Background/Aims: Rectal hyposensitivity (RH), as defined by the London Classification, has been linked to sensory dysfunction caused by diabetes mellitus and Parkinson’s disease (PD); however, its clinical interpretation has not been sufficiently validated. In this study, we aim to explore the correlations between rectal sensory thresholds and the clinical characteristics of patients with functional defecatory disorders. Methods: We reviewed data from patients who underwent high-resolution anorectal manometry and acquired their clinical characteristics using a standardized questionnaire. The associations between RH based on either 1 (borderline RH) or 2 (RH) abnormal rectal sensory thresholds and patients’ clinical and demographic characteristics were analyzed using linear and logistic regression models in the overall sex-stratified populations. Results: We enrolled 2540 patients, of whom 1046 (41.2%) were men. Overall, 150 (5.9%) patients were diagnosed with RH, whereas 422 (16.6%) had borderline RH. Multivariate linear regression analysis revealed that the Cleveland Clinic Constipation Score (CCCS) increased linearly with the increase in the number of abnormal rectal sensory thresholds (effect per threshold: 0.900 [standard deviation: 0.188]). Upon stratification by sex, borderline RH was positively associated with diabetes mellitus, PD, and CCCS (adjusted odds ratio [aOR] = 2.11, 95% confidence interval [1.08, 4.15]; aOR = 1.49 [1.03, 2.14]; aOR = 1.03 [1.01, 1.05], respectively) in women. However, RH was positively associated with only the CCCS. Conclusions Defining RH based on 1 or more abnormal sensory thresholds showed better clinical correlation with patient characteristics. However, further prospective studies are needed to validate these findings before proposing revisions to the current London classification criteria.

Background/Aims: Fexuprazan, a novel potassium-competitive acid blocker, was developed for treating acid-related disorders. Pharmacokinetic and pharmacodynamic properties of fexuprazan, unlike those of proton pump inhibitors, are independent of food effect. This study aims to evaluate differences in efficacy and safety of fexuprazan in patients with erosive esophagitis (EE) according to the timing of dosing. Methods: In this multicenter, open-label noninferiority study, patients who had typical reflux symptoms with endoscopically confirmed EE were randomized 1:1 to receive fexuprazan 40 mg daily 30 minutes before or after meal. Treatment was completed after 2 weeks or 4 weeks when healing was endoscopically confirmed. The primary endpoint was the proportion of patients with healed EE confirmed by endoscopy up to week 4. Safety endpoints included treatment-emergent adverse events (TEAEs). Results: In the prior-to-meal group (n = 89) and after-meal group (n = 86), 4-week EE healing rates were 98.77% and 100.00% (difference, 0.01%; 95% CI, –0.01% to 0.04%) and 2-week EE healing rates were 95.77% and 97.14% (difference, 0.01%; 95% CI, –0.05% to 0.07%), respectively. TEAEs were 9.78% and 8.70% in the prior-to-meal group and the after-meal group, respectively. Conclusions Non-inferiority analysis revealed that taking fexuprazan after meal was non-inferior to taking fexuprazan before meals in patients with EE. The frequency of adverse events was similar between the 2 study groups. The drug is safe and effective for healing EE regardless of the timing of dosing.

Background and Objectives: Outcomes of deferring percutaneous coronary intervention (PCI) without invasive physiologic assessment for intermediate coronary lesions is uncertain.We sought to compare long-term outcomes between medical treatment and PCI of intermediate lesions without invasive physiologic assessment. Methods: A total of 899 patients with intermediate coronary lesions between 50% and 70% diameter-stenosis were randomized to the conservative group (n=449) or the aggressive group (n=450). For intermediate lesions, PCI was performed in the aggressive group, but was deferred in the conservative group. The primary endpoint was major adverse cardiac events (MACE, a composite of all-cause death, myocardial infarction [MI], or ischemia-driven any revascularization) at 3 years. Results: The number of treated lesions per patient was 0.8±0.9 in the conservative group and 1.7±0.9 in the aggressive group (p=0.001). At 3 years, the conservative group had a significantly higher incidence of MACE than the aggressive group (13.8% vs. 9.3%; hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.00–2.21; p=0.049), mainly driven by revascularization of target intermediate lesion (6.5% vs. 1.1%; HR, 5.69; 95% CI, 2.20–14.73;p<0.001). Between 1 and 3 years after the index procedure, compared to the aggressive group, the conservative group had significantly higher incidence of cardiac death or MI (3.2% vs.0.7%; HR, 4.34; 95% CI, 1.24–15.22; p=0.022) and ischemia-driven any revascularization. Conclusions For intermediate lesions, medical therapy alone, guided only by angiography, was associated with a higher risk of MACE at 3 years compared with performing PCI, mainly due to increased revascularization.

Background and Objectives: Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism. Methods: New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area.The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12). Results: YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9–11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, NPPB, and myosin heavy chain 7, MYH7) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes.HDAC8 overexpression stimulated MMP12 and NPPB mRNA levels, while HDAC8 knockdown downregulated these genes. Conclusions YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.

