Background/Aims: Shifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis. Methods: Microbiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to timeof-flight mass spectrometry. Correlation analyses were performed targeting the gut-microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased). Results: Veillonella bacteria, Ruminococcus gnavus, and Streptococcus pneumoniae are cirrhosis-related microbiotas compared with control group. Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella_uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC >0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites. Conclusions Cirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.

Background: and Purpose The influence of imaging features of brain frailty on outcomes were investigated in acute ischemic stroke patients with minor symptoms and large-vessel occlusion (LVO). Methods: This was a retrospective analysis of a prospective, multicenter, nationwide registry of consecutive patients with acute (within 24 h) minor (National Institutes of Health Stroke Scale score=0–5) ischemic stroke with anterior circulation LVO (acute minor LVO). Brain frailty was stratified according to the presence of an advanced white-matter hyperintensity (WMH) (Fazekas grade 2 or 3), silent/old brain infarct, or cerebral microbleeds. The primary outcome was a composite of stroke, myocardial infarction, and all-cause mortality within 1 year. Results: In total, 1,067 patients (age=67.2±13.1 years [mean±SD], 61.3% males) were analyzed. The proportions of patients according to the numbers of brain frailty burdens were as follows: no burden in 49.2%, one burden in 30.0%, two burdens in 17.3%, and three burdens in 3.5%. In the Cox proportional-hazards analysis, the presence of more brain frailty burdens was associated with a higher risk of 1-year primary outcomes, but after adjusting for clinically relevant variables there were no significant associations between burdens of brain frailty and 1-year vascular outcomes. For individual components of brain frailty, an advanced WMH was independently associated with an increased risk of 1-year primary outcomes (adjusted hazard ratio [aHR]=1.33, 95% confidence interval [CI]=1.03–1.71) and stroke (aHR=1.32, 95% CI=1.00–1.75). Conclusions The baseline imaging markers of brain frailty were common in acute minor ischemic stroke patients with LVO. An advanced WMH was the only frailty marker associated with an increased risk of vascular events. Further research is needed into the association between brain frailty and prognosis in patients with acute minor LVO.

Background/Aims: Efficacy of proton pump inhibitors is limited in patients with nonerosive reflux disease (NERD). The aim of this study was to comparatively evaluate the efficacy and safety of esomeprazole with sodium bicarbonate and esomeprazole alone. Methods: This was a multicenter, randomized, double-blind, active-controlled, noninferiority comparative study. A total of 379 patients with NERD were randomly allocated to receive either EsoduoⓇ/sup> (esomeprazole 20 mg with sodium bicarbonate 800 mg) or NexiumⓇ/sup> (esomeprazole 20 mg) once daily for 4 weeks from January 2019 to December 2019. The patients had a history of heartburn for at least 2 days in the week before randomization as well as in the last 3 months and no esophageal mucosal breaks on endoscopy. The primary endpoint was a complete cure of heartburn at week 4. The secondary and exploratory endpoints as well as the safety profiles were compared in the groups at weeks 2 and 4. Results: A total of 355 patients completed the study (180 in the EsoduoⓇ/sup> group and 175 in the NexiumⓇ/sup> group). The proportions of patients without heartburn in the entire 4th week of treatment were not different between the two groups (33.33% in the EsoduoⓇ/sup> group and 35% in the NexiumⓇ/sup> group, p=0.737). There were no significant differences in most of the secondary and exploratory endpoints as well as the safety profiles. Conclusions EsoduoⓇ/sup> is as effective and safe as NexiumⓇ/sup> for managing typical symptoms in patients with NERD (ClinicalTrial.gov identifier: NCT03928470).

