Incidence of invasive fungal diseases in inflammatory bowel disease patients: A nationwide study in South Korea.

BACKGROUND: Limited reports exist regarding invasive fungal diseases (IFDs) in inflammatory bowel disease (IBD) patients. OBJECTIVES: This study aims to investigate the incidence and risk factors of IFDs, specifically invasive candidiasis, aspergillosis and pneumocystosis, in IBD patients in South Korea using nationwide data. PATIENTS/METHODS: A population-based retrospective cohort of 42,913 IBD patients between January 2010 and December 2018 was evaluated using the Health Insurance Review and Assessment database. The primary outcome was the incidence of IFDs, including invasive candidiasis, aspergillosis and pneumocystosis, while the secondary outcome involved analysing the risk factors associated with each specific infection. RESULTS: The study included a total of 42,913 IBD patients, with 29,909 (69.7%) diagnosed with ulcerative colitis (UC) and 13,004 (30.3%) diagnosed with Crohn's disease (CD). IFDs occurred in 166 IBD patients (0.4%), with 93 cases in UC patients and 73 cases in CD patients. The incidence rates of invasive candidiasis, aspergillosis and pneumocystosis in IBD patients were 0.71 per 1000 person-years (PYs), 0.15 per 1000 PYs and 0.12 per 1000 PYs, respectively. The cumulative incidence of invasive candidiasis (adjusted p-value <.001) and Pneumocystosis (adjusted p-value = .012) was found to be higher in CD patients than in UC patients. Each IFD had different risk factors, including IBD subtypes, age at diagnosis, anti-tumour necrotic factor agents or the Charlson comorbidity index. CONCLUSION: Based on nationwide data in South Korea, this study shows that IFDs occur consistently in patients with IBD, albeit with a low frequency.

Comparison of the Pharmacokinetics of CT-P13 Between Crohn's Disease and Ulcerative Colitis.

BACKGROUND: We aimed to compare trough infliximab levels and the development of antidrug antibody (ADA) for 1 year between Crohn's disease (CD) and ulcerative colitis (UC) patients who were biologic-naive, and to evaluate their impact on clinical outcomes. METHODS: This was a prospective, multicenter, observational study. Biologic-naive patients with moderate to severe CD or UC who started CT-P13, an infliximab biosimilar, therapy were enrolled. Trough drug and ADA levels were measured periodically for 1 year after CT-P13 initiation. RESULTS: A total of 267 patients who received CT-P13 treatment were included (CD 168, UC 99). The rates of clinical remission (72% vs. 32.3%, P <0.001) at week 54 were significantly higher in CD than in UC. The median trough drug level (µg/mL) was significantly higher in CD than in UC up to week 14 (week 2, 18.7 vs. 14.7, P <0.001; week 6, 12.5 vs. 8.6, P <0.001; week 14, 3.4 vs. 2.5, P =0.001). The median ADA level (AU/mL) was significantly lower in CD than in UC at week 2 (6.3 vs. 6.5, P =0.046), week 30 (7.9 vs. 11.8, P =0.007), and week 54 (9.3 vs. 12.3, P =0.032). Development of ADA at week 2 [adjusted odds ratio (aOR)=0.15, P =0.026], initial C-reactive protein level (aOR=0.87, P =0.032), and CD over UC (aOR=1.92, P <0.001) were independent predictors of clinical remission at week 54. CONCLUSION: Infliximab shows more favorable pharmacokinetics, including high drug trough and low ADA levels, in CD than in UC, which might result in better clinical outcomes for 1-year infliximab treatment in CD patients.

