Impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease patients complicated with end-stage renal disease.

It is controversial whether hemodialysis affects the efficacy of the antiplatelet agents. We aimed to investigate the impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease (CAD) patients complicated with end-stage renal disease (ESRD). 86 CAD patients complicated with ESRD requiring hemodialysis were consecutively enrolled. After 5-day treatment with aspirin and clopidogrel or ticagrelor, the platelet aggregations induced by arachidonic acid (PLAA) or adenosine diphosphate (PLADP), and the P2Y12 reaction unit (PRU) were measured before and after hemodialysis. The propensity matching score method was adopted to generate a control group with normal renal function from 2439 CAD patients. In patients taking aspirin, the PLAA remained unchanged after hemodialysis. In patients taking clopidogrel, the PLADP (37.26 ± 17.04 vs. 31.77 ± 16.09, p = 0.029) and corresponding clopidogrel resistance (CR) rate (23 [48.9%] vs. 14 [29.8%], p = 0.022) significantly decreased after hemodialysis, though PRU remained unchanged. Subgroup analysis indicated that PLADP significantly decreased while using polysulfone membrane (36.8 ± 17.9 vs. 31.1 ± 14.5, p = 0.024). In patients taking ticagrelor, PLADP, and PRU remained unchanged after hemodialysis. ESRD patients had higher incidences of aspirin resistance (AR) and CR compared to those with normal renal function (AR: 16.1% vs. 0%, p = 0.001; CR: 48.4% vs. 24.8%, p = 0.024). Hemodialysis does not have negative effect on the efficacies of aspirin, clopidogrel and ticagrelor in ESRD patients with CAD. ESRD patients have higher incidences of AR and CR compared with those with normal renal function.Trial registration ClinicalTrials.gov Identifier: NCT03330223, first registered January 4, 2018.

A Predictive Model for Endometrial Carcinoma Based on Hysteroscopic Data.

Objective: The purpose is to establish a model to predict endometrial carcinoma and assess its value in the preliminary diagnosis of endometrial carcinoma. Methods: The data of 381 patients undergoing hysteroscopy were incorporated into the model, including 282 cases in the training cohort and 99 cases in the validation cohort. Significant morphological indexes were selected using the chi-square test and subjected to the binary logistic regression analysis. Besides, the scoring interval was set, and the nomogram of the prediction model was established. Model calibration curves were drawn using the data from the validation cohort. The study was approved by the Ethics Committee of the Affiliated Sir Run Run Hospital of Nanjing Medical University, and written informed consent was obtained from the patients. Results: The sensitivity, specificity, positive predictive value, and negative predictive value of the model were 96.7%, 92.3%, 77.3%, and 99.0%, respectively. Analysis of the receiver operating characteristic curve in the training cohort showed an area under the curve of 0.984 (95% CI: 0.974-0.995). The receiver operating characteristic curve in the validation cohort revealed an area under the curve of 0.976 (95% CI: 0.950-1.000). The calibration curve indicated that the probability in the actual setting was consistent with that predicted by the nomogram in the training cohort. Conclusion: Our model has high sensitivity and specificity in predicting endometrial carcinoma, and helps clinicians to make accurate diagnosis.

Diagnostic Performance and Safety of a Novel Ferumoxytol-Enhanced Coronary Magnetic Resonance Angiography.

BACKGROUND: Currently, noninvasive arteriography for the diagnosis of coronary artery disease is clinically limited to the computed tomography scanning, where patients have to be exposed to the radiation and risks associated with iodinated contrast. We aimed to investigate the diagnostic performance and safety of a novel ferumoxytol-enhanced coronary magnetic resonance angiography (CMRA) in patients with suspected coronary artery disease. METHODS: Thirty patients, 19 males, with a median age of 63 years old, and 17 with renal insufficiency, who were scheduled for invasive coronary angiography, were enrolled. Ferumoxytol was administered intravenously with a dose of 3 mg/kg during CMRA. Images were acquired with an ECG-triggered, navigator-gated, inversion recovery-prepared 3D fast low-angle shot sequence, and the image quality was assessed by a 4-point scale. Eighteen-segment coronary artery model was adopted to evaluate the visibility of the coronary arteries, and the image quality and stenosis were evaluated in nine segments. The diagnostic performance of CMRA is described as sensitivity, specificity, positive and negative predictive values, and accuracy with the invasive coronary angiography results as reference. The patients' vital signs were monitored during CMRA, and their hepatic and renal functions were followed up for 3 months to evaluate the safety of ferumoxytol. RESULTS: Two hundred fifty-two of the 270 study segments were identified by CMRA, and their quality score reached 3.6±0.7. Referring to the invasive coronary angiography results, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ferumoxytol-enhanced CMRA reached 100.0%, 66.7%, 92.3%, 100.0%, and 93.3% respectively in patient-based analysis; 91.4%, 90.9%, 86.5%, 94.3%, and 91.1%, respectively in vessel-based analysis; and 92.3%, 96.7%, 83.7%, 98.6%, and 96.0%, respectively in segment-based analysis. No ferumoxytol-related adverse event was observed during the 3-month follow-up. CONCLUSIONS: Ferumoxytol-enhanced CMRA demonstrated good diagnostic performance and excellent safety in the diagnosis of significant coronary stenosis, providing an alternative to coronary computed tomography angiography for the diagnosis of coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05032937.