Background/Aims: Rectal hyposensitivity (RH), as defined by the London Classification, has been linked to sensory dysfunction caused by diabetes mellitus and Parkinson’s disease (PD); however, its clinical interpretation has not been sufficiently validated. In this study, we aim to explore the correlations between rectal sensory thresholds and the clinical characteristics of patients with functional defecatory disorders. Methods: We reviewed data from patients who underwent high-resolution anorectal manometry and acquired their clinical characteristics using a standardized questionnaire. The associations between RH based on either 1 (borderline RH) or 2 (RH) abnormal rectal sensory thresholds and patients’ clinical and demographic characteristics were analyzed using linear and logistic regression models in the overall sex-stratified populations. Results: We enrolled 2540 patients, of whom 1046 (41.2%) were men. Overall, 150 (5.9%) patients were diagnosed with RH, whereas 422 (16.6%) had borderline RH. Multivariate linear regression analysis revealed that the Cleveland Clinic Constipation Score (CCCS) increased linearly with the increase in the number of abnormal rectal sensory thresholds (effect per threshold: 0.900 [standard deviation: 0.188]). Upon stratification by sex, borderline RH was positively associated with diabetes mellitus, PD, and CCCS (adjusted odds ratio [aOR] = 2.11, 95% confidence interval [1.08, 4.15]; aOR = 1.49 [1.03, 2.14]; aOR = 1.03 [1.01, 1.05], respectively) in women. However, RH was positively associated with only the CCCS. Conclusions Defining RH based on 1 or more abnormal sensory thresholds showed better clinical correlation with patient characteristics. However, further prospective studies are needed to validate these findings before proposing revisions to the current London classification criteria.

Background/Aims: Fexuprazan, a novel potassium-competitive acid blocker, was developed for treating acid-related disorders. Pharmacokinetic and pharmacodynamic properties of fexuprazan, unlike those of proton pump inhibitors, are independent of food effect. This study aims to evaluate differences in efficacy and safety of fexuprazan in patients with erosive esophagitis (EE) according to the timing of dosing. Methods: In this multicenter, open-label noninferiority study, patients who had typical reflux symptoms with endoscopically confirmed EE were randomized 1:1 to receive fexuprazan 40 mg daily 30 minutes before or after meal. Treatment was completed after 2 weeks or 4 weeks when healing was endoscopically confirmed. The primary endpoint was the proportion of patients with healed EE confirmed by endoscopy up to week 4. Safety endpoints included treatment-emergent adverse events (TEAEs). Results: In the prior-to-meal group (n = 89) and after-meal group (n = 86), 4-week EE healing rates were 98.77% and 100.00% (difference, 0.01%; 95% CI, –0.01% to 0.04%) and 2-week EE healing rates were 95.77% and 97.14% (difference, 0.01%; 95% CI, –0.05% to 0.07%), respectively. TEAEs were 9.78% and 8.70% in the prior-to-meal group and the after-meal group, respectively. Conclusions Non-inferiority analysis revealed that taking fexuprazan after meal was non-inferior to taking fexuprazan before meals in patients with EE. The frequency of adverse events was similar between the 2 study groups. The drug is safe and effective for healing EE regardless of the timing of dosing.

Background and Objectives: Outcomes of deferring percutaneous coronary intervention (PCI) without invasive physiologic assessment for intermediate coronary lesions is uncertain.We sought to compare long-term outcomes between medical treatment and PCI of intermediate lesions without invasive physiologic assessment. Methods: A total of 899 patients with intermediate coronary lesions between 50% and 70% diameter-stenosis were randomized to the conservative group (n=449) or the aggressive group (n=450). For intermediate lesions, PCI was performed in the aggressive group, but was deferred in the conservative group. The primary endpoint was major adverse cardiac events (MACE, a composite of all-cause death, myocardial infarction [MI], or ischemia-driven any revascularization) at 3 years. Results: The number of treated lesions per patient was 0.8±0.9 in the conservative group and 1.7±0.9 in the aggressive group (p=0.001). At 3 years, the conservative group had a significantly higher incidence of MACE than the aggressive group (13.8% vs. 9.3%; hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.00–2.21; p=0.049), mainly driven by revascularization of target intermediate lesion (6.5% vs. 1.1%; HR, 5.69; 95% CI, 2.20–14.73;p<0.001). Between 1 and 3 years after the index procedure, compared to the aggressive group, the conservative group had significantly higher incidence of cardiac death or MI (3.2% vs.0.7%; HR, 4.34; 95% CI, 1.24–15.22; p=0.022) and ischemia-driven any revascularization. Conclusions For intermediate lesions, medical therapy alone, guided only by angiography, was associated with a higher risk of MACE at 3 years compared with performing PCI, mainly due to increased revascularization.

Background and Objectives: Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism. Methods: New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area.The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12). Results: YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9–11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, NPPB, and myosin heavy chain 7, MYH7) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes.HDAC8 overexpression stimulated MMP12 and NPPB mRNA levels, while HDAC8 knockdown downregulated these genes. Conclusions YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.

Microplastics (MP) are pervasive environmental pollutants with potential adverse effects on human health, particularly concerning neurotoxicity. This study investigates the accumulation and neurotoxic effects of MP in cerebral organoids and mouse brains. Utilizing in vitro cerebral organoids and in vivo mouse models, we examined the penetration of MP, revealing that smaller MP (50 nm) infiltrated deeper into the organoids compared to larger ones (100 nm). Exposure to 50 nm MP resulted in a significant reduction in organoid viability. Furthermore, total RNA sequencing indicated substantial alterations in neurotoxicity-related gene expression.In vivo, MP-treated mice exhibited notable DNA fragmentation in the hippocampus and cortex, alongside elevated levels of inflammatory markers and neurotoxic metabolites, such as kynurenine (KYN) and 3-hydroxykynurenine (3-HK). Our findings suggest that MP may promote neurotoxicity through the kynurenine pathway, leading to heightened levels of neurotoxic compounds like quinolinic acid. This research highlights the potential for MP to induce neuroinflammatory responses and disrupt normal brain function, underscoring the need for further investigation into the long-term effects of MP exposure on neurological health.

Purpose: The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients. Materials and Methods: We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided. Results: From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient. Conclusion Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.