The effect of biological agent on body composition in patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) is associated with altered body composition, affecting clinical outcomes. We evaluated the impact of biologics on body composition in CD patients. METHODS: This multicenter longitudinal study across four Korean university hospitals conducted from January 2009 to August 2021 retrospectively reviewed data of CD patients with abdominal computed tomography (CT) before and after the biologic treatment. Skeletal muscle area (SMA), visceral fat area (VFA), and subcutaneous fat area (SFA) of the third lumbar vertebra (L3) on CT were measured. Myopenia was defined as L3 skeletal muscle index (SMI) of < 49 and < 31 cm2/m2 for men and women, respectively. RESULTS: Among 112 participants, 79 (70.5%) had myopenia. In the myopenia group, all body composition parameters were significantly increased after the biologic treatment: SMI (37.68 vs. 39.40 cm2/m2; P < 0.001), VFA (26.12 vs. 54.61 cm2; P < 0.001), SFA (44.29 vs. 82.42 cm2; P < 0.001), while no significant differences were observed in the non-myopenia group. In multivariate analysis, penetrating CD (hazard ratio, 5.40; P = 0.020) was the independent prognostic factor for surgery. Operation-free survival rate tended to decrease in the myopenia group (Log-rank test, P = 0.090). CONCLUSIONS: Biological agents can increase all body composition parameters in CD patients with myopenia. These patients are more likely to experience surgery.

Machine Learning-Based prediction of Post-Treatment ambulatory blood pressure in patients with hypertension.

Purpose. Pre-treatment prediction of individual blood pressure (BP) response to anti-hypertensive medication is important to determine the specific regimen for promptly and safely achieving a target BP. This study aimed to develop supervised machine learning (ML) models for predicting patient-specific treatment effects using 24-hour ambulatory BP monitoring (ABPM) data.Materials and Methods. A total of 1,129 patients who had both baseline and follow-up ABPM data were randomly assigned into training, validation and test sets in a 3:1:1 ratio. Utilising the features including clinical and laboratory findings, initial ABPM data, and anti-hypertensive medication at baseline and at follow-up, ML models were developed to predict post-treatment individual BP response. Each case was labelled by the mean 24-hour and daytime BPs derived from the follow-up ABPM.Results. At baseline, 616 (55%) patients had been treated using mono or combination therapy with 45 anti-hypertensive drugs and the remaining 513 (45%) patients had been untreated (drug-naïve). By using CatBoost, the difference between predicted vs. measured mean 24-hour systolic BP at follow-up was 8.4 ± 7.0 mm Hg (% difference of 6.6% ± 5.7%). The difference between predicted vs. measured mean 24-hour diastolic BP was 5.3 ± 4.3 mm Hg (% difference of 6.8% ± 5.5%). There were significant correlations between the CatBoost-predicted vs. the ABPM-measured changes in the mean 24-hour Systolic (r = 0.74) and diastolic (r = 0.68) BPs from baseline to follow-up. Even in the patients with renal insufficiency or diabetes, the correlations between CatBoost-predicted vs. ABPM-measured BP changes were significant.Conclusion. ML algorithms accurately predict the post-treatment ambulatory BP levels, which may assist clinicians in personalising anti-hypertensive treatment.

The prediction of post-treatment BP response is essential to plan the appropriate optimal treatment strategy for achieving the target BP level.The poor predictability of the post-treatment BP level is due to the complex pathophysiology of individual BP response, which can partly explain the poor rate to achieve the target systolic BP.In this current study including both treated and untreated patients with hypertension, machine leaning models predicted the post-treatment mean BP levels on 24-hr ABPM even in high-risk patients and patients with a high BP variability.Model-derived selection and optimisation of anti-hypertension drugs may facilitate prompt achievement of adequate BP control without drug-related complications and avoiding repeating 24-hour ABPM or multiple visits for drug readjustment.

Blood Concentrations of Lead, Cadmium, and Mercury Are Associated With Alcohol-Related Liver Disease.

