse the attention of clinicians.

The Revised International Staging System (R-ISS) is a simple and powerful prognostic tool for multiple myeloma (MM). However, heterogeneity in R-ISS stage is still poorly characterised, hampering improvement of treatments. We used single-cell RNA-seq to examine novel cellular heterogeneity and regular networks in nine MM patients stratified by R-ISS. Plasma cells were clustered into nine groups (P1-P9) based on gene expression, where P1-P5 were almost enriched in stage III.PDIA6 was significantly upregulated in P3 and LETM1 was enriched in P1, and they were validated to be upregulated in the MM cell line and in 22 other patients' myeloma cells. Furthermore, in progression, PDIA6 was newly found and verified to be activated by UQCRB through oxidative phosphorylation, while LETM1 was activated by STAT1 via the C-type lectin receptor-signalling pathway. Finally, a subcluster of monocytes was exclusively found in stage III specifically expressed chemokines modulated by ATF3. A few ligand-receptor pairs (CCL3/CCL5/CCL3L1-CCR1) were obviously active in monocyte-plasma communications in stage III. Herein, this study identified novel molecules, networks and crosstalk pairs in different R-ISS stages of MM, providing significant insight for its prognosis and treatment.

PURPOSE: Percutaneous cannulation is increasingly used for veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, there is limited evidence about the benefit of this approach compared with conventional surgical cannulation. By using a large international database, this study was designed to compare in-hospital outcomes in cardiac shock patients who received femoro-femoral VA-ECMO with percutaneous versus surgical cannulation.METHODS: Adults with refractory cardiogenic shock treated with percutaneous (percutaneous group) or surgical (surgical group) femoro-femoral VA-ECMO between January 2008 and December 2019 were extracted from the international Extracorporeal Life Support Organization registry. The primary outcome was in-hospital mortality. Multivariable logistic regression analyses were performed to assess the association between percutaneous cannulation and in-hospital outcomes.RESULTS: Among 12,592 patients meeting study inclusion, 9,249 (73%) underwent percutaneous cannulation. The proportion of patients undergoing percutaneous cannulation increased from 32% to 84% over the study period (p < 0.01 for trend). In-hospital mortality (53% vs 58%; p < 0.01), cannulation site bleeding (19% vs 22%; p < 0.01), and systemic infection (8% vs 15%; p < 0.01) occurred less frequently in the percutaneous group compared to the surgical group. In adjusted analyses, percutaneous cannulation was independently associated with lower rates of in-hospital mortality (odds ratio [OR] 0.76; 95% CI 0.70-0.84; p < 0.01), cannulation site bleeding (OR 0.70; 95% CI 0.60-0.80; p < 0.01) and systemic infection (OR, 0.63; 95% CI 0.54-0.74; p < 0.01). Severe limb ischemia was more frequently observed in the percutaneous group (5% vs 3%; p < 0.01). However, this association was not significant in adjusted analysis (OR 1.28; 95% CI 0.93-1.62; p = 0.15).CONCLUSIONS: Compared with surgical cannulation, percutaneous cannulation was independently associated with lower in-hospital mortality and fewer complications.

Elevated blood pressure (BP) has been linked to impaired cognition and dementia in older adults. However, few studies have accounted for long-term cumulative BP exposure.The aim of this study was to test whether long-term cumulative BP was independently associated with subsequent cognitive decline, incident dementia, and all-cause mortality among cognitively healthy adults.This study used data from the HRS (Health and Retirement Study) and ELSA (English Longitudinal Study of Ageing). Cumulative BP was calculated as the area under the curve using measurements from wave 0 (1998-1999) to wave 4 (2008-2009) in ELSA and wave 8 (2006-2007) to wave 10 (2010-2011) in the HRS. Outcomes included cognitive decline, incident dementia, and all-cause mortality.A total of 7,566 and 9,294 participants from ELSA and the HRS were included (44.8% and 40.2% men and median age 62.0 years [IQR: 55.0-70.0 years] and 65.0 years [IQR: 58.0-72.0 years], respectively). The median follow-up duration was 8.0 years (IQR: 4.0-8.0 years) and 8.0 years (IQR: 6.0-8.0 years), respectively. Elevated cumulative systolic BP and pulse pressure were independently associated with accelerated cognitive decline (P 0.001 for both), elevated dementia risk (P 0.001 for both), and all-cause mortality (P 0.001 for both), while a significant inverse association was observed for diastolic BP. Strong dose-response relationships were identified, with similar results for the 2 cohorts.Long-term cumulative BP was associated with subsequent cognitive decline, dementia risk, and all-cause mortality in cognitively healthy adults aged ≥50 years. Efforts are required to control long-term systolic BP and pulse pressure and to maintain adequate diastolic BP.

Background. Ferroptosis plays a vital role in hepatocellular carcinoma (HCC). CISD1 is known to regulate ferroptosis negatively. However, the correlations of CISD1 to prognosis in HCC and its potential mechanism remain unclear. Aim. To investigate the expression level and prognostic value of CISD1 in HCC. Methods. Gene expression and clinical data for 33 cancer types in TCGA were downloaded from the UCSC Xena platform. Pan-cancer analysis was performed to determine the expression profile and prognostic value of CISD1 in human cancers. GEO datasets and Human Protein Atlas (HPA) were used to verify the mRNA and protein expression levels. The influence of CISD1 on clinical prognosis in HCC was evaluated using a Kaplan-Meier plotter. The PPI network was constructed using the STRING database and Cytoscape. GO and KEGG pathways were constructed using the “clusterProfiler” R package with the FDR cutoff of 0.05. The methylation at the CISD1 promoter was detected using UALCAN and GEO datasets. The correlations between CISD1 and HCC immune infiltrates were investigated via TIMER. Results. Pan-cancer analysis of TCGA data showed that CISD1 is differentially expressed in multiple tumors. Data of gene expression microarrays reveal that the mRNA expression of CISD1 is higher in HCC than that in normal tissue. The protein level of CISD1, validated by the Human Protein Atlas (HPA) database, was upregulated consistently with mRNA levels in HCC samples. High CISD1 expression was associated with better overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS) in LGG, but with poorer OS, DFS, DSS, and PFS in LIHC. Protein-protein interaction (PPI) analysis and GO/KEGG analysis showed that the PPI network and GO term of CISD1 were mainly associated with energy and iron metabolism. Promoter hypomethylation correlated with overexpression of CISD1. CISD1 expression was positively correlated with infiltrating levels of CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in HCC. Conclusions. These findings suggest that hypomethylation of the CISD1 promoter increases its expression in HCC. CISD1 is associated with prognosis and immune infiltrating levels of CD8+ T cells, macrophages, neutrophils, and DCs in HCC patients. These findings suggest that CISD1 can be used as a prognostic biomarker for determining prognosis in HCC.

