Cancer screening in hospitalized ischemic stroke patients: a multicenter study focused on multiparametric analysis to improve management of occult cancers.

Background/aims: The reciprocal promotion of cancer and stroke occurs due to changes in shared risk factors, such as metabolic pathways and molecular targets, creating a "vicious cycle." Cancer plays a direct or indirect role in the pathogenesis of ischemic stroke (IS), along with the reactive medical approach used in the treatment and clinical management of IS patients, resulting in clinical challenges associated with occult cancer in these patients. The lack of reliable and simple tools hinders the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) approach. Therefore, we conducted a multicenter study that focused on multiparametric analysis to facilitate early diagnosis of occult cancer and personalized treatment for stroke associated with cancer. Methods: Admission routine clinical examination indicators of IS patients were retrospectively collated from the electronic medical records. The training dataset comprised 136 IS patients with concurrent cancer, matched at a 1:1 ratio with a control group. The risk of occult cancer in IS patients was assessed through logistic regression and five alternative machine-learning models. Subsequently, select the model with the highest predictive efficacy to create a nomogram, which is a quantitative tool for predicting diagnosis in clinical practice. Internal validation employed a ten-fold cross-validation, while external validation involved 239 IS patients from six centers. Validation encompassed receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and comparison with models from prior research. Results: The ultimate prediction model was based on logistic regression and incorporated the following variables: regions of ischemic lesions, multiple vascular territories, hypertension, D-dimer, fibrinogen (FIB), and hemoglobin (Hb). The area under the ROC curve (AUC) for the nomogram was 0.871 in the training dataset and 0.834 in the external test dataset. Both calibration curves and DCA underscored the nomogram's strong performance. Conclusions: The nomogram enables early occult cancer diagnosis in hospitalized IS patients and helps to accurately identify the cause of IS, while the promotion of IS stratification makes personalized treatment feasible. The online nomogram based on routine clinical examination indicators of IS patients offered a cost-effective platform for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00354-8.

Associations of type 2 diabetes and the risk of migraine in Chinese populations.

AIM: We aimed to explore the relationship between type 2 diabetes mellitus (T2DM) and the incidence rate of migraine in a Chinese population, and analyze the clinical characteristics of migraine patients with T2DM. METHODS: Data on the study cohort of 9873 individuals were obtained from the China Health and Retirement Longitudinal Study (CHARLS). The incidence rate of migraine from 2015 to 2018 was assessed. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for the relationship between T2DM and the incidence of migraine. In addition, a cross-sectional study including 168 migraine patients was conducted in Xiamen, China. Migraine patients were grouped according to their T2DM status. Multivariable linear regression models were used to estimate ßs and their 95% CIs for the relationship between migraine characteristics and T2DM. RESULTS: The cumulative incidence rate of migraine from 2015 to 2018 in the T2DM group and control group was 7.26% [6.04%.8.65%] and 8.91% [8.27%.9.58%], respectively. The risk of migraine in patients with T2DM was reduced by 21% (HR 0.79 [0.65;0.95]) compared to patients with no T2DM after adjustment for confounders. The cross-sectional study showed that the presence of T2DM significantly reduced migraine frequency and relieved migraine intensity. CONCLUSION: This was the first study to validate that T2DM reduced the risk of migraine in a Chinese population cohort. Patients with migraine and T2DM may experience significant relief from their headache symptoms. Carrying out relevant mechanistic research may help to identify new targets for migraine treatment and contribute to further understanding the impact of T2DM or related metabolic disorders on an individual's health.

Causal effect of air pollution on the risk of cardiovascular and metabolic diseases and potential mediation by gut microbiota.

