Outcomes of non-vitamin K oral anticoagulants for secondary prevention in ischemic stroke with atrial fibrillation.

Previous studies have rarely investigated the role of non-vitamin K oral anticoagulants (NOAC) and warfarin in the secondary prevention of ischemic stroke patients with nonvalvular atrial fibrillation (NVAF). In this study, we compared the effectiveness and safety of NOAC and warfarin for secondary prevention in Korean ischemic stroke patients with NVAF. Based on the Korean National Health Insurance Service Database, this study included 21,064 oral anticoagulants-naïve acute ischemic stroke patients with NVAF between July 2015 and June 2019. The main study outcomes included ischemic stroke, systemic embolism, major bleeding, and death. During the observational periods, NOAC users had a significantly decreased risk of ischemic stroke + systemic embolism (adjusted hazard ratio [aHR] 0.86; 95% confidence interval [CI] 0.78-0.95), ischemic stroke (aHR 0.89; 95% CI 0.81-0.99), major bleeding (aHR 0.78; 95% CI 0.68-0.89), and all-cause death (aHR 0.87; 95% CI 0.81-0.93). Standard-dose NOAC users had a lower risk of ischemic stroke, systemic embolism, and major bleeding events than warfarin users. In contrast, low-dose NOAC users did not differ in risk from warfarin users for all outcomes. In conclusion, NOACs were associated with a lower risk of secondary thromboembolic events and bleeding complications in Korean ischemic stroke patients with NVAF than warfarin.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

The landscape of PBMC methylome in canine mammary tumors reveals the epigenetic regulation of immune marker genes and its potential application in predicting tumor malignancy.

BACKGROUND: Genome-wide dysregulation of CpG methylation accompanies tumor progression and characteristic states of cancer cells, prompting a rationale for biomarker development. Understanding how the archetypic epigenetic modification determines systemic contributions of immune cell types is the key to further clinical benefits. RESULTS: In this study, we characterized the differential DNA methylome landscapes of peripheral blood mononuclear cells (PBMCs) from 76 canines using methylated CpG-binding domain sequencing (MBD-seq). Through gene set enrichment analysis, we discovered that genes involved in the growth and differentiation of T- and B-cells are highly methylated in tumor PBMCs. We also revealed the increased methylation at single CpG resolution and reversed expression in representative marker genes regulating immune cell proliferation (BACH2, SH2D1A, TXK, UHRF1). Furthermore, we utilized the PBMC methylome to effectively differentiate between benign and malignant tumors and the presence of mammary gland tumors through a machine-learning approach. CONCLUSIONS: This research contributes to a better knowledge of the comprehensive epigenetic regulation of circulating immune cells responding to tumors and suggests a new framework for identifying benign and malignant cancers using genome-wide methylome.

Effectiveness and safety of secondary prevention of non-vitamin K oral anticoagulants use by drug type in Asian patients.

BACKGROUND: Although widely used in clinical fields, real-world data on the role of warfarin and non-vitamin K oral anticoagulants (NOACs) for the secondary prevention of thromboembolic complications in ischemic stroke patients with nonvalvular atrial fibrillation (NVAF) are scarce. AIMS: This retrospective cohort study compared the effectiveness and safety of secondary prevention of NOAC and warfarin in ischemic stroke patients with NVAF. METHODS: From the Korean National Health Insurance Service Database, we included 16,762 oral anticoagulants-naive acute ischemic stroke patients with NVAF between July 2016 and June 2019. The main outcomes included ischemic stroke, systemic embolism, major bleeding, and all-cause of death. RESULTS: In total, 1717 warfarin and 15,025 NOAC users were included in the analysis. After 1:8 propensity score matching, during the observation period, all types of NOACs had a significantly lower risk of ischemic stroke and systemic embolism than warfarin (edoxaban: adjusted hazard ratio [aHR], 0.80; 95% confidence interval [CI], 0.68-0.93, rivaroxaban: aHR, 0.82; 95% CI, 0.70-0.96, apixaban: aHR, 0.79; 95% CI, 0.69-0.91, and dabigatran: aHR, 0.82; 95% CI, 0.69-0.97). Edoxaban (aHR, 0.77; 95% CI, 0.62-0.96), apixaban (aHR, 0.73; 95% CI, 0.60-0.90), and dabigatran (aHR, 0.66; 95% CI, 0.51-0.86) had lower risks of major bleeding and all-cause of death. CONCLUSIONS: All NOACs were more effective than warfarin in the secondary prevention of thromboembolic complications in ischemic stroke patients with NVAF. Except for rivaroxaban, most NOACs demonstrated a lower risk of major bleeding and all-cause of death than warfarin.