BACKGROUND: An association between environmental pollutants and alcohol-related liver disease (ALD) has not been determined until now. The objectives of this study were to examine the association of the pollutants with ALD, and whether the pollutants together increased the risk of ALD. METHODS: Data were extracted from the Korea National Health and Nutrition Examination Survey (2010-2013 and 2016-2017; n = 11,993). Blood levels of lead, cadmium, and mercury were measured. ALD was defined by a combination of excessive alcohol consumption and ALD/non-alcoholic fatty liver disease index > 0. The aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 score were used to evaluate ALD FIB. RESULTS: The odds ratios (ORs) of ALD for the highest versus the lowest quartiles of exposure were for lead, 7.39 (95% confidence interval [CI], 5.51-9.91); cadmium, 1.68 (95% CI, 1.32-2.14); and mercury, 5.03 (95% CI, 3.88-6.53). Adjusting for age, gender, smoking, occupation, education, and personal income attenuated the associations but indicated significant positive trends (all Ptrend < 0.001). A positive additive interaction between cadmium and lead was observed. The relative excess OR due to the interaction was 0.96 (95% CI, 0.41-1.51); synergy index = 2.92 (95% CI, 0.97-8.80). Among 951 subjects with ALD, advanced FIB was associated with lead and cadmium (OR, 3.46, 95% CI, 1.84-6.53; OR, 8.50, 95% CI, 2.54-28.42, respectively), but not with mercury. The effect estimates for lead and cadmium remained significant even after adjustment for daily alcohol intake. CONCLUSION: Blood levels of lead, cadmium, and mercury were significantly associated not only with the risk of ALD but also with ALD FIB. Cadmium and lead have synergistic effects that increase the risk of ALD.

Enrichment of Activated Fibroblasts as a Potential Biomarker for a Non-Durable Response to Anti-Tumor Necrosis Factor Therapy in Patients with Crohn's Disease.

We investigated whether the response to anti-tumor necrosis factor (anti-TNF) treatment varied according to inflammatory tissue characteristics in Crohn's disease (CD). Bulk RNA sequencing (RNA-seq) data were obtained from inflamed and non-inflamed tissues from 170 patients with CD. The samples were clustered based on gene expression profiles using principal coordinate analysis (PCA). Cellular heterogeneity was inferred using CiberSortx, with bulk RNA-seq data. The PCA results displayed two clusters of CD-inflamed samples: one close to (Inflamed_1) and the other far away (Inflamed_2) from the non-inflamed samples. Inflamed_1 was rich in anti-TNF durable responders (DRs), and Inflamed_2 was enriched in non-durable responders (NDRs). The CiberSortx results showed that the cell fraction of activated fibroblasts was six times higher in Inflamed_2 than in Inflamed_1. Validation with public gene expression datasets (GSE16879) revealed that the activated fibroblasts were enriched in NDRs over Next, we used DRs by 1.9 times pre-treatment and 7.5 times after treatment. Fibroblast activation protein (FAP) was overexpressed in the Inflamed_2 and was also overexpressed in the NDRs in both the RISK and GSE16879 datasets. The activation of fibroblasts may play a role in resistance to anti-TNF therapy. Characterizing fibroblasts in inflamed tissues at diagnosis may help to identify patients who are likely to respond to anti-TNF therapy.

Clinical Course of Terminal Ileal Ulcers Observed Incidentally During Colonoscopy.

BACKGROUND: Cecal intubation is essential during colonoscopy, and observation of the terminal ileum is performed in most clinical practices. However, data on terminal ileal (TI) ulcers observed incidentally during colonoscopy are rare. AIM: We aimed to identify the characteristics and clinical course of TI ulcers observed incidentally during colonoscopy. METHODS: Between January 2008 and December 2018, medical records from multi-centers reporting asymptomatic subjects who underwent biopsy on TI ulcers during colonoscopy were retrospectively reviewed. The characteristics of endoscopic findings and clinical course of TI ulcers were analyzed, and the factors affecting the clinical course of TI ulcers were evaluated. RESULTS: The median follow-up durations from first to second colonoscopy and from second to third colonoscopy were 20 months (interquartile range, 12-36) and 24 months (interquartile range, 12-34), respectively. A total of 134 subjects were included in the analysis. The histopathologic findings of TI ulcers were mostly chronic or active ileitis/inflammation (92.7%). On the second colonoscopy, 59 (44.0%) patients had no ulcers, 38 (28.4%) showed a decrease in size or number, and 37 (27.6%) patients showed no change in ulcers. Among 62 subjects who underwent a third colonoscopy, 14 (10.4%) had decreased size or number, 10 (7.5%) had no ulcer change, and two (1.5%) had increased ulcer size or number. In multivariate logistic regression analysis, a star shape was the only factor affecting continuation without improvement of incidental TI ulcers. CONCLUSIONS: Most TI ulcers observed incidentally showed no unusual findings on biopsy and improved on follow-up colonoscopy without treatment.