BACKGROUND: Epidemiological studies have explored the relationship between air pollution and cardiovascular and metabolic diseases (CVMDs). Accumulating evidence has indicated that gut microbiota deeply affects the risk of CVMDs. However, the findings are controversial and the causality remains uncertain. To evaluate whether there is the causal association of four air pollutants with 19 CVMDs and the potential effect of gut microbiota on these relationships. METHODS: Genetic instruments for particulate matter (PM) with aerodynamic diameter < 2.5 µm (PM2.5), <10 µm (PM10), PM2.5 absorbance, nitrogen oxides (NOx) and 211 gut microbiomes were screened. Univariable Mendelian randomization (UVMR) was used to estimate the causal effect of air pollutants on CVMDs in multiple MR methods. Additionally, to account for the phenotypic correlation among pollutant, the adjusted model was constructed using multivariable Mendelian randomization (MVMR) analysis to strength the reliability of the predicted associations. Finally, gut microbiome was assessed for the mediated effect on the associations of identified pollutants with CVMDs. RESULTS: Causal relationships between NOx and angina, heart failure and hypercholesterolemia were observed in UVMR. After adjustment for air pollutants in MVMR models, the genetic correlations between PM2.5 and hypertension, type 2 diabetes mellitus (T2DM) and obesity remained significant and robust. In addition, genus-ruminococcaceae-UCG003 mediated 7.8 % of PM2.5-effect on T2DM. CONCLUSIONS: This study firstly provided the genetic evidence linking air pollution to CVMDs and gut microbiota may mediate the association of PM2.5 with T2DM. Our findings highlight the significance of air quality in CVMDs risks and suggest the potential of modulating intestinal microbiota as novel therapeutic targets between air pollution and CVMDs.

Serum neurofilament light chain levels in migraine patients: a monocentric case-control study in China.

PURPOSE: Serum neurofilament light chain (sNfL) can reflect nerve damage. Whether migraine can cause neurological damage remain unclear. This study assesses sNfL levels in migraine patients and explores whether there is nerve damage in migraine. METHODS: A case-control study was conducted in Xiamen, China. A total of 138 migraine patients and 70 healthy controls were recruited. sNfL (pg/mL) was measured on the single-molecule array platform. Univariate, Pearson correlation and linear regression analysis were used to assess the relationship between migraine and sNfL levels, with further subgroup analysis by migraine characteristics. RESULTS: Overall, 85.10% of the 208 subjects were female, with a median age of 36 years. sNfL levels were higher in the migraine group than in the control group (4.85 (3.49, 6.62) vs. 4.11 (3.22, 5.59)), but the difference was not significant (P = 0.133). The two groups showed an almost consistent trend in which sNfL levels increased significantly with age. Subgroup analysis showed a significant increase in sNfL levels in patients with a migraine course ≥ 10 years (ß = 0.693 (0.168, 1.220), P = 0.010). Regression analysis results show that age and migraine course are independent risk factors for elevated sNfL levels, and there is an interaction between the two factors. Patients aged < 45 years and with a migraine course ≥ 10 years have significantly increased sNfL levels. CONCLUSIONS: This is the first study to evaluate sNfL levels in migraine patients. The sNfL levels significantly increased in patients with a migraine course ≥ 10 years. More attention to nerve damage in young patients with a long course of migraine is required.

Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease.

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease (AD). High-frequency stimulation (HFS)-induced long-term potentiation (LTP) has been widely used to study synaptic plasticity, with impaired LTP found to be associated with AD. However, the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated. Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear. Herein, we induced LTP in the hippocampal CA1 region of wild-type (WT) and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region. We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes (DEGs) in mice with normal LTP, and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP. We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction. Among them, we found that the expression of Pygm, which catabolizes glycogen, was also decreased in AD patients. We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice, while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice. Moreover, we showed that PYGM directly regulated energy generation in neurons. Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function, but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.

A national cross-sectional analysis of dietary copper intake and abdominal aortic calcification in the US adults: NHANES 2013-2014.