Stub1 ameliorates ER stress-induced neural cell apoptosis and promotes locomotor recovery through restoring autophagy flux after spinal cord injury.

Endoplasmic reticulum (ER) stress-induced apoptosis and autophagy flux blockade significantly contribute to neuronal pathology of spinal cord injury (SCI). Yet, the molecular interplay between these two distinctive pathways in mediating the pathology of SCI remains largely unexplored. Currently, we aimed at exploring the crucial role of Stub1 in maintaining ER homeostasis and regulating autophagic flux after SCI. Our results demonstrate that Stub1 reduces ER stress induced neuronal apoptosis, promotes axonal regeneration, inhibits glial scar formation and fosters functional recovery by restoring autophagic flux following SCI. Stub1 enhances autophagic flux following SCI by alleviating the permeabilization of lysosomal membrane through activating TFEB. Importantly, we showed that Stub1 promotes the activation of TFEB by targeting HDAC2 for ubiquitination and degradation. Furthermore, the neuroprotective effect of Stub1 on SCI was abrogated by chloroquine administration, underscoring the essential role of Stub1-mediated enhancement of autophagic flux in its protective effects against SCI. Collectively, our data highlights the vital role of Stub1 in regulating ER stress and autophagy flux after SCI, and propose its potential as a promising target for neuroprotective interventions in SCI.

Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.

Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.

Association between soft drink consumption types and risk of lung cancer and all-cancer: A prospective study of PLCO data.

Diet/sugar-free soft drinks are considered to be healthier than regular soft drinks. However, few studies have examined the relationship between the types of soft drinks (regular and diet/sugar-free) and lung cancer (LC)/all-cancer (AC) risk. In this study, we comprehensively assessed the influence of the type of soft drink consumption on LC/AC risk based on the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Multivariable Cox proportional hazards and competing risks Fine-Gray regression models adjusted for relevant confounders were used to estimate hazard ratios (HRs) and subdistribution HRs for different types of soft drink consumption. In the PLCO population, female subgroup, and the ever/current smoker subgroup, consumption of both regular and diet soft drinks was associated with a significantly reduced risk of LC compared with no soft drinks at all. For the non-lung cancer (NLC) risk, consumption of only diet soft drinks had a significant positive association for the total population and female subgroup. Based on our findings, it was suggested that partial replacement of regular soft drinks with diet soft drinks might be beneficial to LC prevention, especially for females and ever/current smokers. Additionally, completely replacing regular soft drinks with diet soft drinks might be detrimental to NLC prevention, especially for females.

Effects of ilaprazole on the steady-state pharmacodynamics of clopidogrel in healthy volunteers: An open-label randomized crossover study.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel. Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 µmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing. Results: IPA was comparable between the two regimens at 0, 10 and 24 h (p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens. Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant. Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2000031482].

Metabolic Obesity Phenotypes and Risk of Lung Cancer: A Prospective Cohort Study of 450,482 UK Biobank Participants.

(1) Background: The association between metabolic obesity phenotypes and incident lung cancer (LC) remains unclear. (2) Methods: Based on the combination of baseline BMI categories and metabolic health status, participants were categorized into eight groups: metabolically healthy underweight (MHUW), metabolically unhealthy underweight (MUUW), metabolically healthy normal (MHN), metabolically unhealthy normal (MUN), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). The Cox proportional hazards model and Mendelian randomization (MR) were applied to assess the association between metabolic obesity phenotypes with LC risk. (3) Results: During a median follow-up of 9.1 years, 3654 incident LC patients were confirmed among 450,482 individuals. Compared with participants with MHN, those with MUUW had higher rates of incident LC (hazard ratio (HR) = 3.24, 95% confidence interval (CI) = 1.33-7.87, p = 0.009). MHO and MHOW individuals had a 24% and 18% lower risk of developing LC, respectively (MHO: HR = 0.76, 95% CI = 0.61-0.95, p = 0.02; MHO: HR = 0.82, 95% CI = 0.70-0.96, p = 0.02). No genetic association of metabolic obesity phenotypes and LC risk was observed in MR analysis. (4) Conclusions: In this prospective cohort study, individuals with MHOW and MHO phenotypes were at a lower risk and MUUW were at a higher risk of LC. However, MR failed to reveal any evidence that metabolic obesity phenotypes would be associated with a higher risk of LC.

