Discordance between Remnant Cholesterol and Low-density Lipoprotein Cholesterol Predicts Cardiovascular Disease: the Kailuan Prospective Cohort Study.

BACKGROUND: Previous studies have shown that remnant cholesterol (RC) was associated with cardiovascular disease (CVD). The study aim to identify the association of RC and the discordance between RC and lipoprotein cholesterol (LDL-C) with CVD. METHODS: Data was obtained from the Kailuan study. RC was calculated as the non high-density lipoprotein cholesterol minus LDL-C. Discordant RC and LDL-C were defined by percentile difference and clinical cutoff points. Cox proportional hazard models were used to explore the association of RC and the discordance between RC and LDL-C with CVD. RESULTS: Total of 96,769 participants were inclued, with the median age of 51.61 years, 79.56% of male. There was a significant association between RC levels and the risk of CVD, with an HR of 1.10 (95% CI, 1.08-1.13) in the continuous analysis. The discordantly high RC group had a significant increase in CVD, MI, and stroke risk, with HRs of 1.18 (95%CI, 1.10-1.26), 1.23 (1.06-1.43), and 1.15 (1.07-1.24), respectively. Compared to the group with low LDL-C and low RC, the group with low LDL-C and high RC had significantly higher incidences of CVD (HR, 1.33 [95% CI, 1.26-1.40]), MI (HR, 1.59 [95% CI, 1.41-1.80]), and stroke (HR, 1.28 [95% CI, 1.20-1.35]). CONCLUSIONS: Elevated levels of RC and discordantly high RC with LDL-C both were associated with the risk of CVD, MI, and stroke. These findings demonstrate the clinical significance of identifying residual risk related to RC.

Shenfu injection alleviate gut ischemia/reperfusion injury after severe hemorrhagic shock through improving intestinal microcirculation in rats.

Background: Shenfu (SF) injection, a traditional Chinese medication, would improve microcirculation in cardiogenic shock and infectious shock. This study was aimed to explore the therapeutic potential of the SF injection in gut ischemia-reperfusion (I/R) injury after severe hemorrhagic shock (SHS) and resuscitation. Furthermore, we also investigated the optimal adm？ inistration timing. Methods: Twenty-four male SD rats were randomly divided into four groups: Sham group (sham, n = 6), Control group (n = 6), SF injection group (SF, n = 6), and Delayed Shenfu injection administration group (SF-delay, n = 6). In SHS and resuscitation model, rats were induced by blood draw to a mean arterial pressure (MAP) of 40 ± 5 mmHg within 1 h and then maintained for 40 min; HR, MAP 'were recorded, microcirculation index [De Backer score, perfused small vessel density (PSVD), total vessel density (TVD), microcirculation flow index score (MFI), flow heterogeneity index (HI)] were analyzed. The blood gas index was detected, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), diamine oxidase (DAO), malondialdehyde (MDA) were measured by ELISA; ZO-1, and claudin-1 were measured by Western blotting. In addition, hematoxylin-eosin (HE) and periodic acid schiff (PAS) staining pathological sections of the intestinal mucosal tissues were also performed. Results: SF injection increased the MAP, relieved the metabolic acidosis degree associated with the hypoperfusion, and improved the intestinal microcirculatory density and perfusion quality after I/R injury. The expression of DAO, MDA in intestinal tissue, and plasma IL-6, TNF-α significantly decreased in the SF injection group compared to the control group. The concentration of ZO-1 and claudin-1 is also higher in the SF injection group. In addition, the HE and PAS staining results also showed that SF injection could decrease mucosal damage and maintain the structure. In the SF-delay group, the degree of intestinal tissue damage was intermediate between that of the control group and SF injection group. Conclusions: SF injection protect the intestine from I/R injury induced by SHS and resuscitation, the mechanism of which might be through improving intestinal microcirculation, reducing the excessive release of inflammatory factors and increasing intestinal mucosal permeability. Furthermore, the protection effect is more pronounced if administration during the initial resuscitation phase.

Puerarin alleviates osteoporosis in rats by targeting the JAK2/STAT3 signaling pathway.