Different therapeutic associations of renin-angiotensin system inhibitors with coronavirus disease 2019 compared with usual pneumonia.

BACKGROUND/AIMS: Although it is near concluded that renin-angiotensin system inhibitors do not have a harmful effect on coronavirus disease 2019 (COVID-19), there is no report about whether angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) offer any protective role. This study aimed to compare the association of ARBs and ACEIs with COVID-19-related mortality. METHODS: All patients with COVID-19 in Korea between January 19 and April 16, 2020 were enrolled. The association of ARBs and ACEIs with mortality within 60 days were evaluated. A comparison of hazard ratio (HR) was performed between COVID-19 patients and a retrospective cohort of pneumonia patients hospitalized in 2019 in Korea. RESULTS: Among 10,448 COVID-19 patients, ARBs and ACEIs were prescribed in 1,231 (11.7%) and 57 (0.6%) patients, respectively. After adjusting for age, sex, and history of comorbidities, the ARB group showed neutral association (HR, 1.034; 95% CI, 0.765 to 1.399; p = 0.8270) and the ACEI groups showed no significant associations likely owing to the small population size (HR, 0.736; 95% CI, 0.314 to 1.726; p = 0.4810). When comparing HR between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia in 2019, the trend of ACEIs showed similar benefits, whereas the protective effect of ARBs observed in the retrospective cohort was absent in COVID-19 patients. Meta-analyses showed significant positive correlation with survival of ACEIs, whereas a neutral association between ARBs and mortality. CONCLUSION: Although ARBs or ACEIs were not associated with fatal outcomes, potential beneficial effects of ARBs observed in pneumonia were attenuated in COVID-19.

Beneficial Effect of Statins in COVID-19-Related Outcomes-Brief Report: A National Population-Based Cohort Study.

OBJECTIVE: Although statins are widely prescribed lipid-lowering drugs, there are concerns about the safety of their use in the context of coronavirus disease 2019 (COVID-19), since statins increase the expression of ACE2 (angiotensin-converting enzyme 2). This study aimed to disclose the association between statins and 60-day COVID-19 mortality. Approach and Results: All patients hospitalized with laboratory-confirmed COVID-19 were enrolled in this study from January 19 to April 16, 2020, in Korea. We evaluated the association between the use of statins and COVID-19-related mortality in the overall and the nested 1:2 propensity score-matched study. Furthermore, a comparison of the hazard ratio for death was performed between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. The median age of the 10 448 COVID-19 patients was 45 years. Statins were prescribed in 533 (5.1%) patients. After adjusting for age, sex, and comorbidities, Cox regression showed a significant decrease in hazard ratio associated with the use of statins (hazard ratio, 0.637 [95% CI, 0.425-0.953]; P=0.0283). Moreover, on comparing the hazard ratio between COVID-19 patients and the retrospective cohort of hospitalized pneumonia patients, the use of statins showed similar benefits. CONCLUSIONS: The use of statins correlates significantly with lower mortality in patients with COVID-19, consistent with the findings in patients with pneumonia. Graphic Abstract: A graphic abstract is available for this article.

Alternative methylation of intron motifs is associated with cancer-related gene expression in both canine mammary tumor and human breast cancer.

BACKGROUND: Canine mammary tumor (CMT) has long been considered as a good animal model for human breast cancer (HBC) due to their pathological and biological similarities. However, only a few aspects of the epigenome have been explored in both HBC and CMT. Moreover, DNA methylation studies have mainly been limited to the promoter regions of genes. RESULTS: Genome-wide methylation analysis was performed in CMT and adjacent normal tissues and focused on the intron regions as potential targets for epigenetic regulation. As expected, many tumor suppressors and oncogenes were identified. Of note, most cancer-associated biological processes were enriched in differentially methylated genes (DMGs) that included intron DMRs (differentially methylated regions). Interestingly, two PAX motifs, PAX5 (tumor suppressive) and PAX6 (oncogenic), were frequently found in hyper- and hypomethylated intron DMRs, respectively. Hypermethylation at the PAX5 motifs in the intron regions of CDH5 and LRIG1 genes were found to be anti-correlated with gene expression, while CDH2 and ADAM19 genes harboring hypomethylated PAX6 motifs in their intron region were upregulated. These results were validated from the specimens originally MBD-sequenced as well as additional clinical samples. We also comparatively investigated the intron methylation and downstream gene expression of these genes using human breast invasive carcinoma (BRCA) datasets in TCGA (The Cancer Genome Atlas) public database. Regional alteration of methylation was conserved in the corresponding intron regions and, consequently, gene expression was also altered in HBC. CONCLUSIONS: This study provides good evidence for the conservation of epigenetic regulation in CMT and HBC, and suggests that intronic methylation can be an important factor in better understanding gene regulation in both CMT and HBC.