BACKGROUND AND AIMS: Copper is an essential dietary element with a crucial role in physiological regulation. However, the relationship between dietary copper intake and abdominal aortic calcification (AAC) remains uncertain. METHODS AND RESULTS: This study encompassed a cohort of 2535 adults aged over 40 years, derived from the National Health and Nutrition Examination Survey 2013-2014. Dietary copper intake from both food sources and supplements was assessed through two 24-h dietary recall interviews. AAC was measured by dual-energy X-ray absorptiometry and classified into 3 groups using the Kauppila score system. Multivariable logistic regression models were constructed to evaluate the association between dietary copper intake and AAC. Among the participants, a total of 771 individuals (30.4%) were diagnosed with AAC, of which 239 (9.4%) exhibited severe AAC. Higher dietary copper intake was significantly associated with a lower incidence of severe AAC. Specifically, for each 1 mg/day increase in dietary copper intake, the incidence of severe AAC decreased by 38% (odds ratios [OR] 0.62, 95% confidence intervals [CI] 0.39-0.98) after adjustment for relevant covariates. Moreover, individuals in the third tertile of copper intake had a 37% lower incidence of AAC compared to those in the first tertile [OR 0.63, 95% CI (0.43-0.95)]. However, no significant associations were found between supplemental copper intake or serum copper levels and AAC. CONCLUSIONS: This study demonstrates that lower dietary copper intake, rather than serum copper levels or supplement copper intake, is significantly associated with a higher prevalence of AAC in adults ≥40 years old in the United States.

Causal relationship between particulate matter 2.5 (PM2.5), PM2.5 absorbance, and COVID-19 risk: A two-sample Mendelian randomisation study.

Background: Several observational studies reported on the association between particulate matter ≤2.5µm (PM2.5) and its absorbance with coronavirus (COVID-19), but none use Mendelian randomisation (MR). To strengthen the knowledge on causality, we examined the association of PM2.5 and its absorbance with COVID-19 risk using MR. Methods: We selected genome-wide association study (GWAS) integration data from the UK Biobank and IEU Open GWAS Project for two-sample MR analysis. We used inverse variance weighted (IVW) and its multiple random effects and fixed effects alternatives to generally predict the association of PM2.5 and its absorbance with COVID-19, and six methods (MR Egger, weighted median, simple mode, weighted mode, maximum-likelihood and MR-PRESSO) as complementary analyses. Results: MR results suggested that PM2.5 absorbance was associated with COVID-19 infection (odds ratio (OR) = 2.64; 95% confidence interval (CI) = 1.32-5.27, P = 0.006), hospitalisation (OR = 3.52; 95% CI = 1.05-11.75, P = 0.041) and severe respiratory symptoms (OR = 28.74; 95% CI = 4.00-206.32, P = 0.001) in IVW methods. We observed no association between PM2.5 and COVID-19. Conclusions: We found a potential causal association of PM2.5 absorbance with COVID-19 infection, hospitalisation, and severe respiratory symptoms using MR analysis. Prevention and control of air pollution could help delay and halt the negative progression of COVID-19.

Mechanically Robust, Recyclable, and Self-Healing Polyimine Networks.

To achieve energy saving and emission reduction goals, recyclable and healable thermoset materials are highly attractive. Polymer copolymerization has been proven to be a critical strategy for preparing high-performance polymeric materials. However, it remains a huge challenge to develop high-performance recyclable and healable thermoset materials. Here, polyimine dynamic networks based on two monomers with bulky pendant groups, which not only displayed mechanical properties higher than the strong and tough polymers, e.g., polycarbonate, but also excellent self-repairing capability and recyclability as thermosets are developed. Owing to the stability of conjugation effect by aromatic benzene rings, the final polyimine networks are far more stable than the reported counterparts, exhibiting excellent hydrolysis resistance under both alkaline condition and most organic solvents. These polyimine materials with conjugation structure can be completely depolymerized into monomers recovery in an acidic aqueous solution at ambient temperature. Resulting from the bulky pendant units, this method allows the exchange reactions of conjugation polyimine vitrimer easily within minutes for self-healing function. Moreover, the introduction of trifluoromethyl diphenoxybenzene backbones significantly increases tensile properties of polyimine materials. This work provides an effective strategy for fabricating high-performance polymer materials with multiple functions.