Whether medical insurance impacts the timely diagnosis in chronic kidney disease (CKD) children is unknown. We aim to examine the extent to which insurance is associated with access to timely diagnosis and different stages of CKD among a large population of children in China.A retrospective, cross-sectional study based on China's national hospitalized record database was carried out. Children aged 0-17 years diagnosed as CKD stages 1-5 between June 1, 2013, and December 31, 2018, were included. A diagnosis of advanced CKD stage (CKD stage 4 or 5) was the primary outcome. Multivariable logistic regression model adjusted for age, sex, cross-regional hospitalization, year of diagnosis, and cause of CKD was used to assess the association between insurance status and the stage of CKD when diagnosed.A total of 10,256 children (median [interquartile range, IQR] age, 12.4 [7.9, 15.4] years) were included. There were 4716 (46.0%) uninsured children in the included population. The insurance coverage was highest in children 13-17 years old (60.9%). The hospitalized charge was highest in stage 5 uninsured children (median [IQR], ¥13,000.89 [7640.63, 24,585.00]). More uninsured children are diagnosed in CKD stage 4 or 5 (48.1%) than insured children (47.5%). Uninsured children had higher odds (odds ratio [OR] 1.20, [95% CI, 1.08-1.32]) of receiving a diagnosis of CKD stage 4 or 5 compared with insured children.Lack of medical insurance was associated with a more advanced stage of CKD when diagnosed in hospitalized children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Diabetes is a common metabolic disease with an increasing incidence in middle-aged and elderly people in recent years. Chronic hyperglycemia is the basic feature of diabetes, which can cause long-term damage to eyes, kidneys, nerves, heart, and blood vessels, resulting in functional decline or even failure. Glycosylated hemoglobin (HbA1c) can be used as an indicator of an individual's blood sugar status over the past 3 months; however, it is slightly affected by ischemic anemia.The data retrieval was performed in the databases of PubMed, Embase, and Ovid-Medline from their inception to April 2021, including keywords such as iron deficiency anemia (IDA), diabetes, HbA1c, immunoassay, and ion-exchange chromatography. After passing of sensitivity and heterogeneity analysis, Review Manager 5.3 was employed for meta-analysis.A total of 6 studies were included in this paper. The analysis results showed that IDA could be considered to have an impact on HbA1c outcomes in non-diabetic populations. In people with diabetes, IDA is not thought to have an impact on HbA1c outcomes.A total of 6 articles were included to discuss the effects of IDA on blood HbA1c in diabetic patients. The study found that when patients with diabetes were tested for blood sugar, the HbA1c did not accurately reflect their blood sugar control over the past 3 months.

BackgroundOutdoor traffic-related air pollution has negative effects on respiratory health. In this study, we aimed to explore the effect of outdoor traffic-related air pollution on chronic obstructive pulmonary disease (COPD) in Guangzhou.MethodsWe enrolled 1,460 residents aged 40 years or older between 21 January 2014 and 31 January 2018. We administered questionnaires and spirometry tests. The distance of participants' residences or locations of outdoor activities from busy roads (as indicators of outdoor traffic-related air pollution), indoor air pollution, and smoking history were queried in the questionnaires.ResultsOf the 1,460 residents with valid survey and test results, 292 were diagnosed with COPD, with a detection rate of 20%. Participants who lived and did their outdoor activities near busy roads had a higher detection rate of COPD. Among residents living at distances of p < 0.05). After adjusting for sex, age, smoking status, family history, and smoking index, the distance of outdoor activities from busy roads was an independent risk factor for COPD. Participants whose outdoor activities were conducted ConclusionsResidents of Guangzhou whose outdoor activities were close to busy roads had a high risk of COPD. Traffic-related air pollution presents a risk to human health and a risk of COPD.

Dynamic or hybrid configurations for extracorporeal membrane oxygenation (ECMO) are needed when patient physiology or clinical conditions change. Dynamic configurations included configurations converting from veno-arterial (V-A) ECMO or veno-venous (V-V) ECMO to other forms. Hybrid configurations included venous-arteriovenous (V-AV) and venovenous-arterial (VV-A) ECMO. This study retrospectively analyzed a total of 3,814 ECMO cases (3,102 adult cases) reported to the Chinese Society of Extracorporeal Life Support from January 1, 2017 to December 31, 2019. Eight-three adult patients had dynamic or hybrid ECMO configurations, whose primary diagnoses included cardiogenic shock (33.7%), cardiac arrest (6.0%), acute respiratory failure (39.8%), septic shock (9.6%), multiple trauma (3.6%), pulmonary hypertension (3.6%), and others (3.6%). Configuration changes occurred in 37 patients with the initial configuration of VA (20 to VV, 13 to V-AV, and 4 to VV-A) and 27 with the initial configuration of VV (7 to VA, and 20 to V-AV). A total of 46 (55.4%) patients received hybrid configurations of V-AV and 10 (12.0%) received VV-A. Patients with the initial configuration of VV who converted to other configurations had higher in-hospital mortality (74.1%) than other initial configurations (VA 45.9%, V-AV 76.9%, VV-A 66.7%, P = 0.021). We concluded that dynamic or hybrid ECMO configurations were used in various underlying diseases, in which V-AV was most commonly used. Patients receiving VV ECMO for respiratory support initially, who then converted to other configurations for both respiratory and circulatory support, had significantly worst outcomes among the groups studied. The initial configuration should be selected carefully after thorough assessment of patient condition.

Projected potential of 2.5–4.0 Å cryo-EM structures for structure-based drug design is not well realized yet. Here we show that a 3.1 Å structure of PRMT5 is suitable for selecting computed poses of a chemical inhibitor and its analogs for enhanced potency. PRMT5, an oncogenic target for various cancer types, has many inhibitors manifesting little cooperativity with MTA, a co-factor analog accumulated in MTAP−/− cells. To achieve MTA-synergic inhibition, a pharmacophore from virtual screen leads to a specific inhibitor (11-2 F). Cryo-EM structures of 11-2 F / MTA-bound human PRMT5/MEP50 complex and its apo form resolved at 3.1 and 3.2 Å respectively show that 11-2 F in the catalytic pocket shifts the cofactor-binding pocket away by ~2.0 Å, contributing to positive cooperativity. Computational analysis predicts subtype specificity of 11-2 F among PRMTs. Structural analysis of ligands in the binding pockets is performed to compare poses of 11-2 F and its redesigned analogs and identifies three new analogs predicted to have significantly better potency. One of them, after synthesis, is ~4 fold more efficient in inhibiting PRMT5 catalysis than 11-2 F, with strong MTA-synergy. These data suggest the feasibility of employing near-atomic resolution cryo-EM structures and computational analysis of ligand poses for small molecule therapeutics.