Background: Janus kinase (Jak) 3 has recently been shown as a beneficial target for the treatment of chronic inflammatory diseases, such as psoriasis and alopecia areata. The role of Jak3 in tissue repair and remodeling is emerging. Objective: This study aimed to investigate the role of Jak3 signaling in the remodeling of the sebaceous gland (SG) during skin wound repair, and the development of in vitro SGs. Methods: Mouse skin tissue (ICR mouse) was obtained from the recovered skin eight days after a 4 mm biopsy punch wound. To observe the role of Jak3, the selective inhibitors WHIp131 and PF06651600 was administered. Formation of in vitro SG was examined using primary sebocyte cultures obtained postnatally from 3-day-old mice. Results: The data showed that SGs showed highly positive signals with anti-isolectin B4, which also used for detection of angiogenetic vessels and the basal epidermis. Isolectin B4 could be a good indicator of SGs. The Jak3 inhibitors significantly reduced the area and volume of SG remodeling with reduced expression of p-Jak3. In addition, the area of cultured intact SG in vitro was significantly decreased in a concentration-dependent manner by Jak3 inhibition. Conclusion These data showed that Jak3 signaling is a potent regulator to develop SGs.Jak3 inhibition did not decrease the number of sebocytes in SGs but decreased the area and volume of SG remodeling. Therefore, Jak3 inhibition may be a potential target for the treatment of SG hyperplasia and associated skin diseases.

Background/Aims: Endoscopic submucosal dissection (ESD) is a curative treatment modality for early gastric neoplasms; however, ESD can be a time-consuming process. To overcome this pitfall, we developed the one-step knife (OSK) approach, which combines an endoscopic knife and injection needle on a single sheath. We aimed to evaluate whether this approach could reduce the ESD procedure time. Methods: This single-blinded randomized multicenter trial at four tertiary hospitals from June 2019 to June 2020 included patients aged 19 to 85 years undergoing ESD. Patients were randomly assigned to two groups (OSK or conventional knife [CK]). The injection time, total procedure time, resected specimen size, submucosal fluid amount, degree of device satisfaction, and adverse events were evaluated and compared between groups. Results: Fifty-one patients were analyzed (OSK: 25 patients and CK: 26 patients). No baseline differences were observed between groups, with the exception of a higher portion of males in the OSK group. The mean injection time was significantly reduced in the OSK group (39.0 seconds) compared to that in the CK group (87.5 seconds, p<0.001). A decrease of more than 10 minutes in the total procedure time (18.0 minutes vs 28.1 minutes, p=0.055) in the OSK group compared to the CK group was observed. Second-look esophagogastroduodenoscopy revealed two delayed bleeding cases in the OSK group that were easily controlled by endoscopic hemostasis. Conclusions OSK reduced the injection time and showed a decrease in total procedure time compared with the CK approach. OSK can be a feasible tool for ESD, especially in difficult cases.

Background/Aims: The prospective Crohn’s Disease Clinical Network and Cohort Study is a nationwide multicenter cohort study of patients with Crohn’s disease (CD) in Korea, aiming to prospectively investigate the clinical features and long-term prognosis associated with CD. Methods: Patients diagnosed with CD between January 2009 and September 2019 were prospectively enrolled. They were divided into two cohorts according to the year of diagnosis: cohort 1 (diagnosed between 2009 and 2011) versus cohort 2 (between 2012 and 2019). Results: A total of 1,175 patients were included, and the median follow-up duration was 68 months (interquartile range, 39.0 to 91.0 months). The treatment-free durations for thiopurines (p<0.001) and anti-tumor necrosis factor agents (p=0.018) of cohort 2 were shorter than those of cohort 1. Among 887 patients with B1 behavior at diagnosis, 149 patients (16.8%) progressed to either B2 or B3 behavior during follow-up. Early use of thiopurine was associated with a reduced risk of behavioral progression (adjusted hazard ratio [aHR], 0.69; 95% confidence interval [CI], 0.50 to 0.90), and family history of inflammatory bowel disease was associated with an increased risk of behavioral progression (aHR, 2.29; 95% CI, 1.16 to 4.50). One hundred forty-one patients (12.0%) underwent intestinal resection, and the intestinal resection-free survival time was significantly longer in cohort 2 than in cohort 1 (p=0.003). The early use of thiopurines (aHR, 0.35;95% CI, 0.23 to 0.51) was independently associated with a reduced risk of intestinal resection. Conclusions The prognosis of CD in Korea appears to have improved over time, as evidenced by the decreasing intestinal resection rate. Early use of thiopurines was associated with an improved prognosis represented by a reduced risk of intestinal resection.