Decreased platelet miR-199a-5p level might lead to high on-clopidogrel platelet reactivity in patients with coronary artery disease.

Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment. Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy. Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway. This study aimed to investigate the association between platelet miRNA levels and clopidogrel efficacy. Here we recruited 508 CAD patients who underwent clopidogrel antiplatelet therapy and determined the platelet reactivity index (PRI) to evaluate antiplatelet reactivity responses to clopidogrel. Subsequently, 22 patients with extreme clopidogrel response were selected for platelet small RNA sequencing. Another 41 CAD patients taking clopidogrel were collected to verify the differentially expressed candidate miRNAs. We found the metabolic types of the CYP2C19 enzyme (based on CYP2C19 * 2 and * 3 polymorphisms) could significantly affect the PRI of CAD patients with or without percutaneous coronary intervention (PCI) in Chinese. A total of 43 miRNAs were differentially expressed in the platelets from the 22 extreme clopidogrel response samples, and 109 miRNAs were differentially expressed in the 13 CYP2C19 extensive metabolizers with extreme clopidogrel response. Platelet miR-199a-5p levels were correlated negatively with PRI after clopidogrel therapy. Studies in cultured cells revealed that miR-199a-5p inhibited the expression of VASP, a key effector protein downstream of the P2Y12 receptor. In conclusion, we found the expression of VASP could be inhibited by miR-199a-5p, and decreased platelet miR-199a-5p was associated with high on-clopidogrel platelet reactivity in CAD patients.

What is the context?● Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment.● Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy.● Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway.What is new?● We found that decreased platelet miR-199a-5p level was associated with high on-clopidogrel platelet reactivity.● Overexpression of miR-199a-5p significantly down-regulated the expression of VASP protein in cultured cells.What is the impact?● The current study provided new insights into the exploration of interindividual variability in clopidogrel response from the perspective of miR-199a-5p and VASP interaction.

Serum glycolipids mediate the relationship of urinary bisphenols with NAFLD: analysis of a population-based, cross-sectional study.

BACKGROUND: Bisphenol A (BPA) and its substitutes bisphenol S (BPS) and bisphenol F (BPF) are endocrine-disrupting chemicals widely used in consumer products, which have been proposed to induce various human diseases. In western countries, one of the most common liver diseases is non-alcoholic fatty liver disease (NAFLD). However, studies on the associations of the three bisphenols with NAFLD in human beings are scarce. METHODS: We included 960 participants aged ≥ 20 years from the NHANES 2013-16 who had available data on levels of urinary BPA, BPS and BPF. The hepatic steatosis index (HSI) > 36 was used to predict NAFLD. Logistic regression analysis and mediation effect analysis were used to evaluate the associations among bisphenols, glycolipid-related markers and NAFLD. RESULTS: A total of 540 individuals (56.3%) were diagnosed with NAFLD, who had higher concentrations of BPA and BPS but not BPF than those without NAFLD. An increasing trend in NAFLD risks and HSI levels was observed among BPA and BPS tertiles (p for trend < 0.05). After adjustment for confounders, elevated levels of BPA or BPS but not BPF were significantly associated with NAFLD. The odds ratio for NAFLD was 1.581 (95% confidence intervals [CI]: 1.1-2.274, p = 0.013) comparing the highest with the lowest tertile of BPA and 1.799 (95%CI: 1.2462.597, p = 0.002) for BPS. Mediation effect analysis indicated that serum high-density lipoprotein cholesterol and glucose had a mediating effect on the relationships between bisphenols and NAFLD. CONCLUSIONS: The present study showed that high exposure levels of BPA and BPS increased NAFLD incidence, which might be mediated through regulating glycolipids metabolism. Further studies on the role of bisphenols in NAFLD are warranted.