Nationwide validation study of diagnostic algorithms for inflammatory bowel disease in Korean National Health Insurance Service database.

BACKGROUND AND AIM: We conducted a nationwide validation study of diagnostic algorithms to identify cases of inflammatory bowel disease (IBD) within the Korea National Health Insurance System (NHIS) database. METHOD: Using the NHIS dataset, we developed 44 algorithms combining the International Classification of Diseases (ICD)-10 codes, codes for Rare and Intractable Diseases (RID) registration and claims data for health care encounters, and pharmaceutical prescriptions for IBD-specific drugs. For each algorithm, we compared the case identification results from electronic medical records data with the gold standard (chart-based diagnosis). A multiple sampling test verified the validation results from the entire study population. RESULTS: A random nationwide sample of 1697 patients (848 potential cases and 849 negative control cases) from 17 hospitals were included for validation. A combination of the ICD-10 code, ≥ 1 claims for health care encounters, and ≥ 1 prescription claims (reference algorithm) achieved excellent performance (sensitivity, 93.1% [95% confidence interval 91-94.7]; specificity, 98.1% [96.9-98.8]; positive predictive value, 97.5% [96.1-98.5]; negative predictive value, 94.5% [92.8-95.8]) with the lowest error rate (4.2% [3.3-5.3]). The multiple sampling test confirmed that the reference algorithm achieves the best performance regarding IBD diagnosis. Algorithms including the RID registration codes exhibited poorer performance compared with that of the reference algorithm, particularly for the diagnosis of patients affiliated with secondary hospitals. The performance of the reference algorithm showed no statistical difference depending on the hospital volume or IBD type, with P-value < 0.05. CONCLUSIONS: We strongly recommend the reference algorithm as a uniform standard operational definition for future studies using the NHIS database.

Gender Specific Differences in Prevalence and Risk Factors for Gastro-Esophageal Reflux Disease.

BACKGROUND: Gender-related factors might play an important role in the development of reflux esophagitis (RE) and symptomatic gastro-esophageal reflux disease (GERD). We aimed to evaluate the prevalence and risk factors for RE and symptomatic GERD and determine whether gender specific differences exist. METHODS: This study was conducted on a health cohort consisting of 10,158 participants who underwent comprehensive health screening. Lifestyles and gastrointestinal symptoms were investigated using a self-reported structured questionnaire. Questionnaires about menstrual status were added for the women. RESULTS: The prevalence of RE in men was significantly higher than that in women (10.6% vs. 2.0%, P < 0.001); however, symptomatic GERD showed predominance in women (6.2% vs. 2.5%, P < 0.001). Although the prevalence of RE gradually increased with the duration of menopause stratified by decade (P = 0.007), that of symptomatic GERD rapidly increased across the menopausal transit in women. Apart from common risk factors of obesity and current smoking for RE, over 70 years of age in women and hiatal hernia and hypertriglyceridemia in men were significant risk factors. In symptomatic GERD, high somatization was a common risk factor. Excessive alcohol drinking was a significant risk factor in men, but not in women. CONCLUSION: This study showed a predominance of RE in men, but a predominance of symptomatic GERD in women. In women, dynamic increase in the prevalence of GERD is closely related to the menopause conditions and its duration. There are specific risk factors for RE and symptomatic GERD according to gender differences.

Predictors of High-Risk Adenoma Occurrence at Surveillance Colonoscopy in Patients Who Undergo Colorectal Adenoma Removal.