A randomized trial to determine the diagnostic accuracy of conventional vs. jumbo forceps biopsy of gastric epithelial neoplasias before endoscopic submucosal dissection; open-label study.

BACKGROUND AND AIMS: Larger biopsy specimens or increasing the number of biopsies may improve the diagnostic accuracy of gastric epithelial neoplasia (GEN). The aims of this study was to compare the diagnostic accuracies between conventional and jumbo forceps biopsy of GEN before endoscopic submucosal dissection (ESD) and to confirm that increasing the number of biopsies is useful for the diagnosis of GEN. RESULTS: The concordance rate between EFB and ESD specimens was not significantly different between the two groups [83.1 % (54/65) in JG vs. 79.1 % (53/67) in CG]. On multivariate analyses, two or four EFBs significantly increased the cumulating concordance rate [coefficients; twice: 5.1 (P = 0.01), four times: 5.9 (P = 0.02)]. But, the concordance rate was decreased in high grade dysplasia (coefficient -40.32, P = 0.006). PATIENTS AND METHODS: One hundred and sixty GENs from 148 patients were randomized into two groups and finally 67 GENs in 61 patients and 65 GENs in 63 patients were allocated to the conventional group (CG) or jumbo group (JG), respectively. Four endoscopic forceps biopsy (EFB) specimens were obtained from each lesion with conventional (6.8 mm) forceps or jumbo (8 mm) forceps. The histological concordance rate between 4 EFB specimens and ESD specimens was investigated in the two groups. CONCLUSIONS: Before ESD, the diagnostic accuracy of GENs was significantly increased not by the use of jumbo forceps biopsy but by increasing the number of biopsies.

Second-look endoscopy is not associated with better clinical outcomes after gastric endoscopic submucosal dissection: a prospective, randomized, clinical trial analyzed on an as-treated basis.

BACKGROUND: The efficacy of routine second-look endoscopy (SLE) to detect or prevent bleeding after gastric endoscopic submucosal dissection (ESD) has not yet been validated. OBJECTIVE: The aim of this study was to determine whether SLE affects clinical outcomes including bleeding and morbidity after gastric ESD. DESIGN: A prospective, randomized, controlled study with consecutive data analyzed on an as-treated basis. SETTING: A single, tertiary-care referral center. PATIENTS: A total of 182 patients. INTERVENTION: Gastric ESD and SLE. MAIN OUTCOME MEASUREMENTS: Incidence of and risk factors related to bleeding after ESD and outcomes by univariate or multivariate analysis. RESULTS: Among 182 patients enrolled, 74 and 81 patients were assigned to the SLE and no-SLE groups, respectively. Two groups were observed closely for 4 weeks. Bleeding occurred after ESD in 21 patients (13.5%). Hemoglobin loss (≥2.0 g/dL) was observed in 20 patients, and melena developed in 1 patient after ESD. However, only 1 patient needed a transfusion. Twelve patients (16.2%) in the SLE group and 9 in the no-SLE group (11.1%) experienced bleeding after ESD. The frequency of bleeding after ESD was not significantly different between the 2 groups (P = .66). There were no risk factors related to bleeding after ESD. LIMITATIONS: Single-center analysis. CONCLUSION: SLE is not routinely necessary because it does not affect clinical outcomes, including bleeding and morbidity after ESD. ( CLINICAL TRIAL REGISTRATION NUMBER: KCT0000146.).

Performance of a full-scale biofilm system retrofitted with an upflow multilayer bioreactor as a preanoxic reactor for advanced wastewater treatment.

To enhance nitrogen removal in an existing microbial contact oxidation (MCO) system with a treatment capacity of 900 m3/d, an upflow multilayer bioreactor (UMBR) was chosen as a preanoxic reactor for the removal of organic matter and nitrate. The removal performance of the retrofitted plant was evaluated during the startup phase at a low temperature in winter. The high removal (>80%) of organic matter and suspended solids in the UMBR provided stable nitrification conditions in the MCO system, as a result of the substantial reduction in organic matter and solids loaded onto the MCO system. This treatment system showed a stable nitrogen removal efficiency of 75.3%, even in the low temperature range 7 to 10 degrees C. Phosphorus was completely removed by chemical precipitation. Production rates of excess sludge, as a function of the loads of influent flowrate and biological oxygen demand (BOD), were 0.022 kg dry solid/m3 wastewater and 0.132 kg dry solid/kg BOD.