A new machine learning algorithm with high interpretability for improving the safety and efficiency of thrombolysis for stroke patients: A hospital-based pilot study.

Background: Thrombolysis is the first-line treatment for patients with acute ischemic stroke. Previous studies leveraged machine learning to assist neurologists in selecting patients who could benefit the most from thrombolysis. However, when designing the algorithm, most of the previous algorithms traded interpretability for predictive power, making the algorithms hard to be trusted by neurologists and be used in real clinical practice. Methods: Our proposed algorithm is an advanced version of classical k-nearest neighbors classification algorithm (KNN). We achieved high interpretability by changing the isotropy in feature space of classical KNN. We leveraged a cohort of 189 patients to prove that our algorithm maintains the interpretability of previous models while in the meantime improving the predictive power when compared with the existing algorithms. The predictive powers of models were assessed by area under the receiver operating characteristic curve (AUC). Results: In terms of interpretability, only onset time, diabetes, and baseline National Institutes of Health Stroke Scale (NIHSS) were statistically significant and their contributions to the final prediction were forced to be proportional to their feature importance values by the rescaling formula we defined. In terms of predictive power, our advanced KNN (AUC 0.88) outperformed the classical KNN (AUC 0.75, p = 0.0192 ). Conclusions: Our preliminary results show that the advanced KNN achieved high AUC and identified consistent significant clinical features as previous clinical trials/observational studies did. This model shows the potential to assist in thrombolysis patient selection for improving the successful rate of thrombolysis.

Changes of plasma Rap1A levels in patients with in-stent restenosis after percutaneous coronary intervention and the underlying mechanisms. / ç»çš®å† çŠ¶åŠ¨è„‰ä»‹å ¥æ²»ç–—æœ¯åŽæ”¯æž¶å† å†ç‹­çª„æ‚£è€ è¡€æµ†Rap1Aæ°´å¹³å˜åŒ–åŠå ¶æœºåˆ¶ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Percutaneous coronary intervention (PCI) is one of the most important treatments for coronary artery disease (CAD). However, in-stent restenosis (ISR) after PCI is a serious complication without effective measures for prevention and treatment. This study aims to investigate the Ras-related protein 1A (Rap1A) level in ISR patients and in the tumor necrosis factor-α (TNF-α)-induced inflammatory injury model of human umbilical vein endothelial cells (HUVECs), to explore the role of Rap1A in regulating TNF-α-induced inflammation in HUVECs and to provide a new potential target for ISR prevention and treatment. METHODS: A total of 60 CAD patients, who underwent PCI between December 2020 and July 2022 from the Department of Cardiovascular Medicine of Xiangya Hospital, Central South University, and re-examined coronary angiography (CAG) 1 year after the operation, were included. After admission, 27 patients were diagnosed with ISR and 33 patients were diagnosed with non-in-stent restenosis (non-ISR) according to the CAG. Clinical data were collected, and the plasma Rap1A level was determined by enzyme linked immunosorbent assay (ELISA). In cell experiments, an inflammatory injury model was established with TNF-α treatment (10 ng/mL, 24 h) in HUVECs. The mRNA and protein expression levels of Rap1A, interlukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1) were measured by real-time reverse transcription PCR and Western blotting. Small interfering RNA (siRNA) was used to explore the role of Rap1A in regulating TNF-α-induced inflammation in HUVECs. RESULTS: Compared with the non-ISR patients, a higher proportion of ISR patients had a history of smoking (P=0.005) and diabetes (P=0.028), and higher levels of glycosylated hemoglobin (HbA1c) (P=0.012), low-density lipoprotein cholesterol (LDL-c) (P=0.014), and hypersensitive C-reactive protein (hs-CRP) (P=0.027). The remaining projects did not show significant differences (all P>0.05). The plasma level of Rap1A in the ISR group was significantly higher than that in the non-ISR group [942.14 (873.28 to 1 133.81) µg/mL vs 886.93 (812.61 to 930.98) µg/mL; P=0.004]. Diabetes, LDL-c, and Rap1A were risk factors for ISR by univariate logistic regression analysis (all P<0.05). The mRNA and protein expression levels of inflammatory factors IL-6 and VCAM-1 were increased in HUVECs after 10 ng/mL TNF-α treatment for 24 h compared with the control group (all P<0.05), while the mRNA and protein levels of Rap1A were increased (both P<0.05). After inhibition of Rap1A in HUVECs, the mRNA and protein expression levels of IL-6 and VCAM-1 were significantly decreased (all P<0.05). CONCLUSIONS: The plasma Rap1A level was significantly elevated in patients with ISR, suggesting that Rap1A may be a potential biomarker for predicting ISR. In the TNF-α- induced HUVECs inflammatory injury model, the expression level of Rap1A was increased. The level of TNF-α-induced endothelial cell inflammation was decreased after inhibition of Rap1A expression, suggesting that Rap1A may be a potential target for the treatment of endothelial cell inflammation in ISR.