OBJECTIVES: Surveillance colonoscopy is recommended after polypectomy because adenoma recurrence is common. The aim of this study was to evaluate the predictors of high-risk adenoma occurrence at surveillance colonoscopy in patients who undergo colorectal adenoma removal and to clarify the association between age and recurrent colorectal adenoma. METHODS: This retrospective study included 563 patients who had colorectal adenomas at baseline colonoscopy and who underwent surveillance colonoscopy. The risk factors for recurrent adenoma were evaluated and the 5-year cumulative incidence rates of overall and high-risk adenoma were compared according to age group. RESULTS: During a mean follow-up period of 3.1 years, 305 (54.2%) patients had overall adenoma recurrence, and 80 (14.2%) patients had high-risk adenoma at surveillance colonoscopy. In a multivariate analysis, old age (≥60 years) and presence of multiple adenomas (3 or more) were significantly associated with high-risk adenoma (p = 0.002 and p = 0.006 respectively). The 5-year cumulative incidence rates of high-risk adenoma were 7.4, 16.7, and 24.1% in the < 50, 50-59, and ≥60 years group respectively (p < 0.001). CONCLUSIONS: Old age (≥60 years) and presence of multiple adenomas (3 or more) were strongly associated with the occurrence of high-risk adenoma at surveillance colonoscopy. The 5-year cumulative incidence of high-grade adenoma was significantly high in the old age group.

A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis.

The cause of inflammatory bowel disease (IBD) is still unknown, but there is growing evidence that environmental factors such as epigenetic changes can contribute to the disease etiology. The aim of this study was to identify newly hypermethylated genes in ulcerative colitis (UC) using a genome-wide DNA methylation approach. Using an Infinium HumanMethylation450 BeadChip array, we screened the DNA methylation changes in three normal colon controls and eight UC patients. Using these methylation profiles, 48 probes associated with CpG promoter methylation showed differential hypermethylation between UC patients and normal controls. Technical validations for methylation analyses in a larger series of UC patients (n = 79) were performed by methylation-specific PCR (MSP) and bisulfite sequencing analysis. We finally found that three genes (FAM217B, KIAA1614 and RIBC2) that were significantly elevating the promoter methylation levels in UC compared to normal controls. Interestingly, we confirmed that three genes were transcriptionally silenced in UC patient samples by qRT-PCR, suggesting that their silencing is correlated with the promoter hypermethylation. Pathway analyses were performed using GO and KEGG databases with differentially hypermethylated genes in UC. Our results highlight that aberrant hypermethylation was identified in UC patients which can be a potential biomarker for detecting UC. Moreover, pathway-enriched hypermethylated genes are possibly implicating important cellular function in the pathogenesis of UC. Overall, this study describes a newly hypermethylated gene panel in UC patients and provides new clinical information that can be used for the diagnosis and therapeutic treatment of IBD.

Identification of radiation-induced aberrant hypomethylation in colon cancer.

BACKGROUND: Exposure to ionizing radiation (IR) results in the simultaneous activation or downregulation of multiple signaling pathways that play critical roles in cell type-specific control of survival or death. IR is a well-known genotoxic agent and human carcinogen that induces cellular damage through direct and indirect mechanisms. However, its impact on epigenetic mechanisms has not been elucidated, and more specifically, little information is available regarding genome-wide DNA methylation changes in cancer cells after IR exposure. Recently, genome-wide DNA methylation profiling technology using the Illumina HumanMethylation450K platform has emerged that allows us to query >450,000 loci within the genome. This improved technology is capable of identifying genome-wide DNA methylation changes in CpG islands and other CpG island-associated regions. RESULTS: In this study, we employed this technology to test the hypothesis that exposure to IR not only induces differential DNA methylation patterns at a genome-wide level, but also results in locus- and gene-specific DNA methylation changes. We screened for differential DNA methylation changes in colorectal cancer cells after IR exposure with 2 and 5 Gy. Twenty-nine genes showed radiation-induced hypomethylation in colon cancer cells, and of those, seven genes showed a corresponding increase in gene expression by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, we performed chromatin immunoprecipitation (ChIP) to confirm that the DNA-methyltransferase 1 (DNMT1) level associated with the promoter regions of these genes correlated with their methylation level and gene expression changes. Finally, we used a gene ontology (GO) database to show that a handful of hypomethylated genes induced by IR are associated with a variety of biological pathways related to cancer. CONCLUSION: We identified alterations in global DNA methylation patterns and hypomethylation at specific cancer-related genes following IR exposure, which suggests that radiation exposure plays a critical role in conferring epigenetic alterations in cancer.