Osteoporosis (OP) is a common chronic progressive bone disease that increases fracture risk in postmenopausal women. Research suggests that puerarin (Pue) may be an effective treatment for OP. This study examined the effects and underlying mechanisms of Pue in treating postmenopausal osteoporosis (PMOP) in rats. Sprague-Dawley (SD) rats underwent bilateral ovariectomy to simulate PMOP and were then treated with subcutaneous injections of Pue. Bone mineral density (BMD) was measured using a bone densitometer. Micro-CT scans assessed femur bone structure and various parameters were calculated: bone volume fraction (BV/TV), bone surface density (BS/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and bone surface area-to-bone volume ratio (BS/BV). Hematoxylin-eosin (HE) staining was employed to observe femoral tissue pathology. Serum levels of bone formation metabolism-related markers-osteocalcin (OC), bone alkaline phosphatase (BALP), and procollagen type I N-terminal propeptide (PINP)-were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in bone tissue were evaluated using Western blotting assay. The results showed improved bone density and reduced bone loss in rats treated with Pue. There were also significant increases in serum levels of OC and BALP, indicating enhanced osteogenesis. Furthermore, there was a decrease in activation of the JAK2/STAT3 pathway in femoral tissue, suggesting a pathway inhibition. These findings indicate that Pue may combat osteoporosis by promoting osteogenesis and inhibiting activation of the JAK2/STAT3 pathway activation.

Cumulative remnant cholesterol burden increases the risk of cardiovascular disease among young adults.

BACKGROUND: Previous studies have shown that remnant cholesterol (RC) was associated with cardiovascular disease (CVD) among middle-aged or older adults. However, lack of evidence on long-term exposures to RC and their role in CVD risk among young adults. We thus aimed to explore the association between cumulative RC burden and CVD in young adults. METHODS: We enrolled participants younger than 45 years free of CVD history in the Kailuan Study who completed the first three health examinations from 2006 to 2010. Cumulative RC burden included cumulative RC burden score, time-weighted cumulative RC, exposure duration of high RC, and time course of RC accumulation. The outcome was the incidence of CVD. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) between cumulative RC burden and CVD risk. RESULTS: A total of 15,219 participants were included (73.70% male, median age 39.13 years). During a median follow-up duration of 8.71 years (interquartile range: 8.4-9.15 years), 502 individuals developed CVD. After adjustment for traditional cardiovascular risk factors, highest risk of CVD was observed in participants with the highest cumulative RC burden score (HR, 1.66; 95% CI, 1.29-2.12), the highest quartile time-weighted cumulative RC (HR,1.50; 95% CI, 1.15-1.96), the longest exposure duration of high RC (HR, 1.71; 95% CI, 1.21-2.42), and those with cumulative RC burden and positive slope (HR, 1.79; 95% CI, 1.35-2.36). CONCLUSIONS: Cumulative RC burden increased the risk of CVD among young adults, suggesting that maintaining low RC levels throughout young adulthood may minimize CVD risk.

Derivation and Validation of a Scoring System for Predicting Poor Outcome After Posterior Circulation Ischemic Stroke in China.

BACKGROUND AND OBJECTIVES: Guidelines for posterior circulation ischemic stroke (PCIS) treatment are lacking and outcome prediction is crucial for patients and clinicians. We aimed to develop and validate a prognostic score to predict the poor outcome for patients with PCIS. METHODS: The score was developed from a prospective derivation cohort named the Third China National Stroke Registry (August 2015-March 2018) and validated in a spatiotemporal independent validation cohort (December 2017-March 2023) in China. Patients with PCIS with acute infarctions defined as hyperintense lesions on diffusion-weighted imaging were included in this study. The poor outcome was measured as modified Rankin scale (mRS) score 3-6 at 3 months after PCIS. Multivariable logistic regression analysis was used to identify predictors for poor outcome. The prognostic score, namely PCIS Outcome Score (PCISOS), was developed by assigning points to variables based on their relative ß-coefficients in the logistic model. RESULTS: The PCISOS was derived from 3,294 patients (median age 62 [interquartile range (IQR) 55-70] years; 2,250 [68.3%] men) and validated in 501 patients (median age 61 [IQR 53-68] years; 404 [80.6%] men). Among them, 384 (11.7%) and 64 (12.8%) had poor outcome 3 months after stroke in respective cohorts. Age, mRS before admission, NIH Stroke Scale on admission, ischemic stroke history, infarction distribution, basilar artery, and posterior cerebral artery stenosis or occlusion were identified as independent predictors for poor outcome and included in PCISOS. This easy-to-use integer scoring system identified a marked risk gradient between 4 risk groups. PCISOS performed better than previous scores, with an excellent discrimination (C statistic) of 0.80 (95% CI 0.77-0.83) in the derivation cohort and 0.81 (95% CI 0.77-0.84) in the validation cohort. Calibration test showed high agreement between the predicted and observed outcomes in both cohorts. DISCUSSION: PCISOS can be applied for patients with PCIS with acute infarctions to predict functional outcome at 3 months post-PCIS. This simple tool helps clinicians to identify patients with PCIS with higher risk of poor outcome and provides reliable outcome expectations for patients. This information might be used for personalized rehabilitation plan and patient selection for future clinical trials to reduce disability and mortality.