Background/Aims: Sepsis-3 criteria and quick Sequential Organ Failure Assessment (qSOFA) have been advocated to be used in defining sepsis in the general population. We aimed to compare the Sepsis-3 criteria and Chronic Liver Failure-SOFA (CLIF-SOFA) scores as predictors of in-hospital mortality in cirrhotic patients admitted to the emergency department (ED) for infections. Methods: A total of 1,622 cirrhosis patients admitted at the ED for infections were assessed retrospectively. We analyzed their demographic, laboratory, and microbiological data upon diagnosis of the infection. The primary endpoint was inhospital mortality rate. The predictive performances of baseline CLIF-SOFA, Sepsis-3, and qSOFA scores for in-hospital mortality were evaluated. Results: The CLIF-SOFA score proved to be significantly better in predicting in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.80; 95% confidence interval [CI], 0.78–0.82) than the Sepsis-3 (AUROC, 0.75; 95% CI, 0.72–0.77, P<0.001) and qSOFA (AUROC, 0.67; 95% CI, 0.64–0.70; P<0.001) score. The CLIF-SOFA, CLIF-C-AD scores, Sepsis-3 criteria, septic shock, and qSOFA positivity were significantly associated with in-hospital mortality (adjusted hazard ratio [aHR], 1.24; 95% CI, 1.19–1.28; aHR, 1.13; 95% CI, 1.09–1.17; aHR, 1.19; 95% CI, 1.15–1.24; aHR, 1.88; 95% CI, 1.42–2.48; aHR, 2.06; 95% CI, 1.55–2.72; respectively; all P<0.001). For CLIF-SOFA scores ≥6, in-hospital mortality was >10%; this is the cutoff point for the definition of sepsis. Conclusions Among cirrhosis patients presenting with infections at the ED, CLIF-SOFA scores showed a better predictive performance for mortality than both Sepsis-3 criteria and qSOFA scores, and can be a useful tool of risk stratification in cirrhotic patients requiring timely intervention for infection.

Objectives: . Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. Methods: . Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. Results: . In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. Conclusion . Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

Background/Aims: Enzymatic analysis of aspartate/alanine aminotransferase (AST/ALT) does not exactly represent the progression of liver fibrosis or inflammation. Immunoassay for AST (cytoplasmic [c] AST/mitochondrial [m] AST) and ALT (ALT1/ALT2) has been suggested as one alternatives for enzymatic analysis. The objective of this study was to evaluate the efficacy of immunoassay in predicting liver fibrosis and inflammation. Methods: A total of 219 patients with chronic hepatitis B (CHB) who underwent hepatic venous pressure gradient (HVPG) and liver biopsy before antiviral therapy were recruited. Serum samples were prepared from blood during HVPG. Results of biochemical parameters including enzymatic AST/ALT and immunological assays of cAST, mAST, ALT1, and ALT2 through sandwich enzyme-linked immunosorbent assay (ELISA) immunoassay with fluorescence labeled monoclonal antibodies were compared with the results of METAVIR stage of live fibrosis and the Knodell grade of inflammation. Results: METAVIR fibrosis stages were as follows: F0, six (3%); F1, 52 (24%); F2, 88 (40%); F3, 45 (20%); and F4, 28 patients (13%). Mean levels of AST and ALT were 121 ± 157 and 210 ± 279 IU/L, respectively. Mean HVPG score of all patients was 4.7 ± 2.5 mmHg. According to the stage of liver fibrosis, HVPG score (p < 0.001, r = 0.439) and ALT1 level (p < 0.001, r = 0.283) were significantly increased in all samples from patients with CHB. ALT (p < 0.001, r = 0.310), ALT1 (p < 0.001, r = 0.369), and AST (p < 0.001, r = 0.374) levels were positively correlated with Knodell grade of inflammation. Conclusions ALT1 measurement by utilizing sandwich ELISA immunoassay can be useful method for predicting inf lammation grade and fibrosis stage in patients with CHB.