Background Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH. Methods Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/myeloid mice were used to show myeloid diapedesis. For SAH, 50 μm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia’s modified SAH score were utilized. P Results IL-6 expression peaked 3 days following SAH (p p p p p p r = 0.96 and r = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p p p Conclusion Correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the p-STAT3 pathway, and IL-6 blockade provides benefit in reducing CV and its consequences mediated by myeloid cell origin diapedesis. Graphical abstract

Background In critically ill patients requiring extracorporeal membrane oxygenation (ECMO) therapy, early initiation of continuous renal replacement therapy (CRRT) and beta-blockade of catecholamine-induced inotropic effects may improve outcomes. Methods A 2 × 2 partial factorial randomized controlled trial in eligible ECMO patients without a clear indication or contraindication to either intervention is centrally randomly assigned to (A) early or conventional-indicated CRRT and/or (B) beta-blocker or usual care. The primary outcome is all-cause mortality at 30 days for both arms. A total of 496 participants provides 80% power to determine a 20% risk reduction in mortality at 30 days with 5% type I error. Discussion This trial will help define the role of early CRRT and beta-blockade in ECMO patients. There have been 89 patients enrolled at 10 hospitals in study A and is ongoing. However, study B was stopped in August 2019 in the absence of any patients being enrolled. Trial registration ClinicalTrials.govNCT03549923. Registered on 8 June 2018. World Health Organization International Clinical Trials Registry Platform (WHO ICTEP) network. The Ethics Committee of Beijing Anzhen Hospital Approval ID is 2018013.

Persistent activation of signal transducer and activator of transcription 3 (STAT3) is frequently reported in cancers and plays important roles in tumor progression. Therefore, directly targeting persistent STAT3 signaling is an attractive cancer therapeutic strategy. The aim of this study is to test the inhibitory efficacy of novel STAT3 small molecule inhibitors, LLY17 and LLL12B, in combination with irradiation in human medulloblastoma cells. Both LLY17 and LLL12B inhibit the IL-6-induced and persistent STAT3 phosphorylation in human medulloblastoma cells. Irradiation using 4 Gy alone exhibits some inhibitory effects on medulloblastoma cell viability, and these effects are further enhanced by combining with either STAT3 inhibitor. Irradiation alone also shows certain inhibitory effects on medulloblastoma cell migration and invasion and the combination of LLY17 or LLL12B with irradiation further demonstrates greater inhibitory effects than monotherapy. STAT3 inhibitor alone or irradiation alone exhibits some suppression of medulloblastoma tumorsphere growth, and the combination of LLY17 or LLL12B and irradiation exhibits greater suppression of tumorsphere growth than monotherapy. Combining either STAT3 inhibitor with irradiation reduces the expression of STAT3 downstream targets, Cyclin D1 and Survivin, and induces apoptosis in medulloblastoma cells. These results support that combination of a potent STAT3 inhibitor such as LLY17 or LLL12B with irradiation is an effective and novel therapeutic approach for medulloblastoma.

Background Small intestine cancers, as an extremely rare tumor type, account only for 3% of all gastrointestinal tumors. Small intestine adenocarcinoma (SIA), representing approximately one-third of all small bowel cancers, has received relatively little attention, both in research efforts and clinical cognizance. Owing to anatomical proximity and rarity, small bowel adenocarcinomas are frequently grouped with colorectal adenocarcinomas. Therefore, a large SIA patient cohort is needed to develop and validate new nomogram prognostic models specific to SIA patients. Methods Patients diagnosed with SIA between 2004 and 2016 were extracted from the Surveillance, Epidemiology, and Final Results (SEER) database. All patients were randomly assigned to the training cohort and the validation cohort (2:1). The basic clinical information, detailed pathological staging, and treatment information of the patients were included in the analysis. Nomograms were shaped following the evaluations of the Cox regression model and verified using the decision curve analysis (DCA), time-dependent receiver operating characteristic (ROC) curves, concordance index (C-index), and calibration curves. Results The entire group comprised 6,947 patients with small intestine adenocarcinoma. According to the results of the multivariate Cox regression analysis, ten variables, including marital status, age, pathological grade, tumor location, T (tumor), N (nodes), M (metastasis) stage, surgery, chemotherapy, and regional nodes examined (RNE), were independent predictors of both of overall survival (OS) and cancer-specific survival (CSS). All significant variables were used to create the nomograms for OS and CSS. Various methods verified the reliability of the nomograms. The C-indexes of the OS and CSS nomogram were 0.756 (95% CI, 0.748-0.764) and 0.771 (95% CI, 0.761-0.781) in the training cohort and 0.748 (95% CI, 0.736-0.760) and 0.767 (95% CI, 0.752-0.781) in the validation cohort. The calibration curve showed good agreement between the nomogram prediction and actual survival. DCA indicated a clear net benefit of these new forecasting models. Conclusions This study built and verified nomograms to predict OS and CSS for rare SIA, which appear to be excellent tools to augment the clinically available evidence to facilitate the discussion between SIA patients and clinicians regarding therapeutic choice.

Background: More than one-fifth of the world’s population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation. Methods: A multicenter, patient- and outcome assessor–blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mm Hg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mm Hg reduction in SBP was also calculated. Results: A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mm Hg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was –5.0 (95% CI, –6.5 to –3.5) mm Hg and –2.8 (95% CI, –3.7 to –1.9) mm Hg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were –10.0 (95% CI, –12.1 to –7.9) mm Hg and –3.8 (95% CI, –5.0 to –2.5) mm Hg, respectively. The effect size did not differ among cuisines ( P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, –0.1 to 0.2; P =0.558). The incremental cost-effectiveness ratio per 1 mm Hg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups ( P =0.259), and none of the adverse events was associated with the intervention. Conclusions: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03882645.

Adenoviral vectors have been used as a gene transfer tool in gene therapy for more than three decades. Here, we introduce a protocol to construct an adenoviral vector by manipulating the genomic DNA of wild-type HAdV-7 by using a DNA assembly method. First, an infectious clone of HAdV-7, pKan-Ad7, was generated by fusing the viral genomic DNA with a PCR product from plasmid backbone, comprising of the kanamycin-resistant gene and the origin of replication (Kan-Ori), through DNA assembly. This was done by designing a pair of PCR primers, that contained ~25 nucleotides of the terminal sequence of HAdV-7 inverted terminal repeat (ITR) at the 5' end, a non-cutter restriction enzyme site for HAdV-7 genome in the middle, and a template-specific sequence for PCR priming at the 3' end. Second, an intermediate plasmid-based strategy was employed to replace the E3 region with transgene-expressing elements in the infectious clone to generate an adenoviral vector. Briefly, pKan-Ad7 was digested with dual-cutter restriction enzyme Hpa I, and the fragment containing the E3 region was ligated to another PCR product of plasmid backbone by Gibson assembly to construct an intermediate plasmid pKan-Ad7HpaI. For convenience, restriction-assembly was used to designate the plasmid cloning method of combined restriction digestion and assembly. Using restriction-assembly, the E3 genes in pKan-Ad7HpaI was replaced with a green fluorescent protein (GFP) expression cassette, and the modified E3 region was released from the intermediate plasmid and restored to the infectious clone to generate an adenoviral plasmid pKAd7-E3GFP. Finally, pKAd7-E3GFP was linearized by Pme I digestion and used to transfect HEK293 packaging cells to rescue recombinant HAdV-7 virus. To conclude, a DNA assembly-based strategy was introduced here for constructing adenoviral vectors in general laboratories of molecular biology without the need of specialized materials and instruments.

Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4‑boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

CD47 performs a vital function in cancer therapy by binding to different SIRPα, thrombospondin 1, and integrin. However, its role in tumor immunity and its correlation with prognosis among many cancer types remain unknown. The raw mRNA expression data of CD47 in cancer patients was downloaded from TCGA and GTEx datasets. The protein expression of CD47 was detected using a microarray. Kaplan Meier analysis and forest plot were performed to compare the effects of high and low expression of CD47 on overall survival in different cancers. In addition, the correlations between CD47 expression and immune cell infiltration, stromal components, immune checkpoint genes, tumor mutational burden (TMB), and microsatellite instability (MSI) were analyzed from the public database. The gene function was determined by Gene Set Enrichment Analysis (GSEA). The expressions of CD47 in CHOL, COAD, ESCA, HNSC, KIRC, STAD, and THCA were higher compared with normal tissues. Elevated expression of CD47 predicted poor prognosis in ACC, KICH, KIRP, LGG, PAAD and UCEC. CD47 expression was strongly associated with immune infiltrating cells among KICH, KIRP, LGG, and PAAD. In addition, significant positive correlations with most immune checkpoint genes including PDCD 1 (PD-1), CD274 (PD-L1), CTLA4 in BLCA, DLBC, KICH, KIRC, LUAD, LUSC, PAAD, PCPG, SKCM, STAD, UCEC, and UVM was noted for the expression of CD47. GSEA analysis demonstrated that CD47 was a key regulator in metabolism-related pathways. These findings provide novel evidence that CD47 could be utilized as a promising prognostic biomarker and combination treatment target in various cancers.

Background and aimsGrowing burden of dementia was considered as a global public health priority as its epidemic scale rises with the world’s population increases in age. In the absence of effective treatment, early identification of decline in cognitive function and risk factors that lead to the onset of dementia is a critical issue. Subclinical atherosclerosis may be a potential risk factor for cognitive impairment and progression to dementia. Research is needed to identify which subclinical atherosclerosis risk factors can better predict cognitive decline.MethodsA total of 1554 participants (mean age 59.81±6.93 years) were enrolled from Beijing Research on Ageing and Vessel and underwent baseline evaluation. Carotid intima-media thickness, carotid plaque and brachial ankle pulse wave velocity (ba-PWV) were selected as subclinical atherosclerosis markers. Cognitive function assessment was conducted by standardised tasks to assess the associations with subclinical atherosclerosis markers.ResultsSignificant associations (pConclusionsPositive associations shown between subclinical atherosclerosis and cognitive function. Subclinical atherosclerosis markers of plaque numbers were significantly associated with global cognitive functioning in MoCA, memory and semantic fluency, while ba-PWV was significantly associated with global cognitive functioning in MoCA and semantic fluency.

Colorectal cancer (CRC) is a prevalent malignancy worldwide. The development of genome sequencing technology has allowed the discovery that epigenetic regulation might play a critical role in CRC tumorigenesis. In the present study, we found that the long noncoding RNA (lncRNA) SNHG4 was dramatically increased in CRC tissue samples and cell lines based on both publicly available and experimental data. SNHG4 knockdown suppressed the viability and colony formation capacity of CRC cells. The expression of CDK1 was considerably increased in CRC tissue samples and cells and had a positive correlation with the expression of SNHG4 in CRC. SNHG4 silencing not only caused S phase cell cycle arrest but also significantly downregulated the CDK1, cyclin B1, and cyclin A2 protein levels in CRC cells. miR-590-3p simultaneously bound to SNHG4 and CDK1. miR-590-3p functioned to inhibit CDK1 expression. miR-590-3p overexpression exerted the same effects on the CRC cell phenotype as SNHG4 knockdown. The effects of si-SNHG4 on CRC cells were significantly reversed by anti-miR-590-3p, indicating that SNHG4 relieved the miR-590-3p-induced inhibition of CDK1 by acting as a competing endogenous RNA (ceRNA). In vivo, SNHG4 silencing inhibited subcutaneously transplanted tumor growth and decreased cell cycle marker levels, whereas miR-590-3p inhibition exerted the opposite effects. The in vivo effects of SNHG4 silencing were also reversed by miR-590-3p inhibition. The SNHG4/miR-590-3p/CDK1 axis influences the cell cycle to modulate CRC cell proliferation and subcutaneously transplanted tumor growth. Further application of this axis still requires analysis using more animal models and clinical investigations.

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.

Recently, the prevalence trend of pulmonary fungal infection (PFI) has rapidly increased. Changes in the risk factors for, distributions of underlying diseases associated with and clinical characteristics of some individual PFIs have been reported in the past decade. However, data regarding PFIs remain uncertain. This study reports the epidemiological characteristics and trends of PFIs over time in recent years. We applied an automated natural language processing (NLP) system to extract clinically relevant information from the electronic health records (EHRs) of PFI patients at the First Affiliated Hospital of Guangzhou Medical University. Then, a trend analysis was performed. From January 1, 2013, to December 31, 2019, 40,504 inpatients and 219,414 outpatients with respiratory diseases were screened, in which 1368 inpatients and 1313 outpatients with PFI were identified. These patients were from throughout the country, but most patients were from southern China. Upward trends in PFIs were observed in both hospitalized patients and outpatients (P