Expression and Prognosis of Differential Gene Troponin T1 Between Right and Left Colon Cancers.

Colorectal cancer (CRC) is one of the most common digestive tract tumors in humans. At present, many scholars believe that the primary site of the tumor has a direct and profound impact on its curative effect. There are significant differences in the expression of many genes, tumor microenvironment, and prognosis between the left and right colon. However, there is a lack of detailed studies on whether the differentially expressed genes in the left and right colon significantly impact the prognosis of patients with CRC. Troponin T1 (TNNT1) is an important gene that affects the prognosis difference between left and right colon cancer screening from "The Cancer Genome Atlas" database. By analyzing the differential gene expression data and clinical data of the left and right hemicolons in the database, the online prognostic database was used to screen the key molecules that significantly affect the tumor immune microenvironment and patient prognosis and to predict their functions and pathways. Quantitative reverse transcription-polymerase chain reaction was used to verify the expression difference of TNNT1 in CRC cell lines SW480 and HCT116, and normal human colorectal epithelial cell line FHC. The relationship between TNNT1 expression in 88 pairs of CRC samples and clinical information and pathologic parameters of patients with CRC was analyzed to judge the impact of TNNT1 expression on patient survival. Database analysis showed that TNNT1 was significantly overexpressed in CRC, and TNNT1 was one of the main differential genes between left colon cancer (LCC) and right colon cancer (RCC). The expression of TNNT1 was significantly increased in RCC, which could lead to poor prognosis of patients. Quantitative reverse transcription-polymerase chain reaction indicated that the expression of TNNT1 was significantly up-regulated in CRC cell lines SW480 and HCT116. Eighty-eight immunohistochemistry (IHC) of CRC tissues and adjacent tissues suggested that the expression of TNNT1 in CRC was significantly higher than that in normal adjacent tissues. By analyzing the clinical information and pathologic indicators matched with these clinical samples, we found that high TNNT1 expression in the primary tumor location (right colon) and high N stage (N2, N3) were unfavorable factors affecting the prognosis of patients with CRC. Multivariate Cox regression analysis suggested that high expression of TNNT1 may be an independent risk factor for the prognosis of patients with CRC. As one of the main differential genes between LCC and RCC, TNNT1 is representative to some extent. Its high expression may be one of the reasons why the prognosis of patients with RCC is worse than that of patients with LCC.

Role of diet in the risks of esophageal adenocarcinoma and squamous cell carcinoma: an updated umbrella review.

PURPOSE: This updated umbrella review aimed to evaluate the evidence regarding the associations between dietary factors and the risks of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify relevant studies. The quality of the included meta-analyses was evaluated using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2). For each association, the number of cases, random effects pooled effect size, 95% confidence intervals (CIs), heterogeneity, 95% prediction interval (PrI), small-study effect, and excess significance bias were recalculated to determine the evidence level. RESULTS: We identified 33 meta-analyses describing 58 dietary factors associated with ESCC and 29 meta-analyses describing 38 dietary factors associated with EAC. There was convincing evidence regarding the association of 2 dietary factors (areca nut and high alcohol) with the risk of ESCC. There was highly suggestive evidence regarding the association of only 1 dietary factor (healthy pattern) with the risk of ESCC. There was suggestive evidence regarding the association of 11 dietary factors with the risk of ESCC, including fruit, citrus fruit, vegetables, pickled vegetables, maté tea, moderate alcohol, hot beverages and foods, hot tea, salt, folate, and vitamin B6. There was convincing evidence regarding the association of one dietary factor (vitamin B6) with the risk of EAC. There was suggestive evidence regarding the association of 4 dietary factors with the risk of EAC, including processed meat, dietary fibre, carbohydrate, and vitamin B12. The convincing evidence regarding the associations between dietary factors and the risks of ESCC and EAC remained robust in sensitivity analyses. CONCLUSIONS: This umbrella review highlighted convincing evidence regarding the associations of areca nut and high alcohol with a higher risk of ESCC. Additionally, an association between vitamin B6 and a decreased risk of EAC was observed. Further research is needed to examine the dietary factors with weak evidence regarding their associations with ESCC and EAC.

Novel High-Performance Glyoxylate Derivative-Based Photoinitiators for Free Radical Photopolymerization and 3D Printing with Visible LED.