Intratumoral heterogeneity impacts the response to anti-neu antibody therapy.

BACKGROUND: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO. In addition, TUBO-P2J was used to establish an intratumoral HER2 heterogenous animal tumor model to evaluate the therapeutic effects of anti-HER2/neu antibody. METHODS: After establishing the cell line, TUBO-P2J was characterized regarding its susceptibility to anti-neu antibody and chemotherapeutics, as well as its metastatic potential in vitro and in vivo. In addition, expression profiles of metastasis related genes were also evaluated. A clinically relevant intratumoral HER2 heterogenous tumor model was established by inoculating mice with tumor cells consisting of TUBO and TUBO-P2J at a ratio of 1,000:1 or 10,000:1. Tumor growth and mouse survival were used to evaluate the therapeutic effects of anti-neu antibody. RESULTS: The TUBO-P2J cell line is a HER2/neu negative and highly metastatic variant of TUBO. This cell line was resistant to anti-neu antibody therapy, and when inoculated subcutaneously, metastasized to the lungs within 14 days. Compared to the parental TUBO cell line, TUBO-P2J displayed an epithelial-mesenchymal transition (EMT) related gene expression profile including: the loss of E-cadherin, and increased Vimentin, Snail, and Twist1 expression. In addition, TUBO-P2J exhibited increased invasion and migration activity, and was resistant to chemotherapy drugs. Finally, mixed tumor implantations experiments revealed that an increased percentage of TUBO-P2J rendered tumors less responsive to anti-neu antibody therapy. CONCLUSION: This study describes a novel model of intratumoral heterogenous metastatic breast cancer in immune competent mice that can be used to develop novel or combined immunotherapies to overcome antibody resistance.

Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn's Disease and Interact with Regulatory Variants for TAP2.

BACKGROUND AND AIMS: Crohn's disease [CD] has a complex polygenic aetiology with high heritability. There is ongoing effort to identify novel variants associated with susceptibility to CD through a genome-wide association study [GWAS] in large Korean populations. METHODS: Genome-wide variant data from 902 Korean patients with CD and 72 179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1621 patients with CD and 4419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term. RESULTS: We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor [LILR] gene cluster [p < 5 × 10-8], with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci [QTL] for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules [p = 4.11 × 10-4], showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (odds ratio [OR] = 0.941, p = 0.686 in non-carriers; OR = 1.45, p = 2.51 × 10-4 in single-copy carriers; OR = 2.38, p = 2.76 × 10-6 in two-copy carriers). CONCLUSIONS: This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer a risk of CD.

Impact of Target Lesion Revascularization on Long-Term Mortality After Percutaneous Coronary Intervention for Left Main Disease.

BACKGROUND: Although target lesion revascularization (TLR) after percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) disease is not rare, its timing of occurrence and prognostic impact on long-term mortality is uncertain. OBJECTIVES: This study sought to investigate TLR incidence over time and its impact on mortality after PCI with drug-eluting stents (DES) for LMCA disease. METHODS: Using a pooled data from 4 multicenter observational registries (IRIS-DES [Interventional Cardiology Research Incorporation Society-Drug-Eluting Stents], IRIS-MAIN [Interventional Cardiology Research Incorporation Society-Left MAIN Revascularization], MAIN-COMPARE [Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization], and PRECOMBAT [PREmier of Randomized COMparison of Bypass Surgery versus AngioplasTy Using Drug-Eluting Stent in Patients with Left Main Coronary Artery Disease]), we evaluated 1,397 patients with LMCA disease treated with DES and available long-term mortality data. The association between TLR and the 10-year risk of mortality was examined by multivariable Cox proportional hazards regression, with TLR as a time-varying covariate. RESULTS: During maximum follow-up of 10 years (median 6.8 years), TLR occurred in 118 patients and its 10-year cumulative incidence was 10.8%. TLR mostly occurred within 2 years after initial PCI and decreased over time: early-stage TLR (within 2 years) in 73 (61.9%) patients and late-stage TLR (beyond 2 years) in 45 (38.1%) patients. Among all TLR patients, 23 patients underwent coronary artery bypass grafting and 95 underwent repeat PCI. In the time-varying multivariable Cox model, the presence of TLR was not significantly associated with an increased risk of mortality (adjusted HR: 0.90; 95% CI: 0.50-1.63; P = 0.73). CONCLUSIONS: Although the incidence of ischemia-driven TLR was mostly common within 2 years after left main PCI, TLR occurred steadily during the 10-year follow-up period. However, given that such patients were optimally revascularized, the prognostic impact of TLR on mortality was not substantial. (Evaluation of the First, Second, and New Drug-Eluting Stents in Routine Clinical Practice [IRIS-DES]; NCT01186133; Observational Study for Left Main Disease Treatment [IRIS-MAIN]; NCT01341327; Ten-Year Outcomes of Stents Versus Coronary-Artery Bypass Grafting for Left Main Coronary Artery Disease [MAIN COMPARE]; NCT02791412; Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease [PRECOMBAT]; NCT00422968).