Identification of PFKFB2 as a key gene for the transition from acute to old myocardial infarction in peripheral blood.

Objective: This study aims to analyze the gene expression profile of peripheral blood in different stages of myocardial infarction (MI) by transcriptome sequencing, and to study the gene expression characteristics of peripheral blood after MI. Methods: Differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were used to identify genes and modules associated with old myocardial infarction (OMI). Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation were applied to analyze the potential functions of genes. Hub genes were identified by Random Forest Classifier. CIBERSORT was used to provide an estimate of the abundance of 22 immune cells in peripheral blood. Quantitative polymerase chain reaction (qPCR) was used to detect gene expression levels in clinical samples. The cellular components (CC) of peripheral blood were counted by an automatic hematology analyzer. Results: Through differential gene analysis and co-expression network analysis, 11 candidate genes were obtained. A random forest classifier identified 10 hub genes. Immune cell distribution of peripheral blood was found that T cell CD4 memory resting, NK cells resting, Dendritic cells activated, Mast cells resting, Monocytes and Neutrophils were correlated with OMI. Spearman correlation analysis found that PFKFB2 is related to the above immune cells. Low expression of PFKFB2 in peripheral blood of OMI was detected in clinical samples, and the relationship between PFKFB2 and peripheral blood immune cell counts was analyzed, which showed monocytes were associated with PFKFB2 in our study. Conclusion: PFKFB2 was low expressed in OMI, and related to the distribution of immune cells. PFKFB2 may play a key role in reflecting the transition from AMI to OMI, and predicting the distribution of immune cells, which provided a new perspective for improving myocardial fibrosis and adverse remodeling.

Influence of genetic polymorphisms in P2Y12 receptor signaling pathway on antiplatelet response to clopidogrel in coronary heart disease.

BACKGROUNDS: Remarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients. METHODS: 539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12-24 h after clopidogrel loading dose or within 5-7 days after initiation of maintain dose clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients). RESULTS: CYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699C > A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P = 0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A + B). CONCLUSION: Our data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms.

The feasibility and accuracy of machine learning in improving safety and efficiency of thrombolysis for patients with stroke: Literature review and proposed improvements.

In the treatment of ischemic stroke, timely and efficient recanalization of occluded brain arteries can successfully salvage the ischemic brain. Thrombolysis is the first-line treatment for ischemic stroke. Machine learning models have the potential to select patients who could benefit the most from thrombolysis. In this study, we identified 29 related previous machine learning models, reviewed the models on the accuracy and feasibility, and proposed corresponding improvements. Regarding accuracy, lack of long-term outcome, treatment option consideration, and advanced radiological features were found in many previous studies in terms of model conceptualization. Regarding interpretability, most of the previous models chose restrictive models for high interpretability and did not mention processing time consideration. In the future, model conceptualization could be improved based on comprehensive neurological domain knowledge and feasibility needs to be achieved by elaborate computer science algorithms to increase the interpretability of flexible algorithms and shorten the processing time of the pipeline interpreting medical images.

Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a metabolically perturbed pathological condition. However, the knowledge of metabolic signatures on outcomes of CAD and their potential causal effects and impacts on left ventricular remodeling remains limited. We aim to assess the contribution of plasma metabolites to the risk of death and major adverse cardiovascular events (MACE) as well as left ventricular remodeling. RESULTS: In a prospective study with 1606 Chinese patients with CAD, we have identified and validated several independent metabolic signatures through widely-targeted metabolomics. The predictive model respectively integrating four metabolic signatures (dulcitol, ß-pseudouridine, 3,3',5-Triiodo-L-thyronine, and kynurenine) for death (AUC of 83.7% vs. 76.6%, positive IDI of 0.096) and metabolic signatures (kynurenine, lysoPC 20:2, 5-methyluridine, and L-tryptophan) for MACE (AUC of 67.4% vs. 59.8%, IDI of 0.068) yielded better predictive value than trimethylamine N-oxide plus clinical model, which were successfully applied to predict patients with high risks of death (P = 0.0014) and MACE (P = 0.0008) in the multicenter validation cohort. Mendelian randomisation analysis showed that 11 genetically inferred metabolic signatures were significantly associated with risks of death or MACE, such as 4-acetamidobutyric acid, phenylacetyl-L-glutamine, tryptophan metabolites (kynurenine, kynurenic acid), and modified nucleosides (ß-pseudouridine, 2-(dimethylamino) guanosine). Mediation analyses show that the association of these metabolites with the outcomes could be partly explained by their roles in promoting left ventricular dysfunction. CONCLUSIONS: This study provided new insights into the relationship between plasma metabolites and clinical outcomes and its intermediate pathological process left ventricular dysfunction in CAD. The predictive model integrating metabolites can help to improve the risk stratification for death and MACE in CAD. The metabolic signatures appear to increase death or MACE risks partly by promoting adverse left ventricular dysfunction, supporting potential therapeutic targets of CAD for further investigation.

Graphene-integrated toroidal resonance metasurfaces used for picogram-level detection of chlorothalonil in the terahertz region.

Toroidal dipole resonance can significantly reduce radiation loss of materials, potentially improving sensor sensitivity. Generally, toroidal dipole response is suppressed by electric and magnetic dipoles in natural materials, making it difficult to observe experimentally. However, as 2D metamaterials, metasurfaces can weaken the electric and magnetic dipole, enhancing toroidal dipole response. Here, we propose a new graphene-integrated toroidal resonance metasurface as an ultra-sensitive chemical sensor, capable of qualitative detection of chlorothalonil in the terahertz region, down to a detection limit of 100 pg/mL. Our results demonstrate graphene-integrated toroidal resonance metasurfaces as a promising basis for ultra-sensitive, qualitative detection in chemical and biological sensing.

APOE interacts with ACE2 inhibiting SARS-CoV-2 cellular entry and inflammation in COVID-19 patients.

Apolipoprotein E (APOE) plays a pivotal role in lipid including cholesterol metabolism. The APOE ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases. Although APOE has recently been associated with increased susceptibility to infections of several viruses, whether and how APOE and its isoforms affect SARS-CoV-2 infection remains unclear. Here, we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients. Utilizing multiple protein interaction assays, we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2; and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2, a key docking site for SARS-CoV-2 Spike protein. In addition, immuno-imaging assays using confocal, super-resolution, and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spike-mediated viral entry into cells. Interestingly, while having a comparable binding affinity to ACE2, APOE4 inhibits viral entry to a lesser extent compared to APOE3, which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2. Furthermore, APOE ε4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed. Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2, which may explain in part increased COVID-19 infection and disease severity in APOE ε4 carriers.