Investigations concerning the glyoxylate moiety as a photocleavable functional group for visible light photoinitiators, particularly in the initiation of free radical photopolymerization remain limited. This study introduces nine innovative carbazole-based ethyl glyoxylate derivatives (CEGs), which are synthesized and found to exhibit excellent photoinitiation abilities as monocomponent photoinitiating systems. Notably, these structures demonstrate robust absorption in the near-UV/visible range, surpassing the commercial photoinitiators. Moreover, the newly developed glyoxylate derivatives show higher acrylate function conversions compared to a benchmark photoinitiator (MBF) in free radical photopolymerization. Elucidation of the photoinitiation mechanism of CEGs is achieved through a comprehensive analysis involving the decarboxylation reaction and electron spin resonance spin trapping. Furthermore, their practical utility is confirmed during direct laser writing and 3D printing processes, enabling the successful fabrication of 3D printed objects. This study introduces pioneering concepts and effective strategies in the molecular design of novel photoinitiators, showcasing their potential for highly advantageous applications in 3D printing.

Self-Assembly of Amphiphilic PDI and NDI Derivatives with Opposite Thermoresponsive Fluorescent Behaviors in Aqueous Solution.

This work presents a study of the thermally induced aggregation of perylene diimide (PDI) and naphthalene diimide (NDI) derivatives modified with oligo ethylene glycol (OEG) chains in aqueous solution. Water-soluble and flexible OEG side chains were introduced into the π-core of glutamate-modified NDI and PDI structures, and the aggregation process was modulated by heating or cooling in water. Interestingly, a rare opposite temperature response of fluorescent behavior from the two amphiphilic chromophores was revealed, in which the PDI exhibited fluorescent enhancement, while fluorescent quenching upon temperature increase was observed from the NDI assembly. The mechanism of thermally induced aggregation is clearly explained by studies with various spectroscopic techniques including UV-visible, fluorescence, 1H NMR, 2D NMR spectroscopy, and SEM observation as well as control experiments operated in DMSO solution. It is found that although similar J-aggregates were formed by both amphiphilic chromophores in aqueous solution, the temperature response of the aggregates to temperature was opposite. The degree of PDI aggregation decreased, while that of NDI increased upon temperature rising. This research paves a valuable way for understanding the complicated supramolecular behaviors of amphiphilic chromophores.

Ultrafast Sunlight-Induced Polymerization: Unveiling 2-Phenylnaphtho[2,3-d]Thiazole-4,9-dione as a Unique Scaffold for High-Speed and Precision 3D Printing.

A series of 15 dyes based on the 2-phenylnaphtho[2,3-d]thiazole-4,9-dione scaffold and 1 compound based on the 2,3-diphenyl-1,2,3,4-tetrahydrobenzo[g]quinoxaline-5,10-dione scaffold are studied as photoinitiators. These compounds are used in two- and three-component high-performance photoinitiating systems for the free radical polymerization of trimethylolpropane triacrylate (TMPTA) and polyethylene glycol diacrylate (PEGDA) under sunlight. Remarkably, the conversion of TMPTA can reach ≈60% within 20 s, while PEGDA attains a 96% conversion within 90 s. To delve into the intricate chemical mechanisms governing the polymerization, an array of analytical techniques is employed. Specifically, UV-vis absorption and fluorescence spectroscopy, steady-state photolysis, stability experiments, fluorescence quenching experiments, cyclic voltammetry, and electron spin resonance spin trapping (ESR-ST) experiments, collectively contribute to a comprehensive understanding of the photochemical mechanisms. Photoinitiation capacities of these systems are determined using real-time Fourier transformed infrared spectroscopy (RT-FTIR). Of particular interest is the revelation that, owing to the superior initiation ability of these dyes, high-resolution 3D patterns can be manufactured by direct laser write (DLW) technology and 3D printing. This underscores the efficient initiation of free radical polymerization processes by the newly developed dyes under both artificial and natural light sources, presenting an avenue for energy-saving, and environmentally friendly polymerization conditions.

A functionalized glass fiber as the adsorbent for efficient analysis of endocrine disruptors in aqueous environments.