To investigate the impact of intra-aortic balloon pump (IABP) on the regional haemodynamics of patients with severe cardiogenic shock undergoing femoro-femoral veno-arterial extracorporeal membrane oxygenation (VA-ECMO).From July 2017 to April 2018, a total of 39 adult patients with cardiogenic shock receiving both IABP and ECMO for circulatory support were enrolled consecutively in a university-affiliated cardiac surgery intensive care unit. The blood flow rates (BFRs) of the bilateral femoral artery (IABP side: iFA, ECMO side: eFA) and carotid artery (left: LCA, right: RCA) and the velocity time integral (VTI) of aortic root were assessed by ultrasonography and compared when IABP was on and off. Seventeen of 39 (43.6%) patients survived to discharge, and 29 (74.4%) survived on ECMO. A total of 172 pairs of data (IABP on and off) were collected in this study, measured on the median of 2.0 (1.0, 4.5) days after patients received VA-ECMO. The BFR on both sides of FA (iFA: 176.4 ± 104.5 vs. 152.2 ± 139.8 mL/min, P 0.01; eFA: 299.3 ± 279.9 vs. 242.4 ± 258.8 mL/min, P 0.01) and the aortic VTI (10.1 ± 4.4 vs. 8.5 ± 4.4 cm, P 0.01) decreased significantly when turning the IABP off, while the BFR on both sides of CA remained unchanged (LCA: 555.7 ± 326.9 vs. 578.6 ± 328.0 mL/min, P = 0.27; RCA: 550.0 ± 331.1 vs. 533.0 ± 303.5 mL/min, P = 0.30). The LCA BFR dramatically increased after turning the IABP off (296.8 ± 129.7 vs. 401.4 ± 278.1 mL/min, P = 0.02) in patients with cardiac stunning (defined as pulse pressure ≤ 5 mmHg). However, there was no significant difference in LCA BFR between IABP-On and IABD-Off (359.6 ± 105.4 mL/min vs. 389.6 ± 139.3 mL/min, P = 0.31) in patients with cardiac stunning receiving a higher ECMO blood flow (3.5 L/min).Concomitant IABP used in patients undergoing femoro-femoral VA-ECMO was associated with increased aortic VTI and BFR in bilateral FA. The change in CA BFR depended on cardiac function. A decreased LCA BFR was observed in patients with cardiac stunning when IABP was turned on, which might be compensated by a higher ECMO blood flow. Further study is needed to confirm the relationship between BFR and extremities and neurological complications.

Evidence suggests the occurrence of depressive symptoms in mid- to late-life inflates the risk for ageing-related morbidity compared to people without depressive symptoms. The eventual association between depressive symptoms in mid- to late-life and long-term (over 10-year) risks for incident dementia, coronary heart disease (CHD), stroke, and morbidity is to be established.This longitudinal cohort study utilized Health and Retirement Study (HRS) of U.S residents aged ≥ 50 years who were interviewed every 2-year during follow-up (average follow-up: 11.6 ± 2.85 years). Trajectories of depressive symptoms were assessed by the Center for Epidemiologic Studies Depression (CES-D) scale from 1994 to 2000 at baseline. Incident dementia, CHD, stroke and all-cause mortality were determined from 2000 to 2018.Among 7810 individuals who were free from dementia, CHD and stroke, five trajectories of depressive symptoms were identified: non-depressed (36.7 %), mild (48.8 %), worsening (7.8 %), improving (4.1 %) and persistent (2.7 %). Compared with those in the non-depressed group, participants with mild, worsening and persistent depressive symptoms had significantly greater hazards of incident dementia (multivariable adjusted hazard ratios and 95 % confidence intervals: 1.32 [1.17-1.48], 1.58 [1.30-1.93], 2.82 [2.17-3.67], respectively), CHD (1.13 [1.03-1.24], 1.47 [1.25-1.73], 1.34 [1.03-1.74], respectively), stroke (1.30 [1.12-1.52], 1.58 [1.23-2.04], 1.71 [1.16-2.53], respectively) and all-cause mortality (1.17 [1.07-1.27], 1.46 [1.27-1.68], 1.66 [1.35-2.06], respectively). The hazards of incident events, except for CHD, were not significantly greater in individuals with improving depressive symptoms.The present findings suggest even sub-clinical threshold depressive symptoms were associated with the hazards of ageing related diseases while such associations were not significant with managed depressive symptoms.

Little is known about the longitudinal association between persistent depressive symptoms and future lung health in the general population.4860 middle-aged and older participants with repeated measurements of depressive symptoms at wave 1 (2002-2003) and wave 2 (2004-2005) and at least two measurements of lung function (waves 2-6, 2004-2013) from the English Longitudinal Study of Ageing, were included in this study. The Center for Epidemiologic Studies Depression Scale (CESD) was used to evaluate depressive symptoms. Participants who had depressive symptoms in both waves 1 and 2 were considered to have persistent depressive symptoms. Linear mixed models were applied to assess longitudinal associations. Cox regression models were fitted to analyze respiratory disease mortality.During an 8-year follow-up, we found that women with persistent depressive symptoms suffered accelerated declines in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), percentage of the FEV1 predicted, percentage of the FVC predicted, and peak expiratory flow, compared with women without depressive symptoms at baseline. Likewise, an elevated risk of respiratory disease mortality (HR: 6.02, 95% CI: 2.30 to 15.79) was observed in women with persistent depressive symptoms compared with women without depressive symptoms. We also observed a dose-response relationship between cumulative depressive symptom scores and subsequent lung health outcomes in women. However, no such association was observed in men.Long-term depressive symptoms might predict an accelerated decline of lung function and higher mortality from respiratory disease among women but not among men over an 8-year follow-up. Further studies are needed to verify our findings.

Background Natural killer (NK) cells-based therapies are one of the most promising strategies against cancer. The aim of this study is to investigate the natural killer cell related genes and its prognostic value in glioma. Methods The Chinese Glioma Genome Atlas (CGGA) was used to develop the natural killer cell-related signature. Risk score was built by multivariate Cox proportional hazards model. A cohort of 326 glioma samples with whole transcriptome expression data from the CGGA database was included for discovery. The Cancer Genome Atlas (TCGA) datasets was used for validation. GO and KEGG were used to reveal the biological process and function associated with the natural killer cell-related signature. We also collected the clinical pathological features of patients with gliomas to analyze the association with tumor malignancy and patients’ survival. Results We screened for NK-related genes to build a prognostic signature, and identified the risk score based on the signature. We found that NK-related risk score was independent of various clinical factors. Nature-killer cell gene expression is correlated with clinicopathological features of gliomas. Innovatively, we demonstrated the tight relation between the risk score and immune checkpoints, and found NK-related risk score combined with PD1/PDL1 patients could predict the patient outcome. Conclusion Natural killer cell-related gene signature can predict malignancy of glioma and the survival of patients, these results might provide new view for the research of glioma malignancy and individual immunotherapy.

Yes-associated protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self-renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic-plus-single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol/CCl

The role of IL‐6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL‐6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild‐type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long‐term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload‐induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL‐6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8‐week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down‐regulated ratio of LC3‐Ⅱ/LC3‐Ⅰ, while in mice after long‐term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time‐points. In H9c2 myoblasts, Bazedoxifene suppressed the IL‐6‐induced STAT3 activation. Moreover, IL‐6 reduced the ratio of LC3‐Ⅱ/LC3‐Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL‐6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice.