Impact of Insulin Receptor Substrate-1 rs956115 and CYP2C19 rs4244285 Genotypes on Clinical Outcome of Patients Undergoing Percutaneous Coronary Intervention.

Background Insulin receptor substrate-1 (IRS-1) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS-1, CYP2C19*2 genotypes, platelet reactivity, and 1-year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention. Methods and Results Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS-1 CG genotype had significantly lower levels of ADP-induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS-1 CG or GG genotype had a 2.09-fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04-4.19; P=0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP-induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19-fold higher risk than those with GG homozygotes (95% CI, 1.13-4.24; P=0.0200). No interaction between IRS-1 and CYP2C19*2 genotypes was observed. Conclusions In patients following percutaneous coronary intervention, IRS-1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09- and 2.19-fold increased cardiovascular risk, respectively, at 1-year follow-up. The association between IRS-1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01968499.

IPRS: Leveraging Gene-Environment Interaction to Reconstruct Polygenic Risk Score.

Background: Polygenic risk score (PRS) is widely regarded as a predictor of genetic susceptibility to disease, applied to individuals to predict the risk of disease occurrence. When the gene-environment (G×E) interaction is considered, the traditional PRS prediction model directly uses PRS to interact with the environment without considering the interactions between each variant and environment, which may lead to prediction performance and risk stratification of complex diseases are not promising. Methods: We developed a method called interaction PRS (iPRS), reconstructing PRS by leveraging G×E interactions. Two extensive simulations evaluated prediction performance, risk stratification, and calibration performance of the iPRS prediction model, and compared it with the traditional PRS prediction model. Real data analysis was performed using existing data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial study to predict genetic susceptibility, pack-years of smoking history, and G×E interactions in patients with lung cancer. Results: Two extensive simulations indicated iPRS prediction model could improve the prediction performance of disease risk, the accuracy of risk stratification, and clinical calibration performance compared with the traditional PRS prediction model, especially when antagonism accounted for the majority of the interaction. PLCO real data analysis also suggested that the iPRS prediction model was superior to the PRS prediction model in predictive effect (p = 0.0205). Conclusion: IPRS prediction model could have a good application prospect in predicting disease risk, optimizing the screening of high-risk populations, and improving the clinical benefits of preventive interventions among populations.

Prediction of acute kidney injury after cardiac surgery: model development using a Chinese electronic health record dataset.

BACKGROUND: Acute kidney injury (AKI) is a major complication following cardiac surgery that substantially increases morbidity and mortality. Current diagnostic guidelines based on elevated serum creatinine and/or the presence of oliguria potentially delay its diagnosis. We presented a series of models for predicting AKI after cardiac surgery based on electronic health record data. METHODS: We enrolled 1457 adult patients who underwent cardiac surgery at Nanjing First Hospital from January 2017 to June 2019. 193 clinical features, including demographic characteristics, comorbidities and hospital evaluation, laboratory test, medication, and surgical information, were available for each patient. The number of important variables was determined using the sliding windows sequential forward feature selection technique (SWSFS). The following model development methods were introduced: extreme gradient boosting (XGBoost), random forest (RF), deep forest (DF), and logistic regression. Model performance was accessed using the area under the receiver operating characteristic curve (AUROC). We additionally applied SHapley Additive exPlanation (SHAP) values to explain the RF model. AKI was defined according to Kidney Disease Improving Global Outcomes guidelines. RESULTS: In the discovery set, SWSFS identified 16 important variables. The top 5 variables in the RF importance matrix plot were central venous pressure, intraoperative urine output, hemoglobin, serum potassium, and lactic dehydrogenase. In the validation set, the DF model exhibited the highest AUROC (0.881, 95% confidence interval [CI] 0.831-0.930), followed by RF (0.872, 95% CI 0.820-0.923) and XGBoost (0.857, 95% CI 0.802-0.912). A nomogram model was constructed based on intraoperative longitudinal features, achieving an AUROC of 0.824 (95% CI 0.763-0.885) in the validation set. The SHAP values successfully illustrated the positive or negative contribution of the 16 variables attributed to the output of the RF model and the individual variable's effect on model prediction. CONCLUSIONS: Our study identified 16 important predictors and provided a series of prediction models to enhance risk stratification of AKI after cardiac surgery. These novel predictors might aid in choosing proper preventive and therapeutic strategies in the perioperative management of AKI patients.