Estrogens and bisphenols are typical endocrine disruptors (EDs) that pose a potential hazard to the human body due to their widespread presence in aqueous environments. In this study, a ß-cyclodextrin porous crosslinked polymer (ß-CD-PCP) was prepared in-situ on a glass fiber surface by a nucleophilic substitution reaction. An effective and sensitive solid phase microextraction method using functionalized glass fiber with ß-CD-PCP coating as the adsorbent was established for the detection of 11 EDs in a water environment. The ß-CD-PCP was in-situ prepared on a glass fiber surface by a nucleophilic substitution reaction. The ß-CD-PCP successfully separated five estrogens (ESTs) and six bisphenols (BPs) through hydrophobic and π-π interactions. The conditions affecting extraction were optimized. Under the optimized conditions, the ESTs obtained a high enrichment effect (1795-2328), low limits of detection (0.047 µg L-1) and a good linearity range (0.2-15.0 µg L-1). Furthermore, the spiked recoveries of analyte ESTs in aqueous environments were between 82.9-115.7 %. The results indicated that the prepared functionalized glass fibers exhibited good adsorption properties, and the established analytical method was reliable for monitoring trace ESTs and BPs in aqueous environments.

Efficacy of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke: a predefined exploratory analysis of a multicenter, double-blind, randomized controlled trial.

BACKGROUND: Ginkgo diterpene lactone meglumine (GDLM) could improve the functional outcome in patients with acute ischemic stroke (AIS). This study aimed to investigate the efficacy of GDLM on cognitive function in patients with AIS. METHODS: This is a predefined exploratory analysis of the Efficacy and Safety of Ginkgo Diterpene Lactone Meglumine in Acute Ischemic Stroke trial, which was primarily designed to investigate the efficacy and safety of GDLM versus placebo on functional outcome at 100 centers in China. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) test. The primary outcomes were changes of MoCA from baseline to Day 14 and Day 90 after randomization. RESULTS: A total of 3163 patients with completed data on MoCA were enrolled. There was statistically significant difference of changes in MoCA scores between the GDLM group and the placebo group from baseline to Day 14 (mean difference, 0.31; 95% confidence interval [CI], 0.08-0.53; P = 0.007) and to Day 90 after randomization (mean difference, 0.47; 95% CI, 0.22-0.72; P < 0.001). Additionally, GDLM was associated with a higher proportion of patients who reached a clinically significant level of improvement in MoCA from baseline to Day 14 (odds ratio [OR], 1.25; 95% CI, 1.08-1.44; P = 0.002) and Day 90 after randomization (OR, 1.21; 95% CI, 1.03-1.41; P = 0.02). Specially, GDLM could significantly improve the scores of visuo-spatial and executive function and language. CONCLUSIONS: In this predefined analysis of patients with AIS, GDLM could improve the 14-day and 90-day cognitive function compared with the placebo.

CT-based Assessment at 6-Month Follow-up of COVID-19 Pneumonia patients in China.

This study aimed to assess pulmonary changes at 6-month follow-up CT and predictors of pulmonary residual abnormalities and fibrotic-like changes in COVID-19 pneumonia patients in China following relaxation of COVID restrictions in 2022. A total of 271 hospitalized patients with COVID-19 pneumonia admitted between November 29, 2022 and February 10, 2023 were prospectively evaluated at 6 months. CT characteristics and Chest CT scores of pulmonary abnormalities were compared between the initial and the 6-month CT. The association of demographic and clinical factors with CT residual abnormalities or fibrotic-like changes were assessed using logistic regression. Follow-up CT scans were obtained at a median of 177 days (IQR, 170-185 days) after hospital admission. Pulmonary residual abnormalities and fibrotic-like changes were found in 98 (36.2%) and 39 (14.4%) participants. In multivariable analysis of pulmonary residual abnormalities and fibrotic-like changes, the top three predictive factors were invasive ventilation (OR 13.6; 95% CI 1.9, 45; P < .001), age > 60 years (OR 9.1; 95% CI 2.3, 39; P = .01), paxlovid (OR 0.11; 95% CI 0.04, 0.48; P = .01) and invasive ventilation (OR 10.3; 95% CI 2.9, 33; P = .002), paxlovid (OR 0.1; 95% CI 0.03, 0.48; P = .01), smoker (OR 9.9; 95% CI 2.4, 31; P = .01), respectively. The 6-month follow-up CT of recent COVID-19 pneumonia cases in China showed a considerable proportion of the patients with pulmonary residual abnormalities and fibrotic-like changes. Antivirals against SARS-CoV-2 like paxlovid may be beneficial for long-term regression of COVID-19 pneumonia.

Low-Density Lipoprotein Cholesterol to Triglyceride Ratio and Clinical Outcomes after Acute Ischaemic Stroke or Transient Ischaemic Attack.