Background Brainstem hemorrhage is an acute and severe neurosurgical disease. Cerebral hemorrhage is surgically treated via hematoma puncture drainage because of its minimally invasive nature. However, the placement of puncture must be extremely accurate due to the special anatomical location of the brainstem and its physiological functions. The present study aimed to evaluate whether the application of a three-dimensional (3D)-printed navigation mold achieved good outcomes in the surgical treatment of brainstem hemorrhage. Material and methods The present study included seven patients (three men and four women aged 40-56 y) who underwent 3D print–assisted hematoma puncture drainage between June 2016 and March 2018 at Binzhou Medical University Hospital. The amount of brainstem hemorrhage was 15-47 mL. We analyzed the basic surgical conditions, deviation distance, and postoperative clinical improvement. Results In all cases, the operation was completed successfully; no patient died or contracted an infection intraoperatively. The end of the puncture tube was located in the hematoma cavity in all cases. The deviation distance ranged from 2.5 to 7.2, and this distance gradually reduced with improvements in the technique. The hematoma drainage achieved satisfactory postoperative outcomes, with improvements in symptoms such as respiratory failure and hyperthermia. Conclusions Use of a 3D-printed navigation mold for puncture drainage of brainstem hemorrhage realized the purpose of individualized and precision medicine, which is important in maintaining the vital signs of patients with severe brainstem hemorrhage.

Objective: Golgi alpha-mannosidase II (GM II) is one of the crucial enzymes in the process of N-glycan processing. The aim of our study was to examine the clinical significance of GM II in patients with clear cell renal cell carcinoma (ccRCC). Methods: Quantitative reverse transcription polymerase chain reaction analysis and immunohistochemical staining were used to analyze GM II expression in patients with ccRCC. The clinical data of 62 patients with ccRCC were collected to analyze the clinical significance of GM II. The clinical significance among GM II expression, clinicopathological staging, and histological grade of ccRCC was explored. Survival analyses were performed to identify the relevance between the expression of GM II and the overall survival of patients with ccRCC. A uni-/multivariate Cox regression model was used to detect risk factors affecting the prognosis of patients with ccRCC. Subsequently, the proliferation and migration of ccRCC cells were detected after transfecting with GM II-short hairpin RNA (shRNA). Results: The results of these comparisons suggested that GM II expression of ccRCC tissues was dramatically higher than that of para-carcinoma tissues (p < 0.05). GM II expression in the high-differentiation group was lower than that in the median- and low-differentiation groups (p < 0.05). GM II expression in stage I and II tissues was lower than that in stage III and IV tissues (p < 0.05). The expression levels of GM II in the group without lymph node metastasis were lower than those in the group with lymph node metastasis (p < 0.05). Survival analysis indicated that patients with ccRCC with high GM II expression generally had decreased overall survival. Uni-/multivariate Cox model analyses further suggested an association between GM II expression and prognosis of patients with breast cancer. High GM II expression is a potential and independent prognostic biomarker in ccRCC. The inhibition of GM II by transfecting with GM II-shRNA could reduce the proliferation and migration of ccRCC. Conclusion: GM II expression in human ccRCC tissues was upregulated compared with that found in normal human renal tissue, and GM II may promote the progression and migration of ccRCC. Furthermore, the GM II gene may be used as a promising tumor marker for the diagnosis and prognosis of ccRCC.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disease that is commonly accompanied by cognitive impairment and various neurological and psychiatric symptoms, advanced image analyses help explore the pathogenesis of this disease. Therefore, this study aimed to explore specific structural and functional alterations and their relationship with the clinical symptoms of anti-NMDAR encephalitis. In this study, twenty-two patients with anti-NMDAR encephalitis after the acute stage and 29 controls received cognitive assessments and magnetic resonance imaging. Grey matter atrophy was measured using voxel-based morphometry, and functional alterations in abnormal regions were subsequently investigated using resting state functional connectivity (RSFC). Finally, correlation analyses were performed to explore the associations between imaging alterations and cognitive assessments. The patients demonstrated significant gray matter atrophy in the bilateral triangle part of the inferior frontal gyrus (triIFG.L and triIFG.R) and right precuneus, decreased RSFC between triIFG.L and bilateral Heschl gyrus (HES), decreased RSFC between triIFG.R and HES.R, decreased RSFC between right precuneus and left cerebellum, and increased RSFC between triIFG.R and left superior frontal gyrus. Further correlation analyses showed that the gray matter volume in triIFG.R and decreased RSFC between triIFG.L and HES.R were associated with decreased memory scores, whereas decreased RSFC between triIFG.R and HES.R was marginally correlated with the disease course in patients. In conclusion, this study suggests that cognitive impairments in patients with anti-NMDAR encephalitis may be mainly associated with gray matter atrophy and abnormal RSFC in the triIFG. These findings provide new insights into anti-NMDAR encephalitis pathogenesis and help explore potential treatments.

Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal canal stenosis (LSCS). The pathomechanisms for LFH have not been fully elucidated. Isobaric tags for relative and absolute quantitation (iTRAQ) technology, proteomics assessments of human ligamentum flavum (LF), and successive assays were performed to explore the effect of clusterin (CLU) upregulation on LFH pathogenesis. LFH samples exhibited higher cell positive rates of the CLU, TGF-β1, α-SMA, ALK5 and p-SMAD3 proteins than non-LFH samples. Mechanical stress and TGF-β1 initiated CLU expression in LF cells. Notably, CLU inhibited the expression of mechanical stress-stimulated and TGF-β1-stimulated COL1A2 and α-SMA. Mechanistic studies showed that CLU inhibited mechanical stress-stimulated and TGF-β1-induced SMAD3 activities through suppression of the phosphorylation of SMAD3 and by inhibiting its nuclear translocation by competitively binding to ALK5. PRKD3 stabilized CLU protein by inhibiting lysosomal distribution and degradation of CLU. CLU attenuated mechanical stress-induced LFH in vivo. In summary, the findings showed that CLU attenuates mechanical stress-induced LFH by modulating the TGF-β1 pathways in vitro and in vivo. These findings imply that CLU is induced by mechanical stress and TGF-β1 and inhibits LF fibrotic responses via negative feedback regulation of the TGF-β1 pathway. These findings indicate that CLU is a potential treatment target for LFH.