Evaluation of the Efficacy and Safety of DW1903 in Patients with Gastritis: A Randomized, Double-Blind, Noninferiority, Multicenter, Phase 3 study.

Background/Aims: H2 receptor antagonists (H2RA) have been used to treat gastritis by inhibiting gastric acid. Proton pump inhibitors (PPIs) are more potent acid suppressants than H2RA. However, the efficacy and safety of low-dose PPI for treating gastritis remain unclear. The aim was to investigate the efficacy and safety of low-dose PPI for treating gastritis. Methods: A double-blind, noninferiority, multicenter, phase 3 clinical trial randomly assigned 476 patients with endoscopic erosive gastritis to a group using esomeprazole 10 mg (DW1903) daily and a group using famotidine 20 mg (DW1903R1) daily for 2 weeks. The full-analysis set included 319 patients (DW1903, n=159; DW1903R1, n=160) and the per-protocol set included 298 patients (DW1903, n=147; DW1903R1, n=151). The primary endpoint (erosion improvement rate) and secondary endpoint (erosion and edema cure rates, improvement rates of hemorrhage, erythema, and symptoms) were assessed after the treatment. Adverse events were compared. Results: According to the full-analysis set, the erosion improvement rates in the DW1903 and DW1903R1 groups were 59.8% and 58.8%, respectively. According to the per-protocol analysis, the erosion improvement rates in the DW1903 and DW1903R1 groups were 61.9% and 59.6%, respectively. Secondary endpoints were not significantly different between two groups except that the hemorrhagic improvement rate was higher in DW1903 with statistical tendency. The number of adverse events were not statistically different. Conclusions: DW1903 of a low-dose PPI was not inferior to DW1903R1 of H2RA. Thus, lowdose PPI can be a novel option for treating gastritis (ClinicalTrials.gov Identifier: NCT05163756).

Determination of the optimal time for premedication with pronase, dimethylpolysiloxane, and sodium bicarbonate for upper gastrointestinal endoscopy.

GOALS AND BACKGROUND: Premedication with pronase, dimethylpolysiloxane, and sodium bicarbonate improves visibility during upper gastrointestinal (UGI) endoscopy. However, the optimal time for this combination to take effect is unknown. We investigated the optimal time of pre-UGI endoscopy medication. STUDY: A randomized, investigator-blind, controlled trial. The 300 patients who were to receive premedication were randomized into 3 groups according to the following medication time before UGI endoscopy: 10 minutes (group A, n=98), 10 to 30 minutes (group B, n=97), and 30 minutes premedication (group C, n=99). Visibility scores (range, 1 to 4, with lower scores indicating better gastric mucosal visibility) were assessed for the antrum, lower body, upper body, and fundus and compared, including the sum of the scores, between the 3 groups. RESULTS: Group B had significantly lower visibility scores for the lower body, upper body, and fundus than group C (P=0.001, 0.009, and 0.002, respectively). Group A obtained significantly lower scores for the antrum and lower body than group C (P=0.007 and 0.005, respectively). The total visibility scores of groups A and B were significantly lower compared with those of group C (P=0.001, 0.003, respectively). CONCLUSIONS: Administration of pronase, dimethylpolysiloxane, and sodium bicarbonate within 30 minutes before UGI endoscopy significantly improved endoscopic visualization. However, the optimal time to achieve the best visibility was between 10 to 30 minutes before UGI endoscopy.