AIMS: Studies showed that low-density lipoprotein cholesterol (LDL-C) to triglyceride (TG) ratio could be used as a predictive parameter of low-density lipoprotein oxidation in vivo and the level of small dense LDL-C. However, whether LDL-C/TG ratio is associated with stroke prognosis remains unclear. We investigated the associations of LDL-C/TG ratio with outcomes in patients with acute ischaemic stroke (AIS) or transient ischaemic attacks (TIA) and explored whether it produced more predictive value than LDL-C and TG. METHODS: Data were derived from the Third China National Stroke Registry (CNSR-III). Multivariable Cox regression for stroke recurrence, composite vascular events and all-cause death and logistic regression for the poor functional outcome (modified Rankin Scale score 3-6) were used. RESULTS: A total of 14123 patients were included. After adjusting for confounding factors, quartile 4 of LDL-C/TG ratio was associated with an increased risk of recurrent stroke (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.03-1.56), composite vascular events (HR,1.23; 95% CI, 1.00-1.52), death (HR,1.70; 95% CI, 1.13-2.54) and poor functional outcome (odds ratio, 1.34; 95% CI, 1.12-1.61) at 3 months follow-up compared with quartile 1. We also found that quartile 4 of LDL-C and TG was positively and negatively associated with poor functional outcome at 3 months, respectively. LDL-C/TG ratio performed better than LDL-C or TG in predicting clinical outcomes. CONCLUSIONS: LDL-C/TG ratio was associated with the risk of stroke recurrence, composite vascular events, death and poor functional outcome in patients with AIS or TIA.

Association and pathways of baseline and longitudinal hemoglobin A1c with the risk of incident stroke: A nationwide prospective cohort study.

AIMS: To investigate the association of baseline and long-term mean hemoglobin A1c (HbA1c) with the risk of stroke. METHODS: A total of 11,220 participants aged over 45 years and without stroke at baseline were enrolled from the China Health and Retirement Longitudinal Study. Mean HbA1c was calculated as the mean of HbA1c at all previous visits before stroke occurred or the end of follow-up. Multivariable-adjusted Cox regressions and Bayesian network were used for the analysis. RESULTS: During a median follow-up of 7.50 years, a total of 626 cases of stroke occurred. The risk of stroke increased with quintiles of baseline and mean HbA1c, the hazard ratio (HR) in Q5 versus Q1 was 1.30 (95 % confidence interval [CI],1.03-1.64) and 1.79 (95 % CI, 1.38-2.34), respectively. Per 1 unit increase in baseline and mean HbA1c was associated with 10 % (HR, 1.10; 95 % CI, 1.02-1.18) an 12 % (HR, 1.12; 95 % CI, 1.05-1.19) higher risk of stroke. Bayesian network analysis showed that the pathway from HbA1c to stroke was through hypertension, dyslipidemia, obesity, and inflammation. CONCLUSIONS: Elevated levels of both baseline and long-term HbA1c were associated with increased risk of stroke, and hypertension and obesity played an important role in the pathway.

Quantification of eosinophilic area and its potential molecular feature in clear cell renal cell carcinoma.

OBJECTIVE: Previous studies have acknowledged the presence of eosinophilic cytoplasm in clear cell renal cell carcinoma, yet the precise quantification method and potential molecular attributes in clear cell renal cell carcinoma remain elusive. This study endeavours to precisely quantify the eosinophilic attribute and probe into the molecular mechanisms governing its presence in clear cell renal cell carcinoma. METHODS: Data from cohorts of clear cell renal cell carcinoma patients who underwent nephrectomy, comprising The Cancer Genome Atlas cohort (n = 475) and Sun Yat-sen University Cancer Center cohort (n = 480), were aggregated to assess the eosinophilic attribute. Additionally, Omics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) (n = 58) were leveraged to explore the potential molecular features associated with eosinophilic clear cell renal cell carcinoma. Employing receiver operating characteristic curve analysis, the proportion of tumour cells with eosinophilic cytoplasm was determined, leading to the classification of each cohort into distinct groups: a clear group (<5%) and an eosinophilic group (≥5%). RESULTS: In both cohorts, the eosinophilic feature consistently correlated with higher International Society of Urological Pathology (ISUP) grade, elevated tumor stage, and the presence of necrosis. Furthermore, the Kaplan-Meier method demonstrated that patients in the eosinophilic group exhibited shorter overall survival or disease-free survival compared with those in the clear group, a pattern reaffirmed in various stratified survival analyses. Intriguingly, within The Cancer Genome Atlas cohort, the pathological characterization of cell cytoplasm (eosinophilic vs. clear) emerged as an independent risk factor for overall survival (hazard ratio = 2.507 [95% confidence interval: 1.328-4.733], P = 0.005) or disease-free survival (hazard ratio = 1.730 [95% confidence interval: 1.062-2.818], P = 0.028) via Cox regression analysis. Moreover, multi-Omics data unveiled frequent BAP1 mutations and down-regulation of Erythroblast Transformation-Specific-Related Gene associated with the eosinophilic feature in clear cell renal cell carcinoma. Additionally, patients with low expression of Erythroblast Transformation-Specific-Related Gene showed worse overall survival (P < 0.001). CONCLUSIONS: The quantification of the eosinophilic feature serves as a robust predictor of clinical prognosis in clear cell renal cell carcinoma. Furthermore, the manifestation of this feature may be linked to BAP1 mutations and the down-regulation of Erythroblast Transformation-Specific-Related Gene in clear cell renal cell carcinoma. Significantly, the expression levels of Erythroblast Transformation-Specific-Related Gene manifest as an exemplary prognostic marker, providing exceptional predictive accuracy for the clinical prognosis in clear cell renal cell carcinoma.