The widespread application of quaternary ammonium compounds (QAC) has posed a serious hazard to the environment and human being, and high concentration of Cl

BackgroundUncertainty remains concerning association between long-term physical activity and incident type 2 diabetes mellitus (DM). We intended to evaluate physical activity participation over a 6-year span and assess association with subsequent 10-year incident DM risk, as well as examine mediation role by obesity.MethodsA total of 9757 community-dwelling adults aged ≥ 50 years in England were included in the population-based cohort. Physical activity participation, including trajectories and cumulative participation were assessed using weighted Z score over a 6-year span from wave 1 (2002–2003) to wave 4 (2008–2009). Incident DM recorded over a 10-year span from wave 4 (2008–2009) to wave 9 (2018–2019) was outcome.Results5 distinct activity trajectories were identified, including persistently low (N=3037, incident DM=282), initially low then improving (1868, 90), initially high then declining (325, 20), persistently moderate (2489, 170), and persistently high (2038, 108). Compared with persistently low, participants of initially low then improving, persistently moderate and high were associated with lower incident DM risk, with multivariable-adjusted hazard ratios (HR) of 0.41 (95% confidence interval [CI]: 0.32 to 0.53, PP=0.004) and 0.49 (95% CI: 0.37 to 0.65, P <0.001), respectively. Elevated cumulative activity was also associated with lower DM risk, with each quintile increment in cumulative weighted Z score corresponding to HR of 0.76 (95% CI: 0.71 to 0.82, P <0.001). Mediation analysis found that body mass index, waist circumference and change in body mass index mediate 10% (P <0.001), 17% (P <0.001) and 9% (P <0.001) of the observed association between activity and incident DM, respectively.ConclusionsFor middle aged and older adults, both gradually improved and persistently active participation in physical activity were associated with subsequent lower risk of incident DM, with obesity playing a potential mediator. Strategies focusing on improving and maintaining active participation in physical activity might be beneficial from DM prevention perspective.

Objective This retrospective study sought to evaluate the efficacy of transit time flow measurement (TTFM) as a means of predicting bypass graft patency as assessed by coronary artery angiography upon 5-year follow-up. Methods Of 311 patients undergone isolated off-pump coronary artery bypass graft surgery from January 2014 through December 2014, 202 (65%) underwent both intraoperative TTFM and angiography at follow-up. 610 grafts, 202 left internal mammary artery grafts and 408 saphenous vein grafts were checked. Any grafts that exhibited Fitzgibbon type B or O lesions upon angiographic evaluation were considered to be failing. Receiver operating characteristic curves were used to identify the optimal TTFM values for predicting graft patency. Results A total of 610 grafts were included in this analysis, including 202 LIMA grafts and 408 SV grafts, of which 107, 129, 129, and 43 anastomosed to DIAG, OM, PDA, and PLA, respectively. LIMA, DIAG, OM, PDA, and PLA bypass grafts had overall patency rates of 95.0%, 74.8%, 73.6%, 71.5%, and 74.4%, respectively, upon 5-year follow up. No significant differences in TTFM values (MGF, PI, and DF) were observed when comparing outcomes associated with individual or sequential SV grafting. MGF was found to be predictive of graft failure regardless of the target vessel (P P P Conclusion LIMA bypass grafts were associated with better 5-year graft patency relative to SV bypass grafts. Similar graft patency rates were observed for both individual and sequential bypass grafts. MGF was able to predict bypass graft failure in patients that underwent off-pump CABG surgery.

Multiple myeloma (MM) accounts for ~10% of all haematologic malignancies. Little is known about high intratumour heterogeneities in patients stratified by the Revised International Staging System (R-ISS). Herein, we constructed a single-cell transcriptome atlas to compare differential expression patterns among stages. We found that a novel cytotoxic plasma cell (PC) population exhibited with NKG7 positive was obviously enriched in stage II patients. Additionally, a malignant PC population with significantly elevated expression of MKI67 and PCNA was associated with unfavourable prognosis and Epstein-Barr virus (EBV) infection in our collected samples. Moreover, ribonucleotide reductase regulatory subunit M2 (RRM2) was found and verified to promote proliferation of MM cell lines, suggesting RRM2 may serve as a detrimental marker in MM. The percentages of CD8Multiple myeloma is a type of bone cancer. It affects the immune cells that make antibodies, known as plasma cells. These immune cells live in the bone marrow. As with many types of cancer, the chance of survival is highest when multiple myeloma is diagnosed early. It has three stages, labelled I, II, and III. People with stage I or II disease have better outcomes than those with stage III, but the exact reasons are unclear. Bone marrow contains lots of different types of cells, which can affect the growth of a tumour. These include cancer-targeting cells, called killer T-cells, and cancer-supporting cells called myeloid cells. Understanding these cells and how they interact could shed light on the different stages of multiple myeloma. One way to do this is to use single cell sequencing, which looks at the genes in use inside each cell at any one time. Zhong, Hao, Zhang, Jiang et al. examined the bone marrow of two healthy donors and nine people with different stages of multiple myeloma. This revealed two new groups of plasma cells. One group, highest in stage II patients, was protective, with the potential to kill cancer cells. The other, highest in people with more aggressive disease, was harmful, with the potential to divide rapidly. The sequencing also identified molecules that might be useful drug targets for the future. These included a gene that drove growth in the dangerous plasma cells, and several that might help tumours escape from the immune system. It is becoming increasingly clear that the environment around a tumour has a huge role to play in its progression. Understanding how this environment changes over time could aid in the development of more targeted treatments. The next step is to find out more about the molecules identified here.

Aim to evaluate self-reported physical activity (PA) participation trajectories over a 6-year span and to assess associations with subsequent cognitive decline, incident dementia and all-cause mortality. Methods population-based cohort of 8,842 community-dwelling adults aged ≥50 years in England. Group-based trajectory modelling was used to identify 6-year trajectories of PA participation. Cognitive decline, incident dementia and all-cause mortality were outcomes. Results five trajectories were identified, including persistently low (N = 2,511), initially low then improving (1,651), initially high then declining (249), persistently moderate (2,422) and persistently high (2,009). Compared with persistently low, participants of initially low then improving and persistently high PA participation experienced decelerated global cognitive decline of 0.012 standard deviation (SD)/year (95% confidence interval [CI]: 0.004–0.021, P = 0.004) and 0.021 SD/year (95% CI: 0.013–0.029, P Conclusion for middle-aged and older adults, both gradually improved and persistently active PA participation were associated with decelerated cognitive decline, lower risk of dementia and all-cause mortality. Strategies focusing on improving and maintaining PA participation could be of significance by attaining considerable neurocognitive and longevity benefits.

Accurate discrimination and diagnosis of low-grade glioma (LGG) and high-grade glioma (HGG) before surgery is clinically important because it affects the patient's outcome and guides the clinicians to select appropriate management. The aim of this study was to evaluate the diagnostic performance of diffusion kurtosis imaging (DKI) for differentiating LGG from HGG.A literature search of the PubMed, Web of Science, Cochrane Library and EMBASE databases was conducted up to December 15, 2020. Studies that evaluated the diagnostic performance of DKI for differentiating LGG from HGG were selected. Retrieved hits were evaluated by the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Summary sensitivity and specificity were determined, and the data analysis was performed using Stata 14.0 and Review Manager 5.3.Thirteen studies with 705 patients were included. The individual sensitivity and specificity of the 13 studies varied from 71% to 100% for sensitivity and 73-100% for specificity. The pooled sensitivity of DKI was 88% (95% confidence interval [CI], 83-91%), and the pooled specificity was 91% (95% CI, 86-95%). The area under the summary receiver operating characteristic curve was 0.93 (95% CI, 0.90-0.95). The pooled diagnostic odds ratio of DKI was 64.85 (95% CI 38.52-109.19). The levels of heterogeneity for sensitivity and specificity across the included studies were high (IDKI demonstrated a high diagnostic performance for differentiation of LGG from HGG.