The efficacy and safety of carbon dioxide insufflation during colonoscopy with consecutive esophagogastroduodenoscopy in moderately sedated outpatients: a randomized, double-blind, controlled trial.

GOALS AND BACKGROUND: Colonoscopy with consecutive esophagogastroduodenoscopy (CCEGD) can be more convenient than performing each procedure individually. There has been no randomized controlled trial comparing carbon dioxide (CO2) versus air insufflations during CCEGD in sedated patients. CO2 insufflation instead of air during CCEGD may reduce abdominal pain and be more comfortable. We investigated the efficacy and safety of CO2 insufflation during CCEGD in moderately sedated outpatients. STUDY: This was a randomized, double-blind, controlled trial. A total of 96 outpatients were randomly assigned to the groups of CO2 or air insufflation. Postprocedure pain was assessed using a 0 to 10 visual analogue scale, and the proportion of pain-free patients was compared between the groups. Waist circumferences and end-tidal CO2 (ETCO2) were measured. RESULTS: Among 96 patients, cecal intubation failed in 2 patients, who were excluded from the analysis. Forty-eight patients in the CO2 and 46 patients in the air group completed the study. There was significant difference between the 2 groups regarding the proportion of pain-free patients 30 minutes after the procedures [air group, 35/46 (76.1%) vs. CO2 group, 44/48 (91.6%)] (P=0.03). However, there was no significant difference in the proportion at 6 and 24 hours after the procedures. The mean increase in waist circumference was greater with air than with CO2 (1.54 vs. 0.18 cm, P<0.001). The ETCO2 measured immediately after the procedures was slightly higher in the CO2 group than in the air group (38.6 vs. 37.2 mm Hg, P=0.02), but the values were within the normal range. No significant adverse events occurred. CONCLUSIONS: CO2 insufflation during CCEGD reduced postprocedural pain and distension compared with air. It was comfortable and safe to use in moderately sedated outpatients.

Efficacy, safety, and predictors of response to infliximab therapy for ulcerative colitis: a Korean multicenter retrospective study.

BACKGROUND/AIMS: Infliximab is currently used for the treatment of moderate-to-severe ulcerative colitis (UC) with an inadequate response to conventional agents. The efficacy and safety of infliximab in Korean patients with UC were assessed. METHODS: This was a retrospective multicenter study including all adult patients who received at least one infliximab infusion for UC. Short- and long-term clinical outcomes and adverse events of infliximab therapy were evaluated, and predictors of response were identified. RESULTS: A total of 134 UC patients were included. The indications for infliximab therapy were acute severe UC in 28%, steroid-dependency in 38%, and steroid-refractoriness in 33%, respectively. The rates of clinical response and remission were 87% and 45% at week 8. In multivariate analysis, we found significant predictors of clinical remission at week 8: immunomodulator-naïve (odds ratio [OR] = 4.89, 95% confidence interval [CI]: 1.44-16.66, P = 0.01), hemoglobin ≥ 11.5 g/dL (OR = 4.47, 95% CI: 1.48-13.45, P = 0.008), C-reactive protein ≥ 3 mg/dL (OR = 4.77, 95% CI: 1.43-15.94, P = 0.01), and response at week 2 (OR = 20.54, 95% CI: 2.40-175.71, P = 0.006). Long-term clinical response and remission rates were 71% and 52%, respectively, and mucosal healing was the only factor influencing long-term response. Adverse events related to infliximab occurred in 15% of patients, and most of them were mild and transient. CONCLUSIONS: Infliximab is effective and safe in the treatment of active UC in Korea. No history of previous immunomodulator use and high baseline C-reactive protein are independent predictors of good response.