Severity and Remission of Metabolic Dysfunction-Associated Fatty/Steatotic Liver Disease With Chronic Kidney Disease Occurrence.

BACKGROUND: The association of the severity of hepatic steatosis in metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) and the remission of MAFLD/MASLD with CKD occurrence is unclear. METHODS AND RESULTS: The study enrolled 79 540 participants from the Kailuan cohort. Hepatic steatosis was diagnosed by ultrasound. MAFLD/MASLD was defined as hepatic steatosis combined with metabolic dysfunction and MASLD further excluded alcohol or other causes of liver disease. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate<60 mL/min per 1.73 m2 or positive proteinuria (≥1+). Hazard ratio (HR) was calculated by Cox regression models. After a median follow-up of 12.9 years, CKD occurred in 20 465 participants. After adjusting for potential confounders, MAFLD was associated with a higher risk of CKD compared with non-MAFLD (HR, 1.12 [95% CI, 1.09-1.16]), and this risk increased with increasing severity of hepatic steatosis (P-trend<0.001). Consistent findings were observed when MASLD was used as the exposure. Compared with persistent non-MAFLD, no statistical difference was found in the risk of CKD in MAFLD remission (HR, 1.04 [95% CI, 0.95-1.15]); however, MASLD remission still had a higher risk of CKD compared with persistent non-MASLD (HR, 1.15 [95% CI, 1.03-1.27]). When grouped according to the prior severity of hepatic steatosis, there was no statistically significant difference in risk of CKD in mild-MAFLD/MASLD remission compared with persistent non-MAFLD/MASLD, but moderated/severe-MAFLD/MASLD remission still had a higher risk. CONCLUSIONS: The risk of CKD in patients with MAFLD/MASLD increased with the severity of hepatic steatosis. Even after remission of the disease, patients with MAFLD/MASLD with prior moderate to severe hepatic steatosis still had a higher risk of CKD.

Sex and Age Differences in the Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and Heart Failure: A Prospective Cohort Study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a risk factor for heart failure (HF) occurrence, but it remains unclear whether the association between MAFLD and HF differs in different sexes and ages. METHODS: A total of 96 576 participants of Kailuan Study were included. MAFLD was defined as presence of hepatic steatosis and metabolic dysfunction and classified as mild and significant by ultrasound. Hazard ratios (HRs) were calculated by Cox regression models. RESULTS: After a median follow-up of 14.0 years, 2939 participants developed HF. Adjusting for confounding factors, mild-MAFLD (HR, 1.27 [95% CI, 1.16-1.39]) and significant-MAFLD (HR, 1.45 [95% CI, 1.31-1.63]) were associated with a higher risk of HF in all participants, and the risk differed by sex (Pinteraction<0.05) and age (Pinteraction<0.001). Compared with non-MAFLD participants, in women, significant-MAFLD was associated with an 84% (HR, 1.84 [95% CI, 1.43-2.37]) increased risk of HF; however, in men, the risk was 36% (HR, 1.36 [95% CI, 1.20-1.53]). In participants under 45 years, mild-MAFLD and significant-MAFLD had a 55% (HR, 1.55 [95% CI, 1.07-2.25]) and 172% (HR, 2.72 [95% CI, 1.87-3.97]) increased risk of HF; however, in participants over 65 years, even significant-MAFLD did not associate with a higher risk of HF (HR, 1.11 [95% CI, 0.92-1.34]). Afterwards, we stratified all participants by both sex and age and found that the risk of MAFLD-associated HF decreased with age in men (Pinteraction<0.05) and women (Pinteraction<0.05), but the sex difference in this risk was only present in participants younger than 45 years (Pinteraction<0.05). CONCLUSIONS: MAFLD greatly increased the risk of HF in women, especially young women. With increasing age, MAFLD-related risk of HF decreased and the difference between men and women disappeared.