Background the course of depression is variable, but it is unknown how this variability over time affects long-term cognitive decline. Objective to examine the relationship of different trajectories of depressive symptoms on rates of subsequent cognitive decline in older adults. Design population-based cohort study. Setting communities in the USA and England. Subjects 17,556 older adults from the Health and Retirement Study and the English Longitudinal Study of Ageing. Methods depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale, and trajectories were calculated using group-based trajectory modelling. Global cognitive function and three cognitive domains of memory, executive function and temporal orientation were assessed for up to 18 years. Results five trajectories of depressive symptoms were identified. Compared with the ‘non-depressed’ trajectory, the ‘worsening depressive symptoms’ trajectory (pooled β = −0.016 standard deviation (SD)/year, 95% confidence interval (CI): −0.021 to −0.010), ‘persistent depressive symptoms’ trajectory (pooled β = −0.016 SD/year, 95% CI: −0.024 to −0.008), and ‘mild depressive symptoms’ trajectory (pooled β = −0.008 SD/year, 95% CI: −0.014 to −0.003) were associated with faster rates of cognitive decline, while no such association was found for the ‘improving depressive symptoms’ trajectory (pooled β = 0.001 SD/year, 95% CI: −0.010 to 0.012). Conclusions subthreshold depressive symptoms are associated with an increased rate of cognitive decline, while individuals who show improving depressive symptoms do not exhibit accelerated cognitive decline. These findings raise the possibility that maintaining depressive symptoms as low as possible and ignoring the clinical threshold, might mitigate cognitive decline in older adults.

BACKGROUND To analyze the relationship between the peripheral blood absolute lymphocyte count (ALC)/absolute monocyte count (AMC) ratio, soluble interleukin 2 receptor (sIL-2R) level, serum programmed cell death 1 (PD-1) level, and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). METHODS A total of 78 patients with DLBCL admitted to hospital and 30 healthy controls were enrolled as the case group and control group between August 2019 and June 2020, respectively. The ALC/AMC ratio and the levels of sIL-2R and serum PD-1 between the 2 groups and among patients with different prognoses were compared. The evaluation efficiency of these 3 factors for the prognosis of DLBCL patients was analyzed by receiver operating characteristic (ROC) curves. The risk factors affecting the 1-year survival rate were analyzed by the Cox hazard model. RESULTS The levels of sIL-2R, AMC, and PD-1 in the case group were significantly higher than those in the control group, while the ALC/AMC ratio was lower than that in the control group (P

ImportanceIt remains unclear whether cystatin C and cystatin C–based kidney function measures are associated with frailty trajectories and physical function decline.ObjectiveTo examine the associations of cystatin C level, cystatin C estimated glomerular filtration rate (eGFRcys), and the difference between eGFRs (eGFRdiff) using cystatin C and creatinine levels with long-term deficit-accumulation frailty trajectories and physical function decline.Design, Setting, and ParticipantsThis prospective cohort study used data from 15 949 participants in the China Health and Retirement Longitudinal Study (CHARLS) and the US Health and Retirement Study (HRS), 2 ongoing nationally representative cohort studies enrolling community-dwelling older people. Biennial surveys, known as waves, are conducted in both the CHARLS and the HRS. Seven-year data from wave 1 (May 2011 to March 2012) to wave 4 (July to September 2018) in the CHARLS and 12-year data from wave 8 (March 2006 to February 2007) to wave 14 (April 2018 to June 2019) in the HRS were assessed, with wave 1 in the CHARLS and wave 8 in the HRS serving as baseline waves. Data were analyzed from February 12 to May 20, 2022.ExposuresBaseline serum cystatin C and creatinine levels. Cystatin C eGFR and creatinine estimated GFR (eGFRcr) were calculated using the 2021 race-free equations developed by the Chronic Kidney Disease Epidemiology Collaboration. The difference between eGFRcys and eGFRcr was calculated by subtracting eGFRcr from eGFRcys.Main Outcomes and MeasuresBased on 12-year follow-up data from the HRS and 7-year follow-up data from the CHARLS, a 29-item deficit-accumulation frailty index (FI) was constructed to assess frailty trajectories at each visit. Physical function decline was evaluated using repeated objective physical function measurements (grip strength and gait speed). Linear mixed models were used to examine longitudinal associations.ResultsAmong 15 949 older adults included in the analysis, 9114 participants were from the HRS (mean [SD] age, 66.2 [10.1] years; 5244 women [57.5%]), and 6835 were from the CHARLS (mean [SD] age, 58.4 [9.8] years; 3477 women [50.9%]). With regard to race and ethnicity, the HRS cohort included 7755 White individuals (85.1%) and 1359 individuals (14.9%) of other races and/or ethnicities (including American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Pacific Islander, and other); all participants in the CHARLS cohort were of Chinese ethnicity. Each SD increment in serum cystatin C was associated with a faster increase in FI in both the HRS cohort (β = 0.050 SD/y; 95% CI, 0.045-0.055 SD/y; P = .001) and the CHARLS cohort (β = 0.051 SD/y; 95% CI, 0.042-0.060 SD/y; P = .001). An inverse association was observed for eGFRCys (HRS cohort: β = −0.058 SD/y; 95% CI, −0.062 to −0.053 SD/y; P = .001; CHARLS cohort: β = −0.056 SD/y; 95% CI, −0.064 to −0.047 SD/y; P = .001). These associations remained after controlling for serum creatinine (β = 0.051 SD/y; 95% CI, 0.042-0.060 SD/y; P = .001) and eGFRcr (β = −0.056 SD/y; 95% CI, −0.064 to −0.047 SD/y; P = .001) in the CHARLS cohort. Similar to the results observed for eGFRcys, each SD increment in the eGFRdiff was associated with a slower increase in FI (β = −0.027 SD/y; 95% CI, −0.035 to −0.018 SD/y; P = .001) in the CHARLS cohort. Similar findings were observed for physical function decline. For example, each SD increment in serum cystatin C was associated with faster decreases in both grip strength (β = −0.006 SD/y; 95% CI, −0.008 to −0.003 SD/y; P = .001) and gait speed (β = −0.007 SD/y; 95% CI, −0.011 to −0.003 SD/y; P = .001) in the HRS cohort and faster decreases in gait speed (β = −0.017 SD/y; 95% CI, −0.027 to −0.006 SD/y; P = .002) in the CHARLS cohort.Conclusions and RelevanceIn this cohort study, cystatin C, eGFRcys, and eGFRdiff were associated with long-term frailty trajectories and physical function decline among community-dwelling older people without frailty. Monitoring kidney function using cystatin C could have clinical utility in identifying the risk of accelerated frailty progression.