Levels of plasma Quaking and cyclooxygenase-2 predict in-stent restenosis in patients with coronary artery disease after percutaneous coronary intervention. / 血浆Quakingå’ŒçŽ¯æ°§åˆé ¶-2æ°´å¹³é¢„æµ‹å† å¿ƒç— æ‚£è€ è¡Œç»çš®å† çŠ¶åŠ¨è„‰ä»‹å ¥æœ¯åŽæ”¯æž¶å† å†ç‹­çª„.

OBJECTIVES: Percutaneous coronary intervention (PCI) is one of the important methods for the treatment of coronary artery disease (CAD). In-sent restenosis (ISR) after PCI for patients suffered from CAD is considered to be an essential factor affecting long-term outcomes and prognosis of this disease. This study aims to investigate the correlation between plasma Quaking (QKI) and cyclooxygenase-2 (COX-2) levels and ISR in patients with CAD. METHODS: A total of 218 consecutive CAD patients who underwent coronary angiography and coronary arterial stenting from September 2019 to September 2020 in the Department of Cardiology of Xiangya Hospital of Central South University were enrolled in this study, and 35 matched individuals from the physical examination center were served as a control group. After admission, clinical data of these 2 groups were collected. Plasma QKI and COX-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Follow-up angiography was performed 12 months after PCI. CAD patients were divided into a NISR group (n=160) and an ISR group (n=58) according to the occurrence of ISR based on the coronary angiography. The clinical data, coronary angiography, and stent features between the NISR group and the ISR group were compared, and multivariate logistic regression was used to explore the factors influencing ISR. The occurrence of major adverse cardiovascular events (MACE) 1 year after operation was recorded. Fifty-eight patients with ISR were divided into an MACE group (n=24) and a non-MACE group (n=34), classified according to the occurrence of MACE, and the plasma levels of QKI and COX-2 were compared between the 2 groups. Receiver operating characteristic (ROC) curves were utilized to analyze the diagnostic value of plamsa levels of QKI and COX-2 for ISR and MACE occurrences in patients after PCI. RESULTS: Compared with control group, plasma levels of QKI and COX-2 in the CAD group decreased significantly (all P<0.001). Compared with the NISR group, the plasma levels of QKI and COX-2 also decreased obviously in the ISR group (all P<0.001), while the levels of high sensitivity C-reactive protein (hs-CRP) and glycosylated hemoglobin (HbAlc) significantly increased (all P<0.001). The level of COX-2 was negatively correlated with hs-CRP (r=-0.385, P=0.003). Multivariate logistic regression analysis showed that high level of plasma QKI and COX-2 were protective factors for in-stent restenosis after PCI, while hs-CRP was a risk factor. ROC curve analysis showed that the sensitivity and specificity of plasma QKI for evaluating the predictive value of ISR were 77.5% and 66.5%, respectively, and the sensitivity and specificity of plasma COX-2 for evaluating the predictive value of ISR were 80.0% and 70.7%, respectively. The sensitivity and specificity of plasma QKI combined with COX-2 for evaluating the predictive value of ISR were 81.3% and 74.1%, respectively. The sensitivity and specificity of plasma QKI for evaluating the prognosis of ISR were 75.0% and 64.7%, respectively. The sensitivity and specificity of plasma COX-2 for evaluating the prognosis of ISR were 75.0% and 70.6%, respectively. The sensitivity and specificity of plasma QKI combined with COX-2 for prognostic evaluation of ISR were 81.7% and 79.4%, respectively. The sensitivity and specificity of plasma COX-2 combined with QKI for evaluating ISR and MACE occurrences in patients after PCI were better than those of COX-2 or QKI alone (P<0.001). CONCLUSIONS: High level of plasma QKI and COX-2 might be a protective factor for ISR, which can also predict ISR patient's prognosis.