One-Year Outcomes of Early Therapy With Ticagrelor vs Clopidogrel in CYP2C19 Loss-of-Function Carriers With Stroke or TIA Trial.

BACKGROUND AND OBJECTIVES: The Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that among Chinese patients with minor ischemic stroke or transient ischemic attack (TIA) who were carriers of CYP2C19 loss-of-function alleles, dual-antiplatelet therapy with ticagrelor-aspirin reduced the 90-day risk of stroke without increased severe or moderate bleeding compared with clopidogrel-aspirin. However, whether dual-antiplatelet therapy with ticagrelor was superior to clopidogrel beyond the 90 days of follow-up remained unclear. In this study, we reported 1-year follow-up outcomes of the CHANCE-2 trial. METHODS: The CHANCE-2 trial is a randomized, double-blind, placebo-controlled trial at 202 centers in China. Patients with a minor stroke or TIA who carried CYP2C19 loss-of-function alleles were randomized within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor and placebo clopidogrel or to receive clopidogrel and placebo ticagrelor for 90 days; both groups received aspirin for the first 21 days. After day 90, treatment was as per the choice of the clinician and the patient. RESULTS: Among 6,412 patients, the proportion of patients on ticagrelor plus aspirin, clopidogrel plus aspirin, ticagrelor alone, clopidogrel alone, aspirin alone, other antiplatelet, and no antiplatelet beyond month 3 to 1 year was 0.09%, 1.56%, 0.13%, 2.66%, 73.65%, 0.78%, and 21.13% in the ticagrelor-aspirin group and 0.03%, 1.63%, 0.19%, 2.60%, 72.83%, 0.66%, and 22.06% in the clopidogrel-aspirin group, respectively. The primary outcome of new stroke occurred in 252 patients (7.91%) in the ticagrelor-aspirin group and 310 patients (9.73%) in the clopidogrel-aspirin group by 1 year of follow-up (hazard ratio 0.80; 95% CI 0.68-0.95; p = 0.007); new stroke beyond 3 months to 1 year occurred in 61 patients (2.07%) and 67 patients (2.32%) (p = 0.48), respectively. Primary safety outcome of severe or moderate bleeding occurred in 17 patients (0.53%) in the ticagrelor-aspirin group and 20 patients (0.63%) in the clopidogrel-aspirin group (p = 0.61). DISCUSSION: For CYP2C19 loss-of-function allele carriers, early dual-antiplatelet therapy with ticagrelor is superior to clopidogrel at 1 year in reducing recurrent stroke. TRIAL REGISTRATION INFORMATION: URL: clinicaltrials.gov. Unique identifier: NCT04078737. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with minor stroke or TIA with TIACYP2C19 loss-of-function, ticagrelor plus aspirin for 21 days is superior to clopidogrel plus aspirin in reducing the 1-year risk of recurrent stroke.

Temporary relationship between sleep duration and depression and its impact on future risk of cardiovascular disease.

BACKGROUND: Although sleep duration and depression were correlated, their temporal sequence and how the sequence influence on future risk of cardiovascular disease (CVD) remained undetermined. This study aimed to explore the temporal relationship between sleep duration and depression, and its association with future CVD risk. METHODS: We included 10,629 middle-aged and elderly participants with repeated measurements of sleep duration and depressive symptoms (measured by Center for Epidemiological Studies-Depression scale [CESD]) at the first two visits from the China Health and Retirement Longitudinal Study. Cross-lagged analysis and mediation analysis were used to examine the temporal relationship between sleep duration and depression and its impact on future risk of CVD. RESULTS: The adjusted cross-lagged path coefficient from baseline sleep duration to follow-up CES-D (ß1 = -0.191; 95 % confidence interval [CI], -0.239 to -0.142) was significantly greatly than that from baseline CES-D to follow-up sleep duration (ß2 = -0.031; 95 % CI, -0.031 to -0.024) (Pdifference < 0.0001). Similarly, the path coefficient from baseline sleep duration to annual changes in CES-D was significantly greater than that from baseline CES-D to annual changes in sleep duration (ß1 = -0.093 versus ß2 = -0.015, Pdifference < 0.0001). The path coefficient from baseline sleep duration to follow-up CES-D in CVD group was significantly greater than that in those without CVD (Pdifference of ß1 = 0.0378). Furthermore, 27.93 % of the total association of sleep duration with CVD was mediated by depression symptoms. CONCLUSIONS: The findings provide evidence that decrease in sleep duration probably precedes the increased in depressive symptoms, and depression partially mediated the pathway from sleep duration